Podcasts about Kras

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We speak with Dr. Georgia Konstantinidou and Dr. Chiara Pozzato from University of Bern about their recent pre-clinical research investigating a new potential treatment approach for KRAS driven cancers. The conversation explores the role of FAK signalling in KRAS driven NSCLC and potential approaches to bypass drug resistance against FAK inhibitors from the molecular mechanisms involved to the impact of their study for the wider cancer research community. This study has been published in EMBO Molecular Medicine and was included in the EACR's Highlights in Cancer Research, a summary of the most interesting and impactful recent papers in cancer research.

Dr. John Sweetenham shares highlights from Day 3 of the 2025 ASCO Annual Meeting, including new research for the treatment of advanced renal cell carcinoma and 2 studies on novel approaches in non-small cell lung cancer. Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my takeaways on selected abstracts from Day 3 of the 2025 ASCO Annual Meeting. Today's selection features studies addressing the treatment of advanced renal cell carcinoma and 2 studies exploring novel approaches in non-small cell lung cancer. My disclosures are available in the transcript of this episode. The first abstract is number 4505. This study, led by Dr. Toni Choueiri of the Dana-Farber Cancer Institute, describes the final analysis of the CheckMate 214 trial, which compared the combination of nivolumab and ipilimumab with sunitinib for the first-line treatment of advanced renal cell carcinoma. The ipi-nivo combination is approved for the frontline treatment of intermediate and poor-risk advanced renal cell carcinoma based on the primary analysis of the CheckMate 214 trial, which demonstrated a higher response rate and longer overall survival compared with sunitinib. Today's presentation provided the final safety and efficacy results for the trial with long-term follow-up of more than 9 years.  The intent-to-treat (ITT) population in this trial comprised 550 patients randomized to nivo and ipi versus 546 who received sunitinib. The final analysis showed sustained long-term benefit for the combination therapy. Patients given nivolumab plus ipi had a 29% reduction in the risk for death compared with sunitinib. For patients with intermediate or poor-risk disease, there was a 31% reduction in the risk of death.   The probability of remaining in response through 8 years was more than doubled with nivolumab plus ipilimumab versus sunitinib in the ITT population at 48% versus 19%, and in the intermediate and poor-risk population at 50% versus 23%. The other important observation is that patients with favorable-risk disease appeared to have a 20% reduction in the risk for death at 9 years and more durable responses. This suggests a possible delayed benefit for ipi and nivo in this group since these differences were not seen in the earlier analysis.   No new safety signals emerged with longer follow-up, and the results confirm the use of ipi and nivo as a standard front-line combination therapy in this disease. Since this combination has been in widespread use for some years, the results are not surprising although the subgroup analysis suggesting benefit in favorable-risk patients is likely to inform practice in the future.   Today's second abstract is number is 8506, which was presented by Dr. Tony Mok from the Chinese University of Hong Kong, describing results from the phase 3 HERTHENA-Lung02 trial. This trial compared the antibody-drug conjugate patritumab deruxtecan with platinum-based chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer following a third-generation tyrosine kinase inhibitor (TKI).  Patritumab deruxtecan, also known as HER3-DXd, comprises a fully human anti-HER3 IgG3 monoclonal antibody conjugated to a topoisomerase 1 inhibitor payload, and showed activity in a previous phase 2 trial in patients relapsing after EGFR TKI and chemotherapy.   In this phase 3 study, this agent was compared with platinum-based chemotherapy in eligible patients with an EGFR-activating mutation who had previously received 1 or 2 EGFR TKIs, at least one of which was a third-generation drug, with relapse or progression after this therapy. Five hundred and eighty-six patients were enrolled, with progression-free survival as the primary endpoint.  The primary analysis showed a 9-month progression-free survival of 29% for the experimental arm compared with 19% for platinum-based chemotherapy, for a hazard ratio of 0.77 and a P value of 0.011. With higher progression-free survival rates at 6 months and 12 months, HER3-DXd also had a better objective response rate (35.2% versus 25.3%) compared with platinum-based chemotherapy (PBC), and HER3-DXd also extended intracranial progression-free survival compared with PBC in patients with brain metastases, with a hazard ratio of 0.75. Grade 3 or more treatment-related adverse events occurred in 73% of patients treated with HER3-DXd and 57% of patients who received PBC. HER3-DXd had a higher rate of grade or more 3 thrombocytopenia, and drug-related interstitial lung disease occurred in 5% of patients in the HER3-DXd arm.   The follow-up will need more time to mature since no overall survival data are currently available, but definitely an agent to watch with interest. Moving on to today's final abstract, 8500, was presented by Dr. Pasi Jänne from the Dana-Farber Cancer Institute, describing results from the phase 2 portion of the KRYSTAL-7 study. This study is exploring the use of a potent KRAS inhibitor, adagrasib, in combination with pembrolizumab in patients with advanced or metastatic KRASG12C- mutated non-small cell lung cancer.  Adagrasib has already received accelerated approval in the U.S. for previously treated locally advanced or metastatic NSCLC with a KRASG12C mutation. A previous report from the KRYSTAL-7 study demonstrated encouraging activity in combination with pembrolizumab in the frontline setting for this patient group who also had more than 50% expression of PD-L1. The presentation today described efficacy and safety data for this drug combination across all PD-L1 expression levels.  One hundred and forty-nine patients with a median age of 67 years were treated with the combination, 104 of whom had PD-L1 expression level results available, representing the so-called biomarker population in this trial. The overall response rate for the entire study population was 44%. In the biomarker population, the overall response rate ranged from 36% in those with less than 1% PD-L1 expression to 61% for those with more than 50% expression. For all patients, the median response duration was just over 26 months, and the median progression-free and overall survival rates were 11 and 18.3 months respectively.    For the biomarker population, the median progression-free and overall survival were highest in those patients with more than 50% PD-L1. No new safety issues emerged from this analysis; the most frequent toxicities were nausea, diarrhea, and increases in transaminases. Immune-related toxicities included pneumonitis, hypothyroidism, and hepatitis. These are important results and the results of the phase 3 portion of KRYSTAL-7, which compares first-line therapy with adagrasib plus pembro versus pembro alone in the KRASG12C mutated/PD-L1 more than 50% group, will be informative. For those patients with lower levels of PD-L1 expression, the authors suggest that the treatment escalation may be beneficial, possibly including the addition of chemotherapy.  That concludes today's report. Thanks for listening and I hope you will join me again tomorrow to hear more top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speaker:    Dr. John Sweetenham    Follow ASCO on social media:     @ASCO on Twitter    @ASCO on Bluesky    ASCO on Facebook    ASCO on LinkedIn     Disclosures:   Dr. John Sweetenham:    No relationships to disclose

Slovenija je ena izmed biotskih vročih točk Evrope. Kako tudi ne, ko pa naše ozemlje leži na stičišču alpske, panonske, dinarske in sredozemske biogeografske regije, zato ga zaznamujejo razgiban relief, raznovrstna kamninska podlaga ter pestre talne in podnebne razmere. Tik pred koncem maja, ko nam travniki zunaj kažejo svoj najbolj bujen obraz, se v Frekvenci X sprašujemo, zakaj so ti tako zelo pomembni za ohranjanje biotske pestrosti in kako se razlikujejo od tako imenovanih zelenih puščav. Obiskali smo nekaj rajskih travniških kotičkov na biosfernih območjih Julijskih Alp, Krasa in Kozjanskega in Obsotelja in za tokratno Frekvenco X spisali pravo senzorno razglednico z njih. Bral: Igor Velše Oddaja je bila posneta na biosfernih območjih Slovenije. V Unescov program Človek in biosfera so v Sloveniji uvrščena štiri biosferna območja: Julijske Alpe, Kras, Kozjansko in Obsotelje ter Mura. To so geološko, klimatsko in tudi kulturno raznolika območja, skupna pa so jim bogastvo biotske raznovrstnosti in navdihujoče prepletanje naravnih vrednot s kulturno dediščino.  

Piše Marija Švajncer, bereta Igor Velše in Sanja Rejc. Svetlano Slapšak, avtorico knjige z naslovom Kje smo? in podnaslovom Ljubljanski steganogram, je vznemirila legenda, po kateri naj bi Ljubljano, v rimskih časih imenovano Emona, ustanovili Jazon in Argonavti. Na ladji Argo so z zlatim runom bežali od Črnega morja po Donavi, navzgor po Savi in potem Ljubljanici. Druga pripoved pravi, da so Argonavti svojo ladjo ob Ljubljanici razstavili in jo čez slovenski Kras prenesli ali prepeljali do Jadranskega morja. Leta 1955 je slovenski matematik Ivo Lah zgodbo o Argonavtih nadgradil za ponazoritev svoje matematične formule. Do obale vodijo številne poti, zato je upošteval možnost, da je bil vsak del ladje Argo iz varnostnih razlogov prepeljan po drugi poti, kar naj bi zmedlo zasledovalce. Avtorica pojasni, kaj pomeni podnaslov knjige. Steganografija je praksa prikrivanja sporočila znotraj drugega sporočila in fizičnega predmeta; steganogram je njen proizvod. »V računalniških / elektronskih kontekstih je to računalniška datoteka, sporočilo, slika ali video, skrit znotraj druge datoteke, sporočila, slike ali videa … V zadnjih letih se v steganografiji uporablja število Lah, podatki se skrivajo v sliki.« Svetlana Slapšak je iz Lahove enačbe razbrala, da matematik v njej operira z nedeljivimi deli ladje. Njeno pozornost sta torej vzbudila nedeljivo in vizualizacija; prav z vizualizacijo je matematik ustvaril steganogram. V zvezi s tem je miturgija tisto, kar je poljubno in nedeljivo, vizualno in akustično, skratka, zgodba, ki je vselej drugačna. »Moj namen ni bil, da premagam pozabo, marveč da spomin miturgično razširim in obenem odstiram tehnike pozabe. Ključni element je tu nedeljivi del.« Svetlana Slapšak pravi, da je roman napisala kot poskus literarne verbaliziranja Lahove formule. Edini žanr, ki romanu ustreza, je menipska satira. Nastala je v poznem helenističnem obdobju in je nekakšna mešanica eseja, retorične vaje, verzov in zapleta, pravzaprav dekonstrukcija vseh teh žanrov. Ključni element je prenos oziroma potovanje. Argonavti se množijo vse do Lahovega števila, prenašajo sporočila in ostajajo nevidni. Samo poznavalci in poznavalke so tisti, ki jih opazujejo, opisujejo in opevajo. Svetlana Slapšak se prepričljivo uvršča mednje. Kot klasična filologinja, antropologinja, poliglotka, plodovita ustvarjalka, temeljita poznavalka zgodovine, umetnosti in številnih drugih področij razgrne svoje bogato znanje. Izobrazba, omika in razgledanost so zanjo vrednote; vedno znova poudarja, kako veliko veljavo imajo v človekovem življenju. V enem od zadnjih poglavij prikaže svojo življenjsko zgodbo, otroštvo in mladost v družini, ki jo ima danes za socialno okolje nižjega srednjega razreda in precej revno, vendar z zmožnostjo preživetja, izobraženo ter s smislom za humor. Piše o predanosti antični demokraciji in poskusom oživljanja prednosti te družbene ureditve. Doživela je veliko prelomnic. Zaradi kritičnih prizadevanj med študentsko stavko leta 1970 so jo politični nasprotniki napadli in ji prebili arkado. Srbska zgodovina se očitno ponavlja. Svetlana Slapšak je bila zmeraj uporniška in pokončna. Zna pa se tudi pošaliti na svoj račun, saj je kljub poudarjenemu intelektualizmu pogosto počela stvari, ki so jo zgolj zabavale in sproščale – od mode, aerobike in joge pa vse do zbiranja kuhinjskih receptov in domiselnega kuhanja. Avtoričino obsežno literarno-esejistično delo ima umetniško vrednost. Omeniti velja vidike eksofonije, se pravi vstopanja v drugi jezik in opuščanja materinščine – iz srbskega jezika v slovenski. Na koncu knjige sta namreč navedeni lektorica in korektorica, ne pa tudi prevajalka. Knjiga je napisana v slikovitem slogu, bogatem besedišču in jezikovno barvito. Posebnost je pisateljičino vživljanje v posamezne literarne like, tako zgodovinske kot mitične osebnosti, bodisi s pozitivnimi bodisi z negativnimi lastnostmi. Svetlana Slapšak je do njih prizanesljiva, se z njimi pogovarja in skuša razumeti njihova dejanja. Kot da bi bili živi, stopajo pred nas Charles Nodier, hči Vuka Karadžića, Gustav Mahler, Medeja, Prešernova Urška, prijateljice in še marsikdo, osebe, ki so tako ali drugače povezane z Ljubljano. Pisateljica kritično vrednoti zapostavljenost žensk, med vojaki pa jih na začetku omeni kar nekaj, ki so svoje ženske ljubili predano in tudi spoštljivo. Družbena kritika preteklosti in sedanjosti je pronicljiva, argumentirana in poglobljena. V knjigi so natisnjene pesmi v izvirnih jezikih, grškem, nemškem in češkem, ter prevodi, na koncu pa so dodane predstavitve, slikarske upodobitve ter fotografije zgodovinskih in miturgijskih likov. Večina prevodov v romanu je delo Božidarja in Svetlane Slapšak, odlomek iz drame Biljane Jovanović je prevedel Darinko Kores. Antropologinja razkriva etimološko ozadje ter se zaustavlja pri glasbenih in literarnih vrhuncih. Seznaniti se je mogoče tudi s simbolnim in mitološkim pomenom različnih živali – od slona, konja in miši, pa vse do krokodila in vrane. Knjiga Svetlane Slapšak Kje smo? je zakladnica novih in novih informacij, iz nje vejeta tudi posebna toplina in očaranost nad brezmejnimi možnostmi človekovega življenja: »Prenos, zmaga nad prostorom, upanje, da je možno znova sestaviti kose v ladjo, ki nas bo nosila daleč, daleč od smrti in blizu tistih, ki jih imamo radi.«

Broadcast from KSQD, Santa Cruz on 5-22-2025: Dr. Dawn explores groundbreaking cancer research using high-throughput "digital twin" analysis to reverse colon cancer cells back to normal states, identifying three master molecular switches that can induce normal cell differentiation without killing the cancer cells, thus avoiding traditional chemotherapy side effects. She discusses remarkable results from Memorial Sloan Kettering showing 80% of patients with mismatch repair deficient tumors, including all 49 rectal cancer patients, saw complete tumor disappearance after six months of dostarlimab immunotherapy, with no recurrence at five years and minimal side effects. The program covers innovative CRISPR applications, including targeting previously "undruggable" cancer mutations like KRAS and BRAF by selectively degrading mutant RNA messages while preserving healthy genes, offering unprecedented precision in cancer treatment. Dr. Dawn explains a clever immunotherapy approach that disguises tumors as pig organs using Newcastle disease virus carrying alpha-gal enzyme, tricking the immune system into mounting fierce attacks against cancer cells, showing promising results in both monkey and human trials. She describes fascinating research using cryoshocked tumor cells as Trojan horses, where liquid nitrogen-treated cancer cells carrying CRISPR gene editing tools directly seek out tumors, offering superior targeting compared to injecting CRISPR. The show reveals how cancers create protective acid walls around themselves to repel immune cells, with individual cancer cells pumping lactic acid away from the tumor center to form pH 5.3 barriers that kill attacking CD8 T cells within hours. Dr. Dawn discusses breakthrough mRNA cancer vaccines for glioblastoma using patients' own tumor cells, showing rapid immune system activation within 48 hours and extending survival in both dogs and humans with this aggressive brain cancer. She explores the "flower code" mechanism where cancer cells gaslight healthy cells through epigenetic manipulation, expressing dominant "flower win" codes to overpower normal cells expressing "flower lose" codes in biological turf wars. The program addresses systemic problems in cancer classification, explaining how organ-based categorization delays access to effective treatments, with patients waiting years for drugs that could help based on molecular profiles rather than tumor location. Dr. Dawn concludes by highlighting medical discrimination against people with Duffy null phenotype, primarily affecting African Americans, whose naturally lower neutrophil counts lead to reduced chemotherapy doses and excluded clinical trial participation despite no increased infection risk.

“A lot of other disease sites, they have some targeted therapies, they have some immunotherapies [IO]. In lung cancer, we have it all. We have chemo. We have IO. We have targeted therapies. We have bispecific T-cell engagers. We have orals, IVs. I think it's just so important now that, particularly for lung cancer, you have to be well versed on all of these,” ONS member Beth Sandy, MSN, CRNP, thoracic medical oncology nurse practitioner at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about lung cancer treatment. Music Credit: “Fireflies and Stardust” by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  Earn 0.5 contact hours of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at courses.ons.org by May 16, 2026. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: Learners will report an increase in knowledge related to lung cancer treatments. Episode Notes  Complete this evaluation for free NCPD.  ONS Podcast™ episode: Episode 359: Lung Cancer Screening, Early Detection, and Disparities ONS Voice articles: Non-Small Cell Lung Cancer Prevention, Screening, Diagnosis, Treatment, Side Effects, and Survivorship Oncology Drug Reference Sheet: Amivantamab-Vmjw Oncology Drug Reference Sheet: Cisplatin Oncology Drug Reference Sheet: Lazertinib Oncology Drug Reference Sheet: Nivolumab and Hyaluronidase-Nvhy Oncology Drug Reference Sheet: Fam-Trastuzumab Deruxtecan-Nxki Optimize Your Testing Strategy and Improve Patient Outcomes With NeoGenomics' Neo Comprehensive™–Solid Tumor Assay Clinical Journal of Oncology Nursing article: Oncogenic-Directed Therapy for Advanced Non-Small Cell Lung Cancer: Implications for the Advanced Practice Nurse ONS Biomarker Database ONS video: What is the role of the KRAS biomarker in NSCLC? Biomarker Testing in Non-Small Cell Lung Cancer Discussion Tool ONS Huddle Cards: Checkpoint inhibitors External beam radiation Monoclonal antibodies Proton therapy To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From This Episode “Unfortunately, because lung cancer is pretty aggressive, we'll see lung cancer mostly in stage IV. So about 50%–55% of all cases are not caught until they are already metastatic, or stage IV. And then about another 25%–30% of cases are caught in stage III, which means they're locally advanced and often not resectable, but we do still treat that with curative intent with concurrent chemoradiation. And then 10%–20% of cases are found in the early stage, and that's stage I and II, where we can do surgical approaches.” TS 2:53 “The majority of radiation that you're going to see is for patients with stage III disease that's inoperable. At my institution, a lot of stage III is inoperable. Now, neoadjuvant immunotherapy has changed that a little bit. But if you have several big, bulky, mediastinal lymph nodes that makes you stage III, surgery is probably not going to be a great option. So we give curative-intent chemoradiation to these patients.” TS 10:51 “Oligoprogression would mean they have metastases but only to one site. And sometimes we will be aggressive with that. Particularly, there's good data, if the only site of progression is in the brain, we can do stereotactic radiation to the brain and then treat the chest with concurrent chemoradiation as a more definitive approach. But outside of that, the majority of stage IV lung cancer is going to be treated with systemic therapy.” TS 15:00 “It's important for nurses to know that there's a lot of different options now for treatment. Probably one of the most important things is making sure patients are aware of what their biomarker status is, what their PD-L1 expression level is, and make sure those tests have been done. … It's good that the patients understand that there's a myriad of options. And a lot of that depends on what we know about their cancer, and then that guides our treatment.” TS 31:05

În cadrul ediției de pe 6 mai a emisiunii Știința360 de pe Radio România Cultural, Dr. Marius Geantă, Președintele Centrului pentru Inovație în Medicină, a comentat ultimele noutăți din domeniul sănătății. În perioada sărbătorilor de iarnă, în Regatul Unit, aportul caloric zilnic poate atinge valori de aproximativ 6000 kcal — similare cu cele înregistrate de cicliștii din Turul Franței — în timp ce nivelul de activitate fizică scade semnificativ. Acest exemplu ilustrativ susține un model alternativ propus de cercetători, conform căruia episoade scurte, dar intense, de dezechilibru energetic — determinate de perturbări ale rutinei zilnice — pot conduce la creșteri ale masei adipoase. Aceste perturbări, denumite „instabilitate comportamentală”, sunt frecvent asociate cu tranziții importante din viață, precum începutul studiilor universitare, debutul parentalității sau alte schimbări majore.Date recente contrazic astfel modelul tradițional conform căruia acumularea țesutului adipos are loc prin mici surplusuri calorice susținute în timp. În locul unei acumulări lente și constante, aceste fluctuații bruște pot avea un impact major asupra masei corporale, fără ca ele să fie neapărat evidente în evaluările medicale periodice.Un studiu recent, publicat în International Journal of Obesity, atrage atenția asupra rolului important al perturbărilor stilului de viață în acumularea excesivă de țesut adipos și evidențiază măsurile necesare pentru prevenirea și intervenția eficientă în aceste situații.Obezitatea este asociată cu un risc crescut de boli cardiovasculare, diabet zaharat de tip 2 și anumite forme de cancer. De asemenea, poate afecta fertilitatea, sănătatea oaselor, dar și calitatea vieții în general, influențând procese esențiale precum mobilitatea și somnul.Mai multe detalii despre subiectele discutate - ▶ De ce marile schimbări din viață ne fac să acumulăm kilograme în plus. Prevenția personalizată ar putea ține obezitatea sub control▶ Nivelurile ridicate de zahăr în sânge în adolescență triplează riscul de afectare cardiacă prematură, mai ales la fete▶ Pacienții care au suferit un infarct miocardic ar trebui să primească tratament cu statină și ezetimib cât mai rapid▶ Testarea mutației KRAS prin biopsie lichidă îmbunătățește prognosticul și ghidarea tratamentului în cancerul pancreatic Ascultă emisiunea pe Radio România Cultural.

''Prvič sem jih videl takoj po vojni. Griče, ki so me spominjali na gola trupla, na katerih ni več niti kože.'' Tako je podobnost med telesom in pokrajino opisal svetovno priznani slikar, grafik in risar Zoran Mušič, rojen 12. februarja 1909 v Bukovici, ki si je še posebej mesto v evropskem likovnem prostoru utrdil prav z ekspresivnimi podobami iz koncentracijskega taborišča Dachau. Ob seriji Nismo poslednji njegov izjemno bogat opus obsega še krajinske motive, portrete in zanj zelo značilne konjičke. Prav zaradi umetnikove veličine in dejstva, da so obe razstavi v okviru programa Evropske prestolnice kulture 2025, na gradu Štanjel Telesa pokrajin in na gradu Dobrovo Pokrajine teles, precej odmevno napovedovali, so se ob odprtju prve v javnosti pojavile kritike, da so mu namenili premalo prostora in da ni nekaterih ključnih del. Kuratorka dr. Nelida Nemec pa pravi, da je izbrala, kar se ji zdi pri Zoranu Mušiču najbolj bistveno predvsem v luči prepletanja telesa in pokrajine, zlivanja enega v drugo. Na pomen tega nas je umetnik sam opozarjal, doda Nemec, a smo bili v preteklosti premalo pozorni. Kakorkoli, z dvema razstavama v okviru EPK 2025 se Zoran Mušič simbolično vrača v domače kraje, na Kras in v Brda. Ob tem velja poudariti, da se tretja soba na razstavi v Štanjelu ne končna – nadaljuje se na gradu Dobrovo, zato bi bilo dobro, da bi si obiskovalci ogledali obe razstavi. Še eno pa pripravljajo čez mejo v palači Attems v Gorici. Dr. Nelida Nemec je pripravila tudi monografijo.

Zahrala si v rozprávkach, ktoré sú v našom zlatom filmovom fonde. Plavčík a Vratko, Popolvár, najväčší na svete, vo filme Miloslava Luthera Zabudnite na Mozarta, ale aj v trojdielnej filmovej sérii Anička Jurkovičová. Tá mapuje život našej prvej slovenskej herečky, ktorej otec bol významný učiteľ a národovec Samuel Jurkovič. Zuzana Frenglová si ako sedemročné dievčatko zahrala aj v známej snímke Slávnosť v botanickej záhrade. Rodáčka z Bratislavy, ktorá vyrastala v Krasňanoch. | Hosť: Zuzana Frenglová (herečka). | Moderuje: Gabika Angibaud. | Tolkšou Nočná pyramída pripravuje Slovenský rozhlas, Rádio Slovensko, SRo1.

Duitsland heeft een nieuwe bondskanselier: Friedrich Merz. Maar zijn aantreden verliep allesbehalve vlekkeloos. Bij de eerste stemming kwam hij onverwacht zes stemmen tekort, een zeldzaamheid in de Duitse politiek. Wat betekent deze valse start voor zijn gezag en leiderschap? Tijs van den Brink bespreekt het met: * René Cuperus, Duitslandkenner * Ulrike Nagel, Duitslandkenner

Piše Kristina Jurkovič, bereta Igor Velše in Sanja Rejc.. Pri knjižnih recenzijah se običajno posvečamo le besedilu, toda če knjigo za odrasle krasijo ilustracije, kar je precej neobičajno, je treba narediti izjemo; še toliko bolj, ko gre za skladen tandem slike in besede, kot je to v avtobiografski pripovedi Moj kraški pristan avtorice Elizabeth Griffin, kjer čarobne črno-bele jedkanice Alfreda Furlanija čudovito prevajajo avtoričina občutja v podobo. To ponazarja že naslovnica, natančno izrisan igličast gozd, skozi katerega se pretika svetloba in v katerega vodi široka pot, ki ni le prispodoba avtoričinih pohajanj po kraški gmajni, marveč tudi raziskovanja svoje življenjske poti. Ta jo je, kot beremo, pred tridesetimi leti prek mnogih stranpoti pripeljala iz Amerike v zgodovinsko in družbeno občutljivo okolje tržaškega zaledja, kjer si je z možem Italijanom ustvarila družino in kjer še danes poučuje angleščino. Kot se za pristno popotnico spodobi, je Griffinova vedoželjno in občutljivo odprta proti drugemu in drugačnosti. V ospredju knjige stoji njeno odkrivanje še vedno krhkega sobivanja Italijanov in zamejskih Slovencev, še vedno razmejene bližine, kar avtorica zelo dobro ponazori na primeru tamkajšnje nižje srednje šole, kamor hodijo tako italijanski kot slovenski dijaki, a je pouk organiziran tako, da se nikoli ne srečajo. Svoja opažanja in občutenja tujosti, tudi izločenosti, vedno skuša razumeti, prav slednje doživi ob spodletelem poskusu, da bi sinova izšolala v slovenskih šolah. Neprijetni izkušnji navkljub ne neha spoštovati in občudovati slovenske skupnosti, njeno močno voljo po samoohranitvi celo povezuje z lastnim bivanjem: ''Kdove,'' si rečem med vožnjo z dela, ''ali moji slušatelji slutijo, da me spominjajo na Kras, ko pa so tako neustrašni, vztrajni in odločni?'' Sama pri sebi se nasmehnem: ''Kjer sem sprva videla zadržanost, zdaj uziram veliko ljubeznivost in lepoto. Nič drugače ni z mojim bivanjem na Krasu.'' Avtorica Elizabeth Griffin se pred nobeno perspektivo ne zapira, nasprotno, odpira ji nove horizonte in zdi se, da jo ravno zavedanje in sprejemanje raznolikosti vedno bolj ukoreninjata v poprej tujem okolju. Njena zgodba pa je tudi lep preplet makro- in mikrosvetov. Prek svojega vrta se poveže s kraško zemljo, na sprehodih s psom Benom odkriva kraški svet in naleti na marsikatero človeško zgodbo, prek ljubečih portretov posameznih prebivalcev prikaže dinamično mikroklimo svojega kraja. Tako v poglavju Trgovec, trgovina, leta eden od temeljev kraja po lastnikovi smrti postane le še ena v vrsti brezdušnih prodajaln, kamor zahaja vedno manj kupcev. Pripoved tkejo zunanje izkušnje in notranji uvidi oziroma refleksije, ki se najtesneje povežejo ob smrti avtoričinega očeta. Na daljših sprehodih intenzivno začuti očetovo prisotnost in tudi sam Kras, ki kot nekakšen čuteč sopotnik vpija njeno razpoloženje. Zave se, da sta oba, vsak na svoj način, njeni zavetni luki pred življenjem in njegovimi pretresi. V jasnosti tega spoznanja zasije tudi kraška pokrajina na zadnji ilustraciji. Moj kraški pristan je lepa, blaga pripoved o sidranju v tuji deželi, ki postane fizični dom, po dušni plati pa umirjeno bivanje v čisti prisotnosti. Doživljanje sveta skozi prizmo Elizabeth Griffin je pravi bralski balzam in želeli bi si, da bi nas v prihodnje popeljala še na kakšno plovbo.

Hoe mooi had het geweest om vandaag, zeven jaar na onze eerste aflevering, nu een reportage te maken van een finale die we wél winnend afsluiten.We waren weer zo dichtbij. Maar helaas, er valt weinig te spoileren, en het terugluisteren kan pijn doen; de bekerherinneringen, het reisverslag vanuit auto en trein, de sfeerfragmenten en de almaar groeiende hoop die in de laatste minuten uiteen spat. Een nieuwe kras op onze toch al gebutste ziel. Zoals we inmiddels weten: er moet een moment komen dat de frustratie plaats maakt voor trots. En we hopen met deze aflevering stiekem een beetje daaraan bij te dragen.

In deze podcast kunt u luisteren naar het gesprek van internist-oncoloog Koos van der Hoeven en longarts Joop de Langen, werkzaam in het Antoni van Leeuwenhoek te Amsterdam, over de laatste ontwikkelingen met betrekking tot de behandeling van longkanker gepresenteerd tijdens The European Lung Cancer Congress 2025. Aan bod komen onder andere de MARIPOSA-, SAVANNAH-, de ADRIATIC- en de 3475A-D77-studie en ontwikkelingen met betrekking tot KRAS-remmers.

In this episode, host Jonathan Sackier speaks with Alexander Spira about cutting-edge advances in lung and colorectal cancer, including EGFR and KRAS-targeted therapies. They also discuss Spira's leadership in oncology research, his thoughts on the evolving ‘town-gown' dynamic in US medicine, and his hopes for the future of cancer care.  Timestamps:  00:00 – Introduction 01:50 – Most memorable family travel adventure 03:30 – What inspired you to go into oncology 05:49 – Three recent publications in lung cancer 07:02 – Real-world data on colorectal cancer 08:15 – Sex/gender differences in non-small cell lung cancer 11:53 – The science of KRAS mutations and drug development 15:07 – Accelerating diagnostics and access to therapies 17:13 – The ‘town-gown' debate in American healthcare 18:09- Three Wishes 

Dlouhé roky hraje v divadle, pro které také píše a režíruje. Dobře ho znají televizní diváci a na filmovém plátně zazářil třeba ve snímcích Bratři či Jedna noc. Objeví se i v novince Vyšehrad Dvje. Do jeho života patří také hudba a s jedním ze svých hudebních projektů brzy pokřtí novou desku s názvem Šmejd.

Dlouhé roky hraje v divadle, pro které také píše a režíruje. Dobře ho znají televizní diváci a na filmovém plátně zazářil třeba ve snímcích Bratři či Jedna noc. Objeví se i v novince Vyšehrad Dvje. Do jeho života patří také hudba a s jedním ze svých hudebních projektů brzy pokřtí novou desku s názvem Šmejd.Všechny díly podcastu Až na dřeň můžete pohodlně poslouchat v mobilní aplikaci mujRozhlas pro Android a iOS nebo na webu mujRozhlas.cz.

Jamie from Krasl talks about a new exhibition coming to Kras later this month. Also Spring classes are starting up soon! See omnystudio.com/listener for privacy information.

“It's been known for quite a while that [KRAS] is a mutation that leads to cancer development, but for really over four decades, researchers couldn't figure out a way to target it. And so, it was often considered something that was undruggable. But all of this changed recently. So about four years ago, in 2021, we had the approval of the first KRAS inhibitor. So it's specifically a KRAS G12C inhibitor known as sotorasib,” Danielle Roman, PharmD, BCOP, manager of clinical pharmacy services at the Allegheny Health Network Cancer Institute in Pittsburgh, PA, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about the KRAS inhibitor drug class. Music Credit: “Fireflies and Stardust” by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  Earn 0.5 contact hours of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at courses.ons.org by April 11, 2027. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: Learners will report an increase in knowledge related to KRAS inhibitors used for cancer treatment. Episode Notes  Complete this evaluation for free NCPD.  ONS Podcast™ episodes: Pharmacology 101 series Cancer Symptom Management Basics series Episode 330: Stay Up to Date on Safe Handling of Hazardous Drugs ONS Voice articles: First KRAS-Targeted Therapy Receives FDA Approval for Lung Cancer Oncology Drug Reference Sheet: Adagrasib Oncology Drug Reference Sheet: Sotorasib ONS books: Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice (second edition) Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (fourth edition) Safe Handling of Hazardous Drugs (fourth edition) ONS course: Safe Handling Basics ONS video: What is the role of the KRAS biomarker in NSCLC? ONS Targeted Therapy Huddle Card ONS Oral Anticancer Medication Learning Library ONS Oral Anticancer Medication Toolkit ONS and NCODA Oral Anticancer Medication Compass Oral Chemotherapy Education Sheets Lumakras® (sotorasib) manufacturer website Krazati® (adagrasib) manufacturer website UpToDate Lexidrug (formerly Lexicomp) To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To find resources for creating an ONS Podcast Club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From This Episode “If we look at specifically non-small cell lung cancer, this KRAS mutation is one of the most frequently detected cancer drivers or driver mutations. It's thought that about a quarter of cases of non-small cell lung cancer have this KRAS mutation, and it's usually a specific amino acid substitution that we see in non-small cell lung cancer, so what's known as KRAS G12C mutation.” TS 2:31 “Both of these agents, sotorasib and adagrasib, have the same mechanism of action. They bind to a pocket, very specifically on the KRAS G12C protein, and they lock it in an inactive state so that it can't cause that downstream uncontrolled signaling to happen. So they're kind of shutting down the signaling, and therefore you don't get that uncontrolled cell growth and proliferation.” TS 4:27 “Another big difference to point out, and one that is often used in clinical practice to differentiate when to use these agents, is specifically adagrasib is known to have activity in patients with metastatic non-small cell lung cancer that have active brain metastases. In the clinical trial, they included patients with active brain metastases, and they found that this drug has great [central nervous system] penetration. And so it may be considered the agent of choice in patients with brain metastases.” TS 7:19 “Other considerations—I think one of the big ones—is that there are a lot of drug interactions. Just specifically calling one out that I think is pretty impactful, is sotorasib has an interaction with acid-suppressing medications. So there is the recommendation to avoid [proton pump inhibitors] and H2 antagonists in patients receiving sotorasib. They can take antacids, but you would need to space those out from their dose of sotorasib.” TS 14:14 “This needs to be a collaborative endeavor to make sure these patients are monitored appropriately. We are putting a lot of responsibility on the patients with all of this. So, again, completely administered generally in the home setting, a lot of monitoring, a lot of adverse effects, need for reporting and management—so there's a lot happening here. And it takes a team to accomplish this and to do it right. And I firmly believe that this is often a collaborative effort between our pharmacy and oncology nursing teams to make this happen. Working together to ensure outreach to patients—I think that patients are often more successful with these medications with early identification of toxicities when we're doing scheduled outreach.” TS 19:44

I had the chance to speak with Petrina Kamiya, Global Head of AI Platforms and VP at Insilico Medicine, as well as President of Insilico Medicine Canada. Insilico Medicine is what Petrina calls a “tech bio”—developing both AI platforms and therapeutic assets, with a flexible model licensing both. Their pharma.ai platform was created to address challenges in drug discovery all the way from target identification to the clinic. In just a few years, they've gone from having two core products to a suite of about 12, all built with a heavy emphasis on validation.When I think about AI in drug development, I think about all the failures in clinical trials. I've always wondered: are the molecules themselves to blame, or is the reason for so many failures rooted in the aspects that surround their testing—like patient selection, procedures, or trial design? Petrina confirmed that the two biggest reasons for failure are safety and efficacy. Many failures are turn out to be preclinical issues—either the wrong target was selected, or the molecule causes unintended side effects. AI and machine learning are being used to better predict both, by identifying high-confidence disease targets and designing safer molecules.But predicting toxicity is still a major challenge. There are models at every stage—from in silico predictions to in vitro and animal models—but each layer adds complexity, and good data to train AI models is notoriously hard to come by. A lot of data around failed molecules never makes it into the public domain because it's proprietary. That means valuable insights about toxicity are often lost, though some substructures known to be problematic are at least captured in public databases. I realize that companies need a return on their investment and even failure data has competitive value. But you have to wonder how much money is wasted chasing dead ends that could have been avoided.The other question I always have is about the mechanics of drug binding. Most approaches focus on the active site—the orthosteric site—where the protein normally interacts with its natural ligand. I asked about the possibility of other strategies like allosteric binding (where a drug binds somewhere else on the protein to inhibit function). Petrina validated that idea along with degraders, which are molecules designed to bring a protein into contact with the cellular machinery that destroys it. These newer modalities, including molecular glues, offer ways to selectively disable problem proteins without relying on traditional binding.Nothing is straightforward. Allosteric sites can offer greater selectivity, which could reduce toxicity. But finding those sites is incredibly difficult because proteins are dynamic and mobile. It's not just about structure; it's about motion within the protein itself and context.The body's backup systems—redundant pathways, mutations, and rescue mechanisms—can undermine even well-designed drugs. This is especially relevant in oncology. Proteins like KRAS have so many variants that it's not enough to design one effective inhibitor—you often need a panel of drugs to address different mutations. Petrina noted that the human body has many fallback mechanisms, which makes targeting disease pathways more difficult but also explains why drugs that seem perfect in vitro don't always deliver in the clinic.Not subscribed? Let's fix that. No spam, just good content wherever I find it.Getting back to clinical trials, AI is mostly being applied operationally right now—to optimize patient selection, identify clinical sites with the right patient profiles, and monitor for trial reporting issues. The big advantage is in stratifying patients to improve the signal-to-noise ratio. As Petrina noted, sometimes a drug works for a subset of patients, but that signal is lost in the broader trial data. That resonated with my previous interview with Kurt Mussina who used AI to identify ideal site locations based on logistics and patient demographics—a very practical, high-impact use of the technology.What if we could recover some therapies that have previously failed because it wasn't tested on the right people? AI could help salvage and reposition those compounds by uncovering hidden signals in the data. You have to believe that improvements in AI will find a few lost nuggets—digging back through data with better tools to find value that's already there.Developing therapies aren't the only application for new molecule discovery. Insilico is also working with companies in the herbicide space, and as Petrina explained, discovering herbicides isn't all that different from designing drugs for people. You still need target specificity, safety, and cost-efficiency—but at an even greater scale of production. If people or animals are exposed, or if the herbicide lingers in the environment, it has to meet a high safety bar.The unique challenge here is complexity and scale. It comes down to economics. We may spare no expense to extend a human life with doses in the milligram range. In agriculture, you're looking for a simple compound that is cheap, can be produced in massive quantities, and can be stored in almost any conditions. It's a new set of constraints.AI in discovery isn't about magic. It's about building better foundations—more accurate models, more validated data, and more thoughtful decision-making—to improve every step from discovery to clinical success.Your deepest insights are your best branding. I'd love to help you share them. Chat with me about custom content for your life science brand. Or visit my website. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit cclifescience.substack.com

Drugi poudarki oddaje: - Nova kolesarska pot na Goriškem na 100 kilometrih povezuje Brda, Kras in Vipavsko dolino; steza Celje-Laško pa še ni nared. - Prebivalce Sermina skrbi, da jih bo nova vpadnica odrezala od drugih krajev in da se bo kakovost bivanja zaradi povečanega prometa poslabšala. - V Grahovem ob Bači končujejo drugi del sanacije plazu. - Bohinj se ponaša s čedalje več festivali, napovedujejo kongres športnih ribičev

Conversation with Jodie Kras, Director Galleries at the Melbourne Art Fair, exploring more than a decade of her rich experience working in the bustling art scenes of Melbourne and Sydney from commercial galleries to prestigious biennales and auction houses.

Molecular differences in the profiles of low grade serous ovarian cancer (LGSOC) and high-grade SOC substantiate the need to find unique, differentiated treatment options for each epithelial ovarian cancer subtype, according to Kathleen N. Moore, MD, MS. CancerNetwork® spoke with Moore, Virginia Kerley Cade Endowed Chair of Cancer Development, associate director of Clinical Research at the Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program and professor in the Section of Gynecologic Oncology the University of Oklahoma Health Sciences Center, about distinguishing low grade serous ovarian cancer from other types of ovarian cancer, current treatment options and clinical trials evaluating new regimens, as well as managing treatment in younger patients with or those seeking to preserve fertility. Moore began by differentiating LGSOC from high grade SOC, stating that this disease typically occurred in younger patients and was primarily characterized by MAP kinase alterations, specifically KRAS and BRAF mutations. She then discussed the emergence of endocrine therapies in this indication owing to the presence of estrogen receptors. Additionally, first line treatment was discussed, with the standard of care defined by primary cytoreduction followed by paclitaxel and carboplatin. She then highlighted multiple clinical trials assessing alternative treatment in this indication, particularly involving the use of letrozole (Femara). Other clinical trials evaluated the use of CDK4/6 inhibition plus fulvestrant or BRAF and MEK inhibition with letrozole, with Moore emphasizing the potential for these studies to shift the treatment paradigm in the frontline setting. Furthermore, she suggested that CDK4/6 inhibition may help enhance responses in patients with recurrent LGSOC. Moore then highlighted treatment concerns for younger patients and those seeking to preserve fertility, while expressing the importance of understanding a patient's goals, which may help optimize outcomes. She concluded by reiterating the importance of designing trials and tailoring treatment considering the molecular profile of LGSOC.

I en tid då biståndslandskapet förändras och stora givare som USA drar tillbaka sitt stöd ökar vikten av ett effektivt internationellt bistånd. I detta avsnitt diskuterar vi utvecklingseffektivitet – ett nyckelbegrepp inom biståndet – och hur Sverige jobbar för att värna principer som nationellt ägarskap, resultatfokus, transparens och ansvarsutkrävande i samarbetet med multilaterala organisationer. I studion: Lennart Wohlgemuth, styrelseledamot i FUF, föreningen för utvecklingsfrågor och med en lång karriär inom biståndet från Sida, UD, IMF och UNDP och som chef för Nordiska Afrikainstitutet. Lennart har, tillsammans med Anna Sjöberg Tibblin, skrivit EBAs underlagsrapport om utvecklingseffektivitet och Sveriges multi-bi-bistånd. Annika Otterstedt, biträdande generaldirektör på Sida och avdelningschef för Sidas resultatavdelning, tidigare biståndsråd i Colombia och Kenya. Programledare Helena Hede Skagerlind, utredningssekreterare och Ravneet Singh, biträdande utredningssekreterare på Expertgruppen för biståndsanalys

Dr Fakih discusses the significance of this approval, key findings from the pivotal CodeBreaK 300 trial (NCT05198934), and how this combination fits into the current KRAS G12C–mutated mCRC treatment paradigm.

In a conversation with CancerNetwork®, Marwan G. Fakih, MD, spoke about the FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix), and how it may affect the treatment paradigm for patients with KRAS G12C-mutant metastatic colorectal cancer (CRC). Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California. According to Fakih, the approval of this combination regimen is a “welcome step” for those with metastatic CRC harboring KRAS G12C mutations. Based on supporting data from the phase 3 CodeBreaK 300 trial (NCT05198934), sotorasib/panitumumab may prolong progression-free survival (PFS) and reduce disease burden in patients while offering improvements in other outcomes vs prior standards of care (SOC) like trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga). Topline data at the time of the approval showed a median PFS of 5.6 months (95% CI, 4.2-6.3) with sotorasib at 960 mg plus panitumumab vs 2.0 months (95% CI, 1.9-3.9) in the SOC arm, in which patients were assigned to receive trifluridine/tipiracil or regorafenib (HR, 0.48; 95% CI, 0.30-0.78; P = .005). Additionally, the overall response rate was 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in each respective arm. Looking ahead, Fakih highlighted the potential next steps for research associated with the sotorasib combination as well as other novel therapeutic strategies in the gastrointestinal cancer space. For example, he described the phase 3 CodeBreaK 301 study (NCT06252649), which will evaluate sotorasib/panitumumab as frontline therapy when administered in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI) vs FOLFIRI plus bevacizumab (Avastin) in metastatic KRAS G12C-mutant CRC. Other novel agents under development in the space include RAS inhibitors and immunotherapy regimens combining CTLA-4 inhibitors with anti–PD-L1 agents. References 1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 12, 2025. https://shorturl.at/1WviB 2. Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301). J Clin Oncol. 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326

Michelle was diagnosed with Stage 3a Adenocarcinoma of the lung in 2011 with the KRAS mutation and is still alive and living well. ORDER MY NEW BOOK SWEET INDULGENCE!!! https://www.amazon.com/Chef-AJs-Sweet-Indulgence-Guilt-Free/dp/1570674248 or https://www.barnesandnoble.com/w/book/1144514092?ean=9781570674242 GET MY FREE INSTANT POT COOKBOOK: https://www.chefaj.com/instant-pot-download MY BEST SELLING WEIGHT LOSS BOOK: https://www.amazon.com/dp/1570674086?tag=onamzchefajsh-20&linkCode=ssc&creativeASIN=1570674086&asc_item-id=amzn1.ideas.1GNPDCAG4A86S Disclaimer: This podcast does not provide medical advice. The content of this podcast is provided for informational or educational purposes only. It is not intended to be a substitute for informed medical advice or care. You should not use this information to diagnose or treat any health issue without consulting your doctor. Always seek medical advice before making any lifestyle changes. Bio: Dr Dana Simpler is a primary care doctor who practiced in Baltimore City until retirement in 2022. She is a graduate of University of Maryland Medical School. She became interested in Lifestyle Medicine after reading The China Study by T. Colin Campbell and Prevent and Reverse Heart Disease by Caldwell Esselstyn. After attending many Lifestyle Medicine conferences geared towards practitioners, she incorporated diet and lifestyle recommendations into her regular medical practice. "I found diet changes had a great impact on my patient's health. While not everyone is open to change, it is important for people to at least be advised what they can do to prevent or reverse their medical conditions."

JCO PO author Dr. Hatim Husain at University of California San Diego, shares insights into his JCO PO article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non–Small Cell Lung Cancer: A Case Series and Literature Review”, one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Dr. Husain discuss how to utilize real-world and clinical trial data to discern the safety of adagrasib (another KRASG12C inhibitor), following sotorasib discontinuation due to hepatotoxicity. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center.  Today, I'm very excited to be joined by Dr. Hatim Hussain, Professor of Medicine at the University of California, San Diego, and author of the JCO Precision Oncology article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS-G12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.” This was one of the top downloaded articles of 2024. And the other interesting thing is we generally don't do podcasts for case reports or case series, so this is one of the very few that we have selected for the podcast.  And at the time of the recording, our guest disclosures will be linked in the transcript.  Dr. Hussain, welcome to our podcast and thank you for joining us today. Dr. Hatim Husain: Thank you Dr. Naqash. Such a pleasure to be here and to speak with you all. Dr. Rafeh Naqash: And for the sake of this podcast, we'll refer to each other using our first names. So again, as I mentioned earlier that this is one of the very few case reports that we have selected for podcasts in JCOPO and the intention was very deliberate because it caters to something that is emerging where we are trying to treat more KRAS mutant patients with different KRAS inhibitors. And you tried to address one very unique aspect of it in this article which pertains to toxicity, especially hepatotoxicity. So for the sake of our listeners who tend to be community oncologists, trainees, academic faculty, can you tell us what are KRAS inhibitors? What is KRAS-G12C? And how do some of these approved KRAS inhibitors try to inhibit KRAS-G12C? Dr. Hatim Husain: Sure. For a long time actually we've not had a selective way to inhibit mutant KRAS. And over the last several years actually now, we've seen some dramatic advances here, particularly with the FDA approval of some of the selective inhibitors against the G12C variant. So KRAS-G12C is an isoform of KRAS that is most common in lung cancer and in fact actually is a transversion mutation in the KRAS gene that is a product of the carcinogen of tobacco. And in fact, the incidence of KRAS-G12C in lung cancer, it's quite astounding where as many KRAS-G12C patients there are, there can be, as you know, more than EGFR patients in certain populations and cohorts. The medicines sotorasib and adagrasib were rationally designed to be selective KRAS-G12C inhibitors. And the way that they do this is that they lock the KRAS protein in the OFF state. KRAS is a protein that oscillates between an ON and an OFF state and by virtue of locking the protein in an OFF state, it has shown inhibition of downstream signaling and mitigation of tumor growth and, in fact, tumor cell death. Dr. Rafeh Naqash: I absolutely love the way you describe the ON and OFF state, the oscillation where the ON is bound to the GTP and the OFF is bound to the GDP. The two KRAS inhibitors as currently FDA approved, as you mentioned, are RAS OFF inhibitors and they're emerging KRAS inhibitors that are RAS ON. So now, as we have known from previous data related to immunotherapy and EGFR TKIs such as osimirtinib where toxicity tends to be a compounded effect when you have osimertinib given within a certain timeline of previous checkpoint therapy, we've seen that in the clinic as the data for these KRAS inhibitors is emerging, you talk about some very interesting aspects and data about what has been published so far with regards to prior use of immunotherapy or chemo immunotherapy and the subsequent use of KRAS inhibitors. Could you elaborate upon that? Dr. Hatim Husain: Sure. So for this population of patients, the first line approved strategy is a strategy that most cases will incorporate immune therapy and chemotherapy. Immune therapy can have some important responses for patients with KRAS-G12C. This may be due to the fact that KRAS-G12C patients may have a higher incidence of prior smoking, perhaps higher mutation burdens in some patients, and perhaps immunogenicity is defined in that context. So the standard of care in the first line currently includes immune therapy or immune therapy and chemotherapy. Where the current FDA approvals for selective G12C inhibitors are are after the first line of therapy. There are a number of trials exploring these medicines in the first line to see if they may be incorporated into a future treatment paradigm. Dr. Rafeh Naqash: Thank you for that explanation. Now, going to what you published in this manuscript, can you help us understand the context of why you looked at this? Even though the data just comprises a case series of a handful of patients, but the observations are very interesting and these are real world scenarios where we often tend to be in situations where an individual has had toxicity on a certain drug and may have some response to that drug, but at the same time, the toxicity is challenging. And then you try to debate whether another drug in the same class might be beneficial without those toxicities. So you've tried to address that to some extent using this data set. So can you elaborate upon the question, the methodology, what you tried to look at, and important observations that you have? Dr. Hatim Husain: Yes, our paper was actually inspired by one of my patients. My patient was a patient who had received chemotherapy and immune therapy and actually in the past, even, you know, additional lines of immune therapies, it was really coming to the edge of where standard treatments would exist. It was right at the same time that these selective inhibitors had been approved and the patient had received sotorasib. And what was remarkable was, when given sotorasib, patient had a very high peak and spike in the transaminases. And we would do different trials of strategies around dose, around interruptions. And it was becoming quite difficult, actually, for the patient to proceed with additional therapy. It was around similar times, actually, and I do want to make a note that the patient was progressing, driven in large fact by the fact that we've had to interrupt the medicine. So we feel and believe that the patient had had inadequate dosing because of the level of toxicity that the patient was having with transaminase increase. So it was around the same time that adagrasib was first commercially available that we were at that point, and we did a trial of adagrasib post-sotorasib, largely driven by necessity, without having additional options to provide this patient in our environment. What was remarkable was when the patient received the adagrasib, there were no spikes in transaminases similar to what we had seen before. And that really led us thinking and to say, “Is this adverse event of transaminase increase or hepatotoxicity, is this a class effect with KRAS-G12C inhibitors, or is it more nuanced than that? Are there different, perhaps, mechanisms by which the medicines may work that may more or less differentially contribute to this adverse event?” And so that inspired us to kind of do a larger analysis, kind of really reach out to a larger network of physicians to gather insights and to gather responses in patients who had had a serial approach of sotorasib and then adagrasib.  What we found in this process was, in fact, actually there were many more cases of patients who resembled my patient, where the sequence of sotorasib going to adagrasib may have demonstrated differential contribution of hepatotoxicity in that context. And that really motivated us to put the publication together to due diligence, and in the publication spend a lot of time to kind of outline each patient case in detail around metrics surrounding time from last immune therapy, the number of days on sotorasib, the best response to sotorasib, the interval between sotorasib and adagrasib, the duration of adagrasib and then the grade of hepatotoxicity seen in each of the contexts, and particularly kind of the adagrasib and patient disease status as well. We were quite inspired by the effort to try to, if we do not have randomized data in comparison of one medicine to another, which we do not at this juncture, we do not have a randomized analysis to really diligently and rigorously compare the rates of AEs across each medicine, and even in sequence, we do not have that with immune therapy. But what we felt was trying to get more analysis of this sequential approach of, if patients had received a medicine, had to be taken off because of toxicity and then actually tried on a new medicine, what were those rates? We felt like that was at least some information to try to get at this question. Dr. Rafeh Naqash: And you bring forward a very important point, which is, a lot of times in the real world setting we don't have cross trial comparisons that can be fully applicable, or we don't have trials that compare two drugs of the same class with respect to the AE profile or efficacy. And observations like the one that you described that led to this study are extremely critical in trying to help answer these questions.  From a data standpoint, and you allude to it to some extent in your manuscript, the trials that are trying to address combination of KRAS-G12C with immunotherapy, especially sotorasib or adagrasib, can you elaborate on that data, what has been published so far and summarize it for our listeners? Dr. Hatim Husain: So there is data from clinical trials looking at patients actually who have received concomitant immune therapy and sotorasib. What was seen in this, in a real world analysis, was that some patients actually who had received sotorasib within a close proximity of immune therapy, as well as a larger study actually which showed in combination there were higher rates of hepatotoxicity in that context. In fact, there were rates of grade 3 hepatotoxicity. And I think built upon that data there's a recognition in the field that we have to be very diligent in terms of even the clinical trial designs in how to understand the pairing between immune therapy and selective G12C inhibitors. There are many trials that are ongoing, one of the studies that is ongoing is known as the KRYSTAL-7 study, which is evaluating adagrasib in combination with pembrolizumab in the first line. And we await more information on that strategy as well. In the context of sotorasib, because of some of the trials that have shown higher rates of hepatotoxicity, there are some additional trials now looking at sotorasib in combination with chemotherapy, and those also have some information that have been reported as well. Dr. Rafeh Naqash: From a drug development standpoint, as you mentioned, there's always a tendency to combine something with something else. And in my practice, and I'm sure in your practice too, when we do early phase trials, many trials are still focused on choosing the maximum tolerated dose, which may be something that we need to gradually move away from as we try to implement these combinations of multiple antibodies plus some of these target agents from maybe the biological optimal dose rather than the maximal tolerant dose is a better way to look at the drugs, the pharmacokinetic profile, and then see what is likely the safest combination with the most appropriate target engagement. Do you have any thoughts on that or insights on that from a drug development perspective? Dr. Hatim Husain: It's a wonderful question and I think it is a very insightful question and understanding of where we are in space right now. And I agree with you that historically, cancer drug development was really hinged upon medicines that perhaps required higher doses to see a benefit or to inch out kind of marginal increases upon where we were at. Now, in combination with medicines that have non-overlapping mechanisms of action, the concept is: Can there actually be more synergy across an approach using combinatorial strategies rather than just additive effects? And I think that in some cases this is being studied with immune therapy, in some cases actually even in the context of other novel mechanisms for cancer therapy. I think that in my practice, I will really try to see how a patient at an approved dose will respond. But definitely I'm open to the concept that there may be a dose that doesn't have to be the maximally tolerated dose, but rather the dose that responses can be seen and perhaps actually at a lower dose than what drives many toxicities. Dr. Rafeh Naqash: I often describe this to my patients as individual patient dose optimization outside of a clinical trial, where I'm sure you've probably done this, where in older adults maybe a lower dose of osimertinib is tolerated better, or a lower dose of sotorasib or adagrasib for that matter, tolerated better with perhaps a similar level of efficacy, since we don't have comparisons between doses and efficacy so far.  So I think in the bigger picture, as we discussed in a nutshell, what I would really like the listeners to understand is as we try to move towards this field of precision medicine targeting more and more of the undruggable genes, there's bound to be a certain level of toxicity patterns that we'll start observing. So I think these real world scenarios which may not be addressed using clinical trials because it is in the real world setting where you cycle one treatment after another after another, which may or may not be allowed in most trials and the real world setting can inform, in certain cases, subsequent trial designs. So I think the most important message, at least that I took from your manuscript, was that these real world observations can make a huge difference and inform practice, even though the data sets may be small. Of course, you want to validate some of these findings in a bigger, broader setting, but proof of concept is there. And I think next time I see an individual in my clinic where I see better toxicity, I'll definitely try to talk to them about subsequent treatment with another KRAS inhibitor, maybe adagrasib or something else, if and when appropriate.  Do you have any closing thoughts on some of these things that we discussed? Dr. Hatim Husain: I just want to leave the audience actually with this concept that sometimes we group targeted therapy side effects as being class effects unanimously. And I do think actually that each inhibitor may have different off target effects on where medicine may act. We don't truly understand the mechanism of hepatotoxicity in the context of selective KRAS-G12C inhibitors. One of the hypotheses may be due to off target cysteine reactivity in the numerous off target binding sites that certain medicines may have over others. And just even qualitatively which off target binding sites there may be, and how that may lead to either immunogenic responses and other organs or such. So I do think that we do need more research to understand the mechanism. But I think where we are at right now in this space is not assuming that all medicines are going to have the exact same toxicity. I think especially when patients may not have other options, this is something to consider as well. Dr. Rafeh Naqash: Thank you so much. Now, outside of the scientific insights, Hatim, I know you a little bit from before. And knowing the kind of work that you've done in precision medicine, I'm really interested to know about where you started, how you started, how things have been, and what kind of advice you have for junior faculty fellows who are interested in this field of precision medicine that is becoming more and more exciting as we progress in the oncology space. Dr. Hatim Husain: Thank you, Rafeh. I will say, actually as a medical student, I was actually very interested in oncology, partly because it was then and still remains one disease or a constellation of diseases that just has such a high psychological burden on patients. And through the experiences I've had, I really can understand and relate with that concept. I did my medical school at Northwestern, residency at the University of Southern California, and then my oncology fellowship at Johns Hopkins University.  And now I've been on faculty at University of California, San Diego, for about 12 years now. It's been a great experience paralleled with the fact that during these last 12 years, I've really seen how the developments in precision oncology, both targeted therapy as well as immune therapy, have really blossomed and unfolded. A large area of my research in my career has kind of focused on cancer genome and integration of novel technologies to really see how they may have clinical application. When I was in my fellowship and as a young faculty, the liquid biopsy was actually coming into development. And this was hinged upon information that had come forward in the prenatal space where some patients actually who were undergoing prenatal testing during pregnancy were found to have complex karyotypes and genomic alterations and then retrospectively found to have cancer.  And doing my fellowship at Johns Hopkins, some of the pioneers in liquid biopsy were my mentors and really kind of instilled in me that passion for really thinking through how cancer genomics can be integrated through time. And some of the research that I have been doing has been looking at clonal evolution of cancer, how cancer is changing over time, and how we can think through the right surveillance strategies to really understand how that change is occurring. The dynamics of ctDNA in retrospective cohorts have been studied and shown that, you know, there can be associations between progression-free survival and other clinical endpoints. The current paper that we are speaking about parallels that in a certain way where, rather than say, looking at clonal evolution and say, the efficacy answer of sotorasib first and then adagrasib and how frequently can adagrasib salvage patients, this looks at it from a different angle around toxicity. And I think that is a key point because, at my core, I really do enjoy the clinical aspect of complex decision making on behalf of patients weighing efficacy and toxicity that they may have as they try to get the best quality of life through this journey. Dr. Rafeh Naqash: Thank you again, Hatim, for all those insights, both from the scientific perspective as well as personal perspective. We appreciate that you chose JCOPO as the destination for your work.  And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Hatem Husain Disclosures Consulting or Advisory Role: AstraZeneca, Foundation Medicine, Janssen, NeoGenomics Laboratories, Mirati Speakers' Bureau: AstraZeneca, Janssen Institution Research Funding: Pfizer, Bristol-Myers Squibb, Regeneron, Lilly Travel, Accommodations, Expenses: AstraZeneca, Janssen, Foundation Medicine  

Accountability. It's a word that can make people squirm, but if you want to see real transformation in your business, you need to embrace it.Today on The Chris LoCurto Show, we're unpacking how accountability creates clarity, aligns teams, and strengthens leadership.We'll cover the essential tools you need to build a culture of accountability and walk through practical strategies to implement it effectively.So if you're ready to learn how to hold your team accountable in a way that fosters growth—without feeling like the bad guy—this episode is for you. Let's dive in.Episode Timestamps and Key TakeawaysAccountability Aligns Teams to Vision, Mission, and Strategy (00:05:47)Discover how accountability keeps your team aligned with the company's mission, vision, and strategy, ensuring everyone moves in the same direction efficiently.Clarity Through KRAs and KPIs (00:12:07)Learn how KRAs and KPIs provide measurable clarity, setting clear expectations for every role and eliminating confusion in performance evaluation.The Power of Structure and Organization (00:20:19)Explore why structured systems, meeting rhythms, and project management tools enhance accountability and reduce miscommunication.High-Quality Communication Builds Trust and Clarity (00:23:35)See how effective communication fosters trust, strengthens relationships, and ensures alignment within your team.Next-Level Leadership LIVE Event 2025 (00:26:46)Get details on our upcoming event in April, where we'll equip you with leadership tools to reduce overwhelm and lead with confidence. Learn more.Coaching, Training, and Supporting Success (00:30:25)Understand how ongoing coaching and training set your team up for success, ensuring accountability becomes a tool for growth rather than micromanagement.Action Items to Build Accountability (00:34:32)Practical steps to implement accountability in your business, from documenting KRAs to fostering open communication and using project management tools.Additional Resources (00:36:29)Related podcast episodes that dive deeper into accountability and communication strategies.Conclusion (00:37:21)Accountability isn't about micromanaging—it's about clarity, alignment, and empowerment. When your team understands their roles, expectations, and goals, they perform at a higher level.Start implementing these strategies today and watch your business transform.If this episode resonated with you, hit that like button, leave a review, and share it with others who need to hear it.Take this information, change your leadership, change your business, and change your life. See you next time!

BUFFALO, NY - February 18, 2025 – A new #researchpaper was #published in Oncotarget, Volume 16, on February 12, 2025, titled “Could Panitumumab with very low dose Capecitabine be an option as a maintenance regimen." In this study, researchers Doaa A. Gamal, Aiat Morsy, and Mervat Omar from Assiut University Hospital, evaluated a new maintenance treatment for metastatic colorectal cancer (mCRC). Their findings suggest that a combination of two drugs—Panitumumab, a targeted therapy that blocks a protein called epidermal growth factor receptor to slow cancer growth, and low-dose Capecitabine, a chemotherapy drug that converts into 5-fluorouracil (5-FU) inside the body to stop cancer cells from growing and dividing—could help extend survival in patients with mCRC. This regimen appears to be both effective and well-tolerated, especially for patients with wild-type KRAS mCRC who had previously responded to treatment. Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Standard treatment often involves a combination of chemotherapy and targeted therapies, but many patients face challenges related to treatment toxicity and resistance, which can lead to treatment interruptions. This study tested whether a lower-intensity maintenance treatment could help keep the cancer under control after initial treatment. The study involved 25 mCRC patients with wild-type KRAS and BRAF, who first received six rounds of standard 5-FU-based chemotherapy with Panitumumab. Patients who responded well then switched to a maintenance treatment of Panitumumab every two weeks and a low, continuous dose of Capecitabine. The results showed that patients had a median progression-free survival of 18 months and a median overall survival of 45 months, indicating a strong potential benefit. Patients with metastases detected at the same time as the primary tumor showed a longer progression-free survival than those with metastases appearing later. The treatment was also well tolerated, with only 8% of patients experiencing severe side effects such as skin rash or diarrhea, which were managed with standard treatments. "In our research, the toxicity profile was very acceptable, and no patients needed to stop treatment or had a dose modification due to toxicity." Finding a way to keep cancer under control while reducing side effects is a major goal in cancer treatment. While other maintenance therapies like Bevacizumab and Cetuximab have been studied, this research suggests that Panitumumab with low-dose Capecitabine could be a promising new option. Panitumumab is already an FDA-approved drug, but its role in maintenance therapy had not been extensively explored. The results of this study suggest that this combination may help delay disease progression while keeping side effects manageable, ultimately improving patients' quality of life. Although larger studies are needed, these findings open the door for further clinical trials to confirm the benefits of this regimen. If validated, this approach could change the standard of care for mCRC patients, particularly those who cannot tolerate more intensive chemotherapy. DOI - https://doi.org/10.18632/oncotarget.28687 Correspondence to - Doaa A. Gamal - doaaalygamaal@gmail.com Video short - https://www.youtube.com/watch?v=wuPSS0EdK-8 To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Featuring articles on asymptomatic severe aortic stenosis, kidney disease, fracture prevention in women, and residual breast cancer, the future of the U.S. physician workforce, mutant KRAS signaling, and manufactured chemicals and children's health; a review article on the identification and treatment of alcohol use disorder; a case report of a man with loss of consciousness and a fall; and Perspectives on striking a balance, on changing Medicare payment to strengthen primary care, and on Schrödinger's cancer.

In this episode, we explore how Key Result Areas (KRAs) are more than just management tools—they're the foundation of a well-run business.KRAs bring clarity, align roles with company goals, and eliminate confusion, helping your team achieve greater productivity and success.If you're ready to streamline your leadership and business processes, this episode is packed with actionable insights, examples, and strategies to help you use KRAs effectively.Episode BreakdownWhat KRAs Are and Why They Matter (00:01:30)KRAs define expected results for each role, creating clarity for both leaders and team members. Discover why they're essential to avoid misalignment and confusion, with examples for various roles.The System Approach to KRAs (00:04:45)KRAs tie directly to your mission, vision, and strategy. Learn how aligning roles with business goals ensures everyone moves in the same direction, illustrated with StratPlan examples.Next-Level Leadership LIVE Event (00:09:26)This April 2-4, join us for three transformative days to learn actionable leadership strategies, reclaim work-life balance, and connect with leaders who share your challenges and goals.How KRAs Prevent Leadership Struggles (00:14:03)Unclear roles lead to shifting expectations and wasted resources. KRAs solve this by providing measurable goals and accountability, ensuring your team operates efficiently.Integrating KRAs into Your Leadership Strategy (00:16:35)Discover how to create KRAs that tie team objectives and KPIs to company success, reducing tough conversations and improving results.Why Revisiting KRAs Is Critical (00:20:09)Regularly reviewing KRAs ensures clarity and growth. Learn a simple process for monthly reviews to keep your team aligned and productive.Additional Resources (00:22:58)For a deeper dive into KRAs, check out Episode 120 (The What, Why, and How of KRAs) and Episode 406 (What Good is a KRA?), available on chrislocurto.com.Final ThoughtsWhether you're new to KRAs or need a refresher, this episode gives you the tools to bring clarity and alignment to your team. Share this episode with a fellow leader and join us for the Next-Level Leadership LIVE Event in April!Take this information, change your leadership, and change your life. See you next time!

In today's episode, we had the pleasure of speaking with Alec Watson, MD, a thoracic oncology fellow in the School of Medicine in the Division of Medical Oncology at the University of Colorado Anschutz Medical Campus in Aurora. In our exclusive interview, Dr Watson discussed the rationale for and key findings from a retrospective analysis examining the ways that oncogene overlap could identify clinically relevant thresholds for MET, KRAS, and HER2 gene copy number gain in non–small cell lung cancer; next steps for this research; and the future implications of these findings.

Welcome to The Chris LoCurto Show! As we kick off the new year, instead of chasing new strategies, let's focus on resetting and recommitting to the essentials that drive success.In this episode, I'm sharing actionable steps to help you align your team, elevate your leadership, and make 2025 your strongest year yet. Let's dive in!Recommit to Discipline in Leadership (00:01:20)Consistency is key. Reset your meeting structures to align your team, ensure accountability, and boost productivity. Examples of effective meetings are shared.Get Out of the Leadership Crazy Cycle (00:05:27)Stop firefighting and start delegating effectively. Tools like the delegation matrix can help you focus on what truly matters.Next-Level Leadership LIVE Event 2025 (00:08:57)Join us April 2-4 for a transformative leadership event. Learn strategies to lead smarter, reclaim your personal life, and connect with like-minded leaders.Engage with Your Business's Financial Health (00:13:40)Dive into your financials! Regularly reviewing your P&L statements, budgets, and forecasts is crucial for making informed decisions.Reevaluate Your Team Communication (00:17:24)Clear expectations and consistent communication prevent accountability gaps. Regular one-on-ones help align your team with your goals.Focus on Accountability and Ownership (00:21:22)Tough conversations become easier with strong accountability. KRAs provide clarity and measurable results to keep your team on track.Action Items (00:25:05)Audit your leadership practices, hold regular meetings, commit to financial reviews, and delegate strategically. Start small and build momentum.Additional Resources (00:27:20)Dive deeper with episodes:532 | Three Rules for Leading Effective Meetings430 | Building Predictability Into Your Business Finances – Part 1120 | KRA: The What, The Why, and The How of Key Result Area523 | How To Kill The Leadership Crazy CycleReflect on one area where you can reset and recommit. Let's lead boldly into 2025!

Welcome to The Chris LoCurto Show! Today, we're diving into a vital topic for leaders: how to build a team that operates without you. If stepping away from your business feels impossible, or if your team relies on you for every decision, this episode is for you.We'll explore the power of delegation, empowering your team, training, and building clarity in mission, vision, and KRAs—all foundational to creating a self-sufficient team. This is part one of a two-part series, so let's dive in!Episode Breakdown1. Introduction (00:00:00)Set yourself free by building a team that thrives independently and elevates your leadership to the next level.2. Next-Level LIVE Event 2025 (00:04:25)Discover practical tools to lead smarter and achieve work-life balance while growing your business.3. Delegation Is Key to an Independent Team (00:09:27)Proper delegation isn't just handing out tasks; it's about giving your team clear expectations, tools, and autonomy to succeed.4. Stop Micromanaging and Start Empowering (00:16:16)Micromanagement kills creativity. Empower your team to solve problems with actionable techniques to foster independence.5. Training and Development – The Gift That Keeps on Giving (00:23:18)Continuous training grows your team's capabilities and aligns them with your mission and vision for long-term success.6. Building Leaders Within Your Team (00:28:51)Developing leaders within your team creates stability and allows you to focus on bigger-picture priorities.7. Clarity in Mission, Vision, and KRAs – No Guesswork (00:35:03)Clarity eliminates confusion—align your team with your mission, vision, and KRAs to keep them on track.8. Making KRAs Work for Your Team (00:37:26)KRAs ensure accountability and smooth operations; grab the free KRA sample linked in the show notes to get started.9. Additional Resources (00:37:59)Check out Episodes 234 (Why You and Your Team Need KRAs) and 555 (Acing Your Goals and Establishing Processes With Your Team) for deeper insights.This is just the beginning of creating a self-sufficient team. Next time, we'll explore cultural communication and accountability systems that hold everything together. Don't miss it!

In a conversation with CancerNetwork® during Pancreatic Cancer Awareness Month, Tanios S. Bekaii-Saab, MD, spoke about various developments in the pancreatic cancer treatment field. Throughout the discussion, Bekaii-Saab weighed the benefits of currently available chemotherapeutic regimens for patients with metastatic disease, discussed research on the potential for precision medicine in those with KRAS wildtype pancreatic ductal adenocarcinoma (PDAC), and detailed ongoing initiatives to improve outcomes among those with RAS mutations and other targetable genomic alterations. Bekaii-Saab is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research, chair and consultant in the Division of Hematology and Medical Oncology at Mayo Clinic in Arizona, and co-leader of Advanced Clinical and Translational Science at Mayo Clinic Cancer Center. Given the prevalence of RAS mutations and other alterations in patients with pancreatic cancer, Bekaii-Saab especially emphasized the use of genomic analysis to inform personalized treatment decision-making in the field. Screening patients to detect aberrations such as microsatellite instability-high tumors, BRAF 600E mutations, KRAS G12C mutations, and NRG1 fusions can open the door for the development and use of targeted agents, which may consequently improve patient outcomes.  Looking ahead, Bekaii-Saab noted the need to adapt the therapies that have shown activity in the later stages of the disease to earlier treatment settings. Although “great work” has been achieved with chemotherapy and surgical techniques, he highlighted the importance of bringing targeted agents to earlier lines of therapy to further increase the likelihood of positive outcomes for patients.  “I have never been more optimistic. I'm always the eternal optimist, but I'm even more optimistic today that we're going to move the needle for our patients with pancreatic cancer and continue to enhance that likelihood of living longer, having a better quality of life, or even increasing the level of a cure for this cancer,” Bekaii-Sabb stated. “Certainly, the future looks bright. We're chipping away, one drug at a time. We can now remove that whole concept of nihilism in pancreatic cancer and look quite optimistically on the future.”

The OSUCCC -James is a leader in the treatment of pancreatic cancer, with the utilization of robotic Whipple surgery, the use of chemotherapy and radiation before surgery, multiple clinical trials designed to find even better ways to treat patients and a large multidisciplinary pancreatic cancer clinic.“We're always thinking about what's the next step and about the patient of tomorrow, that's a huge driver,” said Susan Tsai, MD, MHS, a surgical oncologist who specializes in pancreatic cancer and is Director of the OSUCCC – James Division of Surgical Oncology. “The pancreas helps regulate blood sugars and also helps you digest food,” Tsai explained, adding that it's hard to diagnose, which means patients often come to her with later-stage cancer. “In 70 to 80 percent of the patients we see, they will have recurrent disease somewhere else in their body,” Tsai said, adding this statistic has led to a new way to treat patients. “In the old days we'd often rush patients to surgery to remove the cancer as quickly as possible, but because the recurrence rates were so high maybe that isn't the best way to treat patients. Now, we utilize systematic therapy [chemotherapy and radiation] upfront, before surgery and we're seeing better results.” The development of robotic Whipple surgery to perform the complex and invasive pancreatic cancer surgery is another innovation. Using previous surgical techniques “there was about a 30 percent mortality rate,” Tsai said, adding the advances of the less-invasive and more precise Whipple surgery “practiced at a high-volume comprehensive cancer center such as the James have reduced that to less than 3 percent.” To date, pancreatic cancer has not been a good target for immunotherapy. “Now, we have been able to target a genetic mutation, called KRAS, a gene that drives many different types of cancer,” Tsai said, adding clinical trial are now testing drugs that appear to be able to target KRAS and enable the immune system to recognize and attack them. In another, soon-to-open clinical trial in which Tsai helps lead, the molecular profile of a biopsy of a patient's pancreatic cancer is analyzed to determine which chemotherapy drug to utilize. “This could be a great resource for patients,” Tsai said.

BUFFALO, NY - November 4, 2024 – A new #casereport was #published in Oncotarget's Volume 15 on October 11, 2024, entitled “A case of adenosquamous pancreatic cancer with a KRAS G12C mutation with an exceptional response to immunotherapy.” This case report highlights a remarkable and unexpected response to immunotherapy in a patient with metastatic adenosquamous pancreatic cancer (ASCP), a rare and aggressive form of pancreatic cancer. The study, led by Murtaza Ahmed, Brent K. Larson, Arsen Osipov, Nilofer Azad, and Andrew Hendifar from Cedars-Sinai Medical Center and Johns Hopkins University, provides new hope for ASCP patients, who are traditionally underserved by current treatment options. The team documented a 68-year-old male with metastatic ASCP carrying a KRAS G12C mutation. Unexpectedly, after limited success with standard therapies, the patient's cancer responded significantly to pembrolizumab, a type of immune checkpoint inhibitor, despite the absence of typical markers indicating suitability for immunotherapy. Pancreatic cancer remains one of the most lethal cancer types, with few advancements in effective treatments for its rarer forms, such as ASCP, which accounts for only 1-10% of all pancreatic cancer cases. Traditionally, ASCP has been treated with chemotherapy based on protocols for the more common pancreatic ductal adenocarcinoma, despite the distinct tumor characteristics. This case suggests that ASCP's unique tumor microenvironment may make it more receptive to immunotherapy. Researchers are hopeful that this new understanding will drive clinical trials focused on immunotherapy specifically for ASCP patients, potentially offering new options for those with limited treatment success. “To that point, there is an active multi-center phase 2 trial investigating outcomes and responses to ICI in patients with metastatic or unresectable ASCP or ampullary cancer.” In conclusion, this report signals a potential shift in the treatment of rare and aggressive pancreatic cancer subtypes like ASCP. As oncology increasingly embraces personalized medicine, cases like this one open new avenues for patients who were not responsive to traditional therapies, potentially transforming the management of previously intractable cancers. DOI - https://doi.org/10.18632/oncotarget.28659 Correspondence to - Andrew Hendifar - andrew.hendifar@cshs.org Video short - https://www.youtube.com/watch?v=VnfohGvfMoM Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28659 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, pancreatic cancer, immunotherapy, metastasis About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

In today's episode, we had the pleasure of speaking with David R. Gandara, MD, about biomarker testing in lung cancer. Dr Gandara is the chief medical officer of the International Society of Liquid Biopsy, the co-director of the Center for Experimental Therapeutics in Cancer, and the senior advisor to the director at the University of California Davis Comprehensive Cancer Center in Sacramento, and an adjunct clinical professor in the Translational and Clinical Research Program at the University of Hawaii Cancer Center in Honolulu.  In our exclusive interview, Dr Gandara discussed the optimal use of liquid biopsy for patients with non–small cell lung cancer (NSCLC), the ins and outs of testing for KRAS mutations, and available treatment options for patients with KRAS-mutant NSCLC.

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We love to hear from our listeners. Send us a message. This week, it's another “Business of Biotech-meets-Business-of-RNA” takeover with Circio CEO Erik Digman Wiklund, Ph.D. and guest co-host Anna Rose Welch of Advancing RNA.  While Circio's legacy is in cancer immunology (it still boasts a cancer vaccine candidate targeting KRAS driver mutations), the company made a bold pivot, of sorts, when it committed headlong to the circular RNA future. Now, it's in the throes of fine-tuning a platform for the development of novel circRNA medicines for rare disease, vaccines, and cancer. On this episode of the Business of Biotech, we go deep inside the story behind the pivot, we explore the RNA therapeutic platform-versus-product appetite among biotech investors, and Dr. Digman Wiklund shares insights into the challenges his company overcame to enable such a dramatic shift in focus. Access this and hundreds of episodes of the Business of Biotech videocast under the Listen & Watch tab at bioprocessonline.com. Subscribe to our monthly Business of Biotech newsletter. Get in touch with guest and topic suggestions: matt.pillar@lifescienceconnect.comFind Matt Pillar on LinkedIn: https://www.linkedin.com/in/matthewpillar/

Listen to a soundcast of the June 13, 2024, and June 21, 2024, Augtyro (repotrectinib) for NTRK gene fusion-positive solid tumors and Krazati (adagrasib) for KRAS G12C-mutated colorectal cancer.

Dr. Shaalan Beg and Dr. Arturo Loaiza-Bonilla discuss the potential of artificial intelligence to assist with patient recruitment and clinical trial matching using real-world data and next-generation sequencing results. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host for the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center in Dallas and senior advisor for clinical research at the National Cancer Institute. On today's episode, we will be discussing the promise of artificial intelligence to improve patient recruitment in clinical trials and advanced clinical research. Joining me for this discussion is Dr. Arturo Loaiza-Bonilla, the medical director of oncology research at Capital Health in Philadelphia. He's also the co-founder and chief medical officer at Massive Bio, an AI-driven platform that matches patients with clinical trials and novel therapies.  Our full disclosures are available in the transcript of this episode.   Arturo, it's great to have you on the podcast today.  Dr. Arturo Loaiza-Bonilla: Thanks so much, Shaalan. It's great to be here and talking to you today.  Dr. Shaalan Beg: So we're all familiar with the limitations and inefficiencies in patient recruitment for clinical trials, but there are exciting new technologies that are addressing these challenges. Your group developed a first-in-class, AI-enabled matching system that's designed to automate and expedite processes using real-world data and integrating next-generation sequencing results into the algorithm. You presented work at the ASCO Annual Meeting this year where you showed the benefits of AI and NGS in clinical trial matching and you reported about a twofold increase in potential patient eligibility for trials. Can you tell us more about this study?  Dr. Arturo Loaiza-Bonilla: Absolutely. And this is just part of the work that we have seen over the last several years, trying to overcome challenges that are coming because of all these, as you mentioned, inefficiencies and limitations, particularly in the manual patient trial matching. This is very time consuming, as all of us know; many of those in the audience as well experience it on a daily basis, and it's resource intensive. It takes specialized folks who are able to understand the nuances in oncology, and it takes, on average, even for the most experienced research coordinator or principal investigator oncologist, 25 minutes per trial. Not only on top of that, but in compound there's a lack of comprehensive genomic testing, NGS, and that complicates the process in terms of inability to know what patients are eligible for, and it can delay also the process even further.  So, to address those issues, we at Massive Bio are working with other institutions, and we're part of this … called the Precision Cancer Consortium, which is a combination of 7 of the top 20 top pharma companies in oncology, and we got them together. And let's say, okay, the only way to show something that is going to work at scale is people have to remove their silos and barriers and work as a collaborative approach. If we're going to be able to get folks tested more often and in more patients, assess for clinical trials, at least as an option, we need to understand further the data. And after a bunch of efforts that happened, and you're also seeing those efforts in CancerX and other things that we're working on together, but what we realize here is using an AI-enabled matching system to basically automate and expedite the process using what we call real-world data, which is basically data from patients that are actually currently being treated, and integrating any NGS results and comparing that to what we can potentially do manually. The idea was to do multi-trial matching, because if we do it for one study, yeah, it will be interesting, but it will not show the potential applicability in the real world.  So with all that background, the tool itself, just to give you the punchline of it, was proven highly effective in terms of efficiency. We were able to increase the number of potential matches, and not only that, but reducing the time to the matching. So basically, instead of spending 25 minutes, it could be done in a matter of seconds. And when you compound all that across multiple clinical trials, in this case, it was several sponsors coming together, we were able to reduce the manual effort of seeing patients and testing for clinical trials to basically 1 hour when it would have otherwise taken a ridiculous amount of time. And it was quantified as 19,500 hours of manual work, compared to 1 hour done by the system to uniquely match a cohort of about 5,600 patients that came into the platform. And this was across 23 trials. Now imagine if we can do it for the 14,000 clinical trials currently in clinicaltrials.gov.   So for us, this kind of was an eye-opening situation that if we can increase not only the efficiency but find even more trials by integrating comprehensive genomic testing, which in this case was a twofold increase in eligibility for clinical trials, that gives us not only the opportunity for optimized processes using AI but also a call to action that there is still a lot of under-genotyping. And I know American Cancer Society and ASCO and many others are working hard on getting that into fruition, but we need to have systems that remind us that certain patients are not tested yet and that can improve not only real patients, but the R&D and the process of innovation in the future. Dr. Shaalan Beg: Yeah, it's always an important reminder that even some of the highest impact IT solutions or AI solutions are most effective if they can be integrated into our normal clinical processes and into the normal workflow that we have in our clinics to help clinicians do their work quickly and more efficiently. Can you talk about how, over the last few years, the availability of NGS data in our electronic medical record (EMR) has evolved and whether that's evolving for the better? And what are some next steps in terms of making that data available at EMR so that such solutions can then pull that data out and do clinical trial matching?  Dr. Arturo Loaiza-Bonilla: Yes. So one of the things that we have seen over the last couple of years is because of the applicability of the 21st Century Cures Act, there is less “information blocking,” which is patients not being able to access their information in real time. Now, with the appearance of health exchanges, with patient-centric approaches, which is something that many innovators, including ours, are trying to apply, it's really becoming more relevant. So it's not only helping us to find the patients when they really need to get tested, but also is giving us the opportunity to put those patients into the right treatment pathway when found. Something that's still a challenge and I think we can work by being more collaborative once again – is my dream – is having these pre-screening hubs where no matter where you are in your cancer journey, you just go into that funnel and then are able to see, “Okay, you are in the second-line setting for non-small cell lung cancer, EGFR-mutated. Now, do you have a meta amplification, then you go for this study or this trial. Oh, you haven't been tested yet. You should get tested. You're a pancreas cancer patient who is KRAS wild type; well, there is a significant chance that you may have a biomarker because that's where most patients are enriched for.” So having that opportunity to at scale, just for the whole country, to get those patients access to that information, I think is crucial for the future of oncology. And I think you working at the NCI, more than most, know how the impact of that can help for those underrepresented patients to get more access to better treatment options and whatnot. And we can activate clinical trials as well in new models, decentralized models, adjusting time models, all those things can be leveraged by using biomarker testing in real time. Identification when the patient really needs a trial option or a medication option, because the data is telling us when to activate that in real time. Dr. Shaalan Beg: And identifying the patient for a potential clinical trial is one challenge. In oncology, given a lot of our trials, we are looking to enroll people at a specific time in their disease journey. So we call it first-line or second-line or third-line, becomes the next challenge. So just knowing someone has mutation number 1, 2, or 3 isn't enough to say they would be eligible for a second-line BRAF X, Y and Z mutation at a given trial. I've heard you talk a lot about this last-mile navigation for people once you've identified that they may be a soft match for a clinical trial. Can you talk about what you've seen in the ecosystem being developed on how AI is helping both clinics and patients navigate this last mile from the time they're identified for a clinical trial to the time they actually receive cycle 1, day 1? Dr. Arturo Loaiza-Bonilla: Yeah, absolutely. And that is such a critical point because, as you know, we have helped tons of patients getting trial options in thousands of cases. But even my own patients, I give them a report for trial options and they're like, “Okay, I still need help.” And we have been talking with ASCO, with the American Cancer Society, and many other very good teams, and what we see as an opportunity in technology here is leveraging those cancer journeys to know when the patient really has the opportunity to enroll in a trial, because this is a very dynamic environment. Not only the patient's condition changes because their cancer progresses, the hemoglobin changes, the cancer moves from one place to the other, and there's nuances in between, but also new medications are coming up, studies open and close, sites open and close.  So having this information as a hub, as what we call a command center, is the key to make this happen. And we can use the same tools that we use for Uber or for Instacart or whichever thing you want to do; it's already the same concept. When you need groceries, you don't need groceries every day. But Amazon gives you a ding that's like, “Well, I think you may be running out of milk,” because they already know how often you buy it, or just having the data behind the scenes of how typically these, in this case, patient journeys, may manifest based on the biomarker. So let's say a smoldering multiple myeloma is not the same across. One patient with biomarkers that make them very high risk, the risk of progressing to a multiple myeloma, first-line treatment-eligible patient is going to be much different than someone who has better risk cytogenetics. So using that tool to optimize the cancer journeys of those patients and being able to notify them in real time of new trial options, and also knowing when the patient really has that disease progression so there's a time of activation for trial matching again, the same way you get a credit score for buying a house, then you know exactly what options are in front of you at that very moment. And that is the last-mile component, which is going to be key. What we have seen that we feel is important to invest on, and we have invested heavily on it, is that until the patient doesn't sign the consent form for the clinical trial, that patient is completely unknown to most people. The site doesn't know them because they haven't been there, and they may be there, but they don't know about the options sometimes. But no one's going to invest in getting that patient to the finish line. There's a lot of support for patients on trials, but not before they enroll on trials. And we feel that this is a big opportunity to really exponentially grow the chances of patients enrolling in trials if we support them all the way from the very time they get diagnosed with cancer in any setting. And we can help that patient on a very unique journey to find the trial options using technology. So it's very feasible. We see it once again in many other equally complex tasks, so why not do it in oncology when we have all the bonafides across wanting to do this. Dr. Shaalan Beg: Can you give examples of where you are seeing it done outside of oncology that's a model that one can replicate? Dr. Arturo Loaiza-Bonilla: I mean, oncology is the toughest use case to crack. You have experiences with DCTs in the past and all that. So the big opportunities are for patients, for example, in psychiatry, when they need certain counseling and help. We see that also in medical devices, when people have diabetes and they really need a device specifically for that unique situation, or also for patients with cardiovascular risk that they can in real time get access to novel therapeutics. And that's how they have been able to enroll so quickly. And all these GLP-1 inhibitors, all those models are really almost completely decentralized nowadays in something that we can extrapolate for oncology once we have aligned the ecosystem to make it see them. This is something that we can really revolutionize care while we manage all the complex variables that typically come with oncology uses.  Dr. Shaalan Beg: I would imagine while you translate those learnings from outside of oncology into oncology, a lot of those processes will be human and AI combination activities. And as you learn more and more, the human component becomes a smaller fraction, and the technology and the AI becomes more of a component. Are you seeing a similar transition in the clinical trial matching space as well? Dr. Arturo Loaiza-Bonilla: Yes. So that's why people say humans are going to be replaced. They're not. Patients still want to see a human face that they recognize, they trust. Even family members of mine want to hear from me, even if they are in the top place in the world. What we can change with technology are those things that are typically just friction points. In this case, information gathering, collecting records, getting the data structured in a way that we can use it for matching effectively, knowing in real time when the patient progresses, so we can really give them the chances of knowing what's available in real time. And collecting the information from all these other stakeholders. Like, is the site open? Is the budget approved for that place? Is the insurance allowing the specific … do they have e-consent? Those things can be fully automated because they're just burdensome. They're not helping anyone. And we can really make it decentralized for e-consent, for just getting a screening. They don't need to be screened at the site for something that they're going to receive standard of care. We can really change that, and that's something that we're seeing in the space that is changing, and hopefully we can translate it fully in oncology once we are getting the word out. And I think this is a good opportunity to do so. Dr. Shaalan Beg: You talked about your dream scenario for clinical trial matching. When you think about your dream scenario as a practicing oncologist, what are the AI tools that you are most excited about making their way into the clinic, either wishful thinking or practically? Dr. Arturo Loaiza-Bonilla: I typically get feedback from all over the place on doing this, and I also have my own thoughts. But I always come to this for a reason. We all became physicians and oncologists because we like being physicians. We like to talk to patients. We want to spend the time. I tell folks in my clinic, I will see a thousand patients all the time as long as I don't have to do notes, as long as I don't have to place orders. But of course, they will have to hire 1,000 people ancillary to do all the stuff that we do.  If we can go back and spend all that time that we use on alert fatigue, on clicking, on gathering things, fighting insurance, and really helping align those incentives with clinical trials and biomarker testing and really making it a mankind or a humankind situation where we're all in this really together to solve the problem, which is cancer, that will be my dream come true. So I don't have to do anything that is clerical, that is not really helping me, but I want to use that AI to liberate me from that and also use the data that is generated for better insights. I think that I know my subject of expertise, but there's so many things happening all the time that it is hard to keep up, no matter how smart you are. If the tool can give me insights that I didn't even know, then leverage that as a CME or a board certification, that would be a dream come true. Of course, I'm just dreaming here, but it's feasible. Many of these ideas, as I mentioned, they're not new. The key thing is getting them done. The innovative part is getting stuff done, because I'm sure there's a gazillion people who have the same ideas as I did, but they just don't know whom to talk to or who is going to make it happen in reality. And that's my call to action to people: Let's work together and make this happen. Dr. Shaalan Beg: Well, Arturo, thanks a lot for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Arturo Loaiza-Bonilla: Well, thank you so much for the time and looking forward to having more exchanges and conversations and seeing everyone in the field. Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find a link to the studies discussed today in the transcript of this episode. And if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:  Dr. Shaalan Beg    @ShaalanBeg Dr. Arturo Loaiza-Bonilla @DrBonillaOnc   Follow ASCO on social media: @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures:    Dr. Arturo Loaiza-Bonilla: Leadership: Massive Bio Stock and Other Ownership Interests: Massive Bio Consulting or Advisory Role: Massive Bio, Bayer, PSI, BrightInsight, Cardinal Health, Pfizer, Eisai, AstraZeneca, Regeneron, Verily, Medscape Speakers' Bureau: Guardant Health, Bayer, Amgen, Ipsen, AstraZeneca/Daiichi Sankyo, Natera   Dr. Shaalan Beg:    Consulting or Advisory Role: Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen    Speakers' Bureau: Sirtex    Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics    Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune

In this research paper, researchers demonstrate a promising new treatment option for refractory metastatic gastrointestinal cancers using a combination of two FDA-approved drugs. Researchers Jun Zhang, Lanlan Zhou, Shuai Zhao, and Wafik S. El-Deiry from Fox Chase Cancer Center and Brown University explore the potential of combining TAS102 (trifluridine/tipiracil) and regorafenib as a treatment option for gastrointestinal (GI) cancers. Their research paper, published in Oncotarget's Volume 15 on July 2, 2024, is entitled, “Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.” The Study The combination of two FDA-approved drugs, TAS102 and regorafenib, has shown promising results in preclinical studies. TAS102 is an oral formulation consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). It has been approved by the US FDA for the treatment of refractory metastatic colorectal cancer and metastatic gastric cancer. Regorafenib is a multi-target tyrosine kinase inhibitor that inhibits tumor angiogenesis and cell proliferation and is approved for the treatment of gastrointestinal cancers. Recent studies have shown that TAS102, in combination with regorafenib, can lead to improved survival and restrict tumor progression. The combination therapy has been found effective in multiple gastrointestinal cancer cell lines, including colorectal, gastric, and pancreatic cancers. Full blog - https://www.oncotarget.org/2024/08/09/combining-regorafenib-and-tas102-to-target-gastrointestinal-cancers-and-overcome-cancer-stemness/ Paper DOI - https://doi.org/10.18632/oncotarget.28602 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Video short - https://www.youtube.com/watch?v=tuEmJTkyyGQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28602 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, TAS102, regorafenib, ERK1/2, angiogenesis, microvessel density About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. Pedro Barata and Dr. Lillian Siu discuss recent advances in cancer vaccines and biomarkers, including the potential of the neoantigen and immune modulatory vaccines and the challenges surrounding cancer vaccine development. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host for the ASCO Daily News Podcast today. I'm a GU medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, and an associate professor of medicine at Case Western Reserve University School of Medicine. I'm also an associate editor of the ASCO Educational Book. And today we'll be discussing a timely article that was recently published in the Educational Book titled, “State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers.”   I'm delighted to welcome one of the article's co-authors and a world-renowned oncologist, Dr. Lillian Siu. She is a senior medical oncologist and director of the Phase 1 Program at the Princess Margaret Cancer Center and a professor of medicine at the University of Toronto.  Welcome, Dr. Siu. Dr. Lillian Siu: Thank you, Dr. Barata; it's great to be here. Dr. Pedro Barata: Wonderful. Dr. Siu will discuss new tools for cancer vaccine development, strategies for combating the immunosuppressive and tumor microenvironment. She will also address cancer vaccine guidelines and patient recruitment strategies to optimize patient selection and access to cancer vaccine trials. I should say that Dr. Siu and her co-authors also addressed this topic during an Education Session at the ASCO 2024 Annual Meeting.  Finally, our full disclosures are available in the transcript of this episode.  So again, Dr. Siu, great to be speaking with you today. I'm looking forward to our discussion.  Dr. Lillian Siu: Thank you, Dr. Barata. And before I begin, I want to acknowledge Dr. Jeffrey Weber and Dr. Inge Marie Svane, who both presented during the ASCO session you mentioned. They gave excellent presentations related to the topic of neoantigen vaccines and immune-modulatory vaccines, which we will talk about later. Dr. Pedro Barata: Wonderful. So let's get started. Cancer vaccines are among the most promising frontiers for breakthrough innovations and new strategies in the fight against cancer. The successes in vaccine development during the COVID-19 pandemic, I think, inspired further research in this area. Why do you think it's important that we harness these recent successes and technological advances to really accelerate progress in vaccine development? Dr. Lillian Siu: Absolutely. I think all of us who have lived through COVID really appreciated how important the COVID vaccine development was to all of us. It saved millions of lives. And I think we witnessed a paradigm change in drug development that none of us thought was possible, that we're able to actually bring a concept to a drug from bench to bedside within an extremely short time. That timeline is not something we would ever imagine to have happened, and it did. And I think it gives us hope that perhaps this is not just limited to the COVID vaccine; it's also extrapolatable to other therapeutics – that we can bring promising medicines to our patients in a really expedited timeline, obviously without compromising their safety.  We now know that cancer vaccines have entered a new, or maybe I should say, renewed era of promise. And it's holding promise on many fronts, Pedro, if I may. It's very exciting in the area of molecular residual disease. In other words, a setting where the cancer is treated definitively by surgery or radiation, plus adjuvant treatment. And we know some patients will relapse because we know they're at high risk. And now we also have different ways to detect these microscopic risks, such as by ctDNA, circulating tumor DNA, or biomarkers. And we know that having some therapeutic that can eradicate these cancers at such microscopic levels would be very attractive, especially with low toxicity, and I think cancer vaccine is such a candidate. And of course, we can even look further into the future of using such treatment in cancer prevention, especially in those with high risk of developing cancer, for example, those with hereditary syndromes like lynch syndrome. We're not there yet, but I think it holds that promise.   So I think, going back to your original question, if we can develop such a therapeutic that is showing promise in a very short period of time, it brings the timeline and the hope to a much shorter timeframe to really deliver to our patients in a very timely manner while safeguarding all the important parts, such as safety and tolerability. Dr. Pedro Barata: Wow, those are such important points. I couldn't agree with you, more. It's really exciting. As I think through this, and as I was reading through your piece, I was thinking it would be great if you could highlight some of the novel approaches to personalized neoantigen vaccine development that are driving progress in this space. Dr. Lillian Siu: Absolutely. And during the session, Dr. Weber spoke about the neoantigen vaccine, and he's a pioneer in this space. So I can only try to iterate some of the points he had delivered during his talk. Neoantigen is a very exciting space for immunologists because we know that tumors express these neoantigens. Many of these are unique antigens that are only expressed in tumors, so-called tumor specific antigens, that we can use as our targets, including vaccines, but not limited to vaccines. And with these altered sequences in DNA in different forms, they could be mutations and splice alterations, etc. We expect that we have modified proteins that are expressed by tumor cells, and these become targets for our drug development of vaccines. And now we can have very specific strategies, very sophisticated algorithms to figure out which neoantigens are more so called immunogenic, more likely to stimulate or activate the immune system, and they can be recognized by T cells. So leveraging this knowledge and technology, we have been able to develop especially mRNA vaccines that are deliverable to our patients through different mechanisms, for example, in lipopeptides, etc., so that we can deliver to the patients in a safe way, such that we can use it to deliver vaccines, such as in the MRD setting that I mentioned earlier, as well as in the advanced disease setting. So Dr. Weber, in his presentation, highlighted one of such vaccines that have been tested in a randomized controlled trial that is KEYNOTE-942, which randomized 157 patients to the mRNA vaccine plus pembrolizumab versus pembrolizumab alone in patients with advanced melanoma. This is a vaccine against 34 mutated neoantigens, and it showed a significant difference in the recurrence free survival with a hazard ratio of 0.56. And if you look at the 18-month relapse free survival rate, it was 78.6% versus 62.2%. Obviously, these are still fairly early data and numbers are still small. I think we would definitely look forward to the randomized phase 3 study of neoantigen vaccine in melanoma and other cancers. Dr. Pedro Barata: No, absolutely. And I agree, it's really exciting. Dr. Weber did a fantastic job going through some of that data. So let me ask you Dr. Siu, as you think about this cancer vaccine field, what are the limitations that you'd highlight when you think about cancer vaccine development? What challenges do you encounter, obstacles do you encounter?  Dr. Lillian Siu: There are many, many potential challenges. And to some extent, that's probably why cancer vaccine development has been somewhat slow for the many decades until more recently. We know first of all; the target has to be recognized. So we need immunogenic targets. So I think a lot of the effort has been put into trying to understand which antigens expressed by cancer cells are immunogenic, able to activate the immune system. They're obviously assay based methods. You're going to try and see if you can ex vivo stimulate immune cells on dishes and models, etc. But we need to also develop in silico computerized algorithms, and now with AI, I think that makes it even more tangible and exciting that we can actually understand through a large number of neoantigens or other antigens, whether we can choose the ones that are most likely going to actually stimulate T cells to be activated. And I think that is one area that there is a lot of interest in development, how to really develop ways to select out the most attractive antigens.   I would also want to highlight that the platforms, which is how we deliver the vaccine, can also pose significant challenges. For example, vaccines can be delivered using peptide-based formulation, cell-based formulation, nucleic acids and viral vectors. For some of these formulations, for example, the peptides very often are restricted to HLA. They can be rapidly degraded in the body, such that they become not really visible to the T cells anymore. Some of the formulations can be very complex. For example, the cell-base; it may need to have cells isolated from patients, cultured, stored and transported to the site of delivery, which can be very complex. For some of the nucleic acid vaccines, they can have very low transfection efficiency. It could be at risk for also having, for example, DNA vaccines integrated into the host genome. And then lastly, there's also the immune suppressive environment in the TME, such that it does not really have the effect when you give it repeatedly. It becomes attenuated and no longer effective. So these are some of the challenges associated with cancer vaccines.  Dr. Pedro Barata: Thank you for that summary. I think it's really important for folks out there, including researchers getting into this field, to be aware of potential obstacles they might encounter.  So let me ask you the opposite question as we see more compelling preclinical and clinical data emerging in this field of vaccine development, what is really exciting you the most about the newest technologies that are shaping the future of cancer vaccines, in your opinion?  Dr. Lillian Siu: I think one I want to highlight is the immune-modulatory vaccine that Dr. Svane, Dr. Inge Marie Svane had presented during the presentation at ASCO. This is a completely different strategy from the neoantigen vaccine. It targets antigens in the tumor microenvironment. And we know that in the tumor microenvironment, we have tumor cells, we have immune cells, and there are many types of cell types, including, for example, macrophages, cancer associated fibroblasts, regulatory T cells, etc. And using these particular cell types, we know that we can really develop vaccines that can stimulate the body's immune system to attenuate, to downgrade some of the negative factors in the tumor microenvironment. And this is what Dr. Svane and her group is trying to do. For example, they have an IDO vaccine that is able to actually target these antigens in the tumor microenvironment, and by that, not just suppressing the negative forces, so to speak, but also activate T cells to help attack cancer cells. I think that's a very interesting area. Very early promise has been seen already in non-small cell lung cancer in early phase trials using the immune-modulatory vaccine.  But going back to your question, what kind of advances; I mentioned earlier about having novel ways to select our antigens that are most immunogenic. There are many algorithms that are being developed, and I think we can try and leverage that kind of knowledge from artificial intelligence, machine learning. So I think that's definitely very exciting. There are also new vaccine platforms coming out. For example, there's recent data using modification of peptides, so called amphiphile vaccines, that already show very early promise in colorectal cancer, microsatellite status, colorectal cancer, as well as in pancreatic cancer in the molecular residual disease setting, where these long peptide vaccines targeting KRAS mutants together with adjuvant oligonucleotide DNA, combined together, can actually be given to patients and reduce the chance of cancer relapse in patients with resected colorectal cancer, as well as pancreatic cancer, with endpoints such as ctDNA or biomarker being downregulated. I think that's a very exciting example. Another very exciting example is cell-based vaccines that are being developed in Europe by the NKI Netherlands Cancer Institute Group, where they are looking at plasmacytoid dendritic cells that are loaded with peptides from different tumor associated antigens and then given to patients, which, again, in non-small cell lung cancer, together with pembrolizumab, has yielded very high response rate. And we will almost certainly see more trials coming out using that particular platform with the dendritic cells. So that's just some of the examples of exciting things that are happening in the vaccine field. Dr. Pedro Barata: Thank you. I'm wondering if you can share with our listeners about what really are the existing guidelines for using these new tools for discovery, methods of treatment, and perhaps optimizing patient selection to access trials.  Dr. Lillian Siu: To be honest, the latest guideline that was published from the FDA that I can find is almost 13 years ago in 2011. So I think it is time for a new guidance, or at least a draft guidance, to give some additional support and guidance in terms of what to do with these new treatments from the FDA and perhaps other regulatory agencies as well. I think we're now entering a very exciting time that cancer vaccines are no longer an ineffective therapeutic. It is now showing evidence of efficacy, not just in the advanced setting, but also in the molecular residual disease setting. There're so many questions to be answered, like how to develop these trials in early disease; what's the end point? Can we incorporate them into the neoadjuvant setting, and if so, how do we give these drugs before surgery, and do we give them maintenance after surgery? I think guidance from the regulatory authorities would be extremely helpful and informative to guide academic groups as well as the pharmaceutical sector to develop these agents in the right way. Dr. Pedro Barata: Dr. Siu, this is a fantastic summary, and we certainly are on the cusp of a new dawn of discovery and development in cancer vaccines, and super interesting to hear from you talking about it. Before letting you go, do you have any final thoughts that you'd like to share with the listeners, with all of us about this topic? Dr. Lillian Siu: I think as a drug developer like you are, I'm extremely excited because we now have yet another way to leverage the host immunity as a cancer therapeutic, and it is going to be opening a new door to combination therapy because we can imagine combining these treatments with other immunotherapeutics such as bispecific molecules such as CAR Ts and even vaccine plus vaccine combination is feasible. That came up actually during the session as a question from the audience. Can we combine neoantigen vaccines and immune-modulatory vaccines together? And both of our speakers who presented felt that it was possible. Obviously, we have to understand the sequence question and the endpoints question, but the fact that it opens a new door to combinatorial therapy, not just with immunotherapeutics, but perhaps with other therapeutics as well, antibody drug conjugates, etc., really, I think, is very exciting for this field to become further explored.  I mentioned earlier in the podcast that the whole area of cancer prevention is something that we have not been tapping into for the last decade with vaccines because it has not been very effective. Viral vaccines, of course, HPV and other vaccines targeting viruses, but targeting cancer cells is not something we have been successful using vaccines to prevent cancer from developing. I think we would be very interested to see if this will become a reality in the next decade. I think we would start off with patients with high risk of developing cancers such as, as I mentioned earlier, those with lynch syndrome, those harboring BRCA alterations, for example. Can we use these vaccines to actually prevent the cancers from developing in such high-risk individuals? I think the field is definitely open to that consideration.  Dr. Pedro Barata: Definitely. And I'd like to thank you, Dr. Siu, for sharing these great insights with us today on the ASCO Daily News Podcast. Dr. Lillian Siu: Thank you so much for your time.  Dr. Pedro Barata: And thank you to all the listeners for your time today. You'll find a link to the article discussed today in the transcript of this episode, and I encourage you to check out the 2024 ASCO Educational Book. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So again, thank you so much for your time and see you soon.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:  Dr. Pedro Barata  @PBarataMD  Dr. Lillian Siu  @lillian_siu   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:    Dr. Pedro Barata: Honoraria: UroToday  Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon  Speakers' Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas  Research Funding (Inst.): Blueearth, AVEO, Pfizer, Merck    Dr. Lillian Siu:  Leadership (Immediate family member): Treadwell Therapeutics  Stock and Other Ownership Interests (Immediate family member): Agios   Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen

BUFFALO, NY- July 8, 2024 – A new research paper was published in Oncotarget's Volume 15 on July 2, 2024, entitled, “Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.” Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). Researchers previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. In this new study, researchers Jun Zhang, Lanlan Zhou, Shuai Zhao, and Wafik S. El-Deiry from Fox Chase Cancer Center and Brown University hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. “We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo.” TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. “The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.” DOI - https://doi.org/10.18632/oncotarget.28602 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Video short - https://www.youtube.com/watch?v=tuEmJTkyyGQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28602 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, TAS102, regorafenib, ERK1/2, angiogenesis, microvessel density About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Drs. John Sweetenham and Angela DeMichele discuss potentially ground-breaking abstracts in breast and lung cancer as well as notable research on artificial intelligence and its impact on cancer care, all of which were featured at the 2024 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. My guest today is Dr. Angela DeMichele, the Marianne and Robert McDonald Professor in Breast Cancer Research and co-leader of the Breast Cancer Program at the University of Pennsylvania's Abramson Cancer Center. Dr. DeMichele also served as the chair of the 2024 ASCO Annual Meeting Scientific Program. Today, she'll be sharing her reflections on the Annual Meeting and we'll be highlighting some advances and innovations that are addressing unmet needs and accelerating progress in oncology.  Our full disclosures are available in the transcript of this episode.  Dr. DeMichele, congratulations on a very robust and highly successful program at ASCO24, and thanks for joining us on the podcast today. Dr. Angela DeMichele: Well, thanks so much for having me, Dr. Sweetenham. It's a pleasure to be here.  Dr. John Sweetenham: The presidential theme of the Annual Meeting this year was the "The Art and Science of Cancer Care: From Comfort to Cure." And this was certainly reflected throughout the meeting in Chicago that welcomed more than 40,000 attendees from across the globe. I know our listeners will be interested to hear some of your own reflections from the meeting now that we're on the other side of it, so to spea  Dr. Angela DeMichele: Yes. Well, I will say that playing this role in the annual meeting really was a highlight of my career, and I feel so fortunate to have had the opportunity to do it. We had over 200 sessions, and in many, if not all of these sessions, we really tried to make sure that there was a case that really sort of grounded the session to really help people understand: you're going to hear about science, but how are you going to apply that? Who is the patient for whom this science really is important?  We had over 7,000 abstracts submitted, and our 25 tracks and their chairs really pulled through to find really the best science that we could present this year. I think what you saw really was a representation of that across the board: incredible advances in lung cancer, breast cancer, melanoma, GI cancers; also really cutting-edge technologies: AI, as we'll talk about in a little while circulating markers like ctDNA, new drug development, new classes of drugs. So it was really an exciting meeting. I mean, some highlights for me, I would say, were certainly the Plenary, and we can talk a little bit about that. Also, we had a fantastic ASCO/AACR Joint Session on “Drugging the “Undruggable Target: Successes, Challenges, and the Road Ahead.” And, if any of the listeners have not had a chance to hear this, it's really worth going in and watching this because it really brought together three amazing speakers who talked about the successes in KRAS, and then really, how are we using that success in learning how to target KRAS to now targeting a variety of other previously thought to be undruggable targets. I learned so much. And there's really both the academic and the pharma perspective there. So I'd really encourage watching this session. The other session that I really thought was terrific was one that I was honored to chair, which was a fireside chat (“How and Where Will Public Investment Accelerate Progress in Oncology? A Discussion with the NIH and NCI Directors”) with both Dr. Monica Bertagnolli, who is the director of the NIH, and Dr. Kim Rathmell, who's now the director of the NCI. And boy, I'll tell you, these two incredibly smart, thoughtful, insightful women; it was a great conversation. They were really understanding of the challenges we face conducting research, practicing medicine. And maybe different from leadership at the NIH in the past, they've really taken the approach to say that everything they do is focused on the patient, and they don't limit themselves to just research or just science, that everything that the NIH does, and particularly the NCI does, really has to be focused on making sure we can give patients the best possible care. And I think they're being very thoughtful about building important infrastructure that's going to take us into the future, incorporating AI, incorporating new clinical trial approaches that are going to make it faster and easier to conduct clinical trials and to get the results that we need sooner. So just a few of the highlights, I think, from some really interesting sessions. Dr. John Sweetenham: It certainly was an extremely enriching and impactful ASCO24. And I think that the overall theme of the meeting was extremely well reflected in the content with this amazing mix of really, truly impactful science, along with a great deal of patient-centered healthcare delivery science to accompany it. So, I completely agree with you about that. There was a lot, of course, to take in over the five days of the meeting, but I'm sure that our listeners would be very interested to hear about one or two abstracts that really stood out for you this year.  Dr. Angela DeMichele: Sure. I'm a breast cancer specialist, so I can't help but feel that the late breaking abstract, the DESTINY-Breast06 trial, was really important for the field of breast cancer. So just briefly, this is a study of the antibody drug conjugate T-DxD, trastuzumab deruxtecan. This is a drug that is actually now approved in metastatic breast cancer, really effective in HER2-positive disease. But the question that this trial was trying to answer is, can this drug, which is built with the herceptin antibody against HER2, then linked to a chemotherapeutic molecule, can this work even in the setting of very, very low HER2 expression on a tumor? I think this is an incredibly important question in the field of antibody drug conjugates, of which there are now many across diseases, is how much of the target do you really need to have on the surface of the tumor?  We had seen previously HER2 overexpressing tumors respond really well to this drug. HER2 tumors that have an intermediate level of expression were tested in the DP04 trial, and we saw that even those 2+ intermediate tumors responded well to this drug. The DP06 trial that was presented at ASCO was looking at this group of patients that have even less HER2 on the surface. So we typically measure HER2 by immunohistochemistry as 0, 1+, 2+, or 3+. And this was looking at patients whose tumors were over 0, but were at 1+ or below, so low and ultra-low. And it turned out that compared to treatment of physician's choice, the drug really had quite a lot of activity, even in these patients who have very little HER2 on their tumors, really showing progression-free survival benefits in the HER2-low and HER2-ultra-low groups that were appreciable on the order of about 5 months, additional progression free survival hazard ratios around 0.6, so really demonstrating that utilizing an antibody drug conjugate, where you've got very little target, can still be a way to get that drug to a tumor.   And I think it'll remain to be seen whether other ADCs can have activity at very low levels of IHC expression of whatever target they're designed against. I think one of the tricky things here for implementing this in breast cancer will be how do pathologists actually identify the tumors that are ultra-low because it's not something that we typically do. And so we'll go through a period, I think, of adjustment here of really trying to understand how to measure this. And there are a bunch of new technologies that I think will do a better job of detecting low levels of the protein on the surface of the tumor because the current IHC test really isn't designed to do that. It was only designed to be focused on finding the tumors that had high levels. So we have some newer technologies with immunofluorescence, for example, that can really get down to very low levels. And I think this is going to be a whole new area of ADCs, target detection – how low can you go to still see activity? So I thought that this was an important abstract for many reasons.  I will just say the second area that I was really particularly impressed with and had a big impact on me were the two lung cancer abstracts that were presented in the Plenary, the LAURA trial (LBA4) and the ADRIATIC trial (LBA5). And I think, I've been in the field of oncology for 30 years now, and when I started in the late ‘90s, lung cancer was a disease for which we had very few treatments. If we didn't catch it early and surgery wasn't possible for non-small cell lung cancer, really, it was a horrible prognosis. So we knew this year was the 20th anniversary of the discovery of EGFR as a subtype of lung cancer. That was really, I think, a turning point in the field of non-small cell lung cancer – finding a target. And now seeing the LAURA trial show that osimertinib really had such an enormous impact on progression-free survival amongst these patients who had EGFR-positive non-small cell lung cancer, progression-free survival hazard ratio of 0.16; there was a standing ovation.  And one of the really big privileges of being the Scientific Program Chair is getting to moderate the Plenary Session, and it's a really amazing experience to be standing up there or sitting there while the presenter is getting a standing ovation. But this was well deserved because of the impact this is having on patients with EGFR positive lung cancer. And it was similar with the ADRIATIC trial, which looked at the benefits of adding immunotherapy in limited-stage small-cell lung cancer. Again, a disease that treatment has not changed in 30 years, and so the addition of durvalumab to the standard backbone of chemotherapy for small cell lung cancer had its survival advantage. These patients are living longer and it was really an impressive improvement. And I think it really underscores just the revolution that has happened in lung cancer between targeted therapy and immunotherapy has completely changed the prognosis for patients with this disease. So to me, these were really landmark reports that came out at ASCO that really showed us how far we've come in oncology. Dr. John Sweetenham: Yeah, absolutely. I think that, as you mentioned, those results are truly remarkable, and they reflect extraordinary advances in science. I think we see that both in terms of the therapeutic arena, but also, I think we've started to see it in other areas as well, like symptom control, remote patient monitoring, and so on and so forth, where some of the newer virtual technologies are really having major impacts as well. Dr. Angela DeMichele: Yes, we really wanted to have a focus on artificial intelligence in this meeting, because it's having such an enormous impact on our field in everything from care delivery to diagnostics. I'd love to hear what you thought was the most interesting, because there really was just new data across the board presented. Dr. John Sweetenham: I've actually chosen 3 abstracts which I thought were particularly interesting for a couple of reasons, really. They're all based on virtual health interventions, and I think they're interesting in really reflecting the theme of the meeting, in that they are extremely advanced technology involved in the virtual platforms, a couple of which are artificial intelligence, but very impactful to patients at the same time in terms of remote symptom control, in terms of addressing disparities, and in one case, even influencing survival. So I thought these were three really interesting abstracts that I'll walk the listeners through very quickly.  The first of these was a study, Abstract 1500 (“National implementation of an AI-based virtual dietician for patients with cancer”) which looked at an artificial intelligence-based virtual dietitian for patients with cancer. This is based on the fact that we know nutritional status to be a key driver of patient experience and of cancer outcomes. And as the authors of the presentation noted, 80% of patients look for nutritional support, but many of them don't get it. And that's primarily a workforce issue. And I think that's an important thematic point as well, that these new technologies can help us to address some of the workforce issues we have in oncology. So this was an AI-based platform developed by experts in nutrition and cancer patients, based on peer reviewed literature, and a major effort in terms of getting all of these data up together. And they developed an artificial intelligence platform, which was predominantly text message based. And this platform was called INA. And as this is developing as a platform, there's a machine learning component to it as well. So in theory, it's going to get better and better and better over time.  And what they did in their study was they looked at little over 3,000 patients across the entire country who were suffering from various types of cancer, GU, breast, gynecological malignancy, GI and lung. And most of them had advanced-stage disease, and many of them had nutritional challenges. For example, almost 60% of them were either overweight or obese by BMI. And the patients were entered into a text exchange with the AI platform, which would give them advice on what they should eat, what they shouldn't eat. It would push various guidance and tips to them, it would develop personalized recipes for them, and it would even develop menu plans for the patients. And what's really interesting about this is that the level of engagement from the patients was very high, with almost 70% of patients actually texting questions to this platform. About 80% of the patients completed all of the surveys, and the average time that patients interacted with the platform was almost nine months, so this was remarkable levels of engagement, high levels of patient satisfaction. And although at this point, I think it's very early and somewhat subjective, there was certainly a very positive kind of vibe from patients. Nearly 50% have used the recommended recipes. More than 80% of them thought that their symptoms improved while they were using this platform. So I think as a kind of an assistant for remote management of patients, it's really remarkable. And the fact that the level of engagement was so high also means that for those patients, it's been very impactful.   The second one, this was Abstract 100 (“AI virtual patient navigation to promote re-engagement of U.S. inner city patients nonadherent with colonoscopy appointments: A quality improvement initiative”) looked again at an AI-based platform, which in this case was used in an underserved population to address healthcare disparities. This is a study from New York which was looking at colorectal cancer screening disparities amongst an underserved population, where historically they've used skilled patient navigators to address compliance with screening programs, in this case specifically for colorectal cancer. And they noticed in the background to this study that in their previous experience in 2022, almost 60% of patients either canceled or no-showed for colonoscopy appointments. And because of this and because of the high burden of patients that this group has, they decided to take an AI-based virtual patient navigator called MyEleanor and introduce this into their colorectal cancer screening quality improvement.  And so they introduced this platform in April of 2023 through to the end of the year, and their plan was to target reengagements of around 2,500 patients who had been non adherent with colonoscopy appointments in a previous year. And so the platform MyEleanor would call the patients to discuss rescheduling, it would assess their barriers to uptake, it would offer live transfer to somebody to schedule for them, and then it would go on closer to the point of the colonoscopy to call the patients and give them advice about their prep. And it was very nuanced. The platform would speak in both English and Spanish versions. It could detect nuances in the patient's voice, which might then trigger it to refer the patient to a live agent rather than the AI platform. So, very sophisticated technology. And what was most interesting about this, I think, was that over the eight months of the study, around 60% of patients actually engaged with this platform, with almost 60% of that group, or 33% overall, accepting a live transfer and then going on to scheduling, so that the completion rate for the no show patients went from 10% prior to the introduction of this platform to 19% after it was introduced. So [this is] another example, I think, of something which addresses a workforce problem and also addresses a major disparity within cancer care at the moment by harnessing these new technologies. And I think, again, a great interaction of very, very high-level science with things that make a real difference to our patients.  So, Dr. DeMichele, those are a couple of examples, I think, of early data which really are beginning to show us the potential and signal the impact that artificial intelligence is going to have for our patients in oncology. I wonder, do you have any thoughts right now of where you see the biggest impact of artificial intelligence; let's say not in 20 years from now, but maybe in the next year or two?  Dr. Angela DeMichele: Well, I think that those were two excellent examples. A really important feature of AI is really easing the workload on physicians. And what I hope will happen is that we'll be able to use AI in the very near future as a partner to really offload some of the quite time-consuming tasks, like charting, documentation, that really take us away from face-to-face interaction with patients. I think this has been a very difficult period where we move to electronic medical records, which are great for many reasons, but have really added to the burden to physicians in all of the extra documentation. So that's one way, I think, that we will hope to really be able to harness this. I think the other thing these abstracts indicate is that patients are very willing to interact with these AI chatbots in a way that I think, as you pointed out, the engagement was so high. I think that's because they trust us to make sure that what we're doing is still going to be overseen by physicians, that the information is going to get to us, and that they're going to be guided. And so I think that in areas where we can do outreach to patients, reminders, this is already happening with mammograms and other sorts of screening, where it's automated to make sure you're giving reminders to patients about things that they need to do for some of their basic health maintenance. But here, really providing important information – counseling that can be done by one of these chatbots in a way that is compassionate, informative and does not feel robotic to patients.   And then I was really impressed with, in the abstract on the screening colonoscopy, the ability of the AI instrument to really hear nuances in the patient's responses that could direct them directly to a care provider, to a clinician, if they thought that there might be some problem the patient was experiencing. So again, this could be something that could be useful in triaging phone calls that are coming in from patients or our portals that just feel like they are full of messages, no matter how hard you try to clear them all out, to get to them all. Could we begin to use AI to triage some of the more mundane questions that don't require a clinician to answer so that we can really focus on the things that are important, the things that are life threatening or severe, and make sure that we're getting to patients sooner? So there's just a few ways I really hope it'll help us. Dr. John Sweetenham: Yeah, absolutely. I think we're just scratching the surface. And interestingly enough, in my newsfeed this morning through email, I have an email that reads, “Should AI pick immunotherapy combinations?” So we'll see where that goes, and maybe one day it will. Who knows? Dr. Angela DeMichele There was a great study presented at ASCO about that very thing, and I think that is still early, but I could envision a situation where I could ask an AI instrument to tell me all of the data around something that I want to know about for a patient that could deliver all of the data to me in real time in the clinic to be able to help me make decisions, help me quote data to patients. I think in that way it could be very, very helpful. But it'll still need the physicians to be putting the data into context and thinking about how to apply it to the individual person. Dr. John Sweetenham: Absolutely, yes. And so just to round off, the final abstract that caught my eye, which I think kind of expands on a theme that we saw at an ASCO meeting two or three years ago around the impact of [oncology] care at home, and this was Abstract 1503 (“Acute care and overall survival results of a randomized trial of a virtual health intervention during routine cancer treatment”). So, a virtual platform but not AI in this case. And this was a study that looked at the use of an Integrative Medicine at Home virtual mind-body fitness program. And this was a platform that was used to look at hospital admission and acute care of patients who used it, and also looked at survival, interestingly enough. So what was done in this study was a small, randomized study which looked at the use of virtual live mind, body and fitness classes, and compared this in a randomized fashion to what they called enhanced usual care, which essentially consisted of giving the patients, making available to the patients, some pre-recorded online meditation resources that they could use. And this was applied to a number of patients with various malignancies, including melanoma, lung, gynecologic, head and neck cancers, all of whom were on systemic therapy and all of whom were reporting significant fatigue.  This was a small study; 128 patients were randomized in this study. And what was very interesting, to cut to the chase here, is that the patients who had the virtual mind-body program, compared with the control group, actually were less likely to be hospitalized, the difference there being 6.3% versus 19.1%, respectively. They spent fewer days in the hospital. And remarkably, the overall survival was 24.3 months median for patients in the usual care arm and wasn't reached in those patients who were on the virtual mind-body fitness class platform. So very preliminary data, certainly are going to need more confirmation, but another example of how it appears that many of these non-pharmacological interventions have the potential to improve meaningful endpoints, including hospital stays and, remarkably, even survival. So again, I think that that is very consistent with the theme of this year's meeting, and I found that particularly interesting, too.  I think our time is up, so I want to thank you, Dr. DeMichele, for sharing your insights with us today on the ASCO Daily News Podcast. We really appreciate it. And once again, I want to congratulate you on what was really a truly remarkable ASCO this year.  Dr. Angela DeMichele: Well, thanks so much for having me. It's been a tremendous pleasure to be with you today. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow ASCO on social media:    @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:   Dr. John Sweetenham:   Consulting or Advisory Role: EMA Wellness  Dr. Angela DeMichele: Consulting or Advisory Role (an immediate family member): Pfizer Research Funding (Inst.): Pfizer, Genentech, Novartis, Inviata/NeoGenomics  

Drs. Vamsi Velcheti and Nathan Pennell discuss novel approaches and key studies in lung cancer that were showcased at the 2024 ASCO Annual Meeting, including the Plenary abstracts LAURA and ADRIATIC.   TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. Today, I'm joined by Dr. Nate Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and the vice chair of clinical research at the Taussig Cancer Center in Cleveland Clinic. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Today, we will be discussing practice-changing abstracts and the exciting advances in lung cancer that were featured at the ASCO 2024 Annual Meeting. You'll find our full disclosures in the transcript of the episode. Nate, we're delighted to have you back on the podcast today. Thanks for being here. It was an exciting Annual Meeting with a lot of important updates in lung cancer. Dr. Nate Pennell: Thanks, Vamsi. I'm glad to be back. And yes, it was a huge year for lung. So I'm glad that we got a chance to discuss all of these late-breaking abstracts that we didn't get to talk about during the prelim podcast. Dr. Vamsi Velcheti: Let's dive in. Nate, it was wonderful to see all the exciting data, and one of the abstracts in the Plenary Session caught my attention, LBA3. In this study, the investigators did a comparative large-scale effectiveness trial of early palliative care delivered via telehealth versus in-person among patients with advanced non-small cell lung cancer. And the study is very promising. Could you tell us a little bit more about the study and your take-home messages? Dr. Nate Pennell: Yes, I think this was a very important study. So just to put things in perspective, it's now been more than a decade since Dr. Jennifer Temel and her group at Massachusetts General Hospital did a randomized study that showed that early interventions with palliative medicine consultation in patients with advanced non-small cell lung cancer significantly improves quality of life and in her initial study, perhaps even overall survival. And since then, there have been numerous studies that have basically reproduced this effect, showing that getting palliative medicine involved in people with advanced cancer, multiple different cancer types, really, has benefits.  The difficulty in applying this has been that palliative care-trained specialists are few and far between, and many people simply don't have easy access to palliative medicine-trained physicians and providers. So with that in mind, Dr. Temel and her group designed a randomized study called the REACH PC trial, where 1,250 patients were randomized with advanced non-small cell lung cancer to either in-person palliative medicine visits which is sort of the standard, or one in-person assessment followed by monthly telemedicine video visits with palliative medicine. Primary endpoint was essentially to show that it was equivalent in terms of quality of life and patient satisfaction. And what was exciting about this was that it absolutely was. I mean, pretty much across the board in all the metrics that were measured, the quality-of-life, the patient satisfaction, the anxiety and depression scores, all were equivalent between doing telemedicine visits and in-person visits. And this hopefully will now extend the ability to get this kind of benefit to a much larger group of people who don't have to geographically be located near a palliative medicine program. Dr. Vamsi Velcheti: Yeah, I think it's a great abstract, Nate and I actually was very impressed by the ASCO committee for selecting this for the Plenary. We typically don't see supportive care studies highlighted in such a way at ASCO. This really highlights the need for true interdisciplinary care for our patients. And as you said, this study will clearly address that unmet need in terms of providing access to palliative care for a lot of patients who otherwise wouldn't have access. I'm really glad to see those results. Dr. Nate Pennell: It was. And that really went along with Dr. Schuchter's theme this year of bringing care to patients incorporating supportive care. So I agree with you.  Now, moving to some of the other exciting abstracts in the Plenary Session. So we were talking about how this was a big year for lung cancer. There were actually 3 lung cancer studies in the Plenary Session at the Annual Meeting. And let's move on to the second one, LBA4, the LAURA study. This was the first phase 3 study to assess osimertinib, an EGFR tyrosine kinase inhibitor, in patients with EGFR mutant, unresectable stage III non-small cell lung cancer. What are your takeaways from this study?  Dr. Vamsi Velcheti: This is certainly an exciting study, and all of us in the lung community have been kind of eagerly awaiting the results of the study. As you know, for stage III non-small cell lung cancer patients who are unresectable, the standard of care has been really established by the PACIFIC study with the consolidation durvalumab after definitive concurrent chemoradiation. The problem with that study is it doesn't really answer the question of the role of immunotherapy in patients who are never-smokers, and especially in patients who are EGFR positive tumors, where the role of immunotherapy in a metastatic setting has always been questioned. And in fact, there have been several studies as you know, in patients with EGFR mutation positive metastatic lung cancer where immunotherapy has not been that effective. In fact, in the subgroup analysis in the PACIFIC study, patients with EGFR mutation did not really benefit from adding immunotherapy.  So this is an interesting study where they looked at patients with locally advanced, unresectable stage III patients and they randomized the patients 2:1 to osimertinib versus placebo following concurrent or sequential tumor radiation. The primary endpoint for the study was progression free survival, and a total of 216 patients were enrolled and 143 patients received a study treatment, which is osimertinib, and 73 received placebo. And 80% of the patients on the placebo arm crossed over to getting treatment at the time of progression.  So most of us in the lung cancer community were kind of suspecting this would be a positive trial for PFS. But however, I think the magnitude of the difference was truly remarkable. The median PFS in the osimertinib arm was 39.1 months and placebo was 5.6 months and the hazard ratio of 0.16. So it was a pretty striking difference in terms of DFS benefit with the osimertinib consolidation following chemoradiation. So it was truly a positive study for the primary endpoint and the benefit was seen across all the subgroups and the safety was no unexpected safety signals other than a slight increase in the radiation pneumonitis rates in patients receiving osimertinib and other GI and skin tox were kind of as expected. In my opinion, it's truly practice changing and I think patients with EGFR mutation should not be getting immunotherapy consolidation post chemoradiation. Dr. Nate Pennell: I completely agree with you. I think that this really just continues the understanding of the use of osimertinib in EGFR-mutant lung cancer in earlier stages of disease. We know from the ADAURA trial, presented twice in the Plenary at the ASCO Annual Meeting, that for IB, stage II and resectable IIIA, that you prolong progression free or disease free survival. So this is a very similar, comparable situation, but at an even higher risk population or the unresectable stage III patients. I think that the most discussion about this was the fact that the osimertinib is indefinite and that it is distinct from the adjuvant setting where it's being given for three years and then stopped. But I think all of us had some pause when we saw that after three years, especially in the stage III patients from ADAURA, that there were clearly an increase in recurrences after stopping the drug, suggesting that there are patients who are not cured with a time limited treatment, or at least with 3 years of treatment.  The other thing that is sobering from the study, and was pointed out by the discussant, Dr. Lecia Sequist, is if you look at the two-year disease-free survival in the placebo arm, it was only 13%, meaning almost no one was really cured with chemo radiation alone. And that really suggests that this is not that different from a very early stage IV population where indefinite treatment really is the standard of care. I wonder whether you think that's a reasonable approach. Dr. Vamsi Velcheti: I completely agree with you, Nate, and I don't think we cure a majority of our patients with stage III, and less so in patients who have EGFR-mutant, stage III locally advanced. As you just pointed out, I think very few patients actually make it that far along. And I think there's a very high rate of CNS micrometastatic disease or just systemic micrometastatic disease in this population that an effective systemic therapy of osimertinib can potentially have long term outcomes. But again, we perhaps don't cure a vast majority of them. I think that the next wave of studies should incorporate ctDNA and MRD-based assays to potentially identify those patients who could potentially go off osimertinib at some point. But, again, outside of a trial, I would not be doing that. But I think it's definitely an important question to ask to identify de-escalation strategies with osimertinib. And even immunotherapy for that matter, I think we all know that not all patients really require years and years of immunotherapy. They're still trying to figure out how to use immunotherapy in these post-surgical settings, using the MRD to de-escalate adjuvant therapies. So I think we have to have some sort of strategy here. But outside of a clinical trial, I will not be using those assays here to cite treatments, but certainly an important question to ask.  Moving on to the other exciting late-breaking abstracts, LBA5, the ADRIATIC study. This is another study which was also in the plenary session. This study was designed to address this question of consolidation immunotherapy, post chemo radiation for limited-stage small cell cancer, the treatment arms being durvalumab tremelimumab, and durvalumab observation. So what do you think about the study? This study also received a lot of applause and a lot of attention at the ASCO meeting. Dr. Nate Pennell: It was. It was remarkable to be there and actually watch this study as well as the LAURA study live, because when the disease free survival curves and in the ADRIATIC study, the overall survival curves were shown, the speakers were both interrupted by standing ovation of applause just because there was a recognition that the treatment was changing kind of before our eyes. I thought that was really neat. So in this case, I think this is truly a historic study, not necessarily because it's going to necessarily be an earth shakingly positive study. I mean, it was clearly a positive study, but more simply because of the disease in which it was done, and that is limited-stage small cell lung cancer. We really have not had a change in the way we've treated limited-stage small cell lung cancer, probably 25 years. Maybe the last significant advances in that were the advent of concurrent chemotherapy and radiation and then the use of PCI with a very modest improvement in survival. Both of those, I would say, are still relatively modest advances.  In this case, the addition of immunotherapy, which we know helps patients with small cell lung cancer - it's of course the standard of care in combination chemotherapy for extensive stage small cell lung cancer - in this case, patients who completed concurrent chemo radiation were then randomized to either placebo or durvalumab, as well as the third arm of durvalumab tremelimumab, which is not yet been recorded, and co primary endpoints were overall survival and progression free survival. And extraordinarily, there was an improvement in overall survival seen at the first analysis, with a median overall survival of 55.9 months compared to 33.4 months, hazard ratio of 0.73. So highly clinically and statistically significant, that translates at three years to a difference in overall survival of 56.5%, compared to 47.6%, or almost 10% improvement in survival at three years.  There was also a nearly identical improvement in progression-free survival, also with a hazard ratio of 0.76, suggesting that there's a modest number of patients who benefit. But it seems to be a clear improvement with the curves plateauing out. In my opinion, this is very comparable to what we saw with the PACIFIC study in stage III, unresectable non-small cell lung cancer, which immediately changed practice back when that first was reported. And I expect that this will change practice pretty much immediately for small cell as well. Dr. Vamsi Velcheti: Yeah, I completely agree, Nate. I think it's an exciting advance in patients with limited-stage small cell lung cancer. For sure, it's practice-changing, and I think the results were exciting.  So one thing that really intrigued me was in the extensive-stage setting, the benefit was very mediocre with one-to-two month overall survival benefit in both the PACIFIC and in IMpower trial. Here we are seeing almost two-year of median OS benefit. I was kind of puzzled by that, and I thought it may have to do with patients receiving radiation. And we've seen that with the PACIFIC, and makes you wonder if both the CASPIAN and the IMpower studies actually did not allow consolidation thoracic radiation. Hypothetically, if they had allowed consolidation thoracic radiation, perhaps we would have seen better outcomes. Any thoughts on that? Dr. Nate Pennell: We've been trying to prove that radiation and immunotherapy somehow go together better for a long time. Going back to the first description of the abscopal effect, and I'm not sure if I necessarily believe that to be the case, but in this setting where we truly are trying to cure people rather than merely prolong their survival, maybe this is the situation where it truly is more beneficial. I think what we're seeing is something very similar to what we're seen in PACIFIC, where in the stage IV setting, some people have long term survival with immunotherapy, but it's relatively modest. But perhaps in the curative setting, you're seeing more of an impact. Certainly, looking at these curves, we'll have to see with another couple of years to follow up. But a three-year survival of 56% is pretty extraordinary, and I look forward to seeing if this really maintains over the next couple of years follow up.  Moving beyond the Plenary, there were actually lots of really exciting presentations, even outside the Plenary section. One that I think probably got at least as much attention as the ones that we've already discussed today was actually an update of an old trial that's been presented for several prior years. And I'm curious to get your take on why you thought this was such a remarkable study. And we're talking about the LBA8503, which was the 5-year update from the CROWN study, which looked at previously untreated ALK-positive advanced non-small cell in cancer patients randomly assigned to lorlatinib, the third generation ALK inhibitor, versus crizotinib, the first generation ALK inhibitor. What was so exciting about this study, and why were people talking about it?  Dr. Vamsi Velcheti: Yeah, I agree, Nate. We've seen the data in the past, right? Like on the CROWN data, just first like a quick recap. This is the CROWN study, like the phase 3 study of third generation ALK inhibitor lorlatinib. So global randomized phase 3 study in patients with metastatic disease randomized to lorlatinib versus crizotinib, which is a controller. So the primary endpoint was PFS, and we've seen the results in the past of the CROWN readout quoted, with a positive study and the lorlatinib received FDA approval in the frontline setting. But the current study that was presented at the ASCO annual meeting is a kind of a postdoc analysis of five years. The endpoint for the study with central review stopped at three years, and this is actually a follow up beyond that last readout. Interestingly, in this study, when they looked at the median PFS at five years, the lorlatinib arm did not reach a median PFS even at five years and the hazard ratio is 0.19, which is kind of phenomenal in some ways. At 5 years, the majority of the patients were still on the drug. So that's quite incredible. And the benefit was more profound in patients with brain mets with a hazard ratio of 0.08. And again, speaking to the importance of brain penetrant, small molecule inhibitors, and target therapy, the safety profile, there were no additional safety signals noted in the study. We kind of know about the side effects of lorlatinib already from previous studies readouts. No unusual long-term toxicities.  I should note though, about 40% of patients did have CNS, AEs grade 1, 2 CNS toxicities on the  lorlatinib arm. And the other interesting thing that was also reported in the trial was dose reduction of lorlatinib did not have an impact on the PFS, which is interesting in my opinion. They also did some subgroup analysis, biomarker testing, biomarker populations. Patients who had P53 cooperation did much better with lorlatinib versus crizotinib. So overall, the other thing that they also had shown on the trial was the resistance mechanisms that were seen with lorlatinib were very different than what we are used to seeing with the earlier generation ALK inhibitors. The majority of the patients who develop resistance have bypass mechanisms and alterations in MAP kinase pathway PI3K/MTOR/PTEN pathway, suggesting that lorlatinib is a very potent ALK inhibitor and on target ALK mutations don't happen as frequently as we see with the earlier generation ALK inhibitors.  So I think this really begs the question, should we offer lorlatinib to all our patients with metastatic ALK-positive tumors? I think looking at the long-term data, it's quite tempting to say ‘yes', but I think at the same time we have to take into consideration patient safety tolerability. And again, the competitor arm here is crizotinib. So lorlatinib suddenly seems to be, again, cross trial comparisons, but I think the long-term outcomes here are really phenomenal. But at the same time, I think we've got to kind of think about patient because these patients are on these drugs for years, they have to live with all the toxicities. And I think the patient preferences and safety profile matters in terms of what drug we recommend to patients. Dr. Nate Pennell: I completely agree with you. I think the right answer, is that this has to be an individual discussion with patients. The results are incredibly exciting. I mean, the two-year progression free survival was 70%, and the five-year, three years later is still 60%. Only 10% of people are failing over the subsequent three years. And the line is pretty flat. And as you said, even with brain metastases, the median survival is in reach. It's really extraordinary. Moreover, while we do talk about the significant toxicities of lorlatinib, I thought it was really interesting that only 5% of people were supposedly discontinued the drug because of treatment related AEs, which meant that with dose reduction and management, it seems as though most patients were able to continue on the drug, even though they, as you mentioned, were taking it for several years.  That being said, all of us who've had experience with the second-generation drugs like alectinib and brigatinib, compared to the third-generation drug lorlatinib, can speak to the challenges of some of the unique toxicities that go along with it. I don't think this is going to be a drug for everyone, but I do think it is now worth bringing it up and discussing it with the patients most of the time now. And I do think that there will be many people for whom this is going to be a good choice, which is exciting. Dr. Vamsi Velcheti: Absolutely, completely agree. And I think there are newer ALK inhibitors in clinical development which have cleaner and better safety profiles. So we'll have to kind of wait and see how those pan out.  Moving on to the other exciting abstract, LBA8509, the KRYSTAL-12 study. LBA8509 is a phase 3 study looking at adagrasib versus docetaxel in patients with previously treated advanced metastatic non-small cell cancer with KRASG12C mutation. Nate, there's been a lot of hype around this trial. You've seen the data. Do you think it's practice-changing? How does it differentiate with the other drug that's already FDA approved, sotorasib?  Dr. Nate Pennell: Yeah, this is an interesting one. I think we've all been very excited in recent years about the identification of KRASG12C mutations as targetable mutations. We know that this represents about half of KRAS mutations in patients with non-small cell lung cancer, adenocarcinoma, and there are two FDA-approved drugs. Sotorasib was the first and adagrasib shortly thereafter. We already had seen the CodeBreaK 200 study, which was a phase 3 study of sotorasib versus docetaxel that did modestly prolong progression free survival compared to docetaxel, although did not seem to necessarily translate to an improvement in overall survival. And so now, coming on the heels of that study, the KRYSTAL-12 study compared adagrasib, also the KRASG12C  inhibitor versus docetaxel and those with previously treated non-small cell with KRASG12C. And it did significantly improve progression free survival with a hazard ratio of 0.58. Although when you look at the median numbers, the median PFS was only 5.5 months with the adagrasib arm compared to 3.8 months with docetaxel. So while it is a significant and potentially clinically significant difference, it is still, I would say a modest improvement.   And there were some pretty broad improvements across all the different subgroups, including those with brain metastases. It did improve response rate significantly. So 32% response rate without adagrasib, compared to only 9% with docetaxel. It's about what you would expect with chemotherapy. And very importantly, in this patient population, there was activity in the brain with an intracranial overall response rate among those who had measurable brain metastases of 40%. So certainly important and probably that would distinguish it from drugs like docetaxel, which we don't expect to have a lot of intracranial toxicity. There is certainly a pattern of side effects that go along with that adagrasib, so it does cause especially GI toxicity, like diarrhea, nausea, vomiting, transaminitis. All of these were actually, at least numerically, somewhat higher in the adagrasib arm than in docetaxel, a lot more hematologic toxicity with the docetaxel. But overall, the number of serious adverse events were actually pretty well matched between the two groups. So it wasn't really a home run in terms of favorable toxicity with that adagrasib.  So the question is: “In the absence of any data yet on overall survival, should this change practice?” And I'm not sure it's going to change practice, because I do think that based on the accelerated approval, most physicians are already offering the G12C inhibitors like sotorasib and adagrasib, probably more often than chemotherapy, I think based on perceived improvement in side effects and higher response rates, modestly longer progression-free survival, so I think most people think that represents a modest improvement over chemotherapy. And so I think that will continue. It will be very interesting, however, when the overall survival report is out, if it is not significantly better, what the FDA is going to do when they look at these drugs.  Dr. Vamsi Velcheti: Thanks so much. Very well summarized. And I do agree they look more similar than dissimilar. I think CodeBreaK-200 and the KRYSTAL-12, they kind of are very identical. I should say, though I was a little surprised with the toxicity profile of adagrasib. It seemed, I mean, not significantly, but definitely seemed worse than the earlier readouts that we've seen. The GI tox especially seems much worse on this trial. I'm kind of curious why, but if I recall correctly, I think 5% of the patients had grade 3 diarrhea. A significant proportion of patients had grade 3 nausea and vomiting. And the other complicating thing here is you can't use a lot of the antiemetics because of the QT issues. So that's another problem. But I think it's more comparable to sotorasib, in my opinion.  Dr. Nate Pennell: While this is exciting, I like to think of this as the early days of EGFR, when we were using gefitinib and erlotinib. They were certainly advances, but we now have drugs that are much more effective and long lasting in these patients. And I think that the first-generation inhibitors like sotorasib and adagrasib, while they certainly benefit patients, now is just the beginning. There's a lot of research going on, and we're not going to talk about some of the other abstracts presented, but some of the next generation G12C inhibitors, for example, olomorasib, which did have also in the same session, a presentation in combination with pembrolizumab that had a very impressive response rate with potentially fewer side effects, may end up replacing the first generation drugs when they get a little bit farther along. And then moving on to another one, which I think potentially could change practice. I am curious to hear your take on it, was the LBA8505, which was the PALOMA-3 study. This was interesting in that it compared two different versions of the same drug. So amivantamab, the bispecific, EGFR and MET, which is already approved for EGFR exon 20 non-small cell lung cancer, in this case, in more typical EGFR-mutated non-small cell lung cancer in combination with osimertinib with the intravenous amivantamab, compared to the subcutaneous formulation of amivantamab. Why would this be an important study? Dr. Vamsi Velcheti: I found this study really interesting as well, Nate. And as you know, amivantamab has been FDA approved for patients with exon 20 mutation. And also, we've had, like two positive readouts in patients with classical EGFR mutations. One, the MARIPOSA study in the frontline setting and the MARIPOSA-2, in the second-line post osimertinib setting. For those studies, the intravenous amivantamab was used as a treatment arm, and the intravenous amivantamab had a lot of baggage to go along with it, like the infusion reactions and VTEs and other classic EGFR related toxicity, skin toxicities. So the idea behind developing the subcutaneous formulation of amivantamab was mainly to reduce the burden of infusion, infusion time and most importantly, the infusion related reactions associated with IV formulation.  In a smaller phase 2 study, the PALOMA study, they had looked at various dosing schemas like, subcutaneous formulation, and they found that the infusion related reactions were very, very low with the subcutaneous formulation. So that led to the design of this current study that was presented, the PALOMA-3 study. This was for patients who had classical EGFR mutations like exon 19, L858R. The patients were randomized 1:1 to subcutaneous amivantamab with lazertinib versus IV amivantamab plus lazertinib. The endpoints for the study, it's a non-inferiority study with co primary endpoints of C trough and C2 AUC, Cycle 2 AUC. They were looking at those pharmacological endpoints to kind of demonstrate comparability to the IV formulation. So in this study, they looked at these pharmacokinetic endpoints and they were essentially identical. Both subcutaneous and IV formulations were compatible. And in terms of clinical efficacy as well, the response rate was identical, no significant differences. Duration of response was also identical. The PFS also was comparable to the IV formulation. In fact, numerically, the subcutaneous arm was a little better, though not significant. But it appears like, you know, the overall clinical and pharmacological profile of the subcutaneous amivantamab was comparable. And most interestingly, the AE profile, the skin toxicity was not much different. However, the infusion reactions were substantially lower, 13% with the subcutaneous amivantamab and 66% with IV amivantamab. And also, interestingly, the VTE rates were lower with the subcutaneous version of amivantamab. There was still a substantial proportion of patients, especially those who didn't have prophylactic anticoagulation. 17% of the patients with the subcutaneous amivantamab had VTE versus 26% with IV amivantamab. With prophylaxis, which is lower in both IV and subcutaneous, but still subcutaneous formulation at a lower 7% versus 12% with the IV amivantamab.  So overall, I think this is an interesting study, and also the authors had actually presented some interesting data on administration time. I've never seen this before. Patients reported convenience using a modified score of patient convenience, essentially like patients having to spend a lot of time in the infusion site and convenience of the patient getting the treatment. And it turns out, and no surprise, that subcutaneous amivantamab was found to be more convenient for patients.  So, Nate, I want to ask you your take on this. In a lot of our busy infusion centers, the time it takes for those patients to get the infusion does matter, right? And I think in our clinic where we are kind of fully booked for the infusion, I think having the patients come in and leave in 15, 20 minutes, I think it adds a lot of value to the cancer center operation.  Dr. Nate Pennell: Oh, I completely agree. I think the efficacy results were reassuring. I think the infusion related reaction difference, I think is a huge difference. I mean, I have given a fair amount of amivantamab, and I would say the published IRR rate of 66%, 67% I would say, is maybe even underestimates how many patients get some kind of reaction from that, although it really is a first dose phenomenon. And I think that taking that down to 13% is a tremendous advance. I think fusion share time is not trivial as we get busier and busier. I know our cancer center is also very full and it becomes challenging to schedule people, and being able to do a five-minute treatment versus a five-hour treatment makes a big difference for patients.  It's interesting, there was one slide that was presented from an efficacy standpoint. I'm curious about your take on this. They showed that the overall survival was actually better in the subcu amivantamab arm, hazard ratio of 0.62. Now, this was only an exploratory endpoint. They sort of talk about perhaps some rationale for why this might be the case. But at the very least, I think we can be reassured that it's not less effective to give it and does seem to be more tolerable and so I would expect that this hopefully will be fairly widely adopted. Dr. Vamsi Velcheti: Yeah, I agree. I think this is a welcome change. Like, I think the infusion reactions and the resources it takes to get patients through treatments. I think it's definitely a win-win for patients and also the providers.  And with that, we come to the conclusion of the podcast. Nate, thank you so much for the fantastic insights today. Our listeners will find all the abstracts discussed today in the transcripts of the episode. Thank you so much for joining us today, Dr. Pennell.  Dr. Nate Pennell: Oh, thanks for inviting me. It's always fun to talk about all these exciting advances for our patients. Dr. Vamsi Velcheti: Thanks to our listeners for your time today. You will find links to all the abstracts discussed today in the transcript of the episode. Finally, if you value the insights that you hear from ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers:    Dr. Vamsi Velcheti  @VamsiVelcheti    Dr. Nathan Pennell  @n8pennell    Follow ASCO on social media:      @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures:  Dr. Vamsi Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus  Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  Dr. Nathan Pennell:    Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron   Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi

Lenz discusses the link between HER2 expression and responses with mCRC treatment regimens and how HER2 expression can guide treatment decision-making.

Drs. Vamsi Velcheti and Nathan Pennell discuss key lung cancer abstracts from the 2024 ASCO Annual Meeting, including data from LUMINOSITY and ADAURA, novel therapies in KRASG12C-mutant advanced NSCLC, and the need for effective adjuvant therapies for patients with rare mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at Perlmutter Cancer Center at NYU Langone Health. Today, I'm delighted to welcome Dr. Nathan Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Dr. Pennell is sharing his valuable insights today on key abstracts in lung cancer that will be presented at the 2024 ASCO Annual Meeting. You'll find our full disclosures in the transcript of the episode.  Nate, it's great to have you here on the podcast. Thank you for being here. Dr. Nathan Pennell: Thanks, Vamsi, for inviting me. I'm always excited for the ASCO Annual Meeting, and we have a tremendous amount of exciting lung cancer abstracts. I know we're not going to discuss all of them on this podcast, but even exciting Plenary presentations coming up.  Dr. Vamsi Velcheti: So, one of the abstracts that caught my attention was Abstract 103, the LUMINOSITY trial, which will be presenting the primary analysis at the meeting. So, there's a lot of buzz and excitement around ADCs. Can you comment on this abstract, Nate, and what are your thoughts on key takeaways from this abstract?  Dr. Nathan Pennell: Absolutely, I agree. This is really an exciting new potential target for lung cancer. So historically, when we think about MET and lung cancer, we think about the MET exon 14 skipping mutations which are present in 3% or 4% of adenocarcinoma patients. And we have approved tyrosine kinase inhibitors, small molecule inhibitors that can be very effective for those. What we're talking about here is actually an antibody drug conjugate or ADC telisotuzumab vedotin, which is targeting the MET protein over expression in non-squamous EGFR wild type advanced non-small cell lung cancer. The LUMINOSITY was a single arm, phase 2 study of teliso, and first of all, I think we have to define the patient population. So, these were MET over expressing non-small cell lung cancer by immunohistochemical staining. So, it included both what they considered MET high expression and MET intermediate expression, both of which had to be 3+ IHC positive on 25% to 50% of cells in the intermediate and 50% or higher in the high expressing group. They were treated with the ADC and had pretty promising results, a response rate of 35% in the MET high group and 23% in the intermediate group. Duration of response at nine months and 7.2 months in those two groups, and the PFS was five and a half and six months. So I would say in a previously treated population, this was relatively promising and potentially defines a completely new and unique subgroup of biomarker defined patients. So, Vamsi, I'm curious, though, if this ends up moving forward to further development, what your thoughts are on adding yet another biomarker in non-small cell lung cancer? Dr. Vamsi Velcheti: Yeah, I think it's certainly exciting. I think for this population, we really don't have a lot of options beyond the second line, and even in the second line, docetaxels are low bar. So,I think having more options for our patients is certainly outcome development. And I think MET IHC is relatively easy to deploy in a clinical setting. I think we already test for MET PD-L1 IHC routinely, and now recently, as you know, HER2 IHC given approval for ADCs, HER2 ADCs there in that space. So, I think from a technical standpoint, I don't see a big barrier in terms of adding an additional IHC marker. And usually, the IHC testing is pretty quick. And I think if you have a therapeutic approval based on IHC positivity, I think certainly from an operational standpoint, it shouldn't be a very complicated issue. Dr. Nathan Pennell: Yeah, I agree. This is cheap. It's something that can be done everywhere in the world. And as you said, in addition to diagnostic IHC, we're already looking at PD-L1, and probably moving towards doing that for HER2. This is really wonderful that we're moving into kind of the era of the ADCs, which is opening up a whole new therapeutic group of options for patients. Dr. Vamsi Velcheti: So, the other abstract that caught my attention was like, the Abstract 8005. This is the molecular residual disease MRD analysis from the ADAURA trial. The ADAURA trial, as you all know, is the trial that led to the FDA approval of adjuvant use of osimertinib in patients with EGFR mutant stage 1B through 3A non-small cell lung cancer. And in this trial, osimertinib demonstrated significant improvements in DFS and OS. And in this particular study, Abstract 8005, the authors looked at the role of MRD in predicting DFS in the study. And after 682 patients who were randomized, 36% of the patients had samples to look at MRD post- surgery. And in the trial the MRD status predicted DFS or event free survival at 36 months with a hazard ratio of 0.23. And the MRD status had a median lead time of 4.7 months across both the arms, both osimertinib and the placebo arm. So, suggesting that MRD could potentially identify high risk subgroups of patients post-surgery to tailor personalized approaches potentially in this population. So, Nate, in your practice, of course, we don't have a clinically validated approach yet to kind of use MRD in this setting, but if we have an option to use an MRD based assay, do you think that would potentially be an opportunity to perhaps escalate or de-escalate adjuvant strategies with TKIs in the adjuvant setting? Do you see value in using MRI assays post- surgery? Dr. Nathan Pennell: Yeah, I think this is a really important study because this is such an important topic around adjuvant targeted treatment. So, of course, ADAURA really changed how we treated people with EGFR mutant lung cancer who underwent surgical resection, because we know that the three years of osimertinib significantly improved disease-free survival and overall survival. But there's still a lot of questions being asked about, is that affordable? Obviously, we're putting a lot of resources into three years of treatment, and not everyone necessarily needs it. There may well be people who are cured with surgery alone and adjuvant chemotherapy. And then what about duration? Is three years enough? Do we need even longer treatment, or do we need shorter treatment? And up to date, we haven't really been able to tell people at risk of recurrence other than the pure odds-based risk based on their stage.   And the assay that was used in the ADAURA study was a personalized tumor informed assay based on the resected tumor. It's unclear to me whether this was just a subgroup of people that had this done or whether they tried to do it in all 600 patients and only, it looks like they were successful in about 32% of people. Maybe about a third were able to successfully have a tumor informed assay. So, the first question is, “Can you use this to help guide who needs treatment or not?” And I think what they showed was only about 4% of people in osimertinib arm in 12% had MRD positive at baseline after surgery. So probably, upfront testing is not really going to be all that helpful at determining who's at high risk and needs to be treated.   Interestingly, of those who were positive, though, most of them, or 80% of them, did go MRD negative on osimertinib. And what I found really interesting is that of those who did have a recurrence, 65% of them did have the MRD test turn positive. And as you mentioned, that was about five months prior to being picked up radiographically, and so you can pick them up sooner. And it also looks like about two thirds of recurrences can be identified with the blood test. So that potentially could identify people who are recurring earlier that might be eligible for a more intensive treatment. The other thing that was really interesting is of those who recurred in the osimertinib arm, 68% of them happened after stopping the osimertinib, suggesting that for the majority of patients, even those not necessarily cured, they seem to have disease control while on the osimertinib, suggesting that maybe a longer duration of treatment for those patients could be helpful. The problem is it still isn't necessarily helpful at identifying who those people are who need the longer duration of treatment. So, definitely an important study. I think it could be useful in practice if this was available clinically, especially at monitoring those after completion of treatment. I think as the sensitivity of these MRD assays gets better, these will become more and more important. Dr. Vamsi Velcheti: I think it's a little bit of a challenge in terms of standardizing these assays, and they're like multiple assays, which are currently commercially available. And I think the field is getting really complicated in terms of how you incorporate different assays and different therapeutics in the adjuvant space, especially if you're kind of looking at de-escalating immunotherapeutic strategies at the adjuvant setting, I think, makes it even more challenging. I think exciting times. We definitely need more thoughtful and better studies to really define the role of MRD in the adjuvant space. So, I guess more to come in this space. Dr. Nathan Pennell: Vamsi, I wanted to ask you about another really interesting Abstract 8011. This is a subgroup of the AEGEAN perioperative study for early-stage resected non-small cell lung cancer. This abstract is specifically looking at baseline N2 lymph node involvement in stage 2A-3B with N2 positive patients in an exploratory subgroup analysis. What are your key takeaways from the study?   Dr. Vamsi Velcheti: I felt this was a very interesting abstract for a couple of reasons. As you know, this is the AEGEAN trial, the phase 3 trial that was reported earlier last year. This is a perioperative study of durvalumab plus new adjuvant chemotherapy versus new adjuvant chemotherapy alone and adjuvant durvalumab plus placebo. The study obviously met its primary endpoint, as we all saw, like the event-free survival. And here in this abstract, the authors present an exploratory subgroup analysis of patients who had N2 lymph node involvement prior to study enrollment. So, in this study, they were focusing on perioperative outcomes. And one of the issues that has come up multiple times, as you know, in a lot of these preoperative studies, is the impact of neoadjuvant chemo immunotherapy on surgery or surgical outcomes. And consistently, across a lot of these trials, including the CheckMate 816, about 20% of patients don't end up making it to surgery. So in that light, I think this study and the findings are very interesting. In this study, they looked at patients who had N2 nodal involvement and of the patients with N2 nodal involvement, the surgical operability or the number of patients who completed surgery was similar in both the groups. So, there was no significant difference between patients who received durva versus chemotherapy and also among patients who had N2 subgroup who had surgery, similar proportions of durvalumab and placebo arms had open versus minimally invasive versus pneumonectomy. So durvalumab didn't have a negative impact on the type of surgery that the patients had at the time of surgery. So overall, the findings were consistent with other trials, perioperative trials that we have seen. So, the surgical outcomes were not negatively impacted by adding immunotherapy in the neoadjuvant perioperative space. So, this is consistent with other trials that we have seen. And also, the other issue, Nate, I'd like to get your opinion on is, across the board, in all the perioperative trials we have seen that about 20% of the patients actually don't end up making it a surgery. And of course, most of these perioperative trials, a lot of these patients are stage 3 patients. And my take on this was that there's probably a little bit of a patient selection issue. We generally tend to err on the side of operability when we have a stage 3 patient discussed in the tumor board, sometimes feel like the patient may downstage and could potentially go to surgery. But even in the real world, in stage 3 operable patients, what proportion of patients do you think don't end up going to surgery? Dr. Nathan Pennell: That is such an important question that I don't think we have the best answer to. You're right. All of these perioperative studies have a relatively high- sort of 20% to 30% of people who enroll on the studies don't necessarily go to surgery. And I don't think that they've done as great a job as they could in all of these trials describing exactly what happens to these patients. So in the real world, obviously not everyone would be fit enough to go to surgery or might progress in the time between when they were diagnosed and the time as planned for surgery. But probably more of them would go to surgery if they weren't getting neoadjuvant treatment, because that would be their initial treatment. The question is, of course, is that the right choice? If someone gets 12 weeks or nine weeks of neoadjuvant treatment and then a restaging scan shows that they've had progression with metastatic disease, are those really the people that would have been optimally treated with surgery upfront, or would they just have had recurrence on their first postoperative scan? So, it's really an important question to answer. I think the bigger one is, is the treatment preventing them through toxicity from going to treatment? And I think the studies have generally felt that few patients are missing out on the option of surgery because of toxicity being caused by the IO. And in the AEGEAN study, for example, in this subgroup, a slightly numerically higher percentage of patients in the durvalumab arm actually underwent surgery compared to those who got neoadjuvant chemo. So, it doesn't seem like we're necessarily harming people with the neoadjuvant treatment. But I know that this is a concern for patients and doctors who are undergoing this approach. Dr. Vamsi Velcheti: Definitely, I think having multiple data sets from perioperative trials, looking at the relative impact of IO on the safety and the nature of the surgery is going to be important, and this is a very important study for that reason. Dr. Nathan Pennell: Can I ask you another thing that I thought really interesting about this particular one is they looked at the difference between those with single station N2 and multi station N2. And I know this is one of those, should we be operating on people who have multi station N2 disease? And the AEGEAN study did include people who had multiple N2 stations where perhaps in the pre-IO era, these would have been treated with definitive chemoradiation and not surgery at all. But the disease-free survival hazard ratio was essentially the same for multi station N2 as it was in the overall population. So, has that changed the way we're approaching these patients in these multidisciplinary discussions? Dr. Vamsi Velcheti: Absolutely, Nate. I think surgical operability is in the eye of the beholder. I think it depends on which surgeon sees the patient or how the discussion goes in the tumor boards, as you know. Certainly, I think with this optionality of having a chemo IO option and potential for downstaging, kind of pushes, at least in our practice, more of these patients who are multistation, who would have otherwise gone down the chemoradiation route are now actually going through neo adjuvant chemo IO and with the hope that they would make it to surgery. So, I think it's an interesting change in paradigm in managing our locally advanced patients. So, I think it's certainly interesting, but I guess to your point, there clearly are some patients who probably should just have chemoradiation upfront, and we may be kind of like delaying that definitive chemoradiation approach for at least a subset of patients. So, at the end of the day, I think it's a lot of clinical decision-making and I think there's going to be a little bit of art to managing these patients and it's going to be really hard to define that population for a clinical trial.  Dr. Nathan Pennell: Yeah, clearly, multidisciplinary discussion, still very important for earliest age non-small cell lung cancer patients. If we move back to metastatic lung cancer, let's talk about Abstract 8510 looking at one of our newer, exciting biomarkers, which are the KRASG12Cmutant non-small cell lung cancer. So this is a study of a second generation KRASG12Cinhibitor, olomorasib, which was combined with pembrolizumab, the anti PD-1 antibody, in patients with advanced KRASG12C mutant non-small cell lung cancer. This is something that has been tried before with first generation G12C inhibitors, with some concerns about how safe it was to do that. So, Vamsi, what did you learn from this abstract? Dr. Vamsi Velcheti: Definitely, I think one of the concerns that we've had in other trials is like the cumulative toxicity of adding checkpoint inhibition to G12C inhibitors, especially the sotorasib CodeBreaK trial, where we see increased rates of grade 3, 4 transaminitis. So, it is encouraging to see that some of the newer agents have less of those issues when it comes to combining the checkpoint inhibition. So especially with KRASG12C, as you know, these are patients who are smokers, and often these are patients who have high PDL-1 could potentially also benefit from immunotherapy. In order for these KRASG12C inhibitors, in order to move these targeted therapy options for these patients to the front line, I do think we need to have substantial comfort in combining the checkpoint inhibitors, which is a standard treatment approach for patients in the frontline setting. I think this is exciting, and I think they're also like, as you know, there are other KRASG12C inhibitors also looking to combine with checkpoint inhibition in the frontline settings. So, we'll have to kind of wait and see how the other agents will perform in the setting. Dr. Nathan Pennell: Yeah, I completely agree. I think this is such an important area to explore specifically because unlike our other targeted oncogenes like EGFR and ALK, we have multiple options for these patients, both immunotherapy and targeted treatments. And if we could think about sequencing them or even combining them and if it could be done safely, I think that would be well worth investigating. There still was significant toxicity in this trial; 30% of people had diarrhea, even at the reduced dose, and there was transaminitis at sort of about 20% or so, although probably at a manageable level. But the response rate was really quite promising. And these are all previously IO and mostly G12C TKI pre-treated patients still had a response rate of 63%. And in those who were naive to IO and TKIs, it was 78% response rate. So, if it could be done safely, I think it's definitely worth pursuing this in further trials. Dr. Vamsi Velcheti: And also, there's some data, preclinical data, like looking at G12C inhibition. And also we have known with MET inhibition for a long time that it could potentially augment immune responses and could be having some synergistic effect with IO. So, we'll have to wait and see, I think. But safety is really the top in mind when it comes to combining these agents with checkpoint inhibitors. So, it's really encouraging to see that some of the newer agents may be more combinable IO. Now moving on to the next abstract, and moving on to, again, the early-stage setting. So, Abstract 8052 from our colleagues in Princess Margaret reported outcomes in early-stage non- small cell lung cancer in patients with rare targetable mutation. This is actually becoming increasingly more relevant because we are seeing at least, like with the ALINA data, with the ALK and EGFR, now with ADAURA, we know that these patients don't benefit with adjuvant immunotherapy, especially some of these rare oncogene living mutations, other than like G12C. So I always struggle with this. When you have early-stage patients, with, let's say, a ROS or a RET, where we just don't have data, and we know that those are poor actors because biologically these are aggressive tumors. So, there's a really odd clinical question to ask in terms of, what is the role of adjuvant immunotherapy? Of course, this trial and this abstract are not really addressing that. But what is your take on this abstract? If you could just summarize the abstract for us. Dr. Nathan Pennell: Sure. Well, I think this is incredibly important, and this is an area near and dear to my own heart. And that is, of course, the whole landscape of how we manage early-stage patients has changed with both ADAURA, because we now have effective treatment in the adjuvant setting for EGFR mutant patients, and now more recently with the ALINA trial for adjuvant alectinib for ALK positive patients now being FDA-approved. So, what that means is we actually have to be testing people at diagnosis even before they would be getting adjuvant treatment, and potentially before even surgery to look for these targets. We need the PD-L1 status, we need EGFR and ALK. And if you're going to be looking at these biomarkers, I think there is a reasonable argument to be made that you should be doing broad testing for all of the targetable oncogenes in these patients. There are some studies suggesting that there's value to this and identifying them for treatment at the time of recurrence. But we also know that these patients are at high risk of recurrence and probably need to be investigated, at least in trials for the adjuvant setting. So, this particular study looked at 201 resected, mostly adenocarcinoma patients, and then they basically sequenced them for all of the targeted oncogenes. And they were quite common, perhaps even more common than you might expect in an advanced population. So, 43% of them had KRASG12C mutations, 13% had EGFR Exon 20 mutation, ERBB2 or HER2 mutations found in 11%, MET mutations in 10%, ALK in 7%, ROS1 in 6%, BRAF in 5%, and RET in 2%. So quite common to find these targetable oncogenes in this particular population, perhaps a somewhat biased population at Princess Margaret Hospital, but very common. And then they looked at the outcomes of these patients without targeted adjuvant treatment. And what they found was there was a very high rate of recurrence. So, relapse-free survival was pretty high in these patients across different stages, and generally their prognosis was worse than the more common KRASG12C patients. Most of these, in particular the HER2 mutant patients, seem to have a significantly worse relapse free survival. Interestingly enough, though, that did not carry over to overall survival. Overall survival was better in those who had targetable oncogenes. And my guess is that that probably had to do with the availability of targeted treatments at the time of recurrence that may have impacted overall survival. But I do think that this particularly highlights the need, the unmet need for effective adjuvant treatment in these patients. And most of them, with the exception of KRAS and perhaps BRAF, perhaps MET unlikely to benefit from adjuvant immunotherapy, as you mentioned. And so, I think we really need to be investing in trials of adjuvant targeted treatments in these populations.  Dr. Vamsi Velcheti: Yeah, this is an area that we really don't have a lot of data. But Nate, a question for you. So tomorrow you have a patient with RET fusion, stage 2, N1 disease. What would you do? Would you offer them an adjuvant RET inhibitor? Dr. Nathan Pennell: I think I would search really hard for a trial to give them access. But if you really want to know what I think, and I'm usually willing to tell people what I think, I think the proof of concept is there. I think we know that in the setting of highly effective and very tolerable adjuvant targeted treatment in the EGFR space with osimertinib, in the ALK space with alectinib, if anything, drugs like selpercatinib and pralsetinib in RET fusion positive lung cancer in the advanced setting are just as well tolerated and easily as effective and long lasting. And so, I think if you did a trial and they are doing trials looking at these drugs in the adjuvant space, almost certainly you're going to see the same really dramatic disease-free survival benefit from these treatments, which, at least in the EGFR space, seems to have translated into an improvement in overall survival. And so if I had a stage II or a resected stage 3, especially a RET fusion positive patient today, I would definitely talk to them about off-label use of a RET inhibitor if I could not find a trial. Now, I understand that there are going to be reimbursement issues and whatnot associated with that, but I think the extrapolation is worth discussing. Dr. Vamsi Velcheti: Yeah, I think it's really challenging because some of these fusions are so rare and it's hard to really do large adjuvant trials for some of these rarer subgroups. Nate, fascinating insights. Our listeners will find links to the abstracts we discussed today in the transcript of the episode. And Nate, I look forward to catching up with you at the Annual Meeting, and again after the meeting for our wrap up podcast to discuss the practice-changing lung cancer abstracts and highlights from the Plenary Session. Thank you so much for joining us and sharing your insights today. Dr. Nathan Pennell: Thanks for inviting me. Vamsi. I look forward to touching base after we get to see all the late-breaking abstracts. Like I said, this is, I think, a year for lung cancer with a lot of exciting data, and I know we'll have a lot to talk about. Dr. Vamsi Velcheti And thank you so much to all our listeners for your time. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate and review and subscribe wherever you get your podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti   Dr. Nathan Pennell @n8pennell   Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures: Dr. Vamsi Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi