Jaume Capdevila

45% of patients on daraxonrasib developed acquired resistance, converging on the same target through different routes. KRAS Y64 mutations disrupt the molecular glue directly. Y71 mutations and hypoactive BRAF enhance native RAS-RAF binding so the inhibitor can't displace it. One protein, multiple escape doors. Cancer is pleiotropic. The chemistry has to be.

Beyond daraxonrasib, there are many interesting #ASCO26 abstracts in the hepatobiliary and pancreatic space, spread across tracks and sessions. Hope it helps‼️

Interested in thyroid / endocrine / neuroendocrine neoplasms❓️ Here a practical mini-guide to help navigate #ASCO26 and avoid missing relevant abstracts.

The message in advanced biliary tract cancers is becoming increasingly clear: NGS should no longer be viewed as an approach reserved only for later lines of treatment. In this large international cohort (1049 patients): * Matched targeted therapy achieved a median OS of 23.3 months * Patients with actionable alterations who did not receive matched therapy had the worst outcomes * Nearly 45% of patients may never reach second-line treatment Most common actionable alterations: * BRCA1/2 * FGFR2 fusion * HER2 amplification * IDH1 mutation One particularly striking point: Although BRCA1/2 alterations were among the most common actionable findings in this study, they are still not sufficiently emphasized in some routine BTC testing algorithms and guidelines. Liquid biopsy appears promising, but especially for FGFR2 fusions and HER2 amplifications, it still cannot fully replace tissue-based testing. In advanced biliary tract cancers, precision oncology is no longer becoming “optional” — it is becoming essential. nature.com/articles/s4169… @oncodaily @OncBrothers @ilyassahinMD @Nature @tompowles1

Channing J. Der, PhD, and Jen Jen Yeh, MD, describe the scientific foundations of a phase 1–2 study of daraxonrasib to treat metastatic pancreatic ductal adenocarcinomas. Learn about the science behind the study in the editorial “Advances in RAS Therapeutics for Pancreatic Cancer,” from the University of North Carolina at Chapel Hill (@unc): nej.md/4neOTCE

I am preparing a talk on carcinoid syndrome tomorrow and updating my slides and this is absolutely the best review on the topic you can find out there... Courtesy of @HansHofland1 and team... academic.oup.com/edrv/article/4…

Advances in RAS Therapeutics for Pancreatic Cancer | New England Journal of Medicine @NEJM Insightful review from the KOLs of KRAS and Pancreatic Cancer Dr. Jen Jen Yeh and Dr. Channing Der, the rock stars 🤘👩‍🎤🎸 nejm.org/doi/full/10.10…

1/n Daraxonrasib (RMC-6236), the first-in-human oral 💊RAS(ON) multi-selective tri-complex inhibitor, in previously treated RAS-mutated pancreatic cancer phase I/II study is now published in the New England Journal of Medicine @NEJM A novel💡 way to shut down ⚔️RAS, one of the most important oncogenic drivers in cancer that had long been considered “undruggable.” 🔗nejm.org/doi/full/10.10… Shout out to Brian Wolpin, @CentralParkWMD @GarridoLagunaMD @AlexSpiraMDPhD @salmanpunekar @MeredithPelster @bherzbergmd Nilo Azad Aparna Hegde @DavidHongMD and the whole team who dedicated to this study. @EileenMOReilly #HBP #HumansBeyondPatients

Very excited to report on our lab’s unexpected adventure into subtyping cancer cachexia by way of anatomy, where we study the evolution of the bodies (not the genomes!) of patients with cancer during profound weight loss. Led by Sonia Boscenco. medrxiv.org/content/10.648…

A major impact! Thanks to all the coauthors, clinical research team and our courageous patients who dedicated their time and more at the plenary #ASCO26 @ASCO @ASCOPost 💜

Daraxonrasib in previously treated RAS-mutant PDAC is published in @NEJM ! Better in earlier lines. Less efficacious in later lines. Grade ≥3 TRAEs ~30%- highlighting need to learn about how to manage the side effects. @OncLive @KRASKickers nejm.org/doi/full/10.10…

We're seeing major advances vs pancreatic cancer. Today @NEJM data for daraxonrasib @RevMedicines nejm.org/doi/full/10.10… Context for this first-in-class molecular glue nejm.org/doi/full/10.10…

In a phase 1–2 study of daraxonrasib, treatment-related adverse events of grade 3 or higher occurred in 30% of patients with previously treated RAS-mutated pancreatic cancer, and up to 35% of patients had an objective response. Full study results: nej.md/4f7xfhX Science behind the Study: Advances in RAS Therapeutics for Pancreatic Cancer nej.md/4neOTCE

Resistance mechanisms to RAS(ON) tri-complex inhibitor daraxonrasib ◾️KRAS Y64 mutations: Disrupt drug's binding to RAS ◾️KRAS Y71 mutations: Enhance RAS affinity for RAF, competing with CYPA recruitment ◾️Class III BRAF mutations: Promote RAF dimerization, strengthening RAS-RAF engagement 👉Next steps: Next-generation TCI (RMC-4791) to overcome Y64 resistance, or combination with RAF dimer-breakers for class III BRAF 🔗doi.org/10.1016/j.cell… @CellCellPress @OncoAlert @RonaYaeger

While the me2 companies are still planning on Ph2 dose optimizations, $RVMD had already worked out the comprehensive real-world acquire resistance mechanisms for Darax. One of the most elegant cell signaling papers that I had ever seen I read their prior Biorxiv and never quite understood how BRAF kinase dead mutants confer resistance to Darax. Now they had provided a very clear answer Glad to see all these genius-level people there (including all the investigators on the paper)! cell.com/cell/fulltext/…

#ASCO26 is <4 weeks away! @ASCO Here are the #GI oncology oral abstracts I’m most excited about 👇 ➡️Notable phase 3s: PDAC: RASolute302 ⭐️ HCC: EMERALD-3 & IMBRAVE251 EGC: ATTRACTION 6 & BL-B01D1-305 CC: FIGHT-302 CRC: PUMP (HAI), EPISODE-III (ASA) - HER2+: Tras rezetecan (SHR-A1811) - BRAFm: Tunlametinib in pre-treated Congrats to all the presenters - special shoutout to our 🇨🇦 GI oral presenters & discussants 🤗 See you in Chicago! #GIOncology #CRC #PDAC #RAS #HCC

This is huge news!! Game changer @DavidHongMD @ASCOPost @AACR @MoffittNews @huntsmancancer @PanCAN @KRASKickers Kudos to @FDA and @RevMedicines for this expanded access program to give US patients fighting PDAC early access to daraxonrasib. 👏💪🙏tinyurl.com/2h9zjceh

@GarridoLagunaMD @KRASKickers @DavidHongMD @ASCOPost @AACR @MoffittNews @huntsmancancer @PanCAN @FDA @RevMedicines Hope to have it very soon in EU !!! 🙏🏼🙌🏼

🧬 Buenas noticias en cáncer de tiroides 🔄 Nuevas indicaciones en enfermedad avanzada: 👉 Dabrafenib + trametinib → CDT BRAF V600E RAI-refractario tras ≥1 línea 👉 Selpercatinib → cáncer tiroides RET+ (medular y RAI-refractario) 🎯 La importancia de la medicina de precisión en cáncer de tiroides 🔗 aemps.gob.es/informa/boleti… @aecat_es @TiroSEEN @JHernando3 @Ja_Capdevila

Muy feliz por estas noticias Nuevos avances en #cáncerdetiroides La @AEMPSGOB amplía el uso de terapias dirigidas en cáncer de tiroides avanzado (RET y BRAF V600E), avanzando hacia la medicina personalizada y tratamientos más específicos. aemps.gob.es/informa/boleti…