Podcasts about Trk

Year in Review: Clinical Investigator Perspectives on the Most Relevant New Datasets and Advances in Therapeutic Targets Beyond EGFR for Non-Small Cell Lung Cancer | Faculty Presentation 1: Therapeutic Approaches Targeting ALK, ROS1, RET, TRK and NRG1 — Jessica J Lin, MD CME information and select publications

En este episodio especial de Dame Rueda, el equipo se adentra en el complejo universo de las marcas de motos chinas. Con humor, análisis técnico y experiencias personales, intentan arrojar luz sobre la confusa red de fabricantes, marcas, sub-marcas y fusiones que dominan el sector. El episodio repasa los principales grupos industriales como QJ Motor, Loncin, CF Moto, Zontes, entre otros, y cómo muchas marcas occidentales están hoy fabricando en China. También se debate sobre la calidad, los controles de producción, la percepción del público, y se incluyen visitas a concesionarios y experiencias con modelos como Benelli, Boge, Voge, Zontes, Keeway, MITT, Macbor, FB Mondial, entre muchas otras. El episodio mezcla análisis de mercado, comparativas entre modelos, historia de las marcas y sus fusiones, y debate sobre la evolución tecnológica y la fiabilidad de las motos chinas en el mercado europeo y latinoamericano. Temas tratados: Grupos industriales chinos y su red de marcas (QJ Motor, Loncin, CF Moto…) Marcas europeas e hispanas fabricadas en China (Benelli, MITT, Macbor…) Análisis de calidad, repuestos y servicio postventa Opiniones desde España y México Experiencias personales en concesionarios Comparativas entre modelos populares (TRK, Leoncino, Napoleon, Imperiale…) Evolución del mercado de motos chinas en Europa y Latinoamérica Encuéntranos en: Whatsapp: http://wa.me/34644020615 +34 644 020 615 Email: Damerueda@gmail.com TIENDA: https://www.latostadora.com/shop/damerueda/?shop_trk Youtube: http://www.youtube.com/@damerueda Instagram Dame Rueda: https://acortar.link/bqWGOu Instagram Bicho Raro: https://www.instagram.com/bichoraro_damerueda/?hl=es Instagram Diez-Once: https://www.instagram.com/diezonce_damerueda/?hl=es Instagram TBO en moto: https://www.instagram.com/tboenmoto_damerueda Facebook: https://www.facebook.com/damerueda Telegram: https://t.me/dameruedagrupo Blog Dame Rueda: https://damerueda.home.blog/ Email: Damerueda@gmail.com TikTok: https://www.tiktok.com/@damerueda?_t=8jFKY9ClhWC&_r=1 Playlist Spotify: https://open.spotify.com/playlist/5nuJ547mcCQJPxzKJPL3jq?si=2216c3ad90d74240 Hashtags: #MotosChinas #Benelli #QJMotor #CFMoto #Zontes #Voge #MITT #MotoAventura #DameRueda #PodcastMotero #Motociclismo #Motos2025 #MadeInChina

Send us a textYou can tell a lot about Ted Russell Kamp from his grin.  When he is playing a song or talking about touring, he lights up with a deep joy.  Being an independent artist is not easy calling.  You wear many hats, slog many miles, and suffer setbacks from missing strings to club cancellations.  But those who can show they can take licks and deliver some guitar licks all the same with a sense of fun are the ones who make it.  TRK has 17 albums out and his latest, California Son celebrates not only the free spirit that is California, but also is an anthem of love for his craft of songwriting and his love of those who have supported him through the years.  We get to hear Ted talk about how he started and where he has been in the business.  And we get a wonderful visit to his studio, where he plays us some of his favorite songs, including one with only a bass guitar for accompaniment.  His website is www.tedrussellkamp.com.Support the showWe are always grateful to have you listening to STRUNG OUT. Here are some important links:SUPPORT THE SHOW:https://www.buymeacoffee.com/MartyfineaKMARTIN'S WEBSITE:http://www.MARTINMcCORMACK.COM (note---you can get my weekly bulletin when you sign up on the list!)MARTIN'S MUSIC: Music | Martin Laurence McCormack (bandcamp.com)Martin McCormack | SpotifyMARTIN'S YOUTUBE CHANNELMartin McCormack - YouTubeFACEBOOKFacebook...

HerpTime joins us to talk all things anole, how to keep them, how to breed them, and his philosophies regarding line breeding them. JOIN US ON PATREON: https://www.patreon.com/ReptilesandResearchPRODUCTS TO USE: https://www.amazon.com/shop/reptilesandresearchPHAILOZOO 15% OFF DISCOUNT CODE: R&RPHAILOZOO ENCLOSURES: https://phailozoo.co?sca_ref=8248864.jO3NsidwAzTHE REPTILE KEEPER 15% OFF DISCOUNT CODE: RNR15THE REPTILE KEEPER: https://thereptilekeeper.com/?amc=TRK-7-5601fbEMAIL► reptilesandresearch@gmail.com

Are you up to date on the use of tropomyosin receptor kinase (TRK) inhibitors in pediatric patients with TRK fusion-positive cancers? Credit available for this activity expires: 11/29/25 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/pediatric-trk-fusion-positive-cancer-optimizing-care-trk-2024a1000lmh?ecd=bdc_podcast_libsyn_mscpedu

En esta cápsula de ESMO 2024 EXPRESS, el Dr. Santiago Viteri, oncólogo médico en UOMI Cancer Center de Barcelona, España, nos comenta brevemente las novedades presentadas durante el congreso que, a su parecer, son las más representativas en cáncer de pulmón. Estudio ALKOVE-1: Este estudio evalúa NVL-655. NVL-655 es un inhibidor de tirosina quinasa de cuarta generación específico para ALK, diseñado para evitar la inhibición de TRK, lo que mejora su tolerabilidad, especialmente en pacientes con metástasis cerebrales. El estudio mostró una tasa de respuesta objetiva del 38% en pacientes previamente tratados, destacándose una duración de respuesta de 14.4 meses en aquellos con mutaciones de resistencia ALK​. Estudio ARROS-1: Este estudio fase I-II evaluó zidesamtinib, un inhibidor específico para tumores con fusiones ROS1. Se observó una tasa de respuesta objetiva del 44% en pacientes con mutaciones de resistencia y metástasis cerebrales, mostrando respuestas intracraneales del 50% en los pacientes evaluados​. Estudio MARIPOSA-2: Este estudio fase III combina amivantamab con quimioterapia para pacientes con mutaciones de EGFR que han progresado tras tratamiento con osimertinib. Los datos preliminares sugieren una mejora en el tiempo hasta el siguiente tratamiento, aunque aún no hay significancia estadística en la supervivencia global​. Estudio REZILIENT1: Este ensayo evalúa zipalertinib, un inhibidor de EGFR específico para mutaciones del exón 20. Los resultados muestran una buena tasa de respuesta, con una mayor tolerabilidad comparada con otros inhibidores previos​. Fecha de grabación: 15 de septiembre de 2024

6 hermanos, una viuda y una pasión: La moto. Así arranca la historia de Benelli, una historia tormentosa, cuajada de hitos históricos, de triunfos deportivos, de motos míticas como la “Leoncino” o la “Sei” y que ahora forma parte del importante grupo Qianjiang, pero conserva su corazón, las actividades de diseño, desarrollo y marketing, en Pesaro, en Italia. Entre las marcas de moto italianas, sólo Gilera, fundada en 1909 supera en antigüedad a Benelli, fundada en Pesaro solo dos años más tarde. Una historia que vamos a contaros gracias al apoyo de la marca. Nada mejor que tener una buena madre. Con una Italia convulsa, pues estamos a muy pocos años del comienzo de la “gran Guerra”, una autentica “mamma” italiana sufre un revés muy duro: Enviudar con seis hijos a su cargo. Estamos hablando de Teresa Benelli y de sus hijos Giuseppe, Giovanni, Filippo, Francesco, Domenico y Antonio “Tonino” Benelli. La “mamma” Teresa sobre todo quiere asegurar el pan de sus hijos, conseguirles un trabajo estable y como todos eran aficionados a las motos o a la mecánica decide vender todo, utilizar todos los ahorros en dar formación a sus hijos y crear Benelli Garaje. Manda a sus hijos mayores a estudiar a Suiza y crea este taller de reparación con 6 empleados… de los cuales 5 eran sus propios hijos. “Tonino” no tenía edad de trabajar… su futuro sería otro. Para muchos la “Gran Guerra” fue un desastre… y para otros una oportunidad. Y entre esos otros estuvo Benelli, que durante la Primera Guerra Mundial trabajó mucho para el ejercito italiano, lo que le permitió en 1919 diseñar su propio motor y en 1921 presentar su propia moto. Esta moto con su motor de 2 tiempos evolucionó de 75 a 98 cm3, luego a 125 cm3 y finalmente, hasta 147 cm3 en un prototipo de competición pilotado por el pequeño de la familia, “Tonino”. Pero el motor que permitió la expansión de la marca fue un mono cilíndrico de 175 cm3, con árbol de levas en cabeza movido por engranajes y presentado como una verdadera revolución en 1927 y es que lo era. Entre una guerra y otra Benelli aprovechó a competición para dar a conocer su marca. “Tonino” Benelli ganó 4 campeonatos italianos de velocidad. Pero en esta vida hay que tener suerte: Tonino tuvo primero un accidente que le aparto de la competición en 1932 y 45 años más tarde un accidente de tráfico que acabó con su vida. Mientras tanto Benelli, para hacer frente a su competencia, diseño diversos motores sobrealimentados, entre ellos un magnifico 4 cilindros de 250 cm3 con compresor volumétrico y nada menos que 52 CV a 10.000 rpm… y eso en 1938. Pero estalló la Segunda Guerra Mundial y estos motores con compresor fueron prohibidos… ¡qué pena! Y tras la guerra Benelli debe recomponerse. El cómo hacerlo fue motivo de disputas entre los hermanos, hasta el punto que el mayor, Giuseppe Benelli decide separarse y crear otra empresa diferente: MotoBi. Pero Benelli sale adelante con la creación de nuevos modelos entre los que destaca el “Leoncino” de los que se vendieron alrededor de 50.000 entre 1950 y 1960 y fue todo un éxito. En la década de los 60 las cosas se complican. Por una parte el automóvil se abarata y cada vez más consumidores prefieren comprar un coche a una moto. Pero es que a finales de la década las cosas se complican con la llegada de los japoneses, que ofrecen motos baratas y muy fiables. Pese a todo se ganan dos Mundiales de velocidad en 250, en 1950 con Ambrosini y en 1969 con Carruthers y muchos campeonatos y trofeos nacionales. También se lanzan modelos de éxito, como la Tornado 650 bicilíndrica o la Mojave. Benelli a principio de los 70 está en serias dificultades y el argentino Alessandro De Tomaso, con experiencia en el mundo de las 4 ruedas llega al rescate y compra la marca. ¿Qué hace De Tomaso? Pues dos cosas en mi opinión notables y acertadas. Por un lado, creo una nueva fábrica mucho más moderna y segundo, recuperando la innovación técnica lanzando la Benelli Sei, la primera moto con motor 6 cilindros del mercado y en su momento, un auténtico hito. No se anduvo por las ramas: Pidió a sus ingenieros que copiasen la Honda CB 500 y lanzaron la Benelli 500 Quattro de 1974. Ese motor con dos cilindros más se convirtió en un 750 cm3 e 6 cilindros y luego en una 900 cm3. Pese a todo la competencia japonesa seguía haciendo estragos no solo con las marcas italianas… recordemos que la industria británica de la motocicleta desapareció… en 1988, Benelli está al borde del abismo, otra vez en quiebra y llega otro salvador: Giancarlo Selci, dueño del grupo industrial Biesse. En mi opinión, es una opinión, Benelli pierde un poco el rumbo. Se lanzan los modelos Devil y Scooty que parece que van a sacar a la marca de los números rojos, pero se pierde un poco la “esencia” de la marca. Nueva crisis y nuevo “salvador” en este caso Andrea Merloni, hijo de Vittorio Merloni y dueño de otro grupo industrial, Meloni de Fabriano. Siguen son los scooters, pero con buen criterio vuelve a las motos más grandes, con la Tornado 900 “tre” de 3 cilindros de 2003 y en 2004 la “naked” TnT de 1,130 cm3…. Pero Benelli sigue sin salir del pozo. Y por fin en 2005, Benelli se convierte en Benelli Q.J. o sea pasa a formar parte del grupo Q.J que es Quianjiang. Si te crees que esta historia acaba aquí, te equivocas, porque en 2016 Q.J. es comprada por el grupo GEELY, un monstruo que tiene marcas de coches como Polestar, Lynk & CO, Proton y otras que te sonarán aún más, como Lotus, Smart o Volvo… o sea, que por dinero no será. La idea es fabricar en Italia y en China, pero mantiene la esencia de una marca histórica. El Leoncino 500 y el TRK 502 ambas con el mismo motor bicilíndrico de 500 cm3, 4 válvulas y doble árbol de levas, se fabrican en Pesaro. Que la marca Benelli sigue siendo una marca querida en toda Europa, pero sobre todo en italiana lo demuestra el que la TRK 502 una Trail bastante “endurera” en 2020 fue, el modelo más vendido en Italia. Pero la gama Benelli es en este momento muy amplia con modelos desde 125 mono cilíndrico hasta 300, 500, 750 bicilíndricos y 600 de cuatro cilindros. Parece que la estabilidad ha llegado a Benelli, que sigue haciendo motos con encanto, pero de buena calidad y a buen precio. Decíamos que era una marca muy querida en Europa y en Italia, pero también en España donde la Benelli 250 Elettronica de los años 80 fue muy popular y la Quattro y Sei muy admiradas.

Ocena filma Režiser: Rose Glass Nastopajo: Kristen Stewart, Katy O'Brian, Ed Harris, Jena Malone, Anna Baryshnikov, Dave Franco Piše: Gaja Poeschl Bere: Maja Moll Najnovejši celovečerni film britanske režiserke in scenaristke Rose Glass Kri moje ljubezni je tako večplasten, da bi se verjetno brez težav uvrstil tako med Liffove ekstravagantneže in izbrance festivala žanrskih poslastic Kurja polt kot tudi na programa Festivala LGBT ali Mesto žensk. Intenzivna strastna romanca med zadržano in vase zaprto vodjo lokalne telovadnice Lou in mimo potujočo eksplozivno bodibilderko Jackie, ki okvirja celotno filmsko dogajanje, je namreč predstavljena tako naravno in stvarno, da pušča dovolj prostora tistim resnično perečim družbenim vprašanjem, predvsem družinskemu nasilju. Dogajanje je spretno postavljeno na konec osemdesetih let prejšnjega stoletja, ko po režiserkinih besedah svet še ni zapadel nihilizmu naslednjega desetletja in so bile sanje še vedno visokoleteče, zmaga na regionalnem bodibilderskem tekmovanju pa je v resnici še lahko pomenila odskok v novo, boljše življenje. Ali pa se je tako vsaj zdelo. Jackie in Lou, to je skrajšana oblika imena Louise, v tem je moč slutiti poklon filmu Thelma in Louise, sta si na prvi pogled povsem različni ženski, z nezdružljivima osebnostma in energijo, ki bi prej rušila kot gradila, a obe skrivata temno preteklost in nazadnje je to več kot dovolj trden temelj za njuno ljubezen. Ta pa je, v skladu z žanrom in vzdušjem brezkompromisnega ameriškega jugozahoda, že kmalu po vzcvetu postavljena na hudo preizkušnjo, ko Loujina sestra zaradi nasilnega moža spet konča v bolnišnici, Jackie pa rahlo nepremišljeno stvari vzame v svoje roke. Ko se v vso godljo vmeša še ekscentričen lokalni kralj orožja, je krvav vrhunec v črnohumornem tarantinovskem slogu seveda neizogiben. Dodatno razsežnost filmu Kri moje ljubezni dodaja izjemna kemija med protagonistkama. Tiha, obvladana Lou, polna temnih skrivnosti, se zdi kot na kožo napisana izvrstni Kristen Stewart, ki spretno prehaja med živčnostjo in odločnostjo, med potrebo po obvladovanju in željo po predaji, nepredvidljiva energijska bombica Jackie pa je našla svoje popolno utelešenje v Katy O'Brian, nekdanji poklicni bodibilderki. Trk njunih energij povzroči neverjetno eksplozijo, ki je resnična gonilna sila filma. Kri moje ljubezni je film, ki bo navdušil predvsem žanrske sladokusce, vendar ne gre spregledati, da je v njem tudi veliko pomembnih družbenokritičnih prvin in da skorajda z vsakim kadrom ambiciozno ruši stereotipe ter si drzne iti dlje, kot so šli tovrstni filmi pred njim.

BUFFALO, NY- February 19, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Neurotrophic-tyrosine receptor kinase gene fusion in papillary thyroid cancer: A clinicogenomic biobank and record linkage study from Finland.” Selective tropomyosin receptor kinase (TRK) inhibitors are approved targeted therapies for patients with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Country-specific estimates of NTRK gene fusion frequency, and knowledge on the characteristics of affected patients, are limited. In this new study, researchers Wei Zhang, Arndt A. Schmitz, Roosa E. Kallionpää, Merja Perälä, Niina Pitkänen, Mikko Tukiainen, Erika Alanne, Korinna Jöhrens, Renate Schulze-Rath, Bahman Farahmand, and Jihong Zong from Bayer HealthCare Pharmaceuticals Inc., University of Turku, Turku University Hospital, Technical University Dresden, and Western Finland Cancer Centre identified patients with histologically-confirmed papillary thyroid cancer (PTC) from Finland's Auria Biobank. “The study objectives were to determine the frequency of NTRK gene fusion in patients with PTC in Finland, and to describe co-occurring genetic alternations, clinical characteristics, disease progression, and treatment pathways in NTRK gene fusion positive patients.” TRK protein expression was determined by pan-TRK immunohistochemistry. Immuno-stained tumor samples were scored by a certified pathologist. Gene fusions and other co-occurring gene alterations were identified by next generation sequencing. Patient characteristics and vital status were determined from linked hospital electronic health records (EHRs). Patients were followed from 1 year before PTC diagnosis until death. 6/389 (1.5%) PTC patients had an NTRK gene fusion (all NTRK3); mean age 43.8 years (and none had comorbidities) at PTC diagnosis. Gene fusion partners were EML4 (n = 3), ETV6 (n = 2), and RBPMS (n = 1). Of 3/6 patients with complete EHRs, all received radioactive iodine ablation only and were alive at end of follow-up (median observation, 9.12 years). “In conclusion, NTRK gene fusion is infrequent in patients with PTC. Linkage of biobank samples to EHRs is feasible in describing the characteristics and outcomes of patients with PTC and potentially other cancer types.” DOI - https://doi.org/10.18632/oncotarget.28555 Correspondence to - Jihong Zong - jihong.zong@bayer.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28555 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, NTRK gene fusion, papillary thyroid cancer, clinicogenomic, epidemiology, biobank 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. 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 Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

As care teams seek new ways to engage and support patients with rare cancers, CANCER BUZZ speaks with Jim Palma, executive director of TargetCancer Foundation, a patient-founded nonprofit organization dedicated to supporting patients living with, and researchers focused on, rare cancers. In this episode, hear about the fully remote TRACK (Target Rare Cancer Knowledge) clinical trial and its unique approach to providing access to biomarker testing for patients in community care settings by leveraging technology. “It [access to biomarker testing] really is one of the biggest challenges that patients with rare cancer face, as well as access to interpretation of results in a way that leads them to the right treatment. So, what we've done is developed a [fully remote] clinical trial that offers testing to patients at no cost and eases their ability to enroll in the trial through remote consenting.” – Jim Palma, Executive Director This is the third episode in a podcast series developed in connection with the ACCC education program Emerging Biomarkers: Innovative Therapies for NTRK Gene Fusion Testing and was made possible with support by Bayer. Jim Palma,  Executive Director TargetCancer Foundation Cambridge, MA   Additional Reading/Sources: ·       Emerging Biomarkers: A Spotlight on NTRK Gene Fusion Testing (accc-cancer.org) ·       NTRKers Patient Community & Support (ntrkers.org) ·       NTRK Gene Fusion Infographic (ntrkers.org) ·       NTRK fusion-positive cancers and TRK inhibitor therapy

Building awareness of rare cancers, such as NTRK gene fusion-positive cancers, is critical to improving access to biomarker testing and new treatment options for patients. In this episode, CANCER BUZZ speaks with Susan Spinosa, president and patient founder of NTRKers, an organization created to support patients with NTRK fusion-positive cancer, about her care journey and the importance of testing for NTRK gene fusions. “What we want to have for every patient who is diagnosed with NTRK is accessibility...We need to test for it…it's a rare biomarker but in my mind, it should not be rare—the more testing we do the more routine it will become—and my hope is that 5 or 10 years from now, biomarker testing is routine and NTRK is not rare...” – Susan Spinosa, President of NTRKers This is the second episode in a podcast series developed in connection with the ACCC education program Emerging Biomarkers: Innovative Therapies for NTRK Gene Fusion Testing and was made possible with support by Bayer. Susan Spinosa President and Patient Founder  NTRKers   Additional Reading/Sources: ·       Emerging Biomarkers: A Spotlight on NTRK Gene Fusion Testing (accc-cancer.org) ·       NTRKers Patient Community & Support (ntrkers.org) ·       NTRK Gene Fusion Infographic (ntrkers.org) ·       NTRK fusion-positive cancers and TRK inhibitor therapy  

JCO PO authors Dr. Michael J. Kelley and Dr. Katherine I. Zhou share insights into their JCO PO article, “Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion–positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans.” Host Dr. Rafeh Naqash, Dr. Kelley, and Dr. Zhou discuss the robust Veterans Affairs (VA) National Precision Oncology Program (NPOP), accurate identification of gene fusions, and toxicities landscape of TRK inhibitors. Click here to read the article! 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 JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and assistant professor at the OU Stephenson Cancer Center in the Division of Medical Oncology.   Today, I'm thrilled to be joined by Dr. Michael J. Kelley. Dr. Kelley is the executive director of Oncology for the Department of Veterans Affairs. He's also the chief of Hematology-Oncology at the Durham VA Medical Center, and also a Professor of Medicine at the Duke University School of Medicine. And he's also a member of the Duke Cancer Institute. We are also joined by Dr. Katherine I. Zhou who is a Hematology-Oncology fellow at the Duke University. Dr. Zhou also spent time at the Duke Medical Center as part of her fellowship training, which I believe is how this project that was led by her came to fruition.  So thank you both for joining today. This is going to be, hopefully, of very high interest to our listeners and I look forward to chatting with you both. Dr. Michael Kelley: Great, thanks for having us. Dr. Katherine Zhou: Thank you for having us. Dr. Rafeh Naqash: Thank you so much for joining. So I was very intrigued with this paper, and this paper follows a recent podcast that we had with Dr. Alexander Drilon, who's led some of the NTRK tropomyosin receptor kinase inhibitor studies that have been published in the last several years. And we had a very interesting discussion a couple of weeks back and I felt this was going to be a very interesting subsequent discussion into what was also an interesting discussion with Dr. Drilon. So what caught my attention is obviously the fact that you guys in this report, which is a real-world report, did not exactly see what we generally expect from clinical trials as far as response to target therapies in NTRK fusions.  So before I ask you questions related to this project, one of the very interesting things at least I found was the fact is that the Veterans Health Administration is the largest integrated health system. Studies, whether conducted in the UK, for that matter European countries, or in Canada, they have integrated health systems which we do not. But we do have this advantage of the VA trying to do things in a very unique, centralized manner. So I wanted to ask Dr. Kelley first, how is it that you have implemented this National Precision Oncology Program, the NPOP as you call it, into the VA precision medicine workflow and how does it help in conducting research studies like the one that you published in the JCO Precision Oncology? Dr. Michael Kelley: Yeah, thanks for that question, Dr. Naqash. The NPOP started in 2016 as a national program and right from the beginning it grew out of an effort that was a joint collaboration between both clinical operations in the VA and the Research Office or the Office of Research and Development. It was designed from the very beginning to support discovery, new knowledge generation, and identifying patients for clinical trials in addition to bringing them best-in-class molecular testing and a consultation service.  So it was initially funded out of the Cancer Moonshot 1 in 2016 when President Biden was then Vice President. The VA endorsed the model going forward in 2019 and now it's continued on and grown even bigger, it's expanded both in terms of scope and the complexity of the testing that's been done. So it was offered as services to facilities. They didn't have to do this, but I think they all saw the value of using NPOP to provide this group of services and that's what led to the generation of the robust underlying dataset that Dr. Zhou has used for this paper. Dr. Rafeh Naqash: Definitely. Thank you so much for that explanation. I did not know, and was not well aware, of how robust this program is. So I think it's a great learning opportunity for our listeners to know that a program like this exists. As we all know, there are different platforms, sequencing platforms, that each institution uses, whether it's commercial or whether it's in-house based. But the fact is, until and unless we have big pool datasets like the ones that you have generated or have access to, it's not easy to answer real-world questions.  So first of all, I'd like to congratulate you and the rest of the VA administration to set up a program like this that hopefully is helping in matching the right patients to the right therapies and in clinical trial approvals. Now, before we take a deeper dive into the study that Dr. Zhou led, I did want to ask you, you have access to this amazing centralized platform, what are the kind of sequencing strategies or platforms that you use as part of this program? And is there an incorporation of molecular tumor boards to help understand some of these sequencing results that sometimes can be a little complicated to understand even for oncologists who look at these reports on a daily basis? So could you tell us a little bit more about that, Dr. Kelley? Dr. Michael Kelley: Yeah, certainly. So the VA contracts for the sequencing service, currently we're contracting with Foundation Medicine and Tempus for the comprehensive genomic profiling. There are some other services, and before we started using Foundation, there were two other companies that we used. There is a molecular tumor board. Our molecular oncology tumor board is designed primarily for case-based education. But there's also an asynchronous on-demand consultation service that occurs electronically because we have a unified electronic health record system. So any oncology provider in the country can enter a request through what's called an interfacility consult. It comes to a team, that team vets that, discusses it with the appropriate experts; that includes molecular oncologists, molecular pathologists. A lot of oncology pharmacists have been trained at a course that's at the University of Kentucky.  And we have a lot of experience in doing this since that service was set up in 2016 as well, right from the beginning, because we understood the complexity of the data and the need for every oncologist across our enterprise to have access to the very best interpretation of that.  We also have educational sessions that are integrated into the molecular tumor board time slot we call primers in terms of the underlying science of why you do the interpretations the way you do. And then there's also some additional education that we'll be endeavoring to offer to our staff and our oncologists coming up this year. Dr. Rafeh Naqash: Excellent. It sounds like you definitely have taken this into a very multidisciplinary approach where you're incorporating oncologists, pharmacists, and perhaps even genetic counselors and then, obviously, keeping the patient at the center and trying to find the best possible therapies that are most relevant for that individual.   Now, going to Dr. Zhou's study here. Dr. Zhou, first of all, it's great to see a fellow lead a study and then especially, I think you're our first fellow on the podcast. We've had a lot of different individuals, but we have not had a fellow before. So thanks for coming.  Could you tell us, for our listeners, what drove your interest into NTRK fusions? As we know, they are rare, something that is not commonly seen, and we do have clinical trial data in this space. So what was the idea behind looking at a real-world data set? Did you start out with a hypothesis or were you just interested to see how targeting these fusions in the real-world setting, actually, what kind of results does it lead to? Dr. Katherine Zhou: Yeah, well, first of all, thanks for the question. And I do just want to mention that although I did sort of bring this project to the finish line, it was started by another fellow, Vishal Vashistha. So just wanted to mention that. And I think the interest was really just that NTRK is such a rare fusion and just a difficult one to be able to study, like you said, in the real-world setting. And we have the advantage of having so much data through the VA and through NPOP, specifically. And so having seen such great results with the TRK inhibitors and clinical trials, I think there's this big question of how that translates into the real-world setting. We have the ability to do that with our large patient population. Dr. Rafeh Naqash: Excellent. And again, it's nice to acknowledge the support that you had from the other individual who co-led this study. Now, since you would have, I'm guessing, done most of the analysis here and looked into the whole idea of the kind of results that you saw—and from my understanding, you looked at the entire VA data set and tried to understand first the incidence or frequency of NTRK fusions and also responses to treatment, which I think is the main message—but could you tell us a little bit more about the data set? How did you acquire the data set, and what it took to analyze? Because obviously every project has a very unique story, and I'm guessing there's one very unique story here, since as a fellow you have limited time to do all this interesting work. So how did you navigate that and analyze and work with some of the things that you had to look at to get to the results? Dr. Katherine Zhou: Yeah, so again, this was work that was done with multiple people involved, of course. And we used what we had, the resources we had available, some tools we had available through the VA. So first, looking at NPOP and looking at patients who are sequenced through NPOP, we could just find all the ones who had an NTRK rearrangement of some kind. The second way we went about finding patients was through the CDW or the Corporate Data Warehouse where we could see which patients were prescribed larotrectinib or entrectinib and kind of go backwards from there and see which of those patients had NTRK alterations or specifically NTRK rearrangements. And so we combined the patients from both of those different methods to come up with our cohort at the end of 33 patients with NTRK rearrangements and 12 patients who are treated with TRK inhibitors. Dr. Rafeh Naqash: Excellent. Could you walk us through what was the subsequent analysis as far as how many NTRK fusions? I know you mentioned in the paper about DNA versus RNA-based testing. So how many were DNA-based, how many were RNA-based? I think there's some element of ctDNA-based testing also, or what tumor types those people had so that we get an understanding of what's the landscape of the findings that you had. Dr. Katherine Zhou: Sure. Since this is a real-world setting, as you may expect, the vast majority of the sequencing was done through tissue DNA sequencing, and that was the case. So for the 25 patients who were sequenced through NPOP that we found who had NTRK rearrangements, 23 of them had tissue DNA sequencing. And then one was tissue DNA RNA, and one was cell-free DNA sequencing. And so using that and being able to go back and look at how many patients have been sequenced in NPOP in total, we could kind of come up with a yield, although the numbers are very small. But we do see that there does seem to be probably a lower yield, for example, with cell-free DNA sequencing, as one might expect.  And then looking at our total group of 33 patients, if we look at what types of cancers they had, we did have quite a few patients just based on prevalent tumors at the VA, I think, and in the population, prostate cancer was common, lung cancer, and then we had smaller numbers of colon and bladder, and I think there's a pancreatic cancer patient. We did have some of these rarer tumor types that more commonly have NTRK fusions as well, so like papillary thyroid carcinoma, and salivary gland cancers as well as soft tissue sarcomas. Dr. Rafeh Naqash: Question for you, Dr. Kelley, related to this data set: do you think that given that the denominator that you have is a unique population, the VA population, that's often males, they're usually above the age of 18, could the frequency have been influenced by that denominator where you may not have been able to capture, let's say, some of the rarer tumors that happen in the younger patient population, for that matter? Could that be a little bit of a bias here?  Dr. Michael Kelley: Definitely. The population of veterans that have cancer that is treated in the Veterans Health Administration do represent generally adult males in the United States, but there is some skewing in certain regards. One of them is towards a higher frequency of smoking status. So not current smoking, which is actually about the same as the national average of about 11%, but the former smoking rate is about twice as high as it is in the rest of the United States. So we may have a lower frequency of some actionable variants in cancers in general because there's a higher etiological role for tobacco smoke in our population. But overall, looking at adult men if we look at like EGFR mutations, our incidence of EGFR mutations in adenocarcinoma is similar to what is reported in other real-world evidence bases from the United States, which is significantly lower than that which is found in academic medical centers. Dr. Rafeh Naqash: Thank you. I'm a big fan personally of real-world data sets. I do a lot of this with some other collaborators and generally, I do phase I trials, which is why I'm interested in precision medicine. And two weeks back, actually, I had a patient with prostate cancer, who ended up having NTRK fusion on a liquid biopsy. Now, you do talk about some of this related to in-frame or out-of-frame fusions and how that can have interesting aspects related to the kinase domain functionality and RNA expression. Dr. Zhou, for the sake of our listeners, could you briefly describe why understanding some of that is important and what implications it has? Dr. Katherine Zhou: Yeah, so I think the oncogenic NTRK fusion that we think of and that's being targeted by the TRK inhibitors is a fusion 5-prime of a protein that forms a dimer and on the 3-prime end is the kinase domain of the tropomyosin receptor kinase. And so you have to have some kind of a gene fusion that results in not only the transcription of that RNA fusion, RNA transcript, but then the translation of that fusion protein. So that needs to be, like you mentioned, that has to be in frame so that the entire protein is translated and expressed and it needs to include the kinase domain. It can't be the other end of the NTRK gene. And both of the genes need to be in the same orientation, of course. And then also the partner gene probably matters in that the ones that we know that actually cause activation of this oncogene are the ones that sort of spontaneously dimerize. And so that's a lot of requirements that we don't necessarily see when we just get, for example, a DNA sequencing result that says there's an NTRK rearrangement. Dr. Rafeh Naqash: Excellent way to describe the importance of understanding the functionality of the activated oncogenic fusion. Now, I know here in most of the patients that you have is DNA sequencing and I'm sure you'll talk about some of the results. And when you connect the results to the kind of data that you have, do you think not having the RNA assessment played a role in not knowing perhaps whether those fusions were functionally active?  Dr. Katherine Zhou: Yes, I think we can't know for sure without having the RNA sequencing data. But certainly, that is a pattern in our small number of patients that we saw and something that makes sense just in terms of the mechanism of this oncogenic fusion protein. So I think that is a question of when should we be doing RNA sequencing to confirm that a fusion that we see on DNA sequencing is actually transcribed into RNA and how do we use RNA sequencing in a cost-effective and useful way to be able to detect more of these NTRK fusions that are actually clinically relevant. Dr. Rafeh Naqash: I absolutely agree with you and this is an ongoing debate. I know some platforms, commercial platforms that is, have incorporated RNA sequencing both bulk or whole transcriptome as part of their platform assessments, but it's still not made inroads into some other sequencing platforms that are commercially used. So it's an ongoing debate, but at the same time helping people understand that certain fusions need some level of RNA assessments to understand whether they're functionally active or not. Which again has implications, as you pointed out in terms of therapies are extremely relevant.   Now, going to the results, which again was very interesting, could you tell us about the findings from the therapeutic standpoint that you observed and what your thoughts are about why you saw those results which were very different from what one would have expected?  Dr. Katherine Zhou: Right. So in the clinical trials of larotrectinib and entrectinib, there were quite high objective response rates on the order of 60%, 70%, even almost 80%. In our very small real-world group of 12 patients who were treated with TRK inhibitors, nobody had an objective response and five patients had stable disease and everybody else, the other seven patients, progressed.  And so the question is why did we see such a big difference compared to the trials? I sort of think of this as two big buckets. One is the population that we were looking at. So this is a real-world population. For example, in the clinical trials, there were almost no Black or African American patients, whereas here we had about 30%-40% Black or African American patients.  Because it's a VA population, it was very heavily male, of course, the age groups are also different in that we didn't have children in the VA population whereas children were included in the trials. And the tumor types also differed because I think in the trials, which makes sense, there's a bias towards tumor types that have more NTRK fusions, and some of the tumor types we were looking at are just common tumor types like prostate and lung cancer where NTRK fusions are not common. But just because there are so many patients with these cancers, we did see them. And so certain of these groups, particularly certain racial and ethnic groups as well as certain tumor types, were not really represented in the trial to the extent that we can make conclusions about whether TRK inhibitors are effective in this population. So that's one.  The second part, I think we've already talked about some, is just the method of detecting these NTRK fusions and how many of these NTRK fusions were actually truly producing oncogenic fusion proteins. And I tried to sort of categorize some of these fusions as being canonical in that they've been more studied. We know the partner gene, they are known to produce an oncogenic protein and to respond to TRK inhibitors. But actually of the four patients who had what we called canonical fusions, all four of them had stable disease at least, whereas the ones that were noncanonical mostly did not have a response or have even stable disease and mostly just progressed. And so then you wonder whether they even had the actual target protein we thought we were targeting. So this is where the real-world setting we're not doing the RNA sequencing or this additional testing to confirm that it's an oncogenic fusion protein. Dr. Rafeh Naqash: And I do see in your results there's a patient especially—you pointed out canonical and noncanonical fusions—you have a patient with a papillary thyroid cancer that I believe had a stable disease for close to two years plus. Is there anything interesting apart from an NTRK fusion in that specific patient where certain co-mutation could have played a role or certain other factors that do you think played into the fact that this patient had stable disease but didn't respond on the TRK inhibitor? Dr. Katherine Zhou: I don't have a great answer for that. I think this is one of the cancers that was well represented in the trials and that commonly has NTRK, or more likely has NTRK fusions. And this was a well-studied canonical NTRK fusion. So I think those are all reasons. The question of co-mutations I think is really interesting. We didn't have the data for every single patient, but for the ones we looked at a lot of the time, NTRK fusions are mutually exclusive with other driver mutations. So we didn't see a whole lot of commutations that we could sort of differentiate between responders or stable disease and progression.  Dr. Rafeh Naqash: Thank you. Going to the toxicities, as a phase I trialist myself toxicity is the bane of my existence where we have to label toxicities, attribute toxicities, understand toxicities. The trial, obviously, as you very well know, that in the trials, they didn't have a lot of toxicities that caused patients to come off or required significant dose reductions, which is not the case compared to what you saw. Could you tell us a little bit about the landscape of toxicities for TRK inhibitors and what you saw in your cohort? That, again, I feel was interesting.  Dr. Katherine Zhou: Of the 12 patients, I think two-thirds of them had either dose reduction or interruption or discontinuation, or some combination of the above. The toxicities we saw were more common than, or at least led to discontinuation and interruption and dose reduction more commonly than in the trials. But the toxicities we saw were also seen in the clinical trials. So LFT elevations, creatinine elevations, neurotoxicity, some cytopenias. We didn't actually see a whole lot of that, but those were present as well, and then some sort of nonspecific things like fatigue. And so, as much as we could tell from retrospective trial review, at least these were severe enough to lead to holding the drug. Dr. Rafeh Naqash: Thank you so much, Dr. Zhou. Question for you, Dr. Kelley. Putting this into perspective, the analysis that you did, how would you connect it to other real-world questions that one could answer using these kinds of data sets? So basically, what are the lessons learned from this amazing program that you guys have run successfully and are, I'm guessing, expanding in different directions? And how can you use a program like this to look at some of these unique questions using real-world data sets? Dr. Michael Kelley: There are a couple of, I guess, next steps for us that are based off this study and other information that we've gotten in other analyses from our NPOP data set. So, first of all, access to an RNA-Seq test. So that has been resolved to some extent, in that we now have two options for comprehensive genomic profiling, one of which does have RNA-Seq.  And then the other approach that we're doing is to do more robust data generation. So we're going to be launching a study to collect prospective data on patients who are treated with off-label drugs. And as part of that, we will also have an on-label cohort for rare populations or any investigator in the VA who's interested in a particular drug or a particular genetic variant. They'll be able to tie into this protocol, and we will then collect data from across the system prospectively, which we think will improve the quality to some degree.  And then thirdly, I think there's an opportunity to merge the initial generation of data in rare genetic types or other populations, which are highly selected by doing a distributed type of clinical trial where patients can be enrolled in prospective treatment trials. So we're not just generating data based on their real-world exposure to FDA-approved drugs, but we're generating data as we're developing the new drugs, we can have a much more heterogeneous and representative population of patients enrolled in clinical trials. So this is called the decentralized clinical trial model. We're starting to launch some trials with industry partners in this area to test out the model. If it works, I think we'll be able to help contribute to the knowledge that we all can use in terms of the patient types, the patient characteristics, but also some of the different tumor characteristics, and also to bring clinical trial opportunities to a more representative group. A lot of the initial clinical trials are done in urban areas, rural populations in VA are about a third of our patients live in rural areas, compared to only 14% of the country. So we think this is a very important diversity issue that should be addressed. Those are some of the ways that we're taking a lesson from this trial and other data that we have to sort of bring it forward. Dr. Rafeh Naqash: Those are excellent next steps and I think the kind of work that the VA is doing and this specific program, Precision Oncology Program, the NPOP program is doing, it's definitely setting up a unique standard in the United States where we have been limited by not having a centralized database. So setting something up of this sort hopefully will help answer a lot of these unique, interesting questions as you have access to data. And then the fact that you mentioned decentralized clinical trials and trying to cater to this access issue for patients in the VA system, I think that would be huge.  And again, I congratulate you and your team on these efforts, and once again, thank you for joining us today and making JCO Precision Oncology a destination for your interesting work. We hope to see more of this work subsequently and hopefully, I get a chance to talk to you more about all the exciting stuff that you guys are leading within the VA health system.  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/podcast.  The purpose of this podcast is to educate and 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. Bios: Michael J. Kelley, MD, is Executive Director of Oncology for the Department of Veterans Affairs, Chief of Hematology-Oncology, Durham VA Medical Center, Professor of Medicine at Duke University School of Medicine and Member of the Duke Cancer Institute. Katherine I. Zhou, MD, PhD is a hematology-oncology fellow at Duke University. She also spends time at the Durham VA Medical Center as part of her fellowship training. COIs: Michael J. Kelley, MD Research Funding: Novartis (Inst), Bristol-Myers Squibb (Inst), Regeneron (Inst), Genentech (Inst), EQRx (Inst) Katherine I. Zhou, MD, PhD: No disclosures  

As biomarker testing can play a critical role in the diagnosis of rare cancers, such as NTRK gene fusion-positive cancers, hear what care teams need to know about identifying patients who may be eligible for this testing. In this episode, CANCER BUZZ speaks with Eric Konnick, MD, MS, associate professor of Laboratory Medicine and Pathology and associate director of Genetics and Solid Tumor Laboratory at the University of Washington Medical Center Fred Hutch Cancer Center about the importance of testing for NTRK gene fusions. “It's really important to test our patients for these [NTRK gene fusions] because there are very effective treatments now that can have dramatic effects on the outcome of these patients' disease course, so identifying patients that can be eligible for therapy is critical…” - Eric Konnick, MD, MS This is the first episode in a four-part podcast series developed in connection with the ACCC education program Emerging Biomarkers: Innovative Therapies for NTRK Gene Fusion Testing and was made possible with support by Bayer. Dr. Eric Konnick, MD, MS Associate Professor of Laboratory Medicine and Pathology Associate Director of Genetics and Solid Tumor Laboratory Director of Genetics Preanalytical Services Fred Hutch Cancer Center, University of Washington Medical Center Seattle, WA         Additional Reading/Sources: ·       Emerging Biomarkers: A Spotlight on NTRK Gene Fusion Testing (accc-cancer.org) ·       NTRKers Patient Community & Support (ntrkers.org) ·       NTRK Gene Fusion Infographic (ntrkers.org) ·       NTRK fusion-positive cancers and TRK inhibitor therapy

JCO PO author Alexander E. Drilon, MD, shares insights into his article, “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers” and the article's findings of the activity of larotrectinib in patients with advanced lung cancer harboring NTRK gene fusions. Host Dr. Rafeh Naqash and Dr. Drilon discuss drug development, testing for fusions, resistance mechanisms, and cancer metastases. Click here to read the article!   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 JCO PO articles. I am your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center.  Today we are excited to be joined by Dr. Alexander Drilon, Chief of the Early Drug Development Service and Medical Oncologist on the Thoracic Oncology Service at the Memorial Sloan Kettering Cancer Center and lead author of the JCO Precision Oncology article “Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion–Positive Lung Cancers.” Our guests' disclosures will be linked in the transcript.  Dr. Drilon, welcome to the podcast and thank you for joining us today. We're really excited to be discussing this topic with you.  Dr. Alexander Drilon: It's my pleasure and thank you for the invitation. Dr. Rafeh Naqash: For the sake of this podcast, we will refer to each other using our first names. So, Alex, you've led the development for some of these agents targeting NTRK. So it's really timely that you're coming onto this podcast to not just discuss this very interesting paper that you published in JCO Precision Oncology, but also the general landscape of NTRK. So could you briefly tell us about the history of the drug development process behind NTRK fusions, when it started, how you got involved, and where it stands currently? Dr. Alexander Drilon: Sure. So, as you mentioned, my background is in lung cancer, where when I came on as a fellow, there was a lot of excitement around EGFR and ALK, but then subsequently other oncogene drivers were also discovered and many of them were fusion. So, as we know, ALK in the fuse state is a driver of many tumors, as is ROS1 and RET. And interestingly, NTRK fusions share many similarities with ALK, RET, and ROS1 in that you have an intact kinase domain that's in the three prime position, it's fused to a different gene in the five prime position and basically describes oncogenesis.  And the beautiful thing about NTRK fusions is that they are widely found across many different cancers. And I like to think of these cancers in two major buckets. So there is a bucket for cancers that are rare where we see these NTRK fusions with a very high frequency. And examples here are your secretory carcinomas of the salivary gland and the breast, for example, more congenital fibrosarcoma, where the frequency exceeds 90% in some series, and then there are much more common tumors where the frequency is much lower. So lung cancer is an example where you find it in less than 1% of cases. There are some other tumors like GI cancers also where the frequency is low. And beyond these two major groups, we also see these NTRK fusion-positive cancers occur not just in the adult population, but the pediatric population. All of that thrown together means that it was a really great setup for exploring the activity and safety of targeted therapy in what we call a ‘basket trial' paradigm, where you design a trial and instead of selecting patients based on cancer type, you ignore cancer type and, of course, you accrue by an enrolling alteration, which in this case is the NTRK fusion.  Dr. Rafeh Naqash: Excellent. Thank you for that summary. It's interesting that just yesterday in my phase I clinic, I had an individual who was supposed to go on a certain study, and liquid biopsy came back and showed an NTRK fusion for a very odd presentation of a prostate cancer, which, again, got me thinking about the paper that you published trying to read about NTRK and then this happened and I got thinking about a bunch of other questions. But, for starters, though, from a receptor standpoint and I know you published on this in different journals, could you briefly tell, for the sake of the audience, describe the pathway and the tyrosine kinase signaling and associated resistance pathways that are concurrently acting in a different direction, perhaps, and also discuss briefly from neural development? I know the pathway, the NTRK gene or TRK gene as such is involved in different neuronal signaling aspects. Could you briefly touch on that? Dr. Alexander Drilon: Sure. And thankfully there are a lot of parallels with other things that perhaps some of the listeners are more familiar with. We'll start with the fact that it is a receptor tyrosine kinase, NTRK. It's a gene that encodes a receptor tyrosine kinase just like other receptor tyrosine kinases that may be fused such as ALK, RET, and ROS1. But remember also that other RTKs are EGFR, FGFR, which are also well known. The important thing to remember for NTRK is that you have three different genes, NTRK 1, 2, and 3 that encode three different proteins which are called TRK A, B, and C. And as you intimated, in the non-oncogenic state, these are very important for the development and the maintenance of the nervous system. And in the fused state, of course, similar to other fusions that we spoke about, the chimeric oncoprotein will drive downstream signaling and tumor growth and metastases. And in general, these cancers can be very reliant on downstream signaling in the MAP Kinase pathway but may also on occasion activate other downstream pathways like the PI3 Kinase pathway. Dr. Rafeh Naqash: And I know some of that could potentially play into resistance mechanisms for some of these first or second-generation NTRK inhibitors. From a fusion partner standpoint, the data that I came across that you're very well aware of is different fusion partners, and maybe some have a slightly better prognosis than some other fusions. But, in your practice and in your experience, does it matter what the other fusion partner is if the kinase domain is intact, meaning the signaling for the NTRK gene is intact? Have you seen any differences there from the other fusion partner standpoint? Dr. Alexander Drilon: From a patient-matching perspective, as long as you think the fusion is real, and by that I mean that you look at the report and you're sure the kinase domain is there and you're sure it's in frame, meaning connected well to the five prime partner so that the DNA strand is read through, the five prime partner does not play a major role in my deciding to give a TRK inhibitor or not. I would give anyone with a functional NTRK 1, 2, or 3 fusion a TRK inhibitor. Now, the data on whether or not select fusions do better than others is, I would say, still a little immature and perhaps conditioned by a few things. There are some of the cancers in the first bucket that we talked about, like the secretory carcinomas that harbor a recurrent event such as ETV6 NTRK3. And those cancers, in my experience in clinic, patients with those tumors can be on a TRK inhibitor for a very long time. And it's unclear if that's because of the exact fusion event or if it's because of the cancer type that might be more, say, genomically naïve compared to a gastrointestinal tumor, like a colorectal cancer with an NTRK fusion. So I hesitate to say that there are very strong and convincing data that if you have a particular five prime partner, you'll absolutely do better or worse. So, in the interim, I think the most important piece is just making sure that the event is real and actionable, and if it is, then you can give a TRK inhibitor. Dr. Rafeh Naqash: Thank you so much. I totally agree. And I think, for the sake of our listeners, as we see more and more sequencing being done on patients with cancer in the advanced stage setting especially, it's important to keep in mind when you have something that you can act on that has an actionable target that is FDA approved, then it's important to give the patient that option, especially in rare fusion events such as NTRK or TRK.   Now, you've touched upon this in your paper, but before we go into the details of the paper, specifically, I wanted you to briefly talk about the testing mechanisms which are important for some of these fusions and play into, for example, ROS1 ALK fusions also. Could you tell us what are the most appropriate ways to test for these fusions in patients harboring cancers, both from a tissue standpoint and from a blood-based assay standpoint? Dr. Alexander Drilon: This is a great question because if you don't have a test that's optimally poised to pick up an NTRK fusion, then you can't act on it. And a patient who would have benefited very durably from a TRK inhibitor won't get access to it. So there are different ways of testing for NTRK fusions, and I like to think of the central dogma here where you have DNA becomes RNA becomes protein because that really helps anchor the different types of assays that you might use. We commonly use next-generation sequencing of DNA, but even if you have a very good next-generation sequencing assay, that does have its limitations because there are some fusions that are structurally just difficult to pick up even with a great DNA-based NGS assay.  And for that reason, we and others have found that in tumors that have an equivocal NTRK fusion, or perhaps where you didn't find something but you really suspect that you missed something, particularly in cases where, historically, like congenital fibrosarcoma where you know there's a very good likelihood of finding NTRK fusion, we then reach for an RNA-based assay because at the RNA level, you've removed things like the intra-DNA based capture challenging. And so I think that from a nucleic acid standpoint, leveraging a test that looks both at DNA and RNA, maximizes the likelihood of finding this fusion. And just remember that there are different NGS assays in terms of the approach to design and some might be more Amplicon-based and that's less optimal, but the hybrid-capture-based ones tend to be better. The DNA and RNA tests can be done on tumors, and in blood, you could do a liquid biopsy. It's very hard to fish out RNA in blood given the current technology so we're still limited to circulating tumor DNA which shares the liabilities of doing DNA testing on a tumor sample. But if you find it and it looks real, then it's certainly actionable even if you detect an NTRK fusion with a liquid biopsy.  Now going back to the central dogma there, the third piece which we haven't touched on is protein. And there have been many papers published now on the utility of immunohistochemistry, and this helps you confirm that the TRK A, B, and C proteins are actually expressed. And what tends to happen is in many fusions, the chimeric oncoproteins strongly express as TRK A, B, and C that helps provide a complementary test or assay that confirms that you're dealing with something that is actionable.  So that is a very contemporary approach and a very thorough approach to looking for these NTRK fusions where you do DNA and RNA if possible. And if you still have questions, ask your pathologist to see if they can do Pan-TRK IHC. But depending on the resource environment that you're in, there are older tests like FISH which we use for ALK that can also find these fusions. RT-PCR which only finds particular events, these can detect NTRK fusions but really don't have the breadth and comprehensiveness as the other assays that we discussed like NGS.  Dr. Rafeh Naqash: Thank you so much, Alex, for that amazing summary of all the methods that potentially could help detect this rare but important event. From a therapeutic standpoint, now, taking a deeper dive into your very interesting JCO Precision Oncology paper that looked at larotrectinib data from a pooled analysis of two trials, a phase II and a phase I. Could you tell us a little background about these two trials, the patient population and what kind of data were you trying to evaluate? And then we can discuss some of the interesting results that you showcase in the paper. Dr. Alexander Drilon: It really helps as a background to realize that the initial approach to this was really on a basket trial where the programs for larotrectinib, which is a selective TRK A, B, and C inhibitor, and the other drug entrectinib, which inhibits ROS1 in addition to TRK, really accrued pediatric and adult cancers with NTRK fusions. And this paper pulls out the lung cancer subset and we'll discuss that in detail. But before getting into that, it's important to know that in the tumor agnostic data set of all patients with an NTRK fusion of any type, larotrectinib achieved a response rate of approximately 80%, entrectinib of approaching 60%, and disease control was durable with a median PFS for larotrectinib of approximately 28 months, and with entrectinib numerically, the number was lower at 11 months.   So with that background, this paper in JCO PO, in the interest of featuring the activity for lung cancers with NTRK fusions, pulled out 20 patients with NTRK fusion-positive lung cancers. And the punchline is that the activity was pretty comparable to that seen with a bigger data set. So the objective response rate was 73% and many patients had a partial response, 67% of the cases, 7% had a complete response, and really only a minority had primary progressive disease, 1 patient out of the 15 evaluable patients. These responses and clinical benefit overall were durable and the median duration of response was almost 34 months, with a median progression-free survival of almost 35 and a half months and an overall survival median of 40.7 months.  And just to talk about how that stacks up compared to other targeted therapies, this certainly is in the ballpark of some of the best ALK inhibitors that we have for ALK fusion-positive lung cancer. It's also comparable to osimertinib for EGFR mutant lung cancer. So we can confidently view TRK inhibition in lung cancers with NTRK fusions as a highly-active therapy.  Dr. Rafeh Naqash: Absolutely. I think you touched upon this earlier where in your cohort at least 50% of patients had central nervous system involvement, and it looks like larotrectinib does have CNS activity and benefit. Could you speak to the differences between potential entrectinib and larotrectinib from a CNS efficacy standpoint? And the second part of that question was going to be when you identify this fusion in patients, for example, with lung cancer, now, since TRK does have a role in neuronal development, do you think there is a role for closer CNS monitoring in these patients if they have not had brain metastasis identified because of the fact that they have an NTRK fusion? Is there some predilection for CNS involvement from a metastasis standpoint? It's just something that I've been thinking of over the last couple of days after I saw my patient who does have CNS involvement but with prostate cancer, which I have not seen in the phase I setting in all the prostate patients that I've come across. So what are your thoughts on that?  Dr. Alexander Drilon: These are great questions. In lung cancers with NTRK fusions, there is a proclivity for metastasis to the CNS. And thankfully, both of these TKIs, larotrectinib and entrectinib, do have coverage of the CNS. Now, from a design perspective, the initial thought was perhaps entrechtinib was more CNS-penetrant. But if you look at the overall response rates in patients with brain metastases and the intracranial response rates where you have patients with target lesions in the brain that you're able to measure; if you look across the aisle, entrectinib and larotrectinib have comparable results, with the objective response rate being in the order of 50% to 60% and the intracranial response rate being also in the order of about 50% to 60%. So at the end of the day, it appears as if, despite the previous hypothesis that maybe one drug would work better in the CNS than the other, we're seeing equally good effects with both drugs.  For the second question you asked, it's also a very interesting question because, like you mentioned, the TRK receptors play a role in nervous system development. But we have not observed a much higher frequency of CNS metastases in NTRK fusion-positive lung cancers or cancers in general that I know of, compared to cancers that are wild type for an oncogene or have other oncogenes. So what's more important really to think about when you sort of chew on the fact that these TRK inhibitors are involved in nervous system development are the potential side effects that you may see in patients that you treat with these TRK inhibitors. Dr. Rafeh Naqash: Absolutely. Now, from the therapy standpoint that you discuss here, duration of responses, objective responses that you saw in your analysis were very impressive for these patients with lung cancer. In your clinical practice if you see a lung cancer patient with this fusion and you treat them with larotrectinib or entrectinib, and they have, let's say, de novo CNS metastases that are asymptomatic, do you generally try the targeted therapy first and hold off, perhaps, brain directed therapy in that setting? Similar to what one would do with osimertinib perhaps or alectinib?  Dr. Alexander Drilon: Absolutely. It's the same paradigm because we know that we are seeing in a larger population of patients, just generally good activity, both extracranially and intracranially. The goal is to try to spare patients the extra side effects of doing radiation by only giving the TKI. And in practice, even outside of the trial, in patients that I've treated with CNS metastases, the activity has been very good. Dr. Rafeh Naqash: Thank you so much. Now, all TKI therapies have, unfortunately, resistance mechanisms that come up eventually, in my experience at least. What is your experience as far as understanding resistance mechanisms on TRK-based therapies and potential second options after that, whether it's second-generation TRK inhibitors or subsequent targeted therapies in this space? Dr. Alexander Drilon: Thankfully, this has been looked at extensively and I like to categorize resistance into two major groups. So there's a type of resistance which we call on-target resistance and another type which we call off-target resistance. In simple terms, cancers that acquire on-target resistance are still dependent on the NTRK or TRK pathway. And often what happens is, like with other oncogene-targeted therapy pairs, you see the acquisition of a resistance mutation in the kinase domain of NTRK 1, 2, 3 that either changes the dynamics of the kinase or sort of kicks the drug off of the binding site due to steric hindrance.  And for those patients, companies have designed next-generation TRK inhibitors that abrogate resistance, meaning they were designed so that they would work despite the presence of these resistance mutations. And a few of them include repotrectinib, talatrectinib, and selitrectinib that are thought to have activity, but there are many other newer ones that are currently being explored. I will say that there's proof of concept that has been published as well showing that patients who progress on a first-generation TRK inhibitor like larotrectinib or entrectinib who develop acquired resistance that's on-target can respond very well to a next-generation NTRK inhibitor. And while these aren't approved just yet, these are of course available in clinical trials. Now, the second major group is more problematic. This is off-target resistance. And when I describe this to patients, what I usually say is that the cancer sort of ‘phones a friend' and activates a second gene perhaps that isn't NTRK. And examples of that include KRAS or MET or BRAF, very well-known oncogenes in other contexts, but it leads to a reliance outside of the NTRK or TRK pathway per se, which still effectively reactivates the MAP kinase pathway. What to do in that situation? Well, there are select cases and there have been case reports published of patients who get a combination. Say if it's acquired MET amplification, you give a MET inhibitor with a TRK inhibitor and that combination can work. But in many other cases where you don't have access to a combination on a clinical trial or on compassionate use, then you really default to the standard of care for that cancer type. So if it's lung cancer and they've never had chemotherapy before, then it would be platinum-based chemotherapy, say with pemetrexed and a third drug, perhaps if they have lung adenocarcinoma.  Dr. Rafeh Naqash: Thank you so much. This is definitely an exciting field and exciting time to be in this space of drug development, and especially when we have so many interesting tumor-agnostic approvals that have come along in the last few years and more to come. And you've led a lot of this development with several other leaders in this field. So it was very nice discussing this with you, and hopefully, our listeners find it equally interesting and educationally relevant to what we see day in and day out as we perform more and more sequencing for patients with cancer and try to identify some of these rare or not so rare events that are targetable and can definitely change the course of a patient's therapy and outcomes. So thank you once again, Alex, for the discussion on this paper.  But before we end, we'd like to spend a couple of minutes trying to know about the investigator. So could you tell us a little bit about your career trajectory, how you started your fellowship perhaps, how you ended up in drug development, and how you've successfully contributed so much in this field to date? Dr. Alexander Drilon: Sure. So I'm originally from the Philippines, was born there, finished med school, and really wanted to come to the United States to sort of broaden my education and my residency program in internal medicine, then called St. Luke's Roosevelt under Columbia, had a program that sent people to rotate through Memorial Sloan Kettering Cancer where I currently work. So that was my first exposure with oncology. I fell in love with it and eventually became a fellow, fortunately, at Memorial Sloan Kettering. And I mentioned earlier that during that time I had subspecialized in lung cancer and there was a lot of excitement around targeted therapy for oncogene-driven lung cancer. And that was my point of entry. I saw these drugs work very well and I said that if I were in a position to develop newer agents, perhaps for other oncogenes where there wasn't anything developed just yet, that would be really cool. And that was my entry into the phase I world where things later on expanded really the tumor agnostic interrogation using the same principles that were familiar to me in the lung cancer world. And I think I've been very fortunate with the environment and the ability, especially with good in-house sequencing, to match many patients to these trials. And it's been wonderful to see several of these drugs approved. Larotrectinib was the sort of seminal tumor-agnostic approval of a targeted therapy for the first time by any regulatory body. And like you said, the hope is that we see several more of these. Dr. Rafeh Naqash: Awesome. That sounds like a very interesting, phenomenal journey that you've had, and a lot of it is also probably related to the kind of people that you met, mentors, and other people who helped you along the way. And then, of course, you've done a lot for other fellows and trainees in this space of drug development. So thank you again, Alex, for joining us, and thank you for choosing JCO Precision Oncology as a destination for your work. I look forward to interacting with you further subsequently and hopefully seeing more development in this space of novel therapies for fusions and other interesting targets in the lung cancer space.  So 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.  Bio: Alexander E. Drilon, MD, is a medical oncologist specializing in the treatment of lung cancer. He is chief of early drug development service at Memorial Sloan Kettering Cancer Center. He has clinical expertise in lung cancer and early-phase clinical trials.   COIs Alexander Drilon Honoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerView Consulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare Therapeutics Research Funding: Foundation Medicine Patents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology) Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology

Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs

Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs

Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs

Go online to PeerView.com/FKB860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. New science continues to support a diverse management model for advanced biliary tract cancers (BTCs), including immune-based and targeted platforms, culminating to the first meaningful advancements in frontline therapy for advanced/metastatic BTC in over a decade. Collectively these clinical trends have expanded the use of individualized management strategies, leading to enhanced clinical outcomes for patients with advanced BTC. In this activity, based on a recent live symposium, expert panelists provide data and practical guidance on the current status of care in BTC and new developments related to the use of novel and emerging immunotherapies and targeted options (eg, PD-1 and PD-L1 inhibitors, FGFR, IDH, TRK, and HER2-directed agents). Case presentations explore next-generation care for today's patients with BTC using personalized upfront and sequential treatment management models. Don't miss this chance to get personal with advanced BTC! Upon completion of this activity, participants should be better able to: Summarize the latest clinical evidence supporting the use of immunotherapy and targeted platforms for patients with advanced BTCs; Develop personalized management plans for patients with advanced BTCs based on up-to-date clinical evidence on novel immunotherapeutic and targeted approaches, expert recommendations, comorbidities, and other factors at baseline; and Manage unique safety considerations associated with the use of novel targeted and immunotherapy options for BTCs

Dr. Shannon Westin and her guests, Dr. Paul Frankel, Dr. Judith Karp, and Dr. Robert Maki discuss how to better inform patients of the risks involved in phase 1 clinical trials. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the Journal of Clinical Oncology After Hours podcast, where we do a deep dive on manuscripts that are published in the Journal of Clinical Oncology. We're so excited to have you all here today. I am your host, Shannon Westin, GYN Oncologist at MD Anderson Cancer Center, and it's my great pleasure to serve as the social media editor of the JCO and the host of this podcast. Today we are going to be discussing a very important manuscript titled “Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials”. And I'm joined today by several of the authors, as well as one of our editors that helped to review this paper. But before I start, I'll note that none of our authors have any conflicts of interest to disclose. And with that, I'd like to introduce our guests. First is Dr. Paul Frankel. He's a research professor at the Division of Biostatistics, Department of Computational and Quantitative Medicine, at the City of Hope National Medical Center. Welcome. Dr. Paul Frankel: Hello and thank you. It's a great honor to be here today. Dr. Shannon Westin: Also with Dr. Frankel is Dr. Judith Karp, who is Professor Emerita of Oncology and Medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome. Dr. Judith Karp: Thank you. And I echo exactly what Paul said. Thank you for having me. Dr. Shannon Westin: And then finally, our esteemed Associate Editor of the JCO, Dr. Robert Maki. He's a professor of hematology and medical oncology, a physician leader in developmental therapeutics, clinical leader of the Sarcoma program at the University of Pennsylvania. Dr. Robert Maki: Hi, Shannon. Thanks for having me on the program. Dr. Shannon Westin: Well, it's awesome to have this star-studded group of guests. We are going to try to cover as much details about this important paper as we can in a short period of time. But I encourage you also to check out the JCO to read the paper in full. So first, let's level set. As we start this discussion around phase 1 trials and ethics, maybe, Dr. Mackie, can you start by giving the basics of just phase 1 trials just to make sure everyone's on the same page? Dr. Robert Maki: Sure, absolutely. Since we have people who are listening from different walks of life, that's for sure. Clinical trials in cancer run anywhere from phase 1, 2 to 3. There are also such things as phase 0 and phase 4 trials. But the primary ones we'll discuss today are phase 1 trials. These are the initial tests, be there a brand-new drug never tested before in people, or it might be testing a new combination of treatments, or it might be looking at an already approved drug or an experimental drug in a new population of patients. Let's say you wanted to take a look at a drug in an elderly population. There aren't any data about that in people who are, let's say, 80 or older, and that would constitute a phase 1 trial. The idea of the trial is to start with low doses of a medication and increase the doses in a systematic way, tracking the side-effects that occur with treatment, and then come to an answer as to how you should move forward with the medication in future trials to determine whether the drug is actually active or not and in which setting. The important point, I guess, in that sense is that a phase 1 trial isn't necessarily looking at whether a drug is useful or not, really just looking at the toxicity of the agent or new combination or new setting overall. Dr. Judith Karp: If I could add one thing to that, and I think this is something that has evolved—well, it's evolved over the last 30 years, but in terms of practicality and application, it's really over the last 10 years, roughly speaking. It's also, I think, the opportunity to identify potentially informative biomarkers through a series of pharmacodynamic studies. I'm an old leukemia doctor, and so I've had that capability, if you will, with our diseases because they're so accessible. But I think there's been a new emphasis on that over the last decade. And it's an important one because it becomes a tool for stratifying in phase 2 and ultimately for identifying, hopefully, in a prognostic fashion, who is potentially likely to respond versus not. And if it's a versus not, then you go in a different direction once you got a bunch of—or if you're lucky enough to have a bunch of different directions. Dr. Robert Maki: It's a really important point about looking at so called pharmacokinetic and pharmodynamic markers. How long is the drug staying in the body? What is the body doing to the drug? What is the drug doing to the body? Judith is right on the mark. You can get leukemia cells right out of the body, oftentimes take a look at them directly, whether you're actually hitting the target you think you're hitting. This is a really great place to—and it's often mandatory to get pre- and post-treatment biopsies, even in solid tumor patients, to know if you're actually hitting your target of interest. So, yeah, if you're not achieving that much, then you shouldn't really be moving the drug forward. Dr. Shannon Westin: I agree. And it's so critical because, as we've seen, you know, to your point, Dr. Maki, about the true goals of a phase 1 trial, I think we've done a lot better job of trying to ensure there is efficacy or trying to clarify for whom we are getting efficacy. And I think we all are aware of several drugs that have gotten approvals from an extended so-called phase 1, right? An appropriately selected population. And certainly that's something new over the last five, six, seven years that we've been able to do that. But things like PARP inhibitors in BRCA-mutant populations and TRK fusion inhibitors like Larotrectinib and others in those with NTRK fusions just come to mind kind of quickly. And even more so, we're seeing these focus drugs, right, that are focused on abnormalities in a specific—Exon, like the G12C inhibitors and things like that. So it is interesting to see how drug development is kind of changing in the phase 1 space where we're trying to move that efficacy potentially up earlier and earlier, just to Dr. Karp's point about that biomarker development. So I think it's a really exciting time. Okay, so the next piece I wanted to just make sure, again, to ensure that we're all on the same page, is these are very common trials, I'd say, and certainly the foundation of drug development. Do one of you want to give an estimate of approximately how many phase 1 trials are ongoing currently and maybe how that's changed over time? Are we seeing more phase 1? Less phase 1? About the same? Dr. Paul Frankel: Yeah, I can take a look at that. The number of phase 1 studies that are currently accruing patients today in oncology is around 4500, something like that. I think there's 4451 open clinical trials and phase 1 clinical trials in oncology today. If you look at, let's say, in May of this year, there was 4263. So you're seeing it's increasing. But if you want to look at really the increase, you can look at between 2000 and 2010. There were a little bit over 5000 phase 1 clinical trials that had started in that period, that 10-year period. If you look at the next 10-year period, 2010 to 2020, it's over 10,000 that started. So the number of phase 1 clinical trials is very large, and it's increasing at a rapid rate. And these do set, as you mentioned, the foundation for all the studies that subsequently follow. Dr. Judith Karp: It's very interesting to me that Paul has these numbers in his head. I am not as quantitative as Paul, but we have these increasing numbers of trials, and yet the percentage of patients who go on those trials has not increased at the same rate. There's still that gap where now for children with leukemia—actually, for children with cancers, it's 90%. 90% of those children go on clinical trials. But for adults, it's still around 8 or 10%. It's unfortunate. Dr. Robert Maki: It's a really good point. There really should be more adults being put on clinical trials. But by the same token, not every adult is appropriate for a clinical trial. Let's say you have—there are things you can do that are clinical trials that aren't treatment either. And if it's data collection or patient-reported outcomes, something that we really don't have a lot of information of in a broad manner, there certainly are clinical trials, even if you're getting standards of care in which patients can be enrolled. So you're certainly speaking to a group of people who espouse and promote clinical research wherever it can be done. Dr. Paul Frankel: These clinical trials, I think, are often the best opportunity that patients have. And even though we're going to be talking about issues with consent and other issues with regard to phase 1 clinical trials, they still remain the best option for patients in almost every situation, if you can get on them. Dr. Judith Karp: Yeah. I just think of them as… Dr. Shannon Westin: Yeah, and I think we could have a whole ‘nother podcast of how to expand an exclusion criteria to allow for those patients, but maybe we'll bookmark that for another episode. Paul, you kind of started mentioning, I think, the last place to level set before we get into a little bit more detail from the paper that you all wrote is from regards to informed consent. Can one of you, or more than one, review the importance and challenges of this process for our listeners? Dr. Judith Karp: I'll take a stab at that one. I think the importance of informing a patient, however well we can do it, of what we expect to happen and what we know and what we know we don't know is a very important part of the contract between the physician and the patient. And it's really a partnership, especially for phase 1 trials, where we really know so little. And what we do know is that the patient—these are for treatment trials. We know that there is no therapy widely available for that patient that's going to do that patient any good. So we have to enter into a partnership with the patient to say, “We're going to try something. We know this little bit. We don't know this huge amount.” And so I think that that's really the importance, just ethically, to have the patient be informed. In terms of the challenges, I think that—this is certainly not politically correct, but were I on the receiving end, on the patient end, and somebody gave me a 35-page document to read, I would not for many reasons. In some ways, it's too much information. Most patients are not, by definition, medically sophisticated. That's one. Two, they don't want to read 30 pages. They're either going to sign it, or they're not. And it's confusing. And, yes, you can say to a patient, “Look, take this home, read it, come back in a week, call me in a week,” whatever. There are many instances, certainly in the leukemia field, where you can't do that. You don't have that luxury. So I think that that is a real challenge that we really haven't addressed. And in the good ol' days when all of us physicians really sat down and talked to the patient, then I think that the challenges were much less. And I think that that's key. Dr. Robert Maki: Yeah. I mean, Judith, AML over age 65. You're not going to get most people into remission, and you've got a captive audience because there they are with low counts. And what are you going to do next? We all, in our research, want to follow the Belmont report. We want to respect people. We're looking for studies that offer beneficence, that do no harm. We can't really do no harm a lot of the time, but we can at least minimize harm. And I think it's where the consent process kicks in. And justice, the third tenet of the Belmont report, being sure that we're using well-considered procedures as part of the research. All those are part of those beautiful words that you used, “partnership” and “contract,” that I think are really important in developing that bond with the individual patient who you're going to treat is super critical. Dr. Judith Karp: Yeah, absolutely. And in some senses, the only real informed consent is if the patient has been through it before. Dr. Shannon Westin: Right. Dr. Paul Frankel: So one of the things making it even more challenging, all these challenges exist throughout. And one of the focuses of our paper is that there's been an increasing trend to use designs that specifically target toxicity rather than limit toxicity during the dose finding of the phase 1 study. And so that introduces a whole ‘nother aspect to the consent process. So if you look at those studies, the most common toxicity target, as noted by others, is a 25% DLT rate. And if interpreted directly, that means that these risk-targeting designs, they claim to aim to find the dose where one in four patients are expected to experience a severe or a life-threatening adverse event in the first cycle of therapy, which is usually 28 days. And that's despite dose modifications. And further, most of these designs consider it a positive feature if a large percent of the enrolled patients are treated near the target. Now, whether this is really what the physicians want or not is separate. But one way or the other, what we have noted in our paper is that our collective experience that the actual toxicity target, the targeted risk, whether it's 20%, 25%, or even 33%, is not disclosed to the patient in the initially submitted consent forms that we see. That is a fundamental change in the way we've designed studies, but it requires that we adapt the consent process to this very challenging problem. Dr. Judith Karp: Along those lines, you're talking about toxicity. Any treatment that targets a non-itchy skin rash has got to be a lot less toxic than a drug that is targeting refractory ovarian cancer or leukemia or what have you. And the disease itself is toxic. So I think there has to be a way to approximate and weigh those toxicities, the toxicity of the treatment versus the toxicity of the disease, because the disease is not benign. Dr. Shannon Westin: One of my mentors, Dr. Razelle Kurzrock, used to always say, “The worst toxicity is progression of cancer.” And I completely—that's a very wise woman. But I think it's a really good point. And I think, just to kind of summarize what you all were saying, if we're targeting a certain toxicity level, we just need to make sure that patients are aware of that. And many of them might be willing and would probably be willing to take that for that potential benefit and things they might get out of it, but we need to be more transparent on that kind of individual protocol level. Would you say that's…? Dr. Paul Frankel: That's the critical thing is to be transparent about these things. And certainly certain different treatments which have maybe more curative potential, certain types of diseases, they're going to be more amenable to a higher toxicity threshold. But it depends on the intent of the therapy, and these need to factor into the decision of what's being used, what kind of target and kind of design is being used. That's kind of part of the issue of transparency is once you get that in front of the patient and the physician and they discuss it, you're likely to get people to agree if it's at least a reasonable target. Dr. Robert Maki: The toxicity targets up from some of these Bayesian designs, oftentimes they're kind of guardrails to ensure there's not too little or too much toxicity on a trial. I think people are using more of the rules-based designs, this risk-targeting design, than the classic three plus three simply from the inability to come up with an adequate dose-escalation scheme using three plus three simply from the fact that you're just looking at the prior three patients. If you look at a lot of the kinase inhibitors that have been approved over time, even when they're FDA approved, drugs like lenvatinib or cabozantinib, even in the phase 3 trials, patients had to have their dose reduced two times out of three. And it really speaks to something went awry in the development of these agents if they really were looking for a 16% DLT rate in a classical sense, which is what you get from that three-plus-three design, one out of six people. It's pretty crazy that two thirds of people in a larger population need that dose reduction. So perhaps by putting better guardrails with one of these rule-based designs, we'll actually end up with a schema for treatment of a patient that ends up being more appropriate. Dr. Judith Karp: It would be very interesting, actually, to examine how often we're wrong. It might be very easy. 100% of the time, I would imagine. But how often the so-called RP2D turns out not to be that. And even with phase 3 trials, you never really know a drug until it's out on the street and thousands and thousands and thousands have been treated with that drug or combination. Paul, maybe that's our next study. What do you think? Nah, I can tell you don't like it. Dr. Shannon Westin: This is kind of getting at what Project Optimus is trying to do, right, is getting away from that idea that we have to get to the max dose and instead look at long-term tolerability. And yeah, Robert, I've given quite a bit of lenvatinib and pembrolizumab in my clinic to patients with recurrent endometrial cancer. You can see that that max dose is not the ideal dose for a lot of patients. Now, there are some patients that tolerate just fine, but 70% grade 3/4 toxicity is legitimate, and making sure we're protecting patients from that is really critical. And I want to cover a few more things before we wrap up. I guess we've talked a little bit about what to do on an individual protocol level. Do you all have some recommendations about what can be done at the research/enterprise level to kind of address the issues that we've been discussing today? Dr. Paul Frankel: One of the issues is, if you look at, let's say, clinicaltrials.gov, you'll see that there's very few studies that have both a model consent form or the protocol on clinicaltrials.gov. And I think if you look at all the clinical trials, the number that have both, you can count on one hand. So the question is whether or not there's a way to systematically evaluate whether the consent form is appropriate, whether the target is reasonable, that kind of thing. And it's very hard to do when you don't have a way to assess that information in a systematic way. So one thing that can happen is that the registries could require a model consent form where they could ask for it, encourage it, one way or the other. It's just a simple document. The other thing that they can do is make sure that the protocol summaries, if the design uses a DLT targeting method to at least state what the target is in the protocol summary, that would help quite a bit. And then you can go through and see if this is reasonable or if this has been communicated in the consent form in particular. And so that's one thing that can happen on the enterprise level that would help considerably. Dr. Judith Karp: The only thing I would add to that is that I think a model consent form, a template, is it's surprising that it hasn't been done yet, although, as you say, it's not easy with all of these studies being done by government and pharma and other enterprises. But that has to be modulated for the disease that's being targeted and for the drug. You can't have the same thing for cell cycle cytotoxic agents and immunotherapy because they're totally disparate. And you can't have the same thing for leukemia and breast cancer. The pathogenesis may be the same, but the phenotyping is not. So that's the only thing I would add. Dr. Robert Maki: The patient population involved as well can certainly impact that. Greater or poorer performance status, susceptibility to complications, all that figures into that consent form. So it's not an easy thing to prepare, at least in a coherent way that a patient is going to understand, especially, as you were saying there, with a 40-page tome that reads at somewhere between grade levels 11 and 14. How do you expect a patient with, let's say, an 8th or 9th grade reading level to fight their way through that if they really wanted to understand the side-effects. It's kind of like the teacher in the Charlie Brown cartoons: “Wah wah wah wah, wah, wah, wah, sign here.” So there are many challenges. Dr. Paul Frankel: There's no question that this is a minimum requirement. Having a written consent form is just an absolute minimum. But the conversation that needs to take place, the communication, that's a whole ‘nother level that I think the physicians are better able to address. But it's just the minimum requirement to have something in the document, and it doesn't make the document longer to communicate the targeted risk in some of these studies. There's really no extra effort that's being asked. I mean, the model consents exists. The DLT targeting is stated in the protocol. It's all fairly simple. Dr. Robert Maki: Yeah, it'd be another line or two, wouldn't it? It's just saying here's what our expected rate of toxicity is. And uploading, whether you're a cooperative group, whether you're an industry, whether it's an investigator-initiated trial, some sort of redacted consent form makes a lot of sense. You may not have to have the grid of activities, which oftentimes is now included in one of these cumbersome documents, but at least the description of the treatment and the toxicity would be at least something everybody could agree to. Dr. Judith Karp: Yeah, some kind of a precede or a FAQs, frequently asked questions. What is this? Why are we doing this? Very simple. Dr. Robert Maki: And that's now mandated, I think. They said at NCI, they insist that we have a summary of the trial, and one page or page and a half at the beginning of that long document. That, to me, has been incredibly effective, as have been things like a little drawing of patient and going one randomization and things like that. Simple means can really be powerful, especially on those first two pages before the eyes glaze over. Dr. Judith Karp: Exactly, yeah, a little CONSORT diagram or something like that, very nice, schema. Dr. Shannon Westin: This has been a really awesome discussion, and I think the bottom line is we need to increase our transparency. And it seems—I don't know, after this discussion, I feel like it's a pretty straightforward ask. Are there any downsides to being transparent? I know we've already talked a little bit about patient burden and how we don't think that would add much to that piece. Dr. Judith Karp: The fear that might exist, that, “Oh, my God, if we really tell them what we're going to do, they're not going to do it. They're going to say no.” I don't think that's realistic. I think patients, especially for phase 1, we're dealing with a population of people for whom there is not a reliable, effective therapy available. These patients know that. Many times they've been through rounds and rounds of chemotherapy or immunotherapy or surgery already. So many patients say, “Just give it to me, and I'll sign it.” And you say, “No, no, no, you must read it.” So they say, “Okay, I'll read it. Where do I sign?” Dr. Robert Maki: Done. Exactly. But it's a really important point that I'd also like to highlight, that phase 1 trials aren't just for the patients with performance status 3, very sick. You can certainly impose those earlier in a patient's course, especially in situations where there is not a randomized trial, for example, showing evidence of survival benefit. Short of that, I tend to be more aggressive about putting patients in earlier lines on phase 1 trials simply because it provides more options for them. Dr. Judith Karp: Yes, and I think a good example, as you had brought up, Robert, earlier, the older patient with AML, maybe a myelodysplasia-related AML. There are lots of things you can do, but none of them work. And so is it an opportunity to look at improving the hypomethylating agents where you get a 25% response rate, not much in terms of complete remission, and a year survival, maybe a year and a half survival. Can you improve on that if you add a drug that interrupts the survival pathway targeting BCL? Can you do that? The answer has been yes, but the only way to get there is to do the phase 1 trial initially and then move up the trial schema. Dr. Robert Maki: To your question, Shannon, though, the administrative burden is a small one. It's uploading a document, adding a little bit more to a consent form. It should not be a deal breaker, I would think. Dr. Paul Frankel: There's plenty of burdens on the research team. We certainly don't want to increase that at all, and I don't think this does. One of the questions you mentioned are the downsides of transparency, but some of the upsides also: by having the physicians have more discussion with the patient on some of these issues in a more transparent and lay language, I think, increases the understanding between the physician and the patient. And the physician can take that back to the statistician who's designing the study with the physician and say, “Hey, maybe we need to reconsider this.” There's some upsides in a variety of ways. Transparency and discussion are only going to be improving the ultimate product. And we certainly don't want to find drug doses that end up being a program drug death or unnecessarily hurting patients. Either one are totally unnecessary and unacceptable. Dr. Shannon Westin: Well, great. I think you've made a very clear call to action. I think the last question is how do we get this done besides raising awareness and just kind of setting the bar, right? Because I know, coming from my standpoint as a clinical trialist, it's not something we think to put into the informed consent as we've transitioned to this more risk-targeting type of trial, which I think, as you mentioned, is becoming much more common and over, like, the three plus three and things like that. How do we implement this? Too big of a question? You're like, “You tell me.” Dr. Judith Karp: We, as physicians, have removed ourselves from patients in so many ways. And how do you get it done? You sit down with the patient. And listen, I'm no saint, and none of us are saints, and we all have other things that we have to do, and there are—you know, we're pressed for time and this and that the other. But much of this, yes, full transparency, you have a 20%, a 25% chance of having a dire consequence. That doesn't mean that you will. If you do, it's 100% in you, right? But there's got to be a communication part that goes with it. That's personal. You can't just do it on paper. You need to do it on paper, but you gotta do it with people, too. Dr. Robert Maki: And the discussion point around potential toxicity, all of the visits, extra visits you might have to make, what extra work you might have to go through, versus, let's say, supportive care only if you are at that point. That is an incredibly important point to make to patients, that you really have exhausted many therapies. Is it best just to go with supportive care for whatever time is left? Because this certainly is rolling the dice. You're going to have some side-effects. And what's the chance of benefit in a phase 1 trial? I think that it's higher now these days, simply from the ability of immunotherapy to intervene on so many different diseases. For example, our success rate is higher than the 5% that's quoted previously, but it's not a home run in any case. And we don't want to take away hope, but we also don't want to give false hope. And I think with Paul's paper and your paper have really pointed out how important it is to have that discussion around the degree of toxicity you might have to expect. Dr. Judith Karp: Absolutely. Absolutely. Dr. Shannon Westin: Well, great. I just want to thank you all for such a lively discussion. I learned a ton, and I hope that our listeners did, too. I do want to remind our listeners to check out this paper, “Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials,” published in the JCO. And also check out other episodes of the JCO After Hours podcast to learn more. So thank you all again and have a wonderful day. 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.  

Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma

Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma

Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma

Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma

Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma

Go online to PeerView.com/YNM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative science is poised to transform glioblastoma management by offering the opportunity to enhance conventional management through the use of newer modalities, including tumor treating fields (TTFields) and efficacious systemic therapies. These novel options have been incorporated into clinical practice guidelines and are driving improved outcomes for patients with newly diagnosed and recurrent disease. The current challenge is how best to use these modalities as part of sequential and highly effective combination strategies across glioblastoma treatment settings. In a new “Seminars & Practicum” event from PeerView and the American Brain Tumor Association (ABTA), expert panelists will link current science to practical decisions that can help clinicians “set their sights” on achieving improved outcomes in glioblastoma. Throughout the lecture and case-based segments, the experts will provide context for the real-world impact of glioblastoma, focus on the latest efficacy and safety data on TTFields, discuss TTFields delivery considerations, and address the integration of targeted and biomarker-guided therapies into glioblastoma management. This program will also feature a patient's perspective on how newer modalities have impacted his therapeutic journey. Set your sights on better outcomes in glioblastoma, and join us for this important educational activity! Upon completion of this activity, participants should be better able to: Articulate the roles, mechanisms of action, and key clinical evidence on novel guideline-recommended treatment options, including TTFields, multikinase inhibitors, and gene-directed therapies (eg, TRK inhibitors), for patients with newly diagnosed (post-radiation) or recurrent glioblastoma; Consider clinical trials evaluating innovative treatment strategies as standard therapeutic options for patients with newly diagnosed or recurrent glioblastoma, based on an understanding of their clinical rationales, efficacy, and safety; Develop contemporary, personalized management plans for patients with glioblastoma that incorporate novel therapeutics, expert recommendations, and individual patient needs and preferences; andEmploy proactive, team-based strategies to address practical aspects, including adverse event management, patient education, and disparities in clinical care and research, associated with using novel therapeutics for patients with glioblastoma

Go online to PeerView.com/QKA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this inExchange from PeerView, a multidisciplinary team of experts from oncology, endocrinology, and pathology discuss the advantages of a team-based approach to NTRK fusion testing and TRK inhibition in thyroid cancer. In this 30-minute learning opportunity, you'll hear how endocrinologists can lead the interprofessional charge to enhance outcomes by optimizing NTRK fusion testing and TRK-targeted therapy. This presentation covers the rationale, science, and evidence, and presents actionable strategies for putting the data into practice for patients with fusion-positive thyroid cancer. Upon completion of this activity, participants should be better able to: Explain the rationale for testing for NTRK fusions in patients with thyroid cancer, including their role in disease development and progression and impact on prognosis and treatment algorithms; Cite current efficacy and safety evidence on TRK-targeted therapies in patients with NTRK fusion–positive thyroid cancers; Implement practical strategies to ensure patients with thyroid cancer receive timely and appropriate NTRK fusion testing in order to inform optimal therapeutic decision-making; and Apply best practices for collaboration and coordination of care with multidisciplinary colleagues for patients with NTRK fusion–positive thyroid cancer, including appropriate integration of TRK-targeted therapies into treatment plans and recognition/management of treatment-related adverse events.

Go online to PeerView.com/QKA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this inExchange from PeerView, a multidisciplinary team of experts from oncology, endocrinology, and pathology discuss the advantages of a team-based approach to NTRK fusion testing and TRK inhibition in thyroid cancer. In this 30-minute learning opportunity, you'll hear how endocrinologists can lead the interprofessional charge to enhance outcomes by optimizing NTRK fusion testing and TRK-targeted therapy. This presentation covers the rationale, science, and evidence, and presents actionable strategies for putting the data into practice for patients with fusion-positive thyroid cancer. Upon completion of this activity, participants should be better able to: Explain the rationale for testing for NTRK fusions in patients with thyroid cancer, including their role in disease development and progression and impact on prognosis and treatment algorithms; Cite current efficacy and safety evidence on TRK-targeted therapies in patients with NTRK fusion–positive thyroid cancers; Implement practical strategies to ensure patients with thyroid cancer receive timely and appropriate NTRK fusion testing in order to inform optimal therapeutic decision-making; and Apply best practices for collaboration and coordination of care with multidisciplinary colleagues for patients with NTRK fusion–positive thyroid cancer, including appropriate integration of TRK-targeted therapies into treatment plans and recognition/management of treatment-related adverse events.

Go online to PeerView.com/QKA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this inExchange from PeerView, a multidisciplinary team of experts from oncology, endocrinology, and pathology discuss the advantages of a team-based approach to NTRK fusion testing and TRK inhibition in thyroid cancer. In this 30-minute learning opportunity, you'll hear how endocrinologists can lead the interprofessional charge to enhance outcomes by optimizing NTRK fusion testing and TRK-targeted therapy. This presentation covers the rationale, science, and evidence, and presents actionable strategies for putting the data into practice for patients with fusion-positive thyroid cancer. Upon completion of this activity, participants should be better able to: Explain the rationale for testing for NTRK fusions in patients with thyroid cancer, including their role in disease development and progression and impact on prognosis and treatment algorithms; Cite current efficacy and safety evidence on TRK-targeted therapies in patients with NTRK fusion–positive thyroid cancers; Implement practical strategies to ensure patients with thyroid cancer receive timely and appropriate NTRK fusion testing in order to inform optimal therapeutic decision-making; and Apply best practices for collaboration and coordination of care with multidisciplinary colleagues for patients with NTRK fusion–positive thyroid cancer, including appropriate integration of TRK-targeted therapies into treatment plans and recognition/management of treatment-related adverse events.

Go online to PeerView.com/QKA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this inExchange from PeerView, a multidisciplinary team of experts from oncology, endocrinology, and pathology discuss the advantages of a team-based approach to NTRK fusion testing and TRK inhibition in thyroid cancer. In this 30-minute learning opportunity, you'll hear how endocrinologists can lead the interprofessional charge to enhance outcomes by optimizing NTRK fusion testing and TRK-targeted therapy. This presentation covers the rationale, science, and evidence, and presents actionable strategies for putting the data into practice for patients with fusion-positive thyroid cancer. Upon completion of this activity, participants should be better able to: Explain the rationale for testing for NTRK fusions in patients with thyroid cancer, including their role in disease development and progression and impact on prognosis and treatment algorithms; Cite current efficacy and safety evidence on TRK-targeted therapies in patients with NTRK fusion–positive thyroid cancers; Implement practical strategies to ensure patients with thyroid cancer receive timely and appropriate NTRK fusion testing in order to inform optimal therapeutic decision-making; and Apply best practices for collaboration and coordination of care with multidisciplinary colleagues for patients with NTRK fusion–positive thyroid cancer, including appropriate integration of TRK-targeted therapies into treatment plans and recognition/management of treatment-related adverse events.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Go online to PeerView.com/PUE860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Gene fusions and other key alterations (NTRK, RET, and others) represent actionable targets in a substantial proportion of patients with solid tumors. Appropriate biomarker testing is crucial to identify all alterations that are treatable with current or investigational targeted therapies. Multikinase tyrosine kinase inhibitors (TKIs) have been used to treat such alterations, but they have limited efficacy. Therefore, next-generation TKIs with greater selectivity have been developed and approved for tumor-agnostic indications (such as NTRK alterations) and for specific tumor types (such as RET alterations in lung and thyroid cancers). These newer therapies have demonstrated impressive efficacy with favorable safety profiles, and their use can significantly improve patient outcomes and quality of life. The tumor-agnostic indications are anticipated to expand further, and novel options are also emerging for patients who have developed resistance to standard RET- and TRK-targeted therapies. In this PeerView educational offering, experts on gene fusion-positive solid tumors provide a cutting-edge update on the role and relevance of gene fusions and other key alterations in solid tumors. These KOLs offer guidance on how to best identify patients with gene alterations and discuss accumulating clinical evidence for the best use of targeted therapies, while also providing practical guidance for optimizing multidisciplinary and interprofessional strategies for biomarker testing and use of targeted therapy across solid tumors harboring NTRK and RET fusions and other actionable alterations. Upon completion of this activity, participants should be better able to: Describe the role of NTRK, RET, ALK, and other key genomic alterations in the oncogenesis of solid tumors, the importance of appropriate biomarker testing to identify patients with these alterations, and clinical evidence supporting the use of matched targeted therapies to optimize patient outcomes; Collaborate with the broader cancer care team to identify patients for biomarker testing, select appropriate tests to capture all relevant genomic alterations, including gene fusions, and interpret testing results to guide treatment selection; Apply the latest evidence and guidelines to individualize targeted therapy for patients with cancers harboring NTRK, RET, ALK, and other targetable genomic alterations; and Educate patients about the role of biomarker testing, risks and benefits of targeted therapies, and importance of selecting optimal therapy based on biomarker testing results and patient needs, values, and preferences.

Featuring an interview with Dr Ezra Cohen, including the following topics: Spectrum of targetable mutations in thyroid cancer and impact on treatment selection (0:00) Comparative efficacy of TRK inhibitors in patients with thyroid cancer, including those with CNS disease (6:06) Current and emerging roles of immunotherapy alone and in combination with tyrosine kinase inhibitors for patients with head and neck cancer (10:17) Predicting clinical response to immunotherapy for patients with head and neck cancers (19:47) Role of dose reduction in managing toxicities associated with immunotherapy and targeted agents (26:01) Current and potential roles for cell-free DNA testing and minimal residual disease assessment in the management of head and neck cancer (32:08) Recently reported efficacy data with avasopasem in the treatment of radiation-induced oral mucositis (35:27) Factors affecting response to immunotherapy (42:07) CME information and select publications

Go online to PeerView.com/DRJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to bring modern approaches to the treatment of patients with biliary cancers to your clinical practice? Learn how the treatment paradigm is shifting from conventional chemotherapy to biomarker-guided treatments and immunotherapy in a new event from PeerView and the Cholangiocarcinoma Foundation. Our experts will offer learners a deep dive into the latest science on the biologic rationale for targeting prevalent genetic aberrations in biliary cancers and review key safety and efficacy data from recent pivotal clinical trials of novel strategies. Through discussions of relevant patient scenarios, our panel will offer insight on how to integrate biomarker-guided treatments into clinical practice and practical guidance on identifying patients with advanced biliary cancers who are eligible for targeted treatment. Upon completion of this CE activity, participants will be able to: Summarize the rationale for use and recent efficacy and safety data on newly available and emerging therapeutic strategies for patients with advanced biliary cancers, including FGFR, IDH, TRK, multikinase, HER2, and immune checkpoint inhibitors, Identify patients with advanced biliary cancers who are eligible for treatments with available and emerging therapies targeting FGFR genomic aberrations, multikinase tumor pathways, HER2 alterations, NTRK gene fusions, IDH1/2 mutations, and immune checkpoint pathways, Integrate the latest clinical evidence into the management of patients with advanced biliary cancers, utilizing molecular testing and established and emerging targeted options based on individual tumor characteristics in the context of clinical practice or a clinical trial.

Go online to PeerView.com/DRJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to bring modern approaches to the treatment of patients with biliary cancers to your clinical practice? Learn how the treatment paradigm is shifting from conventional chemotherapy to biomarker-guided treatments and immunotherapy in a new event from PeerView and the Cholangiocarcinoma Foundation. Our experts will offer learners a deep dive into the latest science on the biologic rationale for targeting prevalent genetic aberrations in biliary cancers and review key safety and efficacy data from recent pivotal clinical trials of novel strategies. Through discussions of relevant patient scenarios, our panel will offer insight on how to integrate biomarker-guided treatments into clinical practice and practical guidance on identifying patients with advanced biliary cancers who are eligible for targeted treatment. Upon completion of this CE activity, participants will be able to: Summarize the rationale for use and recent efficacy and safety data on newly available and emerging therapeutic strategies for patients with advanced biliary cancers, including FGFR, IDH, TRK, multikinase, HER2, and immune checkpoint inhibitors, Identify patients with advanced biliary cancers who are eligible for treatments with available and emerging therapies targeting FGFR genomic aberrations, multikinase tumor pathways, HER2 alterations, NTRK gene fusions, IDH1/2 mutations, and immune checkpoint pathways, Integrate the latest clinical evidence into the management of patients with advanced biliary cancers, utilizing molecular testing and established and emerging targeted options based on individual tumor characteristics in the context of clinical practice or a clinical trial.

Go online to PeerView.com/DRJ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to bring modern approaches to the treatment of patients with biliary cancers to your clinical practice? Learn how the treatment paradigm is shifting from conventional chemotherapy to biomarker-guided treatments and immunotherapy in a new event from PeerView and the Cholangiocarcinoma Foundation. Our experts will offer learners a deep dive into the latest science on the biologic rationale for targeting prevalent genetic aberrations in biliary cancers and review key safety and efficacy data from recent pivotal clinical trials of novel strategies. Through discussions of relevant patient scenarios, our panel will offer insight on how to integrate biomarker-guided treatments into clinical practice and practical guidance on identifying patients with advanced biliary cancers who are eligible for targeted treatment. Upon completion of this CE activity, participants will be able to: Summarize the rationale for use and recent efficacy and safety data on newly available and emerging therapeutic strategies for patients with advanced biliary cancers, including FGFR, IDH, TRK, multikinase, HER2, and immune checkpoint inhibitors, Identify patients with advanced biliary cancers who are eligible for treatments with available and emerging therapies targeting FGFR genomic aberrations, multikinase tumor pathways, HER2 alterations, NTRK gene fusions, IDH1/2 mutations, and immune checkpoint pathways, Integrate the latest clinical evidence into the management of patients with advanced biliary cancers, utilizing molecular testing and established and emerging targeted options based on individual tumor characteristics in the context of clinical practice or a clinical trial.

Mile - Rasta ft. MarcquesRayKaz - Deuce ft. SuhnMJ Wemoto - good mood saka huyaProgisthename - MBINGA ft. TRK, Sico ZW, Scar, BlvckSmyth & MJ WemotoRis Monteez - Do The Wo ft. R.PeelsTakura - Push To StartBeav City - Like ThisTeam Bhoo - Kuzvimbisana ft. Schingy & Seven CadreVI The Law - Mzaya ft. Soko Matemai & Kxng MasseyTkae Chidz - SortedTkae Chidz - Ok OkSuhn - MargielasTanto Wavie - MudhipisiVoltz JT - These DaysR.Peels - Zino ft. Voltz JTTanto Wavie - 007Kikky Badass x Crooger - Simudza Gumbo ft. gTbeatsKikky Badass - Kurunga ft. CroogerSaintfloew x Holy Ten - Under PressureHoly Ten - Hanging Nevaskana [Pungwe Music Pro-G Edit]Progisthename x Soko Matemai x MJ Wemoto - KINGTashinga - Sobanyisa ft. Verge & LookatupsSuhn - TwentiesHanna - Boi ft. DeekayDitItVoltz JT - Muranda Achaita KingHoly Ten - SahwiraMitch Uta - Nothing Is FreeProgisthename - Summer Time 16's Edit ft. RayKazKap City - Feel MeNutty O - Handipere PowerNyasha David - Alellah ft. VascoProbeatz - Teremuke ft. CharmabreezyProgisthename x Ivory Blue - NawtiiTama - NdionePoptain x Anita Jaxson - MoreKazz Khalif - Danger ft. MC BushkinDenzel Soka - ChiheraFreeman HKD - What's Your NameBantu vs Simba Tagz - Chocolate Banana Juice (Pro-G Edit)Gemma Griffiths - AvaBantu & Dr. Chaii - Summer Whine ft. Soaky Siren (Pro-G Edit)Ash Fire - JojinaNutty O - FinesseTashamiswa X Delroy - TouchdownTamy Moyo - Do My Own Thing (Pro-G Burna Boy Edit)Tr3y XL x McKnife x The Mystry - Bharanzi ft. Deeno JayKae Chaps - Mwana WevhuBlvckSmyth - HuchiDr. Chaii - Dirty ft. Kida Kudz & Big TobzHakkz - Disaster ft. One AcenS1mba - TwiceTRK - Iwewe NeniProgisthename - Too Much ft. BlvckSmyth (Pro-G Edit)Unknown P - Pain au ChocolatMJ Wemoto x Wrappz SA - Dubai (Pro-G Intro Edit)Reverb7 & Simba Tagz - TsaonaChengeto - Love You MoreProgisthename - Beautiful Escape ft. Savana (Pro-G Outro Edit)Simba Tagz - My Lover ft. Mr. Eazi (Pro-G Amapiano DJ Edit)Garry Mapanzure - Show Me LoveMurphy Cubic x MJ Sings x Amany x Gang O - KoloyiMJ Wemoto - Yapera