Podcasts about tils

Sigrid Haugset delivers the ride of her life, completing an extraordinary 89-kilometre breakaway to win Stage 3 of the Tour de France Femmes and claim the yellow jersey for Uno-X.Tils, Verita and Sarah Gigante unpack how the peloton allowed the race to escape, why the GC favourites could not bring her back, and the mental resilience required to keep fighting with Lotte Kopecky closing fast behind.The team also takes aim at the limited television coverage that meant fans missed the opening kilometres and much of the day's decisive racing. Sarah explains how the lack of live pictures can change the incentives for riders and smaller teams trying to deliver sponsor exposure.Elsewhere, the Free Blasi movement continues to grow, the UCI turns its attention to alleged “bra maxing” in time trials, and all eyes turn toward the pivotal Stage 4 individual time trial. Who has done the specific work, who could lose serious time, and can Marlen Reusser take control of the race?The Domestiques Daily Tour de France Femmes is powered by Black Sheep and Join Cycling.Build your personalised cycling or running plan free for 30 days at join.cc/domestiques.Use code DOMESTIQUES for 20% off Black Sheep.

Enter the Black Sheep Cycling Tour de France Femmes Fantasy League and compete for $3,000 worth of cycling apparel. https://au.blacksheep.cc/pages/femmes-fantasy-league-2026The Tour de France Femmes is here, and Sarah Gigante joins Tils for the ultimate preview of the biggest race in women's cycling.Sarah begins with an honest update on the injury that has kept her out of the Tour, the painful issues caused by the metalwork in her femur and why she is finally riding pain-free again. Then, it is time to break down all nine stages.From the frantic opening stages in Switzerland and the decisive Dijon time trial to Mont Ventoux and a brutal final showdown in Nice, the team picks the riders, breakaways and GC contenders to watch each day.Can Demi Vollering become the race's first repeat winner? Will defending champion Pauline Ferrand-Prévot conquer Mont Ventoux? Can Marlen Reusser turn her time-trial power into yellow, or will Kim Le Court, Anna van der Breggen, Kasia Niewiadoma or rising star Paula Blasiak produce the upset?There is also peloton gossip, fantasy-team strategy, green, polka-dot and white jersey predictions, plus a look at how extreme heat, team strength and race tactics could shape the Tour.The Domestiques will be live throughout the Tour de France Femmes, breaking down every stage and taking you inside the peloton with the riders.Get 30 days free with Join Cycling at join.cc/domestiques.

Enter the Black Sheep Cycling Tour de France Femmes Fantasy League and compete for $3,000 worth of cycling apparel. https://au.blacksheep.cc/pages/femmes-fantasy-league-2026Five Tour titles at 27. Five stage victories. A record-breaking ascent of Alpe d'Huez - and one final attack through the streets of Paris.Tils and Marko wrap up a remarkable 2026 Tour de France, beginning with Tadej Pogačar's demolition of Marco Pantani's Alpe d'Huez record and ending with his unforgettable Montmartre showdown alongside Mathieu van der Poel.They debate whether Pogačar is now cycling's greatest-ever athlete, why he spent the final weekend acting as Isaac del Toro's domestique, and whether his generosity cost him even more history. There's also Remco Evenepoel's finish-line frustration, Richard Carapaz's late charge, the extraordinary crowds on Alpe d'Huez and a full report card for the Tour's biggest winners and losers - including Lidl-Trek, Jayco-AlUla and a disappointing Ineos.Plus, The Domestiques looks ahead to the Tour de France Femmes avec Zwift and announces daily episodes with Sarah Gigante throughout all nine stages.Train free for 30 days with Join Cycling at join.cc/domestiques.

With the podium being reshaped by crashes and withdrawals, the Tour de France heads into a savage final stretch featuring nearly 13,000 metres of climbing across three stages.Tils and Lee break down Jasper Philipsen's Stage 17 victory, the seven-point battle for the green jersey, Michael Matthews' heartbreaking near miss and Lidl-Trek's complicated pursuit of points, stages and team objectives.Then attention turns to the mountains. Stage 18 brings almost 4,000 metres of climbing, Stage 19 finishes on the legendary Alpe d'Huez, and the Queen Stage delivers more than 5,500 metres of elevation. Could Tadej Pogačar take another historic victory and challenge Marco Pantani's long-standing Alpe d'Huez record?The team also preview the final stage into Paris, reveal their plans to bring The Domestiques to Europe and announce daily coverage of the Tour de France Femmes with a very special guest from inside the Women's WorldTour.Join Cycling is offering Domestiques listeners 30 days free, with no credit card required. Visit join.cc/domestiques to get started.The Black Sheep powers the Domestiques and you can use the code DOMESTIQUES for 20% off at Black Sheep.The Domestiques is live throughout the Men's and Women's Tour de France, breaking down the stages and bringing you inside the bunch with the riders. Powered by Black Sheep.

Jonas Vingegaard was woken at 2am. Tadej Pogačar at 5am. Hours later, Vingegaard's Tour ended with a fractured collarbone.Anti-doping testing is essential—but has cycling crossed a line? On the Tour's second rest day, Tils, Marko and Lee unpack the overnight testing controversy and carefully separate what caused Vingegaard's crash from what may have contributed to it. Tils and Marko also reveal the deeply personal reality of the whereabouts system, missed-test anxiety and producing a sample with someone watching.Then it's back to the racing: Remco Evenepoel's breakthrough road-stage victory, Pogačar riding as Isaac del Toro's domestique, Mauro Schmid and Luke Plapp delivering for Jayco-AlUla, and the increasingly fascinating battles for the podium, white and green jerseys.Plus, predictions for the time trial, two ascents of Alpe d'Huez and the final week in Paris.The Domestiques is presented by Black Sheep Cycling at blacksheep.cc. Take 20% off with the code DOMESTIQUES.Try Join Cycling free for 30 days at join.cc/domestiques.

The final 10 kilometres of a Tour de France sprint can look like chaos. To Greg Henderson, it's a puzzle, and one he still wants to solve.The former Grand Tour stage winner and one of the most respected lead-out riders of his generation joins Tils and Lee to dissect the Tour's sprint stages. Greg explains what Olav Kooij got wrong, why Tim Merlier keeps finding a way to win, and how the disappearance of specialist sprint directors is leaving some of the world's fastest riders without a proper plan.They also get into questionable relegations, the speed and danger of modern racing, why today's sprinters need to hit more than 70km/h, and what it takes to come back after a serious crash.Plus: is Tadej Pogačar already the greatest of all time? Do Lance Armstrong's seven Tours still count? And Greg shares three practical sessions for anyone wanting to become a faster, and hopefully better-looking sprinter.The Domestiques is presented by Black Sheep Cycling and supported by Join Cycling. Try Join Cycling free for 30 days by heading to https://join.cc/domestiques

Join Cycling has joined The Domestiques alongside Black Sheep Cycling. Join is an adaptive cycling coaching platform that builds a training plan around your goal, available time and real life. Miss a session, ride longer than planned or need to move things around, and the program adjusts with you. Listeners can try it free for 30 days at join.cc/domestiques, with no credit card required.The Tour reaches its first rest day, but there is no shortage of talking points. Isaac del Toro continues to look completely at home on cycling's biggest stage, while Tadej Pogačar and UAE keep everyone guessing with tactics that suggest they are ready to take control of the race.Chris Hamilton joins Tils and Marko to unpack the brutal heat, Tim Merlier's extraordinary sprint speed, Mads Pedersen's relentless pursuit of green, the rise of Biniam Girmay, and what is really happening inside the bunch. Plus, the team previews a savage Bastille Day stage that could ignite the GC battle all over again.The Domestiques is powered by Black Sheep Cycling and Join Cycling.

The Tour de France is here, and it has wasted no time reminding everyone why it is the biggest race in cycling.This week on The Domestiques, Tils, Marko and Hollywood break down the opening stages of the Tour, from the Barcelona team time trial and Visma's early masterclass, to Pogacar's ominous start, Del Toro's rise, Remco's pressure, the first breakaway chances, and the brutal heat already shaping the race. The first week has barely started, but the GC picture is already shifting.They are joined by EF Education-EasyPost's Harry Sweeny, who gives a brutally honest update on the toughest stretch of his career. After a flying start to the year at Tour Down Under, Harry looked set for a huge European season before illness, knee pain, surgery, chicken pox at altitude, a mystery nerve issue, and a second operation wiped out months of racing.Harry talks through the physical and mental toll, life in Monaco, switching off from cycling, rebuilding from a CTL of 28, staying locked in with EF, and why the Vuelta could still be on the cards.Plus: Hollywood's Tour kit verdict, Marko's Hellride downfall, heat training, AI in cycling, sprinters, GC predictions, and the usual amount of abuse between mates.The Tour is on. The heat is up. And the Sween Dog is rebuilding.

This week on The Domestiques, Tils, Marko and Hollywood are joined by Harry Leask, Olympic silver medallist for Great Britain, former America's Cup cyclor with INEOS Britannia, and current Beach Road weapon making Saturday mornings miserable for anyone brave enough to sit on.Harry takes us inside one of the strangest and most brutal roles in elite sport: powering a high-speed sailing boat from inside a tiny, boiling carbon box, where four riders are locked together, producing massive watts with no control over when the next effort is coming. From rowing at the Tokyo Olympics, to training alongside the INEOS Grenadiers, to discovering Melbourne cycling culture via the Hellride and the Queensmen, Harry's story is as ridiculous as it is impressive.The crew also previews the opening stages of the Tour de France, including the Barcelona team time trial, the first GC flashpoints, the stages to watch, and why the opening weekend could already cause serious damage. There's also European nationals chat, special edition Tour kits, Fashion Corner, running injuries, and the usual amount of unnecessary abuse between friends.The Tour is here. Sleep deprivation begins now.

In today's episode of The Line Podcast, recorded on June 26th, 2026, Matt Gurney and Jen Gerson begin with a rare moment of joy. After decades of delay and political paralysis, there is finally a plan to deal with 24 Sussex Drive. Your hosts don't love every aspect of it, but they're so relieved that someone has finally decided to do something that they're prepared to celebrate. Now comes the hard part: not finding a way to mess it up.This episode of The Line Podcast is brought to you by Cameco. In nuclear energy, timelines and costs matter. Incomplete designs carry real risk of delays and cost overruns. That's why the AP1000 reactor is the right choice for Canada: it is already operating today and ready now to deliver the power we need, with 100 percent Canadian ownership and strong participation from Canadian suppliers. If we are serious about building Canada and powering it on time and on budget, the choice is clear. The AP1000 reactor is the only option that delivers. To learn more, visit ap1000.cameco.com.From there, they turn to the tragic shooting in Montreal that claimed the life of another police officer. Beyond the immediate heartbreak, your hosts focus on two broader issues. First, they argue that the media should have published the shooter's manifesto. By choosing not to do so, they contend, some early reporting ended up being incomplete or inaccurate. Second, they discuss the rush by commentators across the political spectrum to comb through the manifesto looking for evidence that the attacker perfectly represented their opponents — or, failing that, had nothing whatsoever to do with their own side. Matt and Jen argue that modern terrorism is often ideologically incoherent, and that treating every attack as an opportunity for partisan point-scoring will only make it harder to understand and prevent future violence.This episode is also brought to you by Fractional Execs Canada. Need help with a serious business problem? As Canadian businesses grow they often require expert help to solve key business challenges. Fractional Execs Canada have assembled a team of experienced strategists, implementors, sales and marketing operators that can help transform your business into a growth engine. They match you with the right person, or team to move your business forward at a pace your business can manage.Talk to Fractional Execs Canada and discover a better, more collaborative way to take your business and your ‘busyness' in a better direction. Canadian expertise to support the growth of Canadian businesses. Build your business with those that know how.Find them Fractional-Execs.ca.Finally, Jen makes a wardrobe change that only video viewers will fully appreciate before walking Matt through the increasingly strange politics of the Calgary Stampede. What was once simply Alberta's biggest annual celebration is now becoming another front in an ongoing proxy war between competing factions within the broader conservative movement.This episode is also brought to you by BioCanRx, a federally-funded Canadian not-for-profit research network, which helps bring cutting edge cancer immunotherapy research from Canadian scientists from labs to patients in clinical trials –– all in Canada. Cancer is very good at evading your immune system. But in some tumors, researchers find cancer-killing immune cells called tumour infiltrating lymphocytes, or TILs. They get inside the tumour and start fighting — but they're outnumbered and ill equipped. Researchers in Canada and around the world are studying techniques to extract them from a tumour and multiply them in a lab. Once they number in the millions, they're injected back into the tumour to do more damage. Research into this line of attack against cancer is ongoing. There are plenty of unanswered questions, and we're working hard to answer them. Learn more about this and other critical work at BioCanRx.com.All that and more in the latest episode of The Line Podcast. Check out our main page at ReadTheLine.ca, and as ever, like and subscribe.#TheLinePodcast#CanadianPolitics#24Sussex#Montreal#CalgaryStampede#AlbertaPolitics#PoliticalAnalysis#CanadianMedia#LawEnforcement #CurrentAffairs

In today's episode of On The Line, host Matt Gurney is joined by two guests for conversations about housing, politics, and why governments sometimes struggle to explain themselves.This episode is brought to you by BioCanRx. When your immune system recognizes that cancer is a problem, but can't kill it, can science help? This summer we're partnering with BioCanRx, a federally-funded Canadian not-for-profit research network, to learn about cutting edge cancer immunotherapy research that they're helping Canadian researchers bring from labs to patients in clinical trials –– all in Canada.One of the reasons cancers are so destructive is because they find ways to evade your immune system. But in some tumours, researchers find cancer-killing immune cells called "tumour infiltrating lymphocytes," or TILs. These are like infantry grunts choosing to stand their ground during the final fight in a superhero movie. They get inside the tumour and start fighting – –but they're outnumbered and ill equipped. They need reinforcements.Researchers in Canada and around the world are studying techniques to extract them from a tumour and multiply them in a lab environment. Once they number in the millions, they're sent back into the fight. Research into this line of attack against cancer is ongoing, and there are plenty of questions — we'll be covering more of them over the course of the summer. Go to BioCanRx.com to learn more about these new ways of fighting cancer.First up is Mike Moffatt of the Missing Middle Initiative and co-host of the Missing Middle Podcast. He joins Matt to discuss the much-debated “condo bailout” and why, despite the label, it isn't actually a condo bailout at all. Moffatt argues that the government has done itself no favours by communicating the policy so poorly, and walks listeners through what the plan is — and what it isn't. The conversation then broadens into a look at the state of housing in Canada more generally. There are some signs of progress, but the underlying challenges remain enormous, and Moffatt explains why solving them will require much more than a handful of headline-grabbing announcements.This episode is also brought to you by the Forest Products Association of Canada. A stronger forest industry depends on getting goods to market. Forest products move by truck, rail, and ship, and reliability matters. When costs rise or shipments stall, mills, workers, customers, and communities all feel the impact. Stronger trade corridors, better rail performance, labour stability, and reliable transportation should be treated as core parts of Canada's productivity agenda. For a sector rooted in communities and connected to global markets, transportation is transformation. Learn more at FPAC.ca.Then Matt is joined by Andrew MacDougall of Trafalgar Strategy for a look across the Atlantic at the increasingly turbulent state of British politics. They discuss the struggles of now-outgoing Prime Minister Keir Starmer, the rise of Andy Burnham as a potential future national leader, and why so many observers now see the United Kingdom as becoming increasingly difficult to govern. MacDougall argues that the country's problems run deeper than any one politician or party, and offers his own diagnosis of what has gone wrong.It's a pair of conversations about institutions under strain, political communication, and the challenge of governing in an era when public patience is increasingly in short supply.This episode is also brought to you by Cameco. In nuclear energy, timelines and costs matter. Incomplete designs carry real risk of delays and cost overruns. That's why the AP1000 reactor is the right choice for Canada: it is already operating today and ready now to deliver the power we need, with 100 percent Canadian ownership and strong participation from Canadian suppliers. If we are serious about building Canada and powering it on time and on budget, the choice is clear. The AP1000 reactor is the only option that delivers.To learn more, visit ap1000.cameco.com.Check out our main page at ReadTheLine.ca, and as always, like and subscribe.#OnTheLine #Housing #MikeMoffatt #MissingMiddle #CanadaHousing #KeirStarmer #AndyBurnham #UKPolitics #AndrewMacDougall #MattGurney

Al CPK 364, abans del traspàs de Giannis:· Un parell de welos fotent-se gleves per una discussió a la pista de petanca? Pujo, un welo dinyant-la a la pista de petanca després de la discussió? Som-hi!· Aprofitant la finalització dels Playoffs obrim el consultori patreonitzat i responem les preguntes de l'oientat. Entre els ítems principals ens trobem consultes sobre el draft, Jalen Brunson, Pedro Martínez, Biblioteques, Mike Brown, Gelats, carrers, dàtils, Giannis, ... Tot meravellós com sempre. Moltes gràcies per les preguntes i disculpes a la gent que s'ha quedat sense resposta.

The Tour de France is almost here, and the final exams have been handed in. This week on The Domestiques, Tils returns from a wrong turn at Devil's Cardigan, Marko is back from Thailand with tendonitis and a double IPA, and Hollywood delivers one of his firmest fashion rulings yet: socks over leg warmers. No debate.The crew break down Tadej Pogacar's ominous Tour de Suisse performance, where he didn't just win, he looked like he was running testing protocols on the rest of the peloton. They also dive into a brilliant women's Tour de Suisse, Marlen Reusser's return to form, Elise Chabbey's aggression, Tali Appleton's WorldTour stage race result, and the terrifying crash that left Eriska Zigart with a broken jaw.Closer to home, there's Devil's Cardigan, gravel racing, Tils' elite-category farewell, and the sudden arrival of Harry Leesk as a legitimate wattage monster after going toe-to-toe with Brendan “Trekky” Johnston. Plus, Marko explains whether gravel training is really different to road training, Lorenzo Finn announces himself again at the Baby Giro, and the boys hand out their Best Rider on Ground.

Luke Tuckwell joins us after a life-changing weekend. After an incredible week at the Critérium du Dauphiné, the young Australian stunned the cycling world with a breakthrough GC performance, spending time in yellow and finishing second overall against some of the sport's brightest young stars.This week, Tils, Hollywood and Marko break down Tuckwell's ride, what it means for Australian cycling, and whether he's done enough to force his way into a Tour de France selection.We also preview the Tour de Suisse, discuss Isaac Del Toro's frightening form, debate Remco Evenepoel's reported 425-watt FTP, and look at the latest action from the women's peloton and Copenhagen Sprint. And yes, we spend far too much time talking about yellow bibs.Presented by Black Sheep CyclingUse code DOMESTIQUES for 20% off Black Sheep's cycling and running range.

The Giro wraps, the Giro Women kicks off in chaos, and somehow a gel wrapper becomes the biggest villain in cycling. Tils, Hollywood and Marko unpack Jonas Vingegaard's dominant three weeks, Jai Hindley's huge podium, Aussie climbing depth, Lorena Wiebes' brutal 20-gram disqualification, Elisa Balsamo in pink, and the gravel carnage from Australian Nationals and Unbound. Marko pleads his “could've, should've, would've” case after a mechanical nightmare, Trekkie goes massive at Unbound, and the crew launch a new coaching segment on surviving winter training without becoming a full-time Zwift gremlin. Also, Tils learns the hard way that “are you single?” can mean something very different in a bunch ride.

The crew is back together and, somehow, still talking about gravel. This week on The Domestiques, Tils, Marko and Hollywood unpack the latest Giro drama, from breakaway chaos and motorbike controversy to Jai Hindley's podium chances, Jonas Vingegaard's control, and whether the final week can save the race.They also dive into the huge Tour Down Under announcement, with the men's and women's races set to share the same course, same distance and same day in 2027, asking whether it is genuine progress, logistical madness, or a bit of both.Plus, Marko previews his Gravel Nationals title defence, the Women's Giro gets a proper look-in, Connor Wright keeps cooking in Europe, the Enhanced Games gets exactly the respect it deserves, and Hollywood continues his crusade against gravel, subtlety, and basic podcast structure.

Host: Mindy McCulley, MS, Extension Specialist for Instructional Support, Family and Consumer Sciences Extension, University of Kentucky  Guest: Dr Ayman Qasrawi, Assistant Professor of Medicine, (Hematology) and Dr. Ruta Arays, Assistant Professor of Medicine (Medical Oncology), Markey Cancer Center Cancer Conversations Episode 75 Host Mindy McCulley interviews Dr. Ayman Qasrawi (Dr. Q) and Dr. Rita Arays of the UK Markey Cancer Center about multiple‑modality management and interdisciplinary collaboration in treating advanced melanoma. The episode explains tumor‑infiltrating lymphocyte (TIL) and why this personalized immunotherapy can produce durable responses when other options fail. Key takeaways include the multidisciplinary workflow needed to deliver TILs in Kentucky, candidate selection and timing/referral considerations, program availability at UK (and UofL), and implications for future vaccine research and community care.   Connect with the UK Markey Center Online Markey Cancer Center On Facebook @UKMarkey On Twitter @UKMarkey

Two pods. One gravel circus. A whole lot of pea gravel carnage. This week, The Domestiques joins forces with Roadside Podcast and host Jethro Gammie-Nagle to unpack everything from Seven Gravel Race in Nannup, Western Australia. With the event acting as a full-blown dress rehearsal for the UCI Gravel World Championships in October, Matilda Reynolds and Mark O'Brien take us inside their elite races, from Tils chopping off with Tiffany Cromwell and Maria Laurie, to Marko trying to crush souls one climb at a time. There's race breakdowns, tyre chat, collarbone counts, Netflix-level course coverage, kangaroo dodging, questionable podium-kit rules, and a look ahead to what the Europeans are really in for when Worlds hits proper Australian gravel. Plus, the crew dives into the Giro, Jai Hindley, Ben O'Connor, Luke Plapp causing absolute chaos in Hungary, and the upcoming women's racing calendar.A collaboration pod. A gravel therapy session. A warning shot for October.Give the boys a follow at Roadside Cycling Podcast on Apple (https://podcasts.apple.com/au/podcast/roadside-cycling-podcast/id1592269751), Spotify, (https://open.spotify.com/show/4Tx2Rm4TrY09wNVzGdxem3), YouTube (https://www.youtube.com/@Roadsidecycling), and Instagram (https://www.instagram.com/roadsidecyclingpodcast/)A special thank you to Patrick Boere Photography (https://www.instagram.com/patrickboerephoto/) and Daniela Tommasi Photography (https://www.instagram.com/daniela_tommasi_photography/) for supplying the amazing imagery from Seven for this week's Podcast and YouTube artwork

When every batch belongs to a single patient, a single centralized facility cannot serve the world. In Part 2, Chantale Bernatchez moves from process development into the broader consequences of that reality: the manufacturing model built around clinical proximity, the global alliance bringing TIL production to regions with no current access, and the next-generation engineered approaches redefining what these therapies can do.Chantale Bernatchez is Head of Process Development at CTMC, a joint venture between Resilience and MD Anderson Cancer Center. If you missed Part 1, she explained how specific activation changes recovered a failing TIL process from 50% to 95% success in heavily pre-treated patients.Topics discussed:How close collaboration with MD Anderson accelerates clinical development and regulatory readiness (03:08)CTMC's approach to process development and adapting to innovative technologies (05:15)The value of partnership-based models versus traditional CDMO-driven approaches (06:24)Global technology transfer: building alliances to expand access to cell therapies, with a case study in Brazil (07:35)Key barriers and solutions for cell therapy manufacturing in new regions (09:41)Practical advice for scientists starting in GMP manufacturing and process development (10:46)Future directions in CAR T and TIL, including logic-gated CARs, engineered TILs, and in vivo therapies (12:24)The importance of continued innovation and collaboration to expand global patient access (17:39)Smart insight:The choice of manufacturing partner in cell therapy is not a logistics decision. It is a process development decision. CTMC's collaboration-based model exists because many early-stage developers arrive without a process robust enough to hand over. For scientists in small or mid-sized companies, engaging that kind of partnership too late, or on purely transactional terms, is one of the most avoidable risks in early clinical development.If you're interested in exploring further the concepts we touched on, such as cell therapy manufacturing, process control, and scaling living therapies—take a look at these related discussions:Episodes 125 - 126: How to Enhance Cell Engineering Using Mechanical Intracellular Delivery with Armon ShareiEpisodes 109 - 110: Spinning Like Earth: Designing Low-Shear Bioreactors for Better Cell Culture with Olivier DetournayEpisodes 105 - 106: From Proteins to Cell Therapy: Why ATMPs Aren't Just Complex Biologics with Oliver KraemerConnect with Chantale Bernatchez:LinkedIn: www.linkedin.com/in/chantale-bernatchez-22b09511CTMC website: www.ctmc.comSupport the show

The Domestiques are back off the Peaks high and straight into a massive week of racing. We cover Grafton to Inverell, the latest from the ProVelo Super League, Paris-Nice, Tirreno-Adriatico, Trofeo Binda, and a full preview of Milan-San Remo. The crew break down Finlay Walsh's huge win, Pat Eddy's response in Inverell, Isaac del Toro's rise, Van der Poel's form, Vingegaard's strange fashion choice in the freezing rain, and who could shake up the first Monument of the season. Plus, Rhino Keith gets a well-earned shout, Hollywood unpacks life after Peaks, and Tils cops questions about her date.

The crew finally unpack the much-hyped Post Peaks Challenge debrief. Tils, Hollywood and Marko relive the full chaos of the day, from freezing descents and fog on Hotham to missed groups, music failures, pain caves and the push for sub-8 glory. Spoiler alert: Marko, Tils and Hollywood DOMINATED. There's plenty of laughs, a few near-disasters, some very honest suffering, and a proper appreciation for what makes Peaks one of the most special days on the bike. They also touch on Strade Bianche, the ProVelo scene, and the big stories that came out of a huge weekend of racing.

Sarah Poland, MD, lead author of a recently published article in the journal ONCOLOGY titled Advances in Immunotherapy for Breast Cancer, highlighted key findings from her review in a conversation with CancerNetwork®.1 Throughout the discussion, she spoke about: Shifting Perspectives on Immunogenicity: Historically, breast cancer was considered a “cold,” poorly immunogenic tumor due to low tumor mutational burden (TMB) and few tumor-infiltrating lymphocytes (TILs). Poland highlighted how clinical research has shifted this perspective, particularly through the study of triple-negative breast cancer (TNBC), which often exhibits higher PD-L1 expression and immune infiltration.Key Clinical Milestones: The review highlighted foundational data that established immunotherapy as a standard of care: Early-Stage TNBC: The phase 3 KEYNOTE-522 trial (NCT03036488) established pembrolizumab (Keytruda) plus chemotherapy as a standard neoadjuvant treatment for stage II to III TNBC.2 Metastatic TNBC: The phase 3 KEYNOTE-355 trial (NCT02819518) demonstrated the benefit of pembrolizumab in PD-L1–positive metastatic disease.3 Managing Toxicity and Rechallenge: Poland addressed the feasibility of pembrolizumab rechallenge after an immune-related adverse effect (irAE), emphasizing that while possible, it requires a highly individualized approach based on the severity and timing of the initial toxicity.The Future Landscape: Beyond PD-1/PD-L1 inhibitors, the discussion covered emerging technologies that are poised to redefine treatment: Antibody-Drug Conjugates (ADCs): Exploration of novel combinations of ADCs with immunotherapy. Emerging Modalities: The potential role of bispecific antibodies and vaccine trials utilizing tumor antigens. Subtype Expansion: Emerging evidence supporting the efficacy of immunotherapy in hormone receptor–positive and HER2-positive subtypes, moving beyond the traditional focus on TNBC. Unmet Educational Needs: Poland emphasized the importance of resources that connect providers and patients, particularly in translating complex trial data into clinical practice and addressing patient concerns regarding the newest therapies and trials.Poland is from the Department of Medicine in the Section of Hematology/Oncology at The University of Chicago.References1.        Poland S, de Oliveira Andrade M, Nanda R. Advances in immunotherapy for breast cancer. Oncology (Williston Park). 2026;40(1):8-15. doi:10.46883/2026.259210612.        Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa19105493.        Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809

Praėjusią savaitę Aplinkos ministras Kastytis Žuromskas atleido už miškų politiką atsakingą viceministrą Edmundą Mačiežą, apkaltinęs jį bandymu stabdyti Miškų įstatymo procesą ir ryšiais su tuo suinteresuotais lobistais. Dėl to jis žada kreiptis į Vyriausiąją tarnybinės etikos komisiją (VTEK), o Seimo Antikorupcijos komisija dėl ministro pareiškimų pirmadienį šaukia neeilinį posėdį.Pats buvęs viceministras kaltinimus neigia ir sako buvęs „izoliuotas“ nuo ministerijos sprendimų.Dėl atstovavimo miško pramonės interesams ministras taip pat kaltina Aplinkos apsaugos komiteto narį, socialdemokratą Audrių Radvilavičių, kuris prieš tapdamas Seimo nariu yra buvęs Miško darbų rangovų asociacijos pirmininku. Šis taip pat su tuo nesutinka.Pernai Transparency International Lietuvos skyrius (TILS) atlikto tyrimą apie tai, kas siekia daryti įtaką Lietuvos miškų politikoje. Pasak autorių, praėjusios kadencijos metu šiame lauke veikė beveik 120 juridinių ir fizinių asmenų, bet tik devynių veikla buvo registruota oficialiose lobistinės veiklos deklaracijose.Aktyviausios šiame lauke buvo dvi interesų grupės: medienos pramonės atstovai ir aplinkosaugos interesams atstovaujantys asmenys bei organizacijos, kurios laikosi skirtingų strategijų.Tyrimo autoriai pažymi, kad nors pastaraisiais metais registruotų lobistų daugėja, informacija apie sprendimų priėmimą vis dar išsibarsčiusi, o dėl jos ribotumo kartais sunku suprasti, kieno interesai iš tikrųjų nugula į teisės aktus.Laidoje tyrimo išvadas komentuoja TILS, nevyriausybinių organizacijų ir medienos pramonės atstovai bei Aplinkos ministerijos ir VTEK specialistai.Aut. Vaida Pilibaitytė

„Transparency International“ tyrimas atskleidė, kad 54 politikai ir jų sutuoktiniai 2025 metais valdė 109 žiniasklaidos priemones.Fotografas, pusę pasaulio išmaišęs keliautojas Jonas Danielevičius kartu su bendraminte keliautoja Daine Rinkevičiūte kauniečius pakvietė į susitikimą Šančių bibliotekoje, kurioje papasakojo apie aplankytą Grenlandijos miestą Ilulisatą. Keliautojai plaukiojo tarp ledkalnių Disko įlankoje, lankėsi žvejų kaimelyje, ragavo ruonio mėsos ir turėjo trijų dienų žygį šunų kinkiniais per sniego bei ledo dykumas.Vyksta konkursas „LRT Opus talentas“, skirtas naujiems alternatyviosios muzikos atlikėjams bei grupėms.Mirė dizaineris Valentino Garavani.Ved. Donatas Šukelis

Former TDU winner Sarah Gigante joins Tils to break down the World Tour start list, the stages and who will take home the Orche Jersey! This is a deep dive into the first world tour race of the 2026 season!

Sometimes the best stories come wrapped in chaos. Fair warning. The internet and audio were very average on this one. The conversation still cuts through. From the elusive AIS development program to the heart of the WorldTour, Simon Clarke has lived just about every version of professional cycling. Astana. Orica GreenEDGE. Cannondale–Drapac. EF Pro Cycling. Qhubeka–NextHash. Israel–Premier Tech. Few riders can say they have seen the sport change from the inside as many times as he has. Marko, Tils and Hollywood unpack a career defined by resilience, adaptability, and surviving at the highest level for over a decade. Thank you for the support this year on The Domestiques. Ride safe. Check out the Trackhouse by Black Sheep Cycling and Focus Bikes at the TDU.

In this educational, refreshing, and beautifully hopeful episode, Wren, the creator of the Living Our Breast Lives Podcast, is joined by the incredible Metastatic Breast Cancer Thriver, Carolyn Leigh, the President of North Star Cancer Advocacy.In 2018, she was the third member of her family to be diagnosed with metastatic breast cancer, including her mother and uncle. After her metastatic diagnosis, she spent years studying the latest scientific understandings about the immune system and immunotherapies for cancer before launching North Star Cancer Advocacy in 2022 with the aim of providing information to the community and advocating for vast increases in NIH funding. The North Star Board of Directors and the MBC community recently raised $100k to further the research of combining Natural Killer cells (immune system cells) and one of the most promising breast cancer drugs in preclinical development, ErSO-TFPy.In this episode, join me as Carolyn breaks down: - How the inspirational Judy Perkins and TILs therapy reshaped her belief in what's possible- The moment she decided to found North Star- A simple breakdown of MHC I expression and why some immunotherapies succeed while others don't- A crash course in how immunotherapy actually works inside the body- Her mission to raise six figures for immunotherapy-driven clinical trials — and what real success would look like - How and where to access immunotherapy clinical trials- A raw conversation about allyship, momentum, and why the MBC movement can't depend solely on those living with the diseaseCarolyn isn't just an MBC advocate… she's a brilliant mind, a fierce researcher, the president of the North Star Cancer Research Foundation, and a woman determined to change the future of metastatic breast cancer!Living Our Breast Lives Information:Email: livingourbreastlivespodcast1@gmail.comInstagram: @livingourbreastlivesFounder: Wren MorrobelPersonal Instagram: @wren_morrPodcast Guest Speaker: Carolyn Leigh's Information:Email: NorthStarCancerAdvocacy@yahoo.comInstagram: @north.star.cancer.advocacy@north.star.cancer.researchFacebook: North Star Cancer Research FoundationWebsite: NorthStarCancerResearch.orgCRI Clinical Trial Finder:https://cri.careboxhealth.com/en-US/

This week on The Domestiques, Hollywood, Marko and Tils are joined by Australian WorldTour stalwart Chris Hamilton, the road captain, climber and all-round legend who's spent nearly a decade guiding leaders through grand tours, chaos stages and everything in between.We talk team tactics, life inside the peloton, the role of a modern road captain, the biggest changes, and what's next for the quietly brilliant Aussie who's earned huge respect across the WorldTour. Powered by Black Sheep Cycling.

A panel of oncology pharmacists discusses the role oflifileucel in metastatic melanoma and other considerations for using cellular therapy in solid tumors. Featuring Brooke Adams, PharmD, BCOP Natalie Brumwell, PharmD, BCOP Bryant A. Clemons, PharmD, BCOP In a special co-branded episode between Oncology On theGo, hosted by CancerNetwork®, and the American Society for Transplantation and Cellular Therapy (ASTCT)'s program, ASTCT Talks, for American Pharmacists Month, a panel of oncology pharmacists discussed optimal strategies for using cellular therapies as treatment for patients with solid tumors. The panel included Brooke Adams, PharmD, BCOP, a board-certified oncology pharmacist specializing in stem cell transplantation and cellular therapy at the Orlando Health Cancer Institute in Orlando, Florida; Natalie Brumwell, PharmD, BCOP, a board-certified oncology pharmacist specializing in cellular therapy at Memorial Sloan Kettering Cancer Center in New York, New York; and Bryant A. Clemons, PharmD, a board-certified oncology pharmacist specializing in hematology, blood and marrow transplantation, and cellular therapy at the University of Kentucky's Markey Cancer Center in Lexington, Kentucky. The discussion focused on the use of the first commercially available tumor-infiltrating lymphocytes (TILs) for patients with unresectable or metastatic melanoma, lifileucel (Amtagvi), which the FDA granted accelerated approval status to in February 2024.1 The panelists first reviewed supporting data from the phase 2 C-144-01 trial (NCT02360579), in which lifileucel demonstrated an objective response rate of 31.5% (95% CI, 21.1%-43.4%), and a median duration of response that was not reached (NR; 95% CI, 4.1 months-NR) at the time of the approval. Additionally, the group highlighted considerations for dosinginterleukin-2 (IL-2), including management of toxicities and when to hold or discontinue further doses. Following a thorough breakdown of the proper conditions for using lifileucel in melanoma, the panelists concluded by discussing how to build upon an “exciting time for cellular therapy in solid tumors.” As part of optimizing the dosing of lifileucel and other cellular therapies in these patient populations, the experts exchanged ideas on how practices can collaborate across institutions and departments to expand access to novel treatments while helping providers develop comfort in administering these agents. Reference FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed September 30, 2025. https://tinyurl.com/2kweca6x 

In a special co-branded episode between Oncology On the Go, hosted by CancerNetwork®, and the American Society for Transplantation and Cellular Therapy (ASTCT)'s program, ASTCT Talks, for American Pharmacists Month, a panel of oncology pharmacists discussed optimal strategies for using cellular therapies as treatment for patients with solid tumors. The panel included Brooke Adams, PharmD, BCOP, a board-certified oncology pharmacist specializing in stem cell transplantation and cellular therapy at the Orlando Health Cancer Institute in Orlando, Florida; Natalie Brumwell, PharmD, BCOP, a board-certified oncology pharmacist specializing in cellular therapy at Memorial Sloan Kettering Cancer Center in New York, New York; and Bryant A. Clemons, PharmD, a board-certified oncology pharmacist specializing in hematology, blood and marrow transplantation, and cellular therapy at the University of Kentucky's Markey Cancer Center in Lexington, Kentucky. The discussion focused on the use of the first commercially available tumor-infiltrating lymphocytes (TILs) for patients with unresectable or metastatic melanoma, lifileucel (Amtagvi), which the FDA granted accelerated approval status to in February 2024.1 The panelists first reviewed supporting data from the phase 2 C-144-01 trial (NCT02360579), in which lifileucel demonstrated an objective response rate of 31.5% (95% CI, 21.1%-43.4%), and a median duration of response that was not reached (NR; 95% CI, 4.1 months-NR) at the time of the approval. Additionally, the group highlighted considerations for dosing interleukin-2 (IL-2), including management of toxicities and when to hold or discontinue further doses.  Following a thorough breakdown of the proper conditions for using lifileucel in melanoma, the panelists concluded by discussing how to build upon an “exciting time for cellular therapy in solid tumors.” As part of optimizing the dosing of lifileucel and other cellular therapies in these patient populations, the experts exchanged ideas on how practices can collaborate across institutions and departments to expand access to novel treatments while helping providers develop comfort in administering these agents. Reference FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed September 30, 2025. https://tinyurl.com/2kweca6x

In today's episode of Backpacker Radio presented by The Trek brought to you by Topo Athletic, we are joined by Wesley Tils, known on trail as Megaman. Buckle in because oh boy does Megaman have an origin story. After growing up in the Mormon church, leaving the church to become a pro boxer, quitting boxing to give the church another shot and going on a missionary trip as his trial of faith, and ultimately leaving the church for good during this missionary trip, escaping onto the PCT with several church members essentially chasing him in pursuit, Megaman's path to thru-hiking was not exactly conventional. Since hitting the trails, Megaman hasn't stopped hiking, accumulating more than 15,000 miles across 18 long trails in 9 years. We learn about all his adventures, including hikes of the Maah Daah Hey Trail, River to River Trail, his self-made Mexico to Canada Trail called “the fourth crown route, and a goosebump inducing story about an aggressive encounter with a grizzly bear on the CDT. We wrap up the show with our one-minute elevator pitch to convince aliens that humanity deserves to survive, the triple crown of cable channels, share the news of Tara Dower's latest FKT, and deliver a five-minute one-minute gear review of a new free-standing tent from Hyperlite Mountain Gear. Topo Athletic: Use code “TREKFALL15” at topoathletic.com. Gossamer Gear: Use code "LT520" for 20% off LT5 Trekking Poles at gossamergear.com.  Ka'Chava: Get 10% off at kachava.com/backpacker. [divider] Interview with Wesley “Megaman” Tils Wesley's Instagram Wesley's Youtube Time stamps & Questions 00:05:35 - Reminders: Apply to blog for the Trek, take the 2025 AT Thru-Hiker survey, and listen to our episodes ad-free on Patreon! 00:07:30 - Introducing Megaman 00:08:20 - Tell us about your religious upbringing 00:11:30 - Do you ever experience anger while boxing? 00:12:40 - Why did you decide to leave the church? 00:15:25 - How did people react when you left the church? 00:18:02 - What was your mission like? 00:26:00 - How did your family feel about your decision? 00:27:30 - What did your kit look like for your first 200 miles on the PCT? 00:28:29 - How did you go from the PCT to the AT? 00:32:40 - What's your relationship with spirituality and religion now? 00:35:25 - What's your trail name origin story? 00:36:45 - Discussion about Megaman's time on the trail 00:38:30 - When did you know you'd keep thru-hiking? 00:40:20 - How was hiking through the Sierra in a high snow year? 00:45:00 - How was the CDT in 2018? 00:52:20 - Do you remember feeling an adrenaline rush? 00:54:35 - Tell us about the Black Hills/Great Plains Route 00:56:25 - You did the Triple O? 00:57:50 - Tell us about the Maah Daah Hey Trail 01:00:30 - Tell us about the evolution of your gear 01:02:45 - Tell us about your Fourth Crown Route 01:06:00 - What was the most difficult part of the route for you? 01:10:50 - What is the whole route like? 01:17:20 - Is it jarring to come back to society after the Fourth Crown Route? 01:18:10 - What's the coolest thing you've found as an archeologist? 01:20:21 - How do you make your hikes work financially? 01:23:00 - What is the River to River Trail like? 01:24:15 - Tell us about the Ruby Crest Trail 01:25:15 - Tell us about the Mojave-Sonoran Trail 01:26:00 - How was the Hayduke? 01:27:35 - How do you recommend thru-hiking cheaply? 01:29:28 - Trail Superlatives 01:32:20 - What's your hiking plan for 2026? 01:35:05 - What's your plan to document your hike? 01:37:30 - Peak Performance Question: What is your top performance-enhancing or backpacking hack? Segments Trek Propaganda: Tara Dower Smashes Overall Fastest Known Time on the Long Trail by Katie Jackson QOTD:  Aliens give you 60 seconds to convince them humanity deserves to be saved and you can only show them two items - what would they be? Triple Crown of cable channels One-Minute Gear Reviews Mail Bag  5 Star Review [divider] Check out our sound guy @my_boy_pauly/ and his coffee. Sign up for the Trek's newsletter Leave us a voicemail! Subscribe to this podcast on iTunes (and please leave us a review)!  Find us on Spotify, Stitcher, and Google Play. Support us on Patreon to get bonus content. Advertise on Backpacker Radio Follow The Trek, Chaunce, Badger, and Trail Correspondents on Instagram. Follow Backpacker Radio, The Trek and Chaunce on YouTube. Follow Backpacker Radio on Tik Tok.  Our theme song is Walking Slow by Animal Years. A super big thank you to our Chuck Norris Award winner(s) from Patreon: Alex and Misty with NavigatorsCrafting, Andrew, Austen McDaniel, Bill Jensen, Brad & Blair Thirteen Adventures, Bryan Alsop, Carl Houde, Christopher Marshburn, Clint Sitler, Coach from Marion Outdoors, Eric Casper, Erik Hofmann, Ethan Harwell, Gillian Daniels, Go Bills, Greg Knight, Greg Martin, Griffin Haywood, Hailey Buckingham, Matt from Gilbert, AZ, Patrick Cianciolo, Rebecca Brave, Rural Juror, Sawyer Products, SPAM, The Saint Louis Shaman, Timothy Hahn, Tracy ‘Trigger' Fawns A big thank you to our Cinnamon Connection Champions from Patreon: Bells, Benjy Lowry, Bonnie Ackerman, Brett Vandiver, Chris Pyle, David, David Neal, Dcnerdlet, Greg Floravanti “Lumberjack”, Jack Greene, Jeanie, Jeanne Latshaw, Luke Netjes, Merle Watkins, Peter, Quenten Jones, Ruth S, Salt Stain, and Spencer Hinson.

Tils (as she is generally known) grew up in country New South Wales chasing 3 older brothers around the paddock. So it's hardly surprising her first foray into sport was on the rugby league field.Sadly, she had to give up the sport in her early teens because once girls reached a certain age, they were no longer allowed to play against boys - and, of course - there was no girl's league at the time.Fast forward a few years and Tils discovered triathlons. And just 4 years later, she made the jump to the professional ranks - which, in hindsight, she now admits was too early.These days, Tils is an “amateur professional” cyclist who rides at a National level here in Australia with the #1 ranked women's cycling team in Australia - Specialised Women's Racing - including at the Tour Down Under in January, 2019.In this conversation, she shares:- growing up with male athletes as her role models (because there weren't any women with a profile in the sport),- why she says she became a professional triathlete too quickly,- how she 'hated' swimming yet deliberately set out to change her mindset,- her struggle with body image, burnout and the Imposter Complex in her triathlon career,- how she navigates her own "internal bullshit" these days,- her experience of 'Everesting' on the road to Everest Base Camp in Tibet as well as riding parts of the Silk Road through Kyrgyzstan and Kazakhstan, and- whether she's always been the type to 'say yes and figure it out later' (or whether that confidence has developed over time).

Send us a textAI Pathology & Genomics: A New Benchmark for Predicting Gene MutationsIf you still think visual quantification is “good enough” in pathology, think again. In this 27th episode of DigiPath Digest, I break down four transformative abstracts that show how AI is shifting our diagnostic landscape—from breast cancer segmentation to fibrosis assessment, and all the way to spatial immunology and the evolving immunoscore.If you're still relying on manual scoring, static staging systems, or single-marker immunohistochemistry, this episode will challenge you to look deeper—literally and algorithmically.

This week on The OncoAlert Weekly Round Up, we spotlight precision oncology in action with top-tier studies making headlines:

Dr. Diwakar Davar and Dr. Jason Luke discuss novel agents in melanoma and other promising new data in the field of immunotherapy that were presented at the 2025 ASCO Annual Meeting. TRANSCRIPT Dr. Diwakar Davar: Hello. My name is Diwakar Davar, and I am welcoming you to the ASCO Daily News Podcast. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. Today, I'm joined by my colleague and good friend, Dr. Jason Luke. Dr. Luke is a professor of medicine. He is also the associate director of clinical research and the director of the Phase 1 IDDC Program at the University of Pittsburgh's Hillman Cancer Center. He and I are going to be discussing some key advancements in melanoma and skin cancers that were presented at the 2025 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode.  Jason, it is great to have you back on the podcast. Dr. Jason Luke: Thanks again so much for the opportunity, and I'm really looking forward to it. Dr. Diwakar Davar: Perfect. So we will go ahead and start talking a little bit about a couple of key abstracts in both the drug development immunotherapy space and the melanoma space. The first couple of abstracts, the first two, will cover melanoma. So, the first is LBA9500, which was essentially the primary results of RELATIVITY-098. RELATIVITY-098 was a phase 3 trial that compared nivolumab plus relatlimab in a fixed-dose combination against nivolumab alone for the adjuvant treatment of resected high-risk disease. Jason, do you want to maybe give us a brief context of what this is? Dr. Jason Luke: Yeah, it's great, thanks. So as almost all listeners, of course, will be aware, the use of anti–PD-1 immunotherapies really revolutionized melanoma oncology over the last 10 to 15 years. And it has become a standard of care in the adjuvant setting as well. But to review, in patients with stage III melanoma, treatment can be targeted towards BRAF with BRAF and MEK combination therapy, where that's relevant, or anti–PD-1 with nivolumab or pembrolizumab are a standard of care. And more recently, we've had the development of neoadjuvant approaches for palpable stage III disease. And in that space, if patients present, based on two different studies, either pembrolizumab or nivolumab plus ipilimumab can be given prior to surgery for somewhere in the 6- to 9-week range. And so all of these therapies have improved time-to-event endpoints, such as relapse-free or event-free survival. It's worth noting, however, that despite those advances, we've had a couple different trials now that have actually failed in this adjuvant setting, most high profile being the CheckMate-915 study, which looked at nivolumab plus ipilimumab and unfortunately was a negative study. So, with RELATIVITY-047, which was the trial of nivolumab plus relatlimab that showed an improvement in progression-free survival for metastatic disease, there's a lot of interest, and we've been awaiting these data for a long time for RELATIVITY-098, which, of course, is this adjuvant trial of LAG-3 blockade with relatlimab plus nivolumab. Dr. Diwakar Davar: Great. So with that, let's briefly discuss the trial design and the results. So this was a randomized, phase 3, blinded study, so double-blinded, so neither the investigators knew what the patients were getting, nor did the patients know what they were getting. The treatment investigational arm was nivolumab plus relatlimab in the fixed-dose combination. So that's the nivolumab standard fixed dose with relatlimab that was FDA approved in RELATIVITY-047. And the control arm was nivolumab by itself. The duration of treatment was 1 year. The patient population consisted of resected high-risk stage III or IV patients. The primary endpoint was investigator-assessed RFS. Stage and geography were the standard stratifying factors, and they were included, and most of the criteria were balanced across both arms. What we know at this point is that the 2-year RFS rate was 64% and 62% in the nivolumab and nivolumab-combination arms, respectively. The 2-year DMFS rate was similarly equivalent: 76% with nivolumab monotherapy, 73% with the combination. And similar to what you had talked about with CheckMate 915, unfortunately, the addition of LAG-3 did not appear to improve the RFS or DMFS compared to control in this patient population. So, tell us a little bit about your take on this and what do you think might be the reasons why this trial was negative? Dr. Jason Luke: It's really unfortunate that we have this negative phase 3 trial. There had been a lot of hope that the combination of nivolumab with relatlimab would be a better tolerated combination that increased the efficacy. So in the metastatic setting, we do have 047, the study that demonstrated nivolumab plus relatlimab, but now we have this negative trial in the adjuvant setting. And so as to why exactly, I think is a complicated scenario. You know, when we look at the hazard ratios for relapse-free survival, the primary endpoint, as well as the secondary endpoints for distant metastasis-free survival, we see that the hazard ratio is approximately 1. So there's basically no difference. And that really suggests that relatlimab in this setting had no impact whatsoever on therapeutic outcomes in terms of efficacy. Now, it's worth noting that there was a biomarker subanalysis that was presented in conjunction with these data that looked at some immunophenotyping, both from circulating T cells, CD8 T cells, as well as from the tumor microenvironment from patients who were treated, both in the previous metastatic trial, the RELATIVITY-047 study, and now in this adjuvant study in the RELATIVITY-098 study. And to briefly summarize those, what was identified was that T cells in advanced melanoma seemed to have higher expression levels of LAG-3 relative to T cells that are circulating in patients that are in the adjuvant setting. In addition to that, there was a suggestion that the magnitude of increase is greater in the advanced setting versus adjuvant. And the overall summary of this is that the suggested rationale for why this was a negative trial may have been that the target of LAG-3 is not expressed as highly in the adjuvant setting as it is in the metastatic setting. And so while the data that were presented, I think, support this kind of an idea, I am a little bit cautious that this is actually the reason for why the trial was negative, however. I would say we're not really sure yet as to why the trial was negative, but the fact that the hazard ratios for the major endpoints were essentially 1 suggests that there was no impact whatsoever from relatlimab. And this really makes one wonder whether or not building on anti–PD-1 in the adjuvant setting is feasible because anti–PD-1 works so well. You would think that even if the levels of LAG-3 expression were slightly different, you would have seen a trend in one direction or another by adding a second drug, relatlimab, in this scenario. So overall, I think it's an unfortunate circumstance that the trial is negative. Clearly there's going to be no role for relatlimab in the adjuvant setting. I think this really makes one wonder about the utility of LAG-3 blockade and how powerful it really can be. I think it's probably worth pointing out there's another adjuvant trial ongoing now of a different PD-1 and LAG-3 combination, and that's cemiplimab plus fianlimab, a LAG-3 antibody that's being dosed from another trial sponsor at a much higher dose, and perhaps that may make some level of difference. But certainly, these are unfortunate results that will not advance the field beyond where we were at already. Dr. Diwakar Davar: And to your point about third-generation checkpoint factors that were negative, I guess it's probably worth noting that a trial that you were involved with, KeyVibe-010, that evaluated the PD-1 TIGIT co-formulation of vibostolimab, MK-4280A, was also, unfortunately, similarly negative. So, to your point, it's not clear that all these third-generation receptors are necessarily going to have the same impact in the adjuvant setting, even if they, you know, for example, like TIGIT, and they sometimes may not even have an effect at all in the advanced cancer setting. So, we'll see what the HARMONY phase 3 trial, that's the Regeneron cemiplimab/fianlimab versus pembrolizumab control with cemiplimab with fianlimab at two different doses, we'll see how that reads out. But certainly, as you've said, LAG-3 does not, unfortunately, appear to have an impact in the adjuvant setting. So let's move on to LBA9501. This is the primary analysis of EORTC-2139-MG or the Columbus-AD trial. This was a randomized trial of encorafenib and binimetinib, which we will abbreviate as enco-bini going forward, compared to placebo in high-risk stage II setting in melanoma in patients with BRAF V600E or K mutant disease. So Jason, you know, you happen to know one or two things about the resected stage II setting, so maybe contextualize the stage II setting for us based on the trials that you've led, KEYNOTE-716, as well as CheckMate-76K, set us up to talk about Columbus-AD. Dr. Jason Luke: Thanks for that introduction, and certainly stage II disease has been something I've worked a lot on. The rationale for that has been that building off of the activity of anti–PD-1 in metastatic melanoma and then seeing the activity in stage III, like we just talked about, it was a curious circumstance that dating back about 7 to 8 years ago, there was no availability to use anti–PD-1 for high-risk stage II patients, even though the risk of recurrence and death from melanoma in the context of stage IIB and IIC melanoma is in fact similar or actually higher than in stage IIIA or IIIB, where anti–PD-1 was approved. And in that context, a couple of different trials that you alluded to, the Keynote-716 study that I led, as well as the CheckMate 76K trial, evaluated pembrolizumab and nivolumab, respectively, showing an improvement in relapse-free and distant metastasis-free survival, and both of those agents have subsequently been approved for use in the adjuvant setting by the US FDA as well as the European Medicines Agency.  So bringing then to this abstract, throughout melanoma oncology, we've seen that the impact of anti–PD-1 immunotherapy versus BRAF and MEK-targeted therapy have had very similar outcomes on a sort of comparison basis, both in frontline metastatic and then in adjuvant setting. So it was a totally reasonable question to ask: Could we use adjuvant BRAF and MEK inhibitor therapy? And I think all of us expected the answer would be yes. As we get into the discussion of the trial, I think the unfortunate circumstance was that the timing of this clinical trial being delayed somewhat, unfortunately, made it very difficult to accrue the trial, and so we're going to have to try to read through the tea leaves sort of, based on only a partially complete data set. Dr. Diwakar Davar: So, in terms of the results, they wanted to enroll 815 patients, they only enrolled 110. The RFS and DMFS were marginally improved in the treatment arm but certainly not significantly, which is not surprising because the trial had only accrued 16% to 18% of its complete accrual. As such, we really can't abstract from the stage III COMBI-AD data to stage II patients. And certainly in this setting, one would argue that the primary treatment options certainly remain either anti–PD-1 monotherapy, either with pembrolizumab or nivolumab, based on 716 or 76K, or potentially active surveillance for the patients who are not inclined to get treated.  Can you tell us a little bit about how you foresee drug development going forward in this space because, you know, for example, with HARMONY, certainly IIC disease is a part of HARMONY. We will know at least a little bit about that in this space. So what do you think about the stage IIB/C patient population? Is this a patient population in which future combinations are going to be helpful, and how would you think about where we can go forward from here? Dr. Jason Luke: It is an unfortunate circumstance that this trial could not be accrued at the pace that was necessary. I think all of us believe that the results would have been positive if they'd been able to accrue the trial. In the preliminary data set that they did disclose of that 110 patients, you know, it's clear there is a difference at a, you know, a landmark at a year. They showed a 16% difference, and that would be in line with what has been seen in stage III. And so, you know, I think it's really kind of too bad. There's really going to be no regulatory approach for this consideration. So using BRAF and MEK inhibition in stage II is not going to be part of standard practice moving into the future. To your point, though, about where will the field go? I think what we're already realizing is that in the adjuvant setting, we're really overtreating the total population. And so beyond merely staging by AJCC criteria, we need to move to biomarker selection to help inform which patients truly need the treatment. And in that regard, I don't think we've crystallized together as a field as yet, but the kinds of things that people are thinking about are the integration of molecular biomarkers like ctDNA. When it's positive, it can be very helpful, but in melanoma, we found that, unfortunately, the rates are quite low, you know, in the 10% to 15% range in the adjuvant setting. So then another consideration would be factors in the primary tumor, such as gene expression profiling or other considerations.  And so I think the future of adjuvant clinical trials will be an integration of both the standard AJCC staging system as well as some kind of overlaid molecular biomarker that helps to enrich for a higher-risk population of patients because on a high level, when you abstract out, it's just clearly the case that we're rather substantially overtreating the totality of the population, especially given that in all of our adjuvant studies to date for anti–PD-1, we have not yet shown that there's an overall survival advantage. And so some are even arguing perhaps we should even reserve treatment until patients progress. I think that's a complicated subject, and standard of care at this point is to offer adjuvant therapy, but certainly a lot more to do because many patients, you know, unfortunately, still do progress and move on to metastatic disease. Dr. Diwakar Davar: Let's transition to Abstract 2508. So we're moving on from the melanoma to the novel immunotherapy abstracts. And this is a very, very, very fascinating drug. It's IMA203. So Abstract 2508 is a phase 1 clinical update of IMA203. IMA203 is an autologous TCR-T construct targeting PRAME in patients with heavily pretreated PD-1-refractory metastatic melanoma. So Jason, in the PD-1 and CTLA-4-refractory settings, treatment options are either autologous TIL, response rate, you know, ballpark 29% to 31%, oncolytic viral therapy, RP1 with nivolumab, ORR about 30-ish percent. So new options are needed. Can you tell us a little bit about IMA203? Perhaps tell us for the audience, what is the difference between a TCR-T and traditional autologous TIL? And a little bit about this drug, IMA203, and how it distinguishes itself from the competing TIL products in the landscape. Dr. Jason Luke: I'm extremely enthusiastic about IMA203. I think that it really has transformative potential based on these results and hopefully from the phase 3 trial that's open to accrual now. So, what is IMA203? We said it's a TCR-T cell product. So what that means is that T cells are removed from a patient, and then they can be transduced through various technologies, but inserted into those T cells, we can then add a T-cell receptor that's very specific to a single antigen, and in this case, it's PRAME. So that then is contrasted quite a bit from the TIL process, which includes a surgical resection of a tumor where T cells are removed, but they're not specific necessarily to the cancer, and they're grown up in the lab and then given to the patient. They're both adoptive cell transfer products, but they're very different. One is genetically modified, and the other one is not. And so the process for generating a TCR-T cell is that patients are required to have a new biomarker that some may not be familiar with, which is HLA profiling. So the T-cell receptor requires matching to the concomitant HLA for which the peptide is bound in. And so the classic one that is used in most oncology practices is A*02:01 because approximately 48% of Caucasians have A*02:01, and the frequency of HLA in other ethnicities starts to become highly variable. But in patients who are identified to have A*02:01 genotype, we can then remove blood via leukapheresis or an apheresis product, and then insert via lentiviral transduction this T-cell receptor targeting PRAME. Patients are then brought back to the hospital where they can receive lymphodepleting chemotherapy and then receive the reinfusion of the TCR-T cells. Again, in contrast with the TIL process, however, these T cells are extremely potent, and we do not need to give high-dose interleukin-2, which is administered in the context of TIL. Given that process, we have this clinical trial in front of us now, and at ASCO, the update was from the phase 1 study, which was looking at IMA203 in an efficacy population of melanoma patients who were refractory at checkpoint blockade and actually multiple lines of therapy. So here, there were 33 patients and a response rate of approximately 50% was observed in this population of patients, notably with a duration of response approximately a year in that treatment group. And I realize that these were heavily pretreated patients who had a range of very high-risk features. And approximately half the population had uveal melanoma, which people may be aware is a generally speaking more difficult-to-treat subtype of melanoma that metastasizes to the liver, which again has been a site of resistance to cancer immunotherapy. So these results are extremely promising. To summarize them from what I said, it's easier to make TCR-T cells because we can remove blood from the patient to transduce the T cells, and we don't have to put them through surgery. We can then infuse them, and based on these results, it looks like the response rate to IMA203 is a little bit more than double what we expect from lifileucel. And then, whereas with lifileucel or TILs, we have to give high-dose IL-2, here we do not have to give high-dose IL-2. And so that's pretty promising. And a clinical trial is ongoing now called the SUPREME phase 3 clinical trial, which is hoping to validate these results in a randomized global study. Dr. Diwakar Davar: Now, one thing that I wanted to go over with you, because you know this trial particularly well, is what you think of the likelihood of success, and then we'll talk a little bit about the trial design. But in your mind, do you think that this is a trial that has got a reasonable likelihood of success, maybe even a high likelihood of success? And maybe let's contextualize that to say an alternative trial, such as, for example, the TebeAM trial, which is essentially a T-cell bispecific targeting GP100. It's being compared against SOC, investigator's choice control, also in a similarly heavily pretreated patient population. Dr. Jason Luke: So both trials, I think, have a strong chance of success. They are very different kinds of agents. And so the CD3 bispecific that you referred to, tebentafusp, likely has an effect of delaying progression, which in patients with advanced disease could have a value that might manifest as overall survival. With TCR-T cells, by contrast, we see a very high response rate with some of the patients going into very durable long-term benefit. And so I do think that the SUPREME clinical trial has a very high chance of success. It will be the first clinical trial in solid tumor oncology randomizing patients to receive a cell therapy as compared with a standard of care. And within that standard of care control arm, TILs are allowed as a treatment. And so it will also be the first study that will compare TCR-T cells against TILs in a randomized phase 3. But going back to the data that we've seen in the phase 1 trial, what we observe is that the duration of response is really connected to the quality of the response, meaning if you have more than a 50% tumor shrinkage, those patients do very, very well. But even in patients who have less than 50% tumor shrinkage, the median progression-free survival right now is about 4.5 months. And again, as we think about trial design, standard of care options for patients who are in this situation are unfortunately very bad. And the progression-free survival in that population is probably more like 2 months. So this is a trial that has a very high likelihood of being positive because the possibility of long-term response is there, but even for patients who don't get a durable response, they're likely going to benefit more than they would have based on standard chemotherapy or retreatment with an anti–PD-1 agent. Dr. Diwakar Davar: Really, a very important trial to enroll, a trial that is first in many ways. First of a new generation of TCR-T agents, first trial to look at cell therapy in the control arm, a new standard of efficacy, but potentially also if this trial is successful, it will also be a new standard of trial conduct, a new kind of trial, of a set of trials that will be done in the second-line immunotherapy-refractory space. So let's pivot to the last trial that we were going to discuss, which was Abstract 2501. Abstract 2501 is a first-in-human phase 1/2 trial evaluating BNT142, which is the first-in-class mRNA-encoded bispecific targeting Claudin-6 and CD3 in patients with Claudin-positive tumors. We'll talk a little bit about this, but maybe let's start by talking a little bit about Claudin-6. So Claudin-6 is a very interesting new target. It's a target that's highly expressed in GI and ovarian tumors. There are a whole plethora of Claudin-6-targeting agents, including T-cell bispecifics and Claudin-6-directed CAR-Ts that are being developed. But BNT142 is novel. It's a novel lipid nanoparticle LNP-encapsulated mRNA. The mRNA encodes an anti–Claudin-6 CD3 bispecific termed RiboMAB-021. And it then is administered to the patient. The BNT142-encoding mRNA LNPs are taken up by the liver and translated into the active drug. So Jason, tell us a little bit about this agent. Why you think it's novel, if you think it's novel, and let's talk a little bit then about the results. Dr. Jason Luke: So I certainly think this is a novel agent, and I think this is just the first of what will probably become a new paradigm in oncology drug development. And so you alluded to this, but just to rehash it quickly, the drug is encoded as genetic information that's placed in the lipid nanoparticle and then is infused into the patient. And after the lipid nanoparticles are taken up by the liver, which is the most common place that LNPs are usually taken up, that genetic material in the mRNA starts to be translated into the actual protein, and that protein is the drug. So this is in vivo generation, so the patient is making their own drug inside their body. I think it's a really, really interesting approach. So for any drug that could be encoded as a genetic sequence, and in this case, it's a bispecific, as you mentioned, CD3-Claudin-6 engager, this could have a tremendous impact on how we think about pharmacology and novel drug development moving into the future in oncology. So I think it's an extremely interesting drug, the like of which we'll probably see only more moving forward. Dr. Diwakar Davar: Let's maybe briefly talk about the results. You know, the patient population was heavily pretreated, 65 or so patients, mostly ovarian cancer. Two-thirds of the patients were ovarian cancer, the rest were germ cell and lung cancer patients. But let's talk a little bit about the efficacy. The disease control rate was about 58% in the phase 1 population as a whole, but 75% in the ovarian patient population. Now tell us a little bit about the interesting things about the drug in terms of the pharmacokinetics, and also then maybe we can pivot to the clinical activity by dose level. Dr. Jason Luke: Well, so they did present in their presentation at ASCO a proportionality showing that as higher doses were administered, that greater amounts of the drug were being made inside the patient. And so that's an interesting observation, and it's an important one, right? Suggesting that the pharmacology that we classically think of by administering drugs by IV, for example, would still be in play. And that did translate into some level of efficacy, particularly at the higher dose levels. Now, the caveat that I'll make a note of is that disease control rate is an endpoint that I think we have to be careful about because what that really means is sometimes a little bit unclear. Sometimes patients have slowly growing tumors and so on and so forth. And the clinical relevance of disease control, if it doesn't last at least 6 months, I think is probably pretty questionable. So I think these are extremely interesting data, and there's some preliminary sense that getting the dose up is going to matter because the treatment responses were mostly observed at the highest dose levels. There's also a caveat, however, that across the field of CD3 bispecific molecules like this, there's been quite a bit of heterogeneity in terms of the response rate, with some of them only really generating stable disease responses and other ones having more robust responses. And so I think this is a really interesting initial foray into this space. My best understanding is this molecule is not moving forward further after this, but I think that this really does set it up to be able to chase after multiple different drug targets on a CD3 bispecific backbone, both in ovarian cancer, but then basically across all of oncology. Dr. Diwakar Davar: Perfect. This is a very new sort of exciting arena where we're going to be looking at, in many ways, these programmable constructs, whether we're looking at in vivo-generated, in this case, a T-cell bispecific, but we've also got newer drugs where we are essentially giving drugs where people are generating in vivo CAR T, and also potentially even in vivo TCR-T. But certainly lots of new excitement around this entire class of drugs. And so, what we'd like to do at this point in time is switch to essentially the fact that we've got a very, very exciting set of data at ASCO 2025. You've heard from Dr. Luke regarding the advances in both early drug development but also in advanced cutaneous melanoma. And Jason, as always, thank you so much for sharing your very valuable and great, fantastic insights with us on the ASCO Daily News Podcast. Dr. Jason Luke: Well, thanks again for the opportunity. Dr. Diwakar Davar: And thank you to our listeners for taking your time to listen today. You will find the links to the abstracts that we discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers:    Dr. Diwakar Davar    @diwakardavar    Dr. Jason Luke @jasonlukemd Follow ASCO on social media:     @ASCO on Twitter       ASCO on Bluesky   ASCO on Facebook       ASCO on LinkedIn   Disclosures:     Dr. Diwakar Davar:      Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences     Consulting or Advisory Role: Instil Bio, Vedanta Biosciences     Consulting or Advisory Role (Immediate family member): Shionogi     Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences     Research Funding (Inst.): Zucero Therapeutics     Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy     Dr. Jason Luke:     Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX     Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine     Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure     Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)     Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

When I found out that Django developer and Python Software Foundation chair Dawn Wages has a chapter in her upcoming Domain-Driven Django book called “Just Use Postgres”, I knew we had to get her on the show. In this episode of Talking Postgres with Claire Giordano, Dawn breaks down why so many Python and Django developers have such an affinity for Postgres. And we dive into the Djangonaut Space mentoring program (where contributors launch), learn why “free as in puppies” beats “free as in cake” for open source vibes, and dig into why Python is the second-best language for everything.Links mentioned in this episode:Project page: psycopgDocumentation: Psycopg 3 – PostgreSQL database adapter for PythonProject page: PostgreSQL open source projectGit repo: code for PostgreSQL.org websiteConference: PyCon US 2025, happening May 14-22 in PittsburghConference: PGConf.dev 2025 Schedule, happening May 13-16 in Montreal CanadaConference: Prague PostgreSQL Developer Day 2025 (P2D2) Schedule, which took place Jan 28-29Wikipedia page: Model-view-controller software design patternBook: Professional ASP.NET MVC 1.0, affectionately called “the four heads book”Podcast episode: Working in Public with Simon Willison & Marco SlotBlog: Simon Willison's TILs, aka Things I've learnedSimon Willison's Weblog: Here's how I use LLMs to help me write codeSimon Willison's Weblog: How I make annotated presentationsSurvey: Python Developers Survey 2023 ResultsPython Docs: What's new in Python 3.14Mentorship program: Djangonaut SpaceMentorship program: Media & Talks about Djangonaut SpacePodcast episode: Why mentor Postgres developers with Robert HaasSlides: PGConf EU 2024 talk by Claire Giordano about Contributions to Postgres, including maps showing how global the Postgres project isVideo of POSETTE 2024 talk by Paolo Melchiorre: Semantic search with Django, PostgreSQL, & pgvectorVideo of Citus Con 2023 talk: Maps with Django (and PostGIS), by Paolo MelchiorreVideo of Citus Con 2022 talk: Django with PostgreSQL superpowers, by Paolo MelchiorreConference: DjangoCon Africa 2025, happening August 11-15 in Tanzania Calendar invite: LIVE recording of Ep26 of Talking Postgres to happen on Wed Apr 02, 2025 with guest Bruce Momjian, to talk about Open Source Leadership 

BUFFALO, NY – March 12, 2025 – A new #editorial was #published in Oncotarget, Volume 16, on March 10, 2025, titled “COMETgazing – interesting insights, lessons for clinical practice and a call for more precision using the biomarkerSCOPE.” Dr. Mangesh A. Thorat, affiliated with Queen Mary University of London, Homerton University Hospital, and King's College London, discusses new findings suggesting that some women diagnosed with early-stage breast cancer may not need immediate surgery. The editorial is based on results from the COMET trial, which studied women with low- to intermediate-grade ductal carcinoma in situ (DCIS). The findings raise questions about the necessity of surgery and highlight the importance of more precise screening methods for DCIS, ensuring that only those who truly need treatment receive it. Breast cancer screening programs are designed to detect cancer early, but this editorial reinforces the concern that some detected cancers may never become a real threat. The COMET trial compared two strategies for treating breast cancer: standard treatment, which includes surgery and possible additional therapy, versus active monitoring, where patients are closely observed without immediate intervention. The results indicate that many of the invasive cancers diagnosed in the monitoring group were likely present from the start rather than developing from DCIS over time. Dr. Thorat points out that these invasive cancers were often slightly larger, but they did not appear to be aggressive. These findings challenge the assumption that immediate treatment is necessary for all cases of DCIS. Researchers estimate that at least half of the invasive breast cancers in this study either take years to progress or may never progress at all. “The planned long-term follow-up of the trial may shed more light on the median length of lead-time and the proportion of IBCs regressing as well as DCIS progression under different lead-time assumptions.” Current methods for evaluating DCIS rely heavily on histological grading, which has limitations. Dr. Thorat emphasizes the need for more precise tools to determine which DCIS cases require treatment. His previous research suggests that biomarkers, such as multi-clonal estrogen receptor (ER) expression and tumor-infiltrating lymphocytes (TILs), may help predict which DCIS cases are truly at risk of becoming invasive. The editorial also highlights that many women prefer to avoid surgery when possible. In a related study, only 52% of patients in the standard care group followed through with it, indicating that more individuals are willing to consider alternatives to surgery. This fact underscores the importance of developing accurate biomarkers to guide treatment decisions and ensure that patients receive appropriate care without unnecessary interventions. As researchers continue to follow patients from the COMET trial, they hope to learn more about how invasive breast cancers behave over time. Finally, Dr. Thorat encourages clinicians and scientists to rethink breast cancer treatment and develop better ways to identify which patients truly need surgery—and which do not. DOI - https://doi.org/10.18632/oncotarget.28698 Correspondence to - Mangesh A. Thorat - m.thorat@qmul.ac.uk To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. Ryan Augustin and Dr. Jason Luke discuss neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, promising new TIL therapy for advanced melanoma, and the emerging role of CD3 engagers in treatment strategies. TRANSCRIPT Dr. Ryan Augustin: Hello, I'm Dr. Ryan Augustin, your guest host of the ASCO Daily News Podcast today. I'm a medical oncology fellow at Mayo Clinic in Rochester, Minnesota. Joining me today is Dr. Jason Luke, an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Hillman Cancer Center. I had the privilege of working as a postdoc in Jason's translational bioinformatics lab, where we investigated mechanisms of resistance to immunotherapy in melanoma and other cancers.  Today, we'll be discussing 3 important topics, including neoadjuvant immunotherapy and the importance of multidisciplinary team coordination, the impact and practical considerations for incorporating TIL therapy into melanoma, and the current and future use of CD3 engagers in both uveal and cutaneous melanoma.  You'll find our full disclosures in the transcript of this episode.  Jason, it's great to have this opportunity to speak with you today. Dr. Jason Luke: Absolutely. Thanks, Ryan. It's great to see you. Dr. Ryan Augustin: So, to kick things off, Jason, we, of course, have seen tremendous advances in cancer immunotherapy, not only in metastatic disease but also the perioperative setting. Recent data have shown that the use of neoadjuvant therapy can provide not only critical prognostic information but can also help individualize post-resection treatment strategies and potentially even eliminate adjuvant therapy altogether in patients who achieve a pathologic, complete response. This signifies a conceptual shift in oncology with the goal of curing patients with immunotherapy. In triple-negative breast cancer, the KEYNOTE-522 regimen with pembrolizumab is standard of care. In non-small cell lung cancer, there are now four FDA approved chemo-IO regimens in both the neoadjuvant and perioperative settings. And, of course, in melanoma, starting with SWOG S1801 utilizing pembro mono therapy, and now with combined CTLA-4 PD-1 blockade based on results from the NADINA trial, neoadjuvant IO is the new standard of care in high-risk, resectable melanoma. It's important to highlight this because whereas other tumor types have more mature multidisciplinary care, for example, patients with breast cancer are reviewed by the whole team in every center, and every patient with lung cancer certainly benefits from multidisciplinary care conferences, that's not always the case with melanoma, given the relative frequency of cases compared to other tumor types.  Jason, would you say that we have now moved into an era where the integration of a multidisciplinary team and melanoma needs to be prioritized. And why is it important to have multidisciplinary team coordination from the onset of a patient's diagnosis? Dr. Jason Luke: Well, I think those are great questions, Ryan, and I think they really speak to the movement in our field and the great success that we've had integrating systemic therapy, particularly immunotherapy, into our treatment paradigms. And so, before answering your question directly, I would add even a little bit more color, which is to note that over the last few years, we've additionally seen the development of adjuvant therapy into stages of melanoma that, historically speaking, were considered low-risk, and medical oncologists might not even see the patient. To that, I'm speaking specifically about the stage 2B and 2C approvals for adjuvant anti-PD-1 with pembrolizumab or nivolumab. So this has been an emerging complication.  Classically, patients are diagnosed with melanoma by either their primary care doctor or a dermatologist. Again, classically, the next step was referral to a surgeon who had removed the primary lesion, with discussion around nodal evaluation as well. And that paradigm has really changed now, where I think integration of medical oncology input early on in the evaluation of the appropriate treatment plan for patients with melanoma is quite a pressing issue now, both because we have FDA approvals for therapeutics that can reduce risk of recurrence, and whether or not to pursue those makes a big difference to the patient for discussion early on.  And, moreover, the use of systemic therapies now, prior to surgery, of course, then, of course, requires the involvement of medical oncology. And just for an emphasis point on this, it's classically the case, for good reason, that surgeons complete their surgery and then feel confident to tell the patient, “Well, we got it all, and you're just in really good shape.” And while I understand where that's coming from, that often leaves aside the risk of recurrence. So you can have the most perfect surgery in the world and yet still be at very high risk of recurrence. And so it's commonly the case that we get patients referred to us after surgery who think they're just in totally good shape, quite surprised to find out that, in fact, they might have a 20% to 50% risk of recurrence. And so that's where this multidisciplinary integration for patient management really does make a big difference.  And so I would really emphasize the point you were making before, which is that we need multidisciplinary teams of med onc with derm, with surgery early on, to discuss “What are the treatment plans going to be for patients?” And that's true for neoadjuvant therapy, so, for palpable stage 3, where we might give checkpoint inhibitors or combinations before surgery. But it's true even in any reasonably high-risk melanoma, and I would argue in that state, anything more than stage 1 should be discussed as a group, because that communication strategy with the patient is so important from first principles, so that they have an expectation of what it's going to look like as they are followed out over time. And so we're emphasizing this point because I think it's mostly the case at most hospitals that there isn't a cutaneous oncology disease management meeting, and I think there needs to be.  It's important to point out that usually the surgeons that do this kind of surgery are actually either the GI surgeons who do colon cancer or the breast surgeons. And so, given that melanoma, it's not the most common kind of cancer, it could easily be integrated into the existing disease review groups to review these cases. And I think that's the point we really want to emphasize now. I think we're not going to belabor the data so much, but there are enormous advantages to either perioperative or adjuvant systemic therapy in melanoma. We're talking about risk reduction of more than 50%, 50-75% risk reduction. It's essential that we make sure we optimally offer that to patients. And, of course, patients will choose what they think is best for their care. But we need to message to them in a way that they can understand what the risks and benefits of those treatments are and then are well set up to understand what that treatment might look like and what their expectations would be out over time.  So I think this is a great art of medicine place to start. Instead of belaboring just the details of the trial to say, let's think about how we take care of our patients and how we communicate with them on first principles so that we can make the most out of the treatments that we do have available. Dr. Ryan Augustin: That's great, Jason. Very insightful points. Thank you.  So, shifting gears now, I'd also like to ask you a little bit about TIL therapy in melanoma. So our listeners will be aware that TIL is a promising new approach for treating advanced melanoma and leverages the power of a patient's cytotoxic T cells to attack cancer cells. While we've known about the potential of this therapy for some time, based on pioneering work at the NCI, this therapy is now FDA approved under the brand AMTAGVI (Lifileucel) from Iovance Biotherapeutics, making it the first cellular therapy to be approved for a solid tumor. Now, I know TIL therapy has been administered at your institution, Jason, for several years now, under trial status primarily for uveal melanoma using an in-house processing. But for many cancer centers, the only experience with cellular therapy has come under the domain of malignant hematology with CAR T administration. At our institution, for example, we have only recently started administering TIL therapy for melanoma, which has required a tremendous multidisciplinary effort among outpatient oncology, critical care, and an inpatient hematology service that has expertise in cytokine release syndrome.  Jason, where do you see TIL therapy fitting into the metastatic space? Which patients do you think are truly candidates for this intensive therapy? And what other practical or logistical considerations do you think we should keep in mind moving forward? Dr. Jason Luke: Well, thanks for raising this. I think the approval of lifileucel, which is the scientific name for the TIL product that's on the market now. It really is a shift, a landscape shift in oncology, and we're starting in melanoma again, as seems to be commonly the case in drug development. But it's really important to understand that this is a conceptually different kind of treatment, and therefore, it does require different considerations. Starting first with data and then actualization, maybe secondarily, when we see across the accelerated approval package that led to this being available, we quote patients that the response rate is likely in the range of 30%, maybe slightly lower than that, but a meaningful 25% to 30% response rate, and that most of those patients that do have response, it seems to be quite durable, meaning patients have been followed up to four years, and almost all the responders are still in response. And that's a really powerful thing to be able to tell a patient, particularly if the patient has already proceeded through multiple lines of prior standard therapy. So this is a very, very promising therapy.  Now, it is a complicated therapy as well. And so you highlighted that to do this, you have to have a tumor that's amenable for resection, a multidisciplinary team that has done a surgery to remove the tumor, sent it off to the company. They then need to process the TIL out of the tumor and then build them up into a personalized cell product, bring it back, you have to lympho-deplete the patient, re-introduce this TIL. So this is a process that, in the standard of care setting under best circumstances, takes roughly six weeks. So how to get that done in a timely fashion, I think, is evolving within our paradigms. But I think it is very important for people who practice in settings where this isn't already available to realize that referring patients for this should be a strong consideration. And thinking about how you could build your multidisciplinary team in a way to be able to facilitate this process, I think is going to be important, because this concept of TIL is relevant to other solid tumors as well. It's not approved yet in others, but we kind of assume eventually it probably will be. And so I think, thinking through this, how could it work, how do you refer patients is very important.  Now, coming back to the science, who should we treat with this? Well, of course, it's now an air quotes “standard of care option”, so really it ought to be available to anybody. I will note that currently, the capacity across the country to make these products is not really adequate to treat all the patients that we'd want. But who would we optimally want to treat, of course, would be people who have retained a good performance status after first line therapy, people who have tumors that are easily removable and who have not manifested a really rapid disease progression course, because then, of course, that six-week timeline probably doesn't make sense. The other really interesting data point out of the clinical trials so far is it has looked like the patients who got the least amount of benefit from anti-PD-1 immunotherapy, in other words, who progressed immediately without any kind of sustained response, those patients seem to have the best response to TILs, and that's actually sort of a great biomarker. So, this drug works the best for the population of patients where checkpoint inhibitors were not effective. And so as you think about who those patients might be in your practice, as you're listening, I think prioritizing it for primary progression on anti PD-1, again and giving it ahead thought about how would you get the patient through this process or referred to this process very quickly is really important because that lag time is a problem. Patients who have melanoma tend to progress reasonably quickly, and six weeks can be a long time in melanoma land. So, thinking ahead and building those processes is going to be important moving into the future Dr. Ryan Augustin: Definitely appreciate those practical considerations. Jason, thank you.  Moving on to our final topic, I was hoping to discuss the use of immune cell engagers in melanoma. So, similar to CAR T therapy, bispecific T-cell engagers, or BiTEs, as they're commonly known, are standard of care in refractory myeloma and lymphoma. But these antibodies engaging CD-3 on T cells and a tumor specific antigen on cancer cells are relatively new in the solid tumor space. Tarlatamab, which is a DLL-3 and CD-3 bispecific antibody, was recently approved in refractory small cell lung cancer, and, of course, tebentafusp, an HLA-directed CD-3 T cell engager was approved in uveal melanoma in 2022. Both T and NK cell engaging therapies are now offering hope in cancers where there has historically been little to offer. However, similar to our discussion with TIL therapy, bispecifics can lead to CRS and neurotoxicity, which require considerable logistical support and care coordination.  Jason, I was wondering if you could briefly discuss the current landscape of immune cell engagers in melanoma and how soon we may see these therapies enter the treatment paradigm for cutaneous disease. Dr. Jason Luke: I think it is an exciting, novel treatment strategy that I think we will only see emerge more and more. You alluded to the approval of tebentafusp in uveal melanoma, and those trials were, over the course of a decade, where those of us in solid tumor land learned how to manage cytokine release syndrome or the impact of these C3 bispecifics, in a way that we weren't used to. And what I'll caution people is that CRS, as this term, it sounds very scary because people have heard of patients that, of course, had difficult outcomes and hematological malignancies, but it's a spectrum of side effects. And so, when we think about tebentafusp, which is the approved molecule, really what we see is a lot of rash because GP100, the other tumor antigen target, is in the skin. So, patients get a rash, and then people do get fevers, but it's pretty rare to get more than that. So really what you have to have is the capacity to monitor patients for 12 hours, but it's really not more scary than that. So it really just requires treating a few people to kind of get used to these kinds of symptoms, because they're not the full-on ICU level CRS that we see with, say, CAR T-cells.  But where is the field going? Well, there's a second CD3 bispecific called brenetafusp that targets the molecule PRAME, that's in a phase 3 clinical trial now for frontline cutaneous melanoma. And tebentafusp is also being evaluated in cutaneous melanoma for refractory disease. So, it's very possible that these could be very commonly used for cutaneous melanoma, moving into, say, a two-to-four-year time horizon. And so therefore, getting used to what are these side effects, how do you manage them in an ambulatory practice for solid tumor, etc., is going to be something everyone's going to have to learn how to deal with, but I don't think it should be something that people should be afraid of.  One thing that we've seen with these molecules so far is that their kinetics of treatment effect do look slightly different than what we see with more classic oncology therapies. These drugs have a long-term benefit but doesn't always manifest as disease regression. So, we commonly see patients will have stable disease, meaning their tumor stops growing, but we don't see that it shrank a lot, but that can turn into a very meaningful long-term benefit. So that's something that we're also, as a community, going to have to get used to. It may not be the case we see tumors shrink dramatically upfront, but rather we can actually follow people with good quality- of-life over a longer period of time.  Where is the field going? You mentioned tarlatamab in small cell lung cancer, and I think we're only going to see more of these as appropriate tumor antigens are identified in different tumors. And then the other piece is these CD3 engagers generally rely upon some kind of engagement with a T cell, whether CD3 engagers, and so they can be TCR or T-cell receptor-based therapies, although they can be also SCFV-based. But that then requires new biomarkers, because TCR therapy requires HLA restriction. So, understanding that now we're going to need to profile patients based on their germline in addition to the genomics of the tumor. And those two things are separate. But I would argue at this point, basically everybody with cutaneous melanoma should be being profiled for HLA-A(*)0201, which is the major T-cell receptor HLA haplotype that we would be looking for, because whether or not you can get access immediately to tebentafusp, but therefore clinical trials will become more and more important.  Finally, in that T-cell receptor vein, there are also T cell receptor-transduced T cells, which are also becoming of relevance in the oncology community and people listening will be aware in synovial sarcoma of the first approval for a TCR-transduced T cell with afamitresgene autoleucel. And in melanoma, we similarly have TCR-transduced T cells that are coming forward in clinical trials into phase 3, the IMA203 PRAME-directed molecule particularly. And leveraging our prior conversation about TILs, we're going to have more and more cellular based therapies coming forward, which is going to make it important to understand what are the biomarkers that go with those, what are the side effect profiles of these, and how do you build your practice in a way that you can optimally get your patients access to all of these different treatments, because it will become more logistically complicated, kind of as more of these therapies come online over the next, like we said, two to four years kind of time horizon. So, it's very exciting, but there is more to do, both logistically and scientifically. Dr. Ryan Augustin: That's excellent. Thanks, Jason, and thank you so much for sharing your great insight with us today on the ASCO Daily News Podcast. Dr. Jason Luke: Thanks so much for the opportunity. Dr. Ryan Augustin: And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode, and you can follow Dr. Luke on X, formerly known as Twitter, @jasonlukemd. And you can find me, @RyanAugustinMD. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers: @ryanaugustinmd Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures: Dr. Ryan Augustin: No relationships to disclose Dr. Jason Luke: Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Dr. Allison Zibelli and Dr. Erika Hamilton discuss the results of the DESTINY-Breast06 trial in HR+, HER2-low and HER2-ultralow metastatic breast cancer and the A-BRAVE trial in early triple-negative breast cancer, the results of which were both presented at the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Allison Zibelli: Hello, I'm Dr. Allison Zibelli, your guest host of the ASCO Daily News Podcast. I'm an associate professor of medicine and breast medical oncologist at the Sidney Kimmel Cancer Center of Jefferson Health in Philadelphia. My guest today is Dr. Erika Hamilton, a medical oncologist and director of breast cancer research at the Sarah Cannon Research Institute. We'll be discussing the DESTINY-Breast06 trial, which showed a progression-free advantage with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) compared to chemotherapy in hormone receptor-positive HER2-low or HER2-ultralow metastatic breast cancer. We'll address the implications of this study for the community, including the importance of expanding pathology assessments to include all established subgroups with HER2 expression, and the promise of expanding eligibility for antibody-drug conjugates. We'll also highlight advances in triple-negative breast cancer, focusing on the A-BRAVE trial, the first study reporting data on an immune checkpoint inhibitor avelumab in patients with triple-negative breast cancer with invasive residual disease after neoadjuvant chemotherapy.  Our full disclosures are available in the transcript of this episode.  Erika, it's great to have you on the podcast today. Dr. Erika Hamilton: Thanks so much, Allison. Happy to join. Dr. Allison Zibelli: Antibody-drug conjugates are rapidly changing the treatment landscape in breast cancer. The data from the DESTINY-Breast06 trial suggests that trastuzumab deruxtecan may become a preferred first-line treatment option for most patients with HER2-low or HER2-ultralow metastatic breast cancer after progression on endocrine therapy. First, could you remind our listeners, what's the definition of HER2-ultralow and what were the findings of this trial? Dr. Erika Hamilton: Yeah, those are fantastic questions. Ultralow really has never been talked about before. Ultralow is part of a subset of the IHC zeros. So it's those patients that have HER2-tumor staining that's less than 10% and incomplete but isn't absolutely zero. It's even below that +1 or +2 IHC that we have classified as HER2-low. Now, I think what's important to remember about D-B06, if you recall, D-B04 (DESTINY-Breast04) was our trial looking at HER2-low, is that D-B06 now included HER2-low as well as this HER2-ultralow category that you asked about. And it also moved trastuzumab deruxtecan up into the frontline. If you recall, D-B04 was after 1 line of cytotoxic therapy. So now this is really after exhausting endocrine therapy before patients have received other chemotherapy. And what we saw was an improvement in progression-free survival that was pretty significant: 13.2 months versus 8.1 months, it was a hazard ratio of 0.62. And you can ask yourself, “well, was it mainly those HER2-low patients that kind of drove that benefit? What about the ultralow category?” And when we look at ultralow, it was no different: 13.2 months versus 8.3 months, hazard ratio, again, highly significant. So I think it's really encouraging data and gives us some information about using this drug earlier for our patients with hormone receptor-positive but HER2-negative disease.  Dr. Allison Zibelli: I thought this study was really interesting because it's a patient population that I find very difficult to treat, the hormone receptor-positive metastatic patient that's not responding to endocrine therapy anymore. But it's important to mention that T-DXd resulted in more serious toxicities compared to traditional chemotherapy in this study. So how do you choose which patients to offer this to? Dr. Erika Hamilton: Yeah, those are both great points. So you're right, this is after endocrine therapy. And in fact, about 85% of these patients had received at least 2 prior lines of endocrine therapy. So I have some people kind of asking, “Well, if endocrine therapy really isn't benefiting everyone in the second-line setting post-CDK, should we just move to the ADCs?” And, no, probably we should really make sure that we're exhausting endocrine therapies for those patients that are going to benefit. And once we determine somebody has endocrine-resistant disease, that's when we would think about switching. In terms of the side effects, I think you're right. It's mainly ILD that's probably the more serious side effect that we worry about a little bit with trastuzumab deruxtecan. The good news is, through multiple trials, we've gotten a little bit better at managing this. We've pretty much all but eliminated any fatal cases of ILD, definitely less than 1% now. ILD rates, depending on what study you look for, kind of ranges in that 10% to 15% range. Any grade ILD on D-B06 was 11.3%. So really kind of making sure that we look for ILD at scans, making sure that patients are educated to tell us about any new pulmonary symptoms: cough, exertional dyspnea, shortness of breath at rest, etc. But I think the most common side effects that we really deal with on a daily basis with trastuzumab deruxtecan, luckily, is nausea, which we've gotten better at managing with the 2- or 3-drug antiemetic regimen, and probably a little bit of fatigue as well. Dr. Allison Zibelli: Thank you. So, I think for most people in the community, the sticking point here will be expanding pathology assessments to include all of the subgroups, including the ultralow. Most patients in the community are not testing for HER2-low and HER2-ultralow now. Dr. Erika Hamilton: Historically, we kind of all did HER2 IHC, right? And then as FISH became available, there were a lot of institutions that moved to FISH and maybe didn't have IHC anymore. And now, at least in my institution, we do both. But I think it's a very important point that you made that IHC was really designed to pick out those patients that have HER2-high, the 3 pluses or the FISH amplified cases. It was not to tell the difference between a 1+ or a 2+ or a 0 that's not quite a 0 and a 1+. So I think you're right. I think this is tough. I probably have a little bit more of an interesting take on this than some people will. But data from ASCO, not this year but in 2023, there was actually a pretty eloquent study presented where they looked at serial biopsies in patients, and essentially, if you got up to 4 or 5 biopsies, you were guaranteed to have a HER2-low result. Now, this didn't even include ultralow, which is even easier. If we know we include ultralow, we're really talking about probably 85% to 90% of our patients now that have some HER2 expression. But if we biopsy enough, we're guaranteed to get a HER2 low.  And so I think the question really is, if we know IHC wasn't really designed to pick out these ultralows, and we know kind of greater than 90% of patients are going to have some expression, did we kind of develop this drug a little bit backwards? Because we thought we understood HER2, and the reality is this drug is a little bit more like a sacituzumab govitecan, where we don't test for the TROP2. Should we really be kind of serial biopsying these patients or should maybe most patients have access to at least trying this drug?  Dr. Allison Zibelli: So I don't think that most of my patients will really be happy to sign up for serial biopsies. Dr. Erika Hamilton: Agreed. Dr. Allison Zibelli: Do we have any emerging technologies for detecting low levels of HER2? You talked about how the IHC test isn't really designed to detect low levels of HER2. Do you think newer detection techniques such as immunofluorescence will make a difference, or will we have liquid biopsy testing for this? Dr. Erika Hamilton: Yeah, I think liquid biopsy may be a little bit hard, just because some of those circulating tumor cells are more of a mesenchymal-type phenotype and don't necessarily express all of the same receptors. Normally, if they're cytokeratin-positive, they do, but certainly there is a lot out there looking at more sensitive measures. You mentioned immunofluorescence, there are some even more quantitative measures looking at lower levels of HER2. I definitely think there will be. I guess, ultimately, with even the IHC zeros that are the less than 10% incomplete staining, having a PFS that was absolutely no different than the HER2 low, I guess the question is, how low can we really go? We know that even the IHC zeros doesn't mean that there's no HER2 expression on the cell surface. It just means that maybe there's a couple of thousand as opposed to 10,000 or 100,000 copies of HER2. And so it really appears that perhaps this drug really is wedded to having a lot of HER2 expression. So ultimately, I wonder how much we're going to have to use those tests, especially with what we know about tumor heterogeneity. We know that if we biopsy 1 lesion in the liver, biopsy a lymph node, or even another lesion in the liver, that the HER2 results can have some heterogeneity. And so ultimately, my guess is that most people have some HER2 expression on their breast cancer cells. Dr. Allison Zibelli: So maybe we're going to be using this for everybody in the future. Dr. Erika Hamilton: It certainly seems like we keep peeling back the onion and including more and more patients into the category that are eligible to receive this. I agree. Dr. Allison Zibelli: Let's move on to triple-negative breast cancer, namely the A-BRAVE trial. This was an interesting trial for patients that did not get neoadjuvant immunotherapy and testing 2 groups. The first group was those with residual disease after neoadjuvant conventional chemotherapy. The second group was people with high-risk disease identified upfront that had upfront surgery. The study found that adjuvant avelumab did not improve disease-free survival versus observation, which was the study's primary endpoint. But interestingly, there was a significant improvement in 3-year overall survival and distant disease-free survival. Can you give us your thoughts on that? Dr. Erika Hamilton: Yeah, I think this study was really interesting. Right now, the standard for our patients with larger or node-positive triple-negative cancers is KEYNOTE-522. It's a pretty tough regimen. It's kind of 2 sequential uses of 2 chemotherapies, so 4 chemotherapy agents total with pembrolizumab. But you're right, this study looked at those that had residual disease after neoadjuvant that didn't include immunotherapy, or those patients that didn't get neoadjuvant therapy, went to surgery, and then were receiving chemotherapy on the back end. I'm going to give you the numbers, because you're right. The 3-year disease-free survival rates were not statistically significant. It was 68.3% among those that had avelumab, 63.2% with those that had observation only. So the difference was 5.1% in favor of avelumab, but it wasn't statistically significant. A p value of 0.1, essentially. But when we looked at the 3-year overall survival rates, we saw the same pattern, those patients with the avelumab doing better, but it was 84.8% overall survival and not, unfortunately, dying, versus 76.3%. So the magnitude of benefit there was 8.5%, so about 3% higher than we saw for disease-free survival, and this was statistically significant.  So is this going to change practice for most patients? I probably don't think so. I think for our patients that have larger tumors that's recognized upfront or have node positivity, we're probably going to want to use neoadjuvant chemo. Being able to get a PCR is very prognostic for our patients and enables us to offer things on the back end, such as PARP inhibitors or further chemotherapy of a different type of chemotherapy. But for our patients that go to surgery and maybe the extent of their disease just isn't recognized initially, this could be an option. Dr. Allison Zibelli: I agree. I think this will be a really useful regimen for patients where we get the surprise lymph node that we weren't expecting, or somebody who comes to us, maybe without seeing the medical oncologist, who got upfront surgery. So I thought this was really interesting. What kind of translational studies do you think we're going to do to try and understand which patients would benefit from avelumab? Dr. Erika Hamilton: Yeah, I think that's a great question, and honestly, it's a question that we haven't really answered in the neoadjuvant setting either. Immunotherapy in breast cancer is just a little bit different than it is in some other diseases. We have a benefit for those patients that are PD-L1 positive in the first line. We really haven't seen benefit for metastatic outside of first line. And then in neoadjuvant, it was among all comers. We don't have to test for PD-L1. And now we have this avelumab data from A-BRAVE. I think the question is, is there's probably a subset of patients that are really getting benefit and a subset that aren't. And I don't know that PD-L1 testing is the right test. We know a lot of people are looking at TILs, so kind of lymphocytes that are infiltrating the tumor, a variety of other kind of immunologic markers. But my guess is that eventually we're going to get smart enough to tease out who actually needs the immunotherapy versus who isn't going to benefit. But we're not quite there yet. Dr. Allison Zibelli: Thank you, Erika, for sharing your valuable insights with us on the ASCO Daily News Podcast today. Dr. Erika Hamilton: Thanks so much for having me.  Dr. Allison Zibelli: And thank you to our listeners for joining us. You'll find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you like this podcast and you value our insights, please take a moment to rate, review, and subscribe wherever you get your podcasts. It really helps other people to find us. So thank you very much for listening today.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today's speakers:  Dr. Allison Zibelli Dr. Erika Hamilton @ErikaHamilton9   Follow ASCO on social media:  @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures: Dr. Allison Zibelli:  None Disclosed   Dr. Erika Hamilton: Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson   Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics

Hvorfor OL-fotball for herrer ikke er helt rått, hva Danmarks rikeste fotballspiller skal bruke penger på og litt om TILs motstander i Serieligaen, Kilmarnock. Og selvsagt : hva er det beste navnet i årets Serieliga?Kast dere med i FPL-ligaen vår, med kode: k6eaej Hosted on Acast. See acast.com/privacy for more information.

We love to hear from our listeners. Send us a message.KSQ Therapeutics' CSO, Micah Benson, Ph.D., joins Erin Harris to discuss how Tumor-Infiltrating Lymphocytes (TILs) as a treatment modality have the potential to treat a variety of solid tumor types. Benson explains KSQ's Phase 1/2 clinical study, KSQ-001EX, which consists of TILs in which the SOCS1 gene is inactivated by CRISPR/Cas9 gene editing. In addition to solid tumors, Benson also addresses the therapeutic potential for autoimmune disease.

Breast cancer immunotherapy has shown promise, but its clinical efficacy remains limited, especially for hormone receptor positive (HR+)/HER2-negative breast cancer. While immune checkpoint inhibitors combined with chemotherapy have benefitted some early-stage and metastatic triple-negative breast cancer patients, HR+/HER2-negative cases have seen fewer improvements. Recent neoadjuvant trials indicate that early-stage HR+/HER2-negative breast cancers might respond better to immunotherapy strategies that amplify tumor-infiltrating lymphocytes (TILs) through dual PD-(L)1/CTLA-4 checkpoint inhibition before surgery and chemotherapy. This approach could enhance the immune response in the tumor microenvironment and improve outcomes for this challenging breast cancer subtype. Increased TILs are associated with improved neoadjuvant chemotherapy (NACT) responses across breast cancer subtypes. Recently, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women's Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School hypothesized that amplifying TILs via dual checkpoint blockade would enhance the response to subsequent NACT in breast tumors. Full blog - https://www.oncotarget.org/2024/06/20/impact-of-dual-immunotherapies-before-surgery-in-hr-her2-negative-breast-cancer/ Paper DOI -https://doi.org/10.18632/oncotarget.28567 Correspondence to - Haven R. Garber - hrgarber@mdanderson.org Video short - https://www.youtube.com/watch?v=PHpndZJHB_c Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28567 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, breast cancer, ER positive, immunotherapy, neoadjuvant chemotherapy, tumor microenvironment About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Dr. John Sweetenham shares highlights from Day 4 of the 2024 ASCO Annual Meeting, including exciting new data from the IMROZ trial in multiple myeloma, adjuvant therapy for triple-negative breast cancer in A-BRAVE, and the front-line treatment of advanced renal cell carcinoma in JAVELIN Renal-101. TRANSCRIPT Dr. John Sweetenham: I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my top takeaways on selected abstracts from Day 4 of the 2024 ASCO Annual Meeting.   Today's selection features 3 randomized prospective trials in the first-line treatment of multiple myeloma, adjuvant therapy for triple negative breast cancer, and the frontline treatment of advanced renal cell carcinoma, all of which provide important new data.   My full disclosures are available in the transcript of this episode. The first of today's abstracts is number 7500. This abstract, presented by Dr. Thierry Facon from the Department of Hematology at the University of Lille in France, describes the results of the IMROZ study. This was a multicenter phase 3 study comparing a current standard first-line regimen for transplant ineligible patients with myeloma VRd with the same combination plus an additional agent, isatuximab.  The combination of bortezomib, lenalidomide and dexamethasone, known as VRd, is currently a standard first-line regimen for patients with multiple myeloma, both transplant eligible and ineligible. Previous phase 3 studies have shown that the addition of an anti-CD38 antibody to triplet regimens improves outcomes in newly diagnosed patients. Based on early phase clinical trial data showing promising response rates with isatuximab, the IMROZ study was conducted to compare isatuximab VRd with VRd alone in patients who were either ineligible for transplant or had no immediate indication for transplant. IMROZ was a global study conducted in 21 countries that involved 446 patients randomly assigned 3:2 to induction therapy with Isa-VRd followed by continuous Isa-Rd or induction therapy with VRd followed by Rd alone. The rate of complete response or better was approximately 75% with Isa-VRd compared with 64% with VRd alone. Very good partial response or better was achieved in 89% of patients with Isa-VRd, compared with around 83% of those with VRd alone. With a median follow-up at 5 years, Isa-VRd followed by Isa-Rd had reduced the risk of progression or death by 40.4% compared with VRd alone. The 60-month progression-free survival rate was 63% for Isa-VRd compared with around 45% with VRd alone, and the progression-free survival benefit was maintained in most of the analyzed subgroups. Minimal residual disease negativity was also measured in this study in both the intent to treat population and those patients who achieved a complete response. For example, in the intent to treat population, the MRD negative rate was 58% with Isa-VRd compared with around 43% with VRd alone. There were also higher rates of sustained MRD negativity for 12 months or longer among patients assigned to Isa-VRd compared with VRd alone, reflecting deeper responses in the Isa-VRd arm. Although overall survival data is still immature, data from an interim analysis showed a favorable trend in the Isa-VRd arm with 22.4% risk reduction compared with VRd alone. There was little additional toxicity from the inclusion of isatuximab with the VRd regimen and the quality-of-life data were comparable and stable in both arms of the study. The investigators concluded that although overall survival data are immature, there is a trend in favor of Isa-VRd and this, combined with the favorable response, toxicity and progression-free survival data, establish isatuximab VRd as a potential new standard of care for newly diagnosed multiple myeloma patients not eligible for transplant. There was some discussion regarding the potential use of this regimen in patients over 80 years of age since the upper age limit was capped in IMROZ at 80 years. Although there are concerns for tolerance of the 4-drug regimen in the older patient group, it seems likely that this will be adopted, especially for those with good performance status and without major comorbidities.   Next up is LBA500. This abstract reports results of the A-BRAVE trial. This trial, presented by Dr. Pier Franco Conte from the University of Padova, Italy, was a phase 3 randomized trial to assess the efficacy of the immune checkpoint inhibitor avelumab in 2 groups of patients: those with early triple negative breast cancer, with residual disease after neoadjuvant chemotherapy; and those at high risk after primary surgery and adjuvant chemotherapy. As Dr. Conte explained in the introduction to this trial, there is a fairly compelling rationale for the use of checkpoint inhibitors in triple negative breast cancer. The disease has been shown to be more immunogenic than the other breast cancer types with immune biomarkers such as TILs and PDL-1 expression associated with better prognosis, added to which, data in metastatic breast cancer show a correlation between PDL-1 expression and checkpoint inhibitor response. In the A-BRAVE study, 477 high risk patients who had completed local, regional, and systemic treatment with curative intent were stratified according to adjuvant or post neoadjuvant status and randomized 1:1 to receive avelumab at 2-week intervals for 52 weeks or to observation only. Results of the study showed a non-statistically significant improvement in three-year disease-free survival in the overall intent to treat population at 5.1% and in the post neoadjuvant patients at 6.2%. Overall survival was a secondary endpoint in this trial. The results show a significant improvement in overall survival of 8.1% in the intent-to-treat population and a very similar improvement in the post-neoadjuvant patients. The authors reported good tolerance of avelumab, although in total almost 30% discontinued treatment at some point. In their conclusion, the investigators state that the 34% reduction in the risk of death suggests a potential role for avelumab in early triple negative breast cancer patients at high risk after primary surgery or with invasive disease after neoadjuvant chemotherapy. Correlative studies are planned on tumor plasma and feces in this study. These are interesting and somewhat tantalizing results, suggesting a real effect from avelumab. Although confounded somewhat by the sample size, it will be important to see how these results mature with further follow-up.   Today's third selected abstract is number 4508 reporting the final analysis of the JAVELIN Renal 101 phase 3 trial in patients with advanced renal cell carcinoma. This study compared the combination of axitinib plus avelumab with sunitinib in this patient group. The trial included 886 patients, of whom around 61% of those in the combination group and around 65% of those in the monotherapy group were PDL-1 positive. In the initial analysis from the JAVELIN Renal 101 study, after at least 6 months of follow-up, avelumab and axitinib significantly improved progression-free survival over sunitinib in patients with PDL-1 positive tumors and in the overall population with advanced renal cell carcinoma. In the fall cohort, the median progression-free survival with the combination was 13.8 months compared with only 8.4 months with sunitinib, and based on those results, the combination received FDA approval as a first-line treatment for patients with advanced renal cell carcinoma in May of 2019. The progression-free survival observed in the initial analysis was confirmed with a new long-term analysis in the overall population. Median progression-free survival with avelumab and axitinib was 13.9 months compared with only 8.5 months with sunitinib and the median duration of response with the combination was 19.4 months versus 14.5 months with sunitinib. However, no difference in overall survival was seen. At 60 months, the overall survival in the combination group was 38.8% and 36.2% with sunitinib. In patients who were PDL-1 positive at 60 months, overall survival with a combination was 37.1% compared with 33.4% with sunitinib.  Despite the sustained difference in progression-free survival seen with this combination, the discussant at this session pointed out that most oncologists are unlikely to recommend a combination which has not been shown to improve overall survival when published studies have reported on 4 combinations which do positively impact overall survival in this patient group. Despite the good tolerance of this regimen, it seems unlikely to be a preferred frontline regimen in advanced renal carcinoma moving forward.  That concludes today's report. Thanks for listening and we hope you have enjoyed listening to our top takeaways from ASCO24. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review and subscribe wherever you get your podcasts.   Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness

Dr. Diwakar Davar and Dr. Jason Luke discuss key abstracts from the 2024 ASCO Annual Meeting that explore triplet therapy in advanced melanoma, TIL cell therapy in immune checkpoint inhibitor–naive patients, and other novel approaches that could shape the future of immunotherapy in melanoma and beyond.  TRANSCRIPT Dr. Diwakar Davar: Hello and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Diwakar Davar. I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to have my friend and colleague, Dr. Jason Luke, on the podcast today to discuss key abstracts in melanoma and immunotherapy that will be featured and highlighted at the 2024 ASCO Annual Meeting. Dr. Luke is an associate professor of medicine, the director of the Cancer Immunotherapeutic Center, as well as the associate director for clinical research at the University of Pittsburgh's Hillman Cancer Center.  You will find our full disclosures in the transcript of this episode.  Jason, as always, it's a pleasure to have you on this podcast to hear your key insights on trials in the immunotherapy space and melanoma development paradigm, and to have you back on this podcast to highlight some of this work.  Dr. Jason Luke: Thanks so much for the opportunity to participate. I always enjoy this heading into ASCO.  Dr. Diwakar Davar: We're going to go ahead and talk about three abstracts in the melanoma space, and we will be starting with Abstract 9504. Abstract 9504 essentially is the RELATIVITY-048 study. It describes the efficacy and safety of the triplet nivolumab, relatlimab, and ipilimumab regimen in advanced PD-1 naive melanoma. So in this abstract highlighted by Dr. Ascierto and colleagues, they report on the results of this phase 2 trial in this setting. By way of background, PD-1 inhibitors and immune checkpoint inhibitors starting in PD-1 and CTLA-4, as well as PD-1 and LAG-3, are all FDA-approved on the basis of several pivotal phase 3 trials, including KEYNOTE-006, CheckMate-066, CheckMate-067, and most recently, RELATIVITY-047. Jason, can you briefly summarize for this audience what we know about each of these drugs, at least the two combinations that we have at this time?  Dr. Jason Luke: For sure. And of course, these anti PD-1 agents, became a backbone in oncology and in melanoma dating back to more than 10 years ago now, that response rates in the treatment-naive setting to anti PD-1 with either pembrolizumab or nivolumab are roughly in the range of mid-30s to high-40s. And we've seen clinical trials adding on second agents. You alluded to them with the seminal study being CheckMate-067, where we combined a PD-1 antibody and CTLA-4 antibody or nivo + ipi. And there the response rate was increased to approximately 56%. And more recently, we have data combining PD-1 inhibitors with anti-LAG-3. So that's nivolumab and relatlimab. Now, in that trial, RELATIVITY-047, the overall response rate was described as 43%. And so that sounds, on a first pass, like a lower number, of course, than what we heard for nivolumab and ipilimumab. We have to be cautious, however, that the cross-trial comparison between those studies is somewhat fraught due to different patient populations and different study design. So I think most of us think that the response rate or the long-term outcomes between PD-1, CTLA-4, and PD-1 LAG-3 are probably roughly similar, albeit that, of course, we have much better or much longer follow up for the nivo + ipi combo.  The one other caveat to this, of course then, is that the side effect profile of these two combinations is distinct, where the incidence of high-grade immune-related adverse events is going to be roughly half with nivolumab and relatlimab, a combination of what you would see with the nivolumab and ipilimumab. So that has caused a lot of us to try to think about where we would use these different combinations. But we do see that all of these treatments can land a durable long-term response in the subset of patients that do have an initial treatment benefit. The landmark, I think, for the field has been the 7-and-a-half-year median overall survival that we've seen with PD-1 plus CTLA-4, nivo + ipi; of course, we don't have such long-term follow up for PD-1 and LAG-3. But I think that's the setting for thinking about the rationale for combining a triplet regimen of PD-1, CTLA-4, and LAG-3. Dr. Diwakar Davar: So, Jason, in your mind, given the difference in the disparity and durability of the responses for the 067 regimen of nivo-ipi, and the RELATIVITY-047 regiment of nivo-rela, what is the standard of care in the U.S., and how does it change in the rest of the world, knowing that nivo-rela is not necessarily approved in all jurisdictions? Dr. Jason Luke: So this is a major complication in our field, is that there is perhaps not complete agreement across the world in terms of what the frontline standard of care should be. I think most United States investigators, or those of us that really treat melanoma most of the time, would suggest that a combination regimen, given the enhanced response rate and longer-term outcomes, should be the consideration for the majority of patients. In fact, in my practice, it's hard to think of who I would treat with a monotherapy PD-1 approach in the PD-1 naive setting. So either nivo + ipi or nivo + rela. As you alluded to however, in other regulatory settings throughout the world, combinations might not actually even be approved at this point. So PD-1 monotherapy would be the backbone of that setting. It does set up some complications when you think about a comparator arm; say you were going to look at various combinations, probably PD-1 monotherapy would be the worldwide comparator. You have to understand though, in the United States, I think that that's a less attractive option. Dr. Diwakar Davar: So in RELATIVITY-047, Dr. Ascierto and his colleagues are looking at generating a triplet. And in this case, they looked at this in the context of frontline metastatic melanoma, 46 patients. Very interestingly, the dose of ipilimumab studied here was 1 mg/kg through 8 weeks, not the 3 mg/kg every three weeks times four doses using 067, or even the low dose ipilimumab regimen that you studied in the second line setting, which was 1 mg/kg every 3 weeks for 4 doses. So let's talk about the results and specifically the implications of potentially studying lower doses of ipi. Dr. Jason Luke: I appreciate you raising that point. I think it's really important as we think about this dataset because this triplet regimen is not by any means the only version of a triplet that could be developed using these agents. So just to give the high-level numbers from the abstract, we see from these data that the overall response rate is described as 59% and 78%, a disease control rate with patients having an unreached link. So duration of response of unreached, and then the progression-free survival at about 5 months. So those are really interesting data. But as was alluded to, it's not totally clear to me that that's the best that we could do with this regimen.   Now, you alluded to this low-dose ipilimumab schedule at 1 mg/kg every 8 weeks, and it's really important to note that we have no benchmark for that regimen in melanoma oncology. And in fact, the one study that used that regimen, which was the adjuvant study of nivolumab and ipilimumab, known as CheckMate915, is in fact the only immune checkpoint inhibitor study in melanoma oncology that was actually negative. That study noted no benefit to adding ipilimumab at 1 mg/kg every 8 weeks on top of nivolumab, again, the adjuvant setting. So it's a little bit curious to then understand what it means in this study to have that amount of ipilimumab added to the rela-nivo backbone. And that manifests in a few different ways. We see the response rate here at 59%. Again, if you compare that just against the standard nivo + ipi dosing schedule, it's about the same. So is that really an advantage to having the triplet as compared to just doing standard nivo + ipi?   We do see that it manifests in a slightly lower rate of grade 3/4 immune-related adverse events, at 39%. That's a little bit lower than what we'd expect for standard nivo + ipi. But again, I think that that emphasizes to me the possibility that some efficacy was left on the table by using this very low dose ipilimumab regimen. I think that's really a concern. It's not clear to me that these triplet data really differentiate from what we'd expect with the already approved regimen of nivo + ipi. Therefore, it makes it difficult to think about how would we really want to move this regimen forward, or should there be more work done about dose and schedule to optimize how we might want to do this?  Dr. Diwakar Davar: As far as triplet therapy in the context of frontline metastatic melanoma, meaning triplet immune therapy, because there are at least several targeted therapy triplets that are FDA-approved, [but] not necessarily widely utilized. How would you summarize the future for triplet therapy? Do you think it's potentially attractive? Do you think it's very attractive with some caveats? Dr. Jason Luke: Well, I think it's attractive, and we have 3 independently active agents. And so I do think it's a priority for the field to try to figure out how we could optimize the therapy. We've had such a revolution in melanoma oncology, talking about 7.5-year median survival from CheckMate-067, but that still implies that 7.5 years, half the patients have passed away. There's more to do here. And so I do think it should be a priority to sort this out. I guess I would be cautious, though, about advancing this regimen directly to a phase 3 trial because it doesn't seem clear to me that this is optimized in terms of what the outcome could be. If we're willing to tolerate higher rates of toxicity from other dose schedules of nivo-ipi alone, then I think we should do a little bit more here to potentially explore the space that might be possible to increase that overall response rate a little more without getting into a completely exaggerated toxicity profile that would be unacceptable. So, I do think it's exciting, but there's possibly more to do before really think about going big time with this. Dr. Diwakar Davar: Great. So now we'll switch gears and move from frontline metastatic melanoma to the second line and beyond looking at a new agent and contextualizing the effects of that actually in the frontline settings. So Abstract 9505 describes the efficacy and safety of lifileucel, which is essentially autologous tumor-infiltrating lymphocyte cell therapies, also known as TIL, in combination with pembrolizumab in patients with ICI naive, so not necessarily pretreated, but ICI naive metastatic or unresectable melanoma. This is data from the IOV-COM-202 Cohort 1A oral abstract presented by Dr. Thomas and colleagues. In this abstract, Dr. Thomas and colleagues are presenting data from the 1A cohort, which is the phase 2 portion of the frontline trial that is evaluating autologous TIL with pembro in checkpoint inhibited naive metastatic melanoma.  By way of background, TIL is FDA approved on the basis of several cohorts from a phase 2 trial. The data has been presented multiple times now by Drs. Sarli, Chesney, and multiple colleagues of ours. And essentially autologous TIL, which is generated from a surgical procedure in which a patient undergoes a surgery to extract a tumor from which T cells are then grown after ex vivo expansion and rapid expansion protocol. The entire procedure was essentially pioneered by several colleagues at the NCI, primarily Dr. Steve Rosenberg, and this approach produces objective response rates of approximately 31% to 36%. And the most recent publication demonstrated that at median follow up of approximately 2 years, the median duration of response was not reached. The median OS was about 14 months and PFS was about 4 months or so. So, can you contextualize the results of the abstract in the frontline setting? And then we'll talk a little bit about where we think this is going to go. Dr. Jason Luke: So I think this is a timely study given the recent approval. And in the abstract presented here, we see an early data cut from the PD-1 naive study, as you alluded to. So here we had 22 patients and distributed across various states of advanced melanoma. Ten out of the 22 had M1C, but there also were smatterings of earlier M1A and M1B at 18.2% and 9.1%. So this is important, as we think who the treatment population is that's going to be optimized with a TIL procedure. The median sum of diameters, meaning how much tumor burden the patients have, was about 5.5cm, and I'll note that that's a relatively modest amount of tumor burden, albeit not that unusual for an early-stage trial. So of the patients that participated, 8 had BRAF mutations so that's 36%. That's not that high, but it's reasonable. And I think the important overlying number, the response rate so far in the study, with about 17 months of follow up, was 63.6%, and that includes 22% or 23% having complete response. So those are interesting data.  And another point that was made in the abstract, which we've all seen, is that responses to TIL, all of immunotherapy but especially TIL, do seem to mature over time, meaning they deepen over time. So it's possible the response rate could go up some extent as we watch this study advance. So I think these are exciting data on some level. Also, a 63.6% response rate sounds pretty impressive, but we do have to put that in the context of a double checkpoint blockade, which we just got done discussing, gives you almost a 60% response rate, 59% response rate. So then the question really is: Is it worth the amount of effort that we could go into generating a TIL product in a treatment naive patient, and put them through the lymphodepletion that is associated with TIL and the high dose interleukin 2 treatment that accompanies the reinfusion of the TIL, if you're going to get a response rate that's roughly the same as what you would get if you gave them off the shelf nivo plus ipilimumab?  At this point it's a little bit hard to know the answer to that question. I think it could be possible that the answer is yes, because we don't know exactly which populations or patients are most likely to benefit from each of these therapies. And if it could be teased out who's not going to benefit to nivo + ipi from the get-go, then of course, we would want to offer them a therapy that has that frontline potential, durable, long-term response. But I have to say, on a one-to-one with TIL therapy, you get a lot of toxicity initially with the treatment; with nivo + ipi on the back end, you get a fair amount of toxicity with the treatment. How are we going to judge those two things? And I think we probably need a larger dataset to really have a good handle on that.  So these are interesting early data, but it's not totally clear to me that even if this holds up all the way through the trial, and we're going to talk about the design of the registration trial here in a second, a 60% response rate on its own without further biomarker stratification is a little bit hard for me to see in clinical practice why we would want to do that, given we can already just go off the shelf and give checkpoint inhibitors. Dr. Diwakar Davar: So that brings us to TILVANCE-301. So TILVANCE is a phase 3 trial. It's a registration intent trial by our Iovance colleagues evaluating the pembro-TIL regimen versus pembrolizumab alone. So in this phase 3 trial, approximately 670 patients will be randomized to either arm A, which is lifileucel + pembro. And in this arm A, patients are going to be getting lifileucel with the tumor resection, non-myeloablative lymphoid depletion, the lifileucel and abbreviated course of high-dose IL-2, and thereafter, continued pembro for the study mandated duration versus arm B, where patients will be getting just pembrolizumab monotherapy per label. Arm B patients, per the design, may cross over to receive TIL monotherapy at the time of central-blinded, radiology-confirmed disease progression.   The study design otherwise is fairly routine and, per most of our registration trials these days, patients have actually been permitted to receive neoadjuvant and adjuvant therapy, including checkpoint inhibitors, as long as the receipt of the therapy was more than 6 months prior to the inclusion of the patient in that registration trial. The dual primary efficacy endpoints as stated are BICR-assessed objective response rate as well as PFS, and the key secondary endpoint is overall survival.   So Jason, what are your thoughts on the study design and potentially the regulatory implications, particularly given, one, the control arm of pembro monotherapy, and two, the role of TIL crossover to receive TIL monotherapy at the time of BICR mandated progression for arm B? Dr. Jason Luke: So this goes to a few points that we've touched on already in the discussion here. When we think about the primary endpoints for this study, with one of them being overall response rate, one has to assume that that's a given that they would get that. I feel like that's a low bar. And we go back to that cross-trial comparison. If their results end up being that the response rates are about 60%, I don't know that that differentiates necessarily from what's already available in the field with combination immune checkpoint blockade. For the purposes of the study that would mean it's a positive study, so I think that would probably be good. But again, the comparator to pembrolizumab monotherapy, I think some of us would argue, isn't really consistent with what we would do with a patient in our clinic. So it's not that it's bad per se, but I think there's going to be a whole lot of cross-trial comparison. So if the study is positive, that would be good for getting the drug available. It's still a bit hard though, based on the preliminary data that I've seen, to imagine how this would have uptake in terms of utilization as a frontline therapy.  You alluded to the crossover, and I think there, the assumption is that patients who get TIL therapy as a second line perhaps would have an attenuated benefit. But I'm not sure that's really true. It certainly looks from the data that we have, like the patients who benefit most from TIL are going to be those who didn't respond to anti PD-1 in the front line. So I'm not sure how much difference there's going to be between first- and second-line TIL therapy, but those data will kind of wait to be seen. So I think it's an important study. Of course, the accelerated approval of TIL as a later line therapy is dependent on this trial being positive. So there is some risk that if this trial ended up not being positive, that that could have regulatory implications on the utility or availability of TILs, a subsequent line therapy. But all of these, I guess we'll have to wait to see the results. We do hope for a positive trial here, although I think it'll be nuanced to sort of interpret those data given that pembrolizumab monotherapy control arm.  Dr. Diwakar Davar: Fantastic. So we've learned a lot about TIL, both its use in the second-line setting and this very exciting but potentially risky frontline trial that is ongoing at some centers in the United States and certainly a lot of ex-U.S. enrollment.   So we'll now pivot to a related product which actually belongs to a much larger class of agents that are antigen specific T-cell therapies in a variety of different formats. And that is Abstract 9507, which is the “Phase 1 safety and efficacy of IMC-F106C, a PRAME × CD3 ImmTAC bispecific, in post-checkpoint cutaneous melanoma (CM).” Now, in this abstract, Dr. Omid Hamid and colleagues reported the results of this phase 1 trial. As a disclosure, I'm an investigator and the last author on this manuscript. Jason, it would be important for our audience, for us to maybe firstly, outline the PRAME as a target, and then the ImmTAC as a platform prior to discussing these results. So let's start with the target PRAME, which I think is a target that you know well. So why don't you start with the target and we'll talk a little bit about that and then the platform? Dr. Jason Luke: Yeah, so I think for the audience, being aware of PRAME, or the Preferentially Expressed Antigen in Melanoma, is going to be quite important moving into the future. So PRAME as a therapeutic target is a cancer testis antigen that's overexpressed in tumor tissues. And of course the name has melanoma in it, but it's not uniquely present in melanoma. So the expression patterns of PRAME as a target are very high in melanoma. So in cutaneous disease, this is upwards of almost 100%, somewhere between 95% and 100%, in metastatic melanoma tissues. And PRAME has several different roles on a molecular level, although I don't think for our purposes here, it's so much important to be aware of them, but rather that this is a very highly expressed target, which then can make it attractive for using T cell receptor-based therapies. And so in the case we're talking about here on the ImmTAC platform, that's a CD3 PRAME×CD3 bispecific approach. But of course there are other approaches that can also be taken, such as TCR T cells that directly go after PRAME itself. Dr. Diwakar Davar: Let's now talk about the platform and how it differs from some of the other antigen targeting platforms that you have just alluded to. I think the Immtac platform is basically a fusion protein comprising engineered TCRs with a CD3 specific short chain variable fragment. And then the engineered TCR therefore binds antigens in an HLA dependent fashion. But you know quite a lot about some of these alternative platforms, and I think it'll be important to contextualize for the audience the difference between ImmTAC, which is a prototype drug that is already approved in the context of tebentafusp. But how does this differ from some of the other more nuanced platforms, such as the Immatics TCR or TCR platform and TScan TCRT nanoplasmonic platform.  Dr. Jason Luke: Right. So the ImmTAC platform as alluded to is already approved on the market with tebentafusp, which is the gp100-CD3 bispecific molecule. And the advantage of that approach is infusion off the shelf of a drug. The downside of it is that it is a weekly dosing strategy as it stands now. And there are some complicated disease kinetics associated with treatment response, which we'll come back to in the context of the PRAME bispecific. Those are, in contrast with T-cell receptor-transduced T cells, as an alternative strategy, which is a form of adopted cell transfer. So we just got done talking about TIL therapy, which of course, is trying to take lymphocytes out of the tumor and grow them up and then give them back. Here with TCR-transduced T cells, we're talking about taking leukopak from the blood and then using different transfection approaches to try to insert into the lymphocytes of the patient a T cell receptor that recognizes to a certain cancer antigen, in this case, PRAME.  So you alluded to a couple of different companies that have different platforms to do this. Immatics has a molecule called IMA 203, for which there have been data disclosed in the past year, again showing some very interesting responses in patients who have highly refractory melanoma. That process, though, again, does require lymphodepletion before you reinfuse the cells. Again, in contrast, the ImmTAC, which is an off the shelf revenue administer, there you have to make the product and then bring the patient back, lymphodeplete, and give the cells back. Immatics platform uses a viral transfection vector. The T scan approach that you alluded to before uses an approach of a mixed system on multiple HLA backgrounds to try to get past HLA-A*02:01 only, and in this case, uses a plasmid-based transfection syndrome that perhaps can be more broadly utilized given the lack of a lentiviral vector.   So this is a complicated area of technology that starts to get into immune engineering, and I think for the purposes of this discussion, we don't want to belabor it. But both of these technologies, talking about the CD3 bispecific with the off the shelf aspect of it and the adoptive cell transfer, each of these using a T cell receptor-based therapy to try to go after PRAME, I think have very high upsides, and I think we'll initially see it in melanoma over the next year or so. But this is likely to be relevant to multiple tumor types beyond melanoma.  Dr. Diwakar Davar: So let's discuss the results of this phase 1 trial. IMC-F106C, like all other ImmTAC, is administered intravenously and does require step-up dosing. You alluded to the fact that the tebentafusp was approved, and it's one of those drugs that is fortunately otherwise administered weekly, which can be difficult for the patient and requires at least the patient spend the first 3 doses overnight under some kind of monitoring, whether it's in the hospital or extended outpatient monitoring, for at least 23 hours. The efficacy of this agent and this platform appears to be surprising in that you tend to see a relatively low RECIST response rate. We'll have you comment a little bit on why that is the case and what may be the role of ctDNA, as opposed to conventional RECIST in assessing response.   At least in this trial, they mandated pre-testing, but did not require it for study enrollment. And pre-positivity was defined using immunohistochemistry with a relatively low H-score of 1%. And the molecular response definition was a 0.5 log or a 68% ctDNA reduction just prior to the first imaging assessment. So how do you contextualize the results? But maybe before you talk a little bit about the results, the ctDNA aspect, that was a recent publication by Drs. Rich Carvajal, Alex Shoushtari, and I think you are also involved in that.  Dr. Jason Luke: So, I think an interesting observation around tebentafusp has been that ctDNA may be a better predictor of long-term outcomes. And how you define ctDNA response is still something that the field is grappling with, albeit that I think is going to be an important consideration as we think about these novel therapies, these ImmTACs and other CD3 engagers moving into the future. But for the purposes of the abstract here, we see that in the population of patients treated, there were 46 patients with cutaneous melanoma. The majority got monotherapy with IMC-F106C, and that's the PRAME bispecific. So 40 patients that got monotherapy and six who got a combination with checkpoint inhibitor. All these patients had prior treatment with immunotherapy, and most of them had PD-1 and CTLA-4 antibody with a small spanner that also had BRAF inhibitors.  In terms of that PRAME testing that you alluded to, based on the immunohistochemistry H-score greater than 1%, 35 out of 40 patients were positive, so they defined 5 as negative. And we could come back if we have time, but there are other ways to do PRAME testing as well that I think may become unique for different agents, maybe an important biomarker. In the data, 31 out of the 46 patients were RECIST evaluable. The outcomes of those patients were to note that the response rate was 13%, which was four partial responses. But 35% of patients had tumor regression with a disease control rate at 65%. It was clear that there was an enrichment by PRAME positivity for both progression free and overall survival. So those patients who had obvious positivity essentially had a doubling of the PFS and more than the doubling of the OS, 2.1 to 4.1 months for TFS and landmark OS, 40% to 94%. So I think these are quite intriguing data.  It does suggest that for the vast majority of patients, we do see some induction of the antitumor effect, albeit that RECIST might undercall the effect. And so this may become another area where the ctDNA monitoring might be able to help us to understand who is likely to have really long-term benefit from this therapy. And given the number of emerging treatments that we have for melanoma, we might be able to really focus in on that group of patients in terms of optimizing how we would use this drug moving into the future. Dr. Diwakar Davar: So you talked about a response rate, and at first glance, this response rate is a little underwhelming. We're talking about 4 out of 31 RECIST evaluable patients, 13%. So it's in the double digits, but barely. So how enthusiastic are you about the results? How does it contrast with at least the publicly known data from other brain targeting approaches, such as the IMA203 agent, understanding that while they may be all targeting somewhat the same target, they are actually extraordinarily different platforms. One's off the shelf, one's highly customized. How do you contextualize the results? How would it contrast with other cellular approaches?  Dr. Jason Luke: I think it's important, again, to emphasize the point you made, which is that they're very different kinds of treatments. So even though they both target PRAME, they're going to be differently useful, and they could be quite useful for different groups of patients. And so here we see that there is a subfraction of patients who are deriving long-term benefit. And we commonly have an argument in our field about, is overall response rate really a useful monitor that describes a patient-centric outcome? While, of course, patients like to know their tumors are shrinking, what they want the most is for the tumors not to get worse and for them not to pass away from cancer. So I think I'm enthusiastic about these results, but emphasizing the point that we need to better understand who is going to benefit the most from this CD3 bispecific PRAME approach and how we're going to be able to harness that into long term benefit for patients because there's no doubt that an off the shelf therapy has a high degree of value relative to adoptive cell transfer, which sort of requires a big wind up.   So when you say, what does it contrast with? Well, the data for IMA203 has shown more than a 50% response rate in patients with more than 5 lines of therapy for metastatic disease. That really looks quite exciting. And several of those patients are now out for quite an extended period, meaning 2 years or more given only a single dose of IMA203. But again, the caveat being, you have to make the cell product for the patient, and that takes time. You lymphodeplete the patient, not all patients can tolerate that in the refractory disease setting, and then they have to be able to tolerate the reinfusion of the cells. And so this drug, IMC-F106C, looks very promising. Moving into the earlier phase trial that we'll talk about, I think the TCR T cell program has a lot of upsides for patients, especially with refractory disease. And so I think these two different approaches are really on parallel tracks. They both target PRAME, but I don't think they necessarily need to be compared one to one, as if they're going to go head-to-head with each other. Dr. Diwakar Davar: So now we'll talk a little bit about the frontline setting, because on the basis of some of these results, Immunocore is now exploring IMC-F106C frontline melanoma. This trial is actually being presented as a trial in progress at this meeting by Georgina Long and colleagues. Some of us are co-authors in that abstract. And in this study, HLA-A*02:01 positive patients with advanced unresectable melanoma will be randomized one to one to the combination of IMC-F106C, which actually, I think after this meeting will be known as bre-ni in combination with nivolumab versus nivolumab regimens, which will either be nivo or nivo-rela, investigators choice and likely dependent on region. So what do you think of the challenge of this trial? We talked about some of the challenges of the TILVANCE trial earlier. But what is going to be the challenge of this trial and in this setting, particularly given the response rates that we've seen so far? Dr. Jason Luke: Yeah, so, similar to comments we had before, thinking about what the optimal control arm is for a study like this is difficult, and so that'll be important as we think about interpreting the results. One has to assume for the purpose of this conversation that it is a positive trial, and that adding the PRAME bispecific theory does lead to an improvement in progression free survival relative to those in checkpoint alone approaches. And I think the magnitude of that difference is going to be of some relevance. And then I think importantly, also figure out who needs this treatment and who's going to benefit long term are going to be really important considerations.  We alluded to how this drug requires an intensive dosing period at the get go, and so telling patients that they need to come in weekly or bi-weekly initially for some number of weeks before they switch to a longer-term intermittent regimen, that comes with real world considerations for patients, their families, their finances, etc. So the benefit has to be clearly obvious that makes it worthwhile doing that, again, because a default could be giving drugs that we've had for 10 years with the nivolumab and ipilimumab. So there's going to be a lot of cross-trial comparison that is going to necessarily have to take place here to think about what these results really mean in the context of other available therapies.  I think the study is reasonable to do. I think this is a very active agent. There's no doubt there's a subset of patients who seem to benefit a lot from it. And I would just emphasize the point that that's probably going to be the most important thing to really drill down on is under the assumption there's a positive trial, we need to know who those people are so we could optimize giving this kind of a treatment to them. Dr. Diwakar Davar: I guess one important point to underscore what Jason said about potential predictive biomarkers, I think as part of the presentation, Dr. Hamid and colleagues will be talking about a candidate predictive biomarker of this agent, which is potentially class specific and not necessarily agent specific of a T cell signature that potentially could define patients who are more likely to benefit from this agent.  So, Jason, as always, thank you for sharing your expertise and insights with the team today. We certainly look forward to catching up again for our wrap up episode after the annual meeting where we'll talk about some of the data that we could not talk about, particularly the late breaking abstracts and other key advances that will shape the future of, certainly the field of immunotherapy and melanoma, potentially the field of cancer immunotherapy at large. Dr. Jason Luke: Oh, thanks very much for the opportunity. Dr. Diwakar Davar: And thank you to our listeners today. You'll find the links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on this podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. So thank you, and we'll see you soon.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Diwakar Davar   @diwakardavar   Dr. Jason Luke   @jasonlukemd      Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:       Dr. Diwakar Davar:     Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences    Consulting or Advisory Role: Instil Bio, Vedanta Biosciences    Consulting or Advisory Role (Immediate family member): Shionogi    Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences    Research Funding (Inst.): Zucero Therapeutics    Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy       Dr. Jason Luke:    Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine    Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure    Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)    Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio      

Topics covered in this episode: zoxide Smart CLIs with Typer Python recommended officially by the US Government Textual tutorials at Mouse vs Python Extras Joke Watch on YouTube About the show Sponsored by ScoutAPM: pythonbytes.fm/scout Connect with the hosts Michael: @mkennedy@fosstodon.org Brian: @brianokken@fosstodon.org Show: @pythonbytes@fosstodon.org Join us on YouTube at pythonbytes.fm/live to be part of the audience. Usually Tuesdays at 11am PT. Older video versions available there too. Michael #1: zoxide zoxide is a smarter cd command, inspired by z and autojump. It remembers which directories you use most frequently, so you can "jump" to them in just a few keystrokes. zoxide works on all major shells and platforms. Brian #2: Smart CLIs with Typer Rahul Pai Lots of TILs here, even though I've been using Typer for years. Examples of Auto-detection of arguments and types based on type hints Help text is a smidge clunkier Prompting for missing arguments Defaulting to an enviromental variable for missing args Print help if no args given Explicit app and subcommands with a comparison to argparse Reusable commands with result_callback Several topics covered in comparison with argparse See also Testing argparse Applications Michael #3: Python recommended officially by the US Government The US government explicitly recommends memory safe languages. Python is one of them The comparison to big tech by Samuel is interesting Brian #4: Textual tutorials at Mouse vs Python Mike Driscoll Most recently Creating a Modal Dialog For Your TUIs in Textual Textualize already has some pretty great documentation at textual.textualize.io But it's cool to see some different tutorials on it. Extras Brian: Is UV the FUTURE of Python PACKAGING?

Whilst down in Australia for the Tour Down Under and the Deakin University Road Race, our very own Matilda Raynolds sat down with Heidi Franz, rider for Lifeplus Wahoo, for a chat. They discussed Heidi's last couple of years in the sport, how cycling should differ from gymnastics, popular Aussie phrases you should know, and much more.We hope you enjoy this bonus Wheel Talk episode, and Abby, Loren and Gracie will be back later this week to chat about Setmana Valenciana and the upcoming Omloop Het Nieuwsblad.

Whilst down in Australia for the Tour Down Under and the Deakin University Road Race, our very own Matilda Raynolds sat down with Heidi Franz, rider for Lifeplus Wahoo, for a chat. They discussed Heidi's last couple of years in the sport, how cycling should differ from gymnastics, popular Aussie phrases you should know, and much more.We hope you enjoy this bonus Wheel Talk episode, and Abby, Loren and Gracie will be back later this week to chat about Setmana Valenciana and the upcoming Omloop Het Nieuwsblad.

Matilda Raynolds, or Tils as she's known to the members of the Wheel Talk Podcast Discord group (available to members of Escape Collective), joins Gracie and Abby on the podcast this week with some insider information on the Tour Down Under and some thoughts on the upcoming Cadel Evans Great Ocean Road Race.And, as promised, here is a link to G Flips's cover of Cruel Summer by Taylor Swift.

Matilda Raynolds, or Tils as she's known to the members of the Wheel Talk Podcast Discord group (available to members of Escape Collective), joins Gracie and Abby on the podcast this week with some insider information on the Tour Down Under and some thoughts on the upcoming Cadel Evans Great Ocean Road Race.And, as promised, here is a link to G Flips's cover of Cruel Summer by Taylor Swift.

This week we will discuss a rare type of cancer.  Our guest on today's show is Chris White.  Mucosal melanoma is a rare but aggressive disease usually diagnosed in advanced stages. Unlike most melanomas, which start in the skin, mucosal melanoma starts in the moist membranes that line the inside of the body, including the digestive tract. All melanomas start in pigmented cells called melanocytes. Mucosal melanoma accounts for 1.4 percent of all melanomas, according to a 2018 review in Melanoma Management. ​Most mucosal melanoma cases start in the lining of the head, neck, anus, vagina or vulva. Cases inside the gastrointestinal tract are less prevalent. The disease may be called invasive if it's spread deep into the tissue and metastatic if it's spread to distant parts of the body, such as the liver or lungs. ​​Mucosal melanoma hasn't been linked to any specific causes. Generally, older people are diagnosed, with the median age being 70. While the rate of skin melanoma cases has risen in the past 20 years, the rate of mucosal melanoma has always been fairly similar over time. ​ More About Our Guest Chris's story begins in Colorado Springs where he was born in 1982. His parents and two siblings moved to Irvine California where he grew up before moving to North Texas. He received his Associates of Arts degree at Collin College, followed by his BA at University Texas Dallas in 2005. After college, his career path included time in the in the oil and gas industry, working with independent SAP contract consultants as well as working in the Golf department at Gleneagles Country Club in Plano, Texas. His career path took a turn in 2016 when he worked in the home building industry as a construction manager. An avid snowboarder, he has always been active, enjoying outdoor activities. His cancer journey began in the summer of 2018 when what he had believed was a hemorrhoid actually turned out to be cancer. Not just any cancer, but the diagnosis was Anorectal Mucosal Melanoma which is an extremely aggressive cancer with a low survival rate.  The following months included multiple surgeries, immunotherapies, chemotherapy and radiation. Despite the treatments, the cancer had metastasized throughout his body to his lungs, liver, kidneys and brain. His health was declining rapidly, and without any other options, he was fortunate enough to qualify as the last patient admitted to a TILs Therapy Clinical Trial at the University of Colorado Health Cancer Care located at the Philip Anschutz Medical Campus in Aurora Colorado. The TILs therapy was done in January of 2020 and within less than a year the tumors were gone. Not in remission but gone. The TILS therapy is revolutionary in that it eradicates the tumor rather than leaving it dormant. This clinical trial for TILS therapy saved his life. He was able to go back to work in homebuilding but realized his passion is sharing his cancer survival story. Currently he works as a Certified Melanoma Educator through the Melanoma Research Foundation. He is involved with many melanoma patient advocacy groups throughout the world listening to other stories while sharing his own via group chats, industry panels and forums any format that can offer some patient the comfort that there may a cure for their cancer. Any contribution to the MRF aids the fight against Melanoma and Chris thanks you for your support and generosity. ​