RELIGHT: PIII 1L gastric cancer 🇨🇳, now published in JCO. "Positive", but put it next to CheckMate and it suddenly loses its luster. Retlirafusp is a PD-L1/TGF-B bispecific. The study randomized 731 patients with HER2-negative gastric/GEJ adenocarcinoma to retlirafusp + CAPOX vs placebo + CAPOX. OS 16.8 vs 10.4 mo, HR 0.53 PFS 7.6 vs 5.5 mo, HR 0.52 Looking at the Chinese cohort in CheckMate-649, CPS ≥5 cohort (nivo + chemo vs chemo) results are strikingly similar: OS 15.5 vs 9.6 mo, HR 0.54 PFS 8.5 vs 4.3 mo, HR 0.52 Given a plain PD-1 inhibitor produced essentially the same hazard ratios here it is hard to see what TGF-β is adding. Chemo alone hasn't been standard for years, and the authors acknowledge the protocol was locked before PD-1 + chemo became SoC in China. RELIGHT shows retlirafusp beats chemo; we already knew that. Why am I posting about it? Well, it is another striking example that China has woken up to clinical trials and is running laps around the rest of the world in terms of speed, cost and efficiency. Anyone who has watched a trial sit in contracting for months knows reform is overdue (someone please teach me how to efficiently move legal forward). @OncoAlert @TheGutOncLab @Onco_Nexus

There is no such thing as “too young for cancer.” I keep writing this because apparently some people still need to read it. Our new @TheGutOncLab paper on early-onset cholangiocarcinoma is out, and the message is simple: Early-onset cancers aren't just a colorectal disease, and these patients are routinely ignored at diagnosis. Sydney Towle helped early onset cholangiocarcinoma into the public eye via TikTok, but her experience with delayed diagnosis was sadly the norm. Our data show the problem at scale. We looked at >116,000 patients with cholangiocarcinoma, including >5,000 diagnosed before 50. ❌ Younger patients had 24% higher odds of waiting >30 days for a diagnosis ⌛️ Median diagnostic delay was two months 🙍‍♀️ Young women were particularly affected The problem, as it seems, was getting to the diagnosis. Early-age cancer is bigger than #EACRC#. One liner? Young people get cancer too. When they tell us something is wrong, we should listen. Thanks for the opportunity to contribute @UGrewalMD @Onco_Nexus @OncoAlert @OncoDailyGI

GI Oncology saw some major changes in NCCN this week. 🔥 🧬 1. Daraxonrasib is officially in the pancreatic cancer guidelines You knew it was coming, now it is here. Preferred, Category 1. Use it. RASolute-302 in previously treated metastatic PDAC: OS: 13.2 vs 6.6 months, HR 0.40 PFS: 7.3 vs 3.5 months, HR 0.45 Subsequent therapy, and importantly it also sneaks into 1L as “useful in certain circumstances,” although only 2B for fit patients (but still there, YAY). So no, we are not throwing FOLFIRINOX/NALIRIFOX in the garbage (yet). But a RAS inhibitor is now a standard treatment for pancreatic cancer. 🔵 2. Zanidatamab + tislelizumab in NCCN for HER2+ GEA Zanidatamab + tislelizumab + chemo vs trastuzumab + chemo: PFS: 12.4 vs 8.1 months, HR 0.63 OS: 26.4 vs 19.2 months, HR 0.72 NCCN now lists zanidatamab-based therapy as Preferred first-line treatment. But… Category 2A. Why? 2A still means uniform NCCN panel consensus (≥85%) that the treatment is appropriate (so yes, you should be using this for these patients), but officially reflects lower-level evidence than Category 1. Except HERIZON was a randomized phase III trial with positive outcomes. So why 2A? Two informed guesses. 1. No US patients were enrolled. It was a large international study, and frankly the incredibly diverse patients I see in NYC probably look more like a global trial population than many historical US trials. 2. The control arm didn't include PD-1. HERIZON compared against trastuzumab + chemo, while our current US standard for PD-L1 CPS ≥1 is pembrolizumab + trastuzumab + chemo. But before we poo-poo HERIZON because of the comparator, let's look at what those studies actually achieved. KEYNOTE-811, CPS ≥1: PFS 10.9 months OS 20.1 months HERIZON: PFS 12.4 months OS 26.4 months Of course, no one would ever compared across trials. 😅 But HERIZON's own trastuzumab/chemo control arm had an OS of 19.2 months. This wasn't a control arm falling over. To me, these data show a real advance in HER2 therapy. If you’re using it, do watch for the diarrhea. NCCN specifically recommends antidiarrheal prophylaxis with zanidatamab and avoiding bolus 5-FU. Grade ≥3 diarrhea was 24.8% with the quadruplet but can be controlled and is only during the first few treatments. 3. And very briefly, MATTERHORN FLOT + durvalumab was upgraded 2B → 2A for PD-L1 <1 and diffuse-type EGJ adenocarcinoma. Overall MATTERHORN: 2-year EFS 67.4% vs 58.5%, HR 0.71, with pCR 19.2% vs 7.2%. Love seeing forward progress in GI Oncology. @TheGutOncLab @OncoAlert @Onco_Nexus @oncodaily

Just landed in Bermuda for the DAVA GI Malignancies Summit. 🇧🇲 Everyone thinks conference = vacation. Most of the time, I barely make it outside the conference room. The goal is to develop relationships, come up with new ideas (or move old ones forward), and come home with at least one new study, treatment, or piece of knowledge that can help the patients I see on Monday. Grateful to be in the room and to be part of a GI oncology community that keeps pushing the science forward. There is always more to learn, more to build, and hopefully more we can do for our patients. Want to follow along virtually? And maybe, just maybe, I’ll make it to the beach this time. 🏖️ #DavaGI# @DAVAOnc @Onco_Nexus @TheGutOncLab @OncoAlert

Fecal Transplant for ICI Colitis Control? Immune checkpoint inhibitors are nothing short of amazing. We are curing patients who previously had a prognosis measured in months. Looking at you, MSI-H mCRC. 🥹 But they have downsides. While much of oncology is focused on getting MORE patients to benefit from ICI, there is another important question: Can we make them less toxic? Enter this study just published in Cell Reports Medicine. 13 patients with ICI-induced diarrhea/colitis received fecal microbiota transplant as FIRST-LINE treatment. 💩🥤 <- Poop Milkshake The results? 💩 10/13 had a clinical response ⚡ Median time to improvement: 1.5 DAYS ✅ 8/10 responders remained in remission during follow-up And this was without starting with the usual steroids/biologics. Only the patients who failed FMT went on to standard immunosuppression. Yes, the study is tiny. Yes, we need randomized data. But the microbiome looks like it has major implications for immunotherapy, both for efficacy AND toxicity. Looking forward to larger studies. And absolutely keeping this one in my back pocket for refractory ICI colitis. 💩 @TheGutOncLab @OncoAlert @Onco_Nexus

World Lung is in full swing, which means the press releases are coming fast (before the papers or the sessions). 🫁 Why do we care in GI? Because all the shiny things start in lung and eventually make their way over here. HARMONi-2 compared ivonescimab vs pembrolizumab in PD-L1+ advanced NSCLC. We already knew the PFS result was kind of wild (in a China-only study): 11.1 vs 5.8 months HR 0.51 Now OS: 🔥 30.8 vs 22.6 months 🔥 HR 0.73 PD-L1 ≥50%: HR 0.58 PD-L1 1–49%: HR 0.85 So now this PD-1 x VEGF bispecific has beaten pembrolizumab for both PFS and OS in a randomized phase III trial. Yes, China only. Yes, pembro monotherapy is not really the comparator most of us would want for PD-L1 1–49%. Still. An 8-month OS difference is quite a bit. GI oncologists should be paying attention because this is already cooking in the first line mCRC setting with HARMONi-GI3. mFOLFOX6 + ivonescimab vs mFOLFOX6 + bevacizumab Is this an end-run around patent protection laws and PD1/PDL1's run out of time? (yes) Does the strategy have synergystic benefit? Time will tell. @OncoAlert @TheGutOncLab @Onco_Nexus

This week's OncoAlert 🚨 Newsletter is packed with practice-changing data: REGISTER TO GET IT 👉 The latest oncology news, trials, and practice-changing data — all in one place. 🔴 **LUNG:** DeLLphi-305 shows an OS benefit with **tarlatamab + durvalumab** in extensive-stage SCLC. Plus, new insights into **lazertinib** resistance/ctDNA clearance and **osimertinib** in uncommon EGFR mutations. 🟠 **GI:** Promising Phase 1 data explore **L-glutamine + gemcitabine/nab-paclitaxel** in advanced pancreatic cancer. 🔵 **GU:** New data on perioperative treatment strategies in **high-risk prostate cancer** and fracture risk with **abiraterone**. 🟣 **BREAST:** New insights into pCR with neoadjuvant THP in **HER2+ disease** and biomarkers in **stage I TNBC**. 🌍 **PLUS:** Meet **AcuVox** — a free platform helping oncology professionals track the trials, treatments, and topics generating the most attention at major cancer congresses. 👉 **Stay informed. Stay ahead. Read this week’s OncoAlert Newsletter.** #OncoAlert# #Oncology# #CancerResearch# #LungCancer# #BreastCancer# #ProstateCancer# #PancreaticCancer# @matteolambe @aftimosp @E_de_Azambuja @DrSGraff @ErikaHamilton9 @double_whammied @maryam_lustberg @raalbany @hoperugo @stolaney1 @LoiSher @JaniceTNBCmets @montypal @DrDanielHeng @apolo_andrea @DrChoueiri @PGrivasMDPhD @TiansterZhang @neerajaiims @amerseburger @sonpavde @drenriquegrande @tompowles1 @cdanicas @nataliagandur @realbowtiedoc @Onco_Cifu88 @scocmem @FernandoOnco @ElisaAgostinett @to_be_elizabeth @Erman_Akkus @MarioBalsaMD @DrMirallas @GIMedOnc @UOzkerim @DrRishabhOnco @PaulJiL @DaisukeKotani @DraMartinezLago @p_ciracimd @BenWestphalen @CentralParkWMD @graokane @amandaNizamMD @DrVilmaPBarcia

And just like that, adagrasib + cetuximab is no longer FDA approved for KRAS G12C colorectal cancer. The accelerated approval was officially withdrawn September 1 after KRYSTAL-10 failed to confirm benefit. We talked about KRYSTAL-10 when it was presented earlier this year. The phase III randomized 461 patients in 2L to adagrasib + cetuximab vs chemotherapy ± VEGF inhibition. It missed both primary endpoints: ▪️PFS: 7.5 vs 8.1 months, HR 0.89
▪️OS: 21.6 vs 21.7 months, HR 0.83 Hard to argue with a negative phase III trial. But I still like the idea of a chemo free option. Response rate was 47% vs 16%. That could matter for some patients (like those who you need just a little more shrinkage to enable crative intent therapy). KRYSTAL-10 asked whether adagrasib + cetuximab was better than chemotherapy in 2L. It wasn’t. That doesn’t mean the concept of KRAS G12C + EGFR blockade was wrong. And it doesn’t mean there aren’t patients for which this isnt valuable. Anyone celebrating this should look themselves in the mirror; this is a tool that has just been removed from our arsenal. However, the FDA did exactly what the system is designed to do; pull back if the Ph III doesnt pan out after accelerated approval. @OncoAlert @TheGutOncLab @Onco_Nexus

Was great to put my hematology hat back on and work alongside @UGrewalMD and @TimothyJBrownMD on this accompanying JCO article where we propose a 3 part framework for bringing TPO agonists into routine clinical practice for GI Oncology patients. We have the right tools to help patients maintain dose intensity; we just need to use them. @OncoAlert @TheGutOncLab @Onco_Nexus

FOLFOXIRI + cetuximab may not be as crazy as it sounds. But it is every bit as toxic as you'd expect. 🚽 For anyone wondering what might happen if we combined ALL THE THINGS in MSS mCRC, we have the randomized phase II DEEPER: 359 patients with 1L RAS WT mCRC mFOLFOXIRI + cetuximab vs mFOLFOXIRI + bevacizumab Overall: no PFS or OS benefit. Cetuximab with deeper responses: 57.3% vs 46.0%. And in the exploratory left-sided, RAS/BRAF WT subgroup (bear in mind ~30% didn't have known BRAF status): ▪️PFS: 14.8 vs 11.9 months, HR 0.71 ▪️OS: 50.2 vs 40.2 months, HR 0.74 Patients with extrahepatic disease seemed to do better and the effect washed out with liver limited disease: OS 50.2 vs 38.6 months, HR 0.60 Great? But the downside; TRIPLETE already showed us that adding irinotecan to FOLFOX + panitumumab didn't help. What it did do is cause Grade ≥3 diarrhea > 20%. 🚽🚽🚽 So no, triplet + anti-EGFR is not a new standard. But potentially it keys in on some interesting disease biology. And perhaps, once in a blue moon, if someone is feeling exceptionally aggressive with a grossly metastatic, YOUNG, left-sided RAS/BRAF WT patient? Well, maybe... @TheGutOncLab @OncoAlert @Onco_Nexus

Wishing @TimothyJBrownMD the best as he takes the next step in his journey. As someone who mentored, published, and ran interventional IITs, I look up to him immensely and we will certainly keep working together in the @TheGutOncLab and hopefully on projects with @NateraGenetics. Do wonder how UTSW GI Onc is going to fill in the massive void he (and several others) have left behind…

For Daraxonrasib 1st STEP Enroll in the (ON)Path Patient Support Program Confirm that your (ON)Path Enrollment Form has been submitted with your provider. @GIMedOnc -pls retweet - perhaps links to HCP portal info?

🚨 NEST is a big deal, and now fully published. 24 patients with localized CRC. BOT + BAL (CTLA4 + PD1) before surgery. 60% with major responses. We’ve been inching toward neoadjuvant therapy in colon cancer for years. FOxTROT tried it with chemotherapy and showed there was something there. NICHE then showed us that neoadjuvant immunotherapy can be wildly effective in dMMR/MSI-H colon cancer (I'm still pushing to rename this to Chalabi's disease). The real question has always been: can we make this work in pMMR/MSS disease? NEST says yes. Among the 22 pMMR tumors: 🔥 41% major pathologic response 🔥 32% pCR 🔥 59% had ≥50% tumor regression And no treatment-related delays to surgery. Chalabi's tumors (dMMR)? 100% MPR. It’s only a phase II, but a 32% pCR rate in pMMR colon cancer with immunotherapy is kind of insane. NEST is telling us MSS is be coming through the IO door next. And now we have ROBBIN (the phase III) coming. Get ready. Neoadjuvant therapy is going to become a much bigger part of how we treat colon cancer. This is where CRC is going. 🧬🔥 @OncoAlert @oncodaily @Onco_Nexus @TheGutOncLab

🚨 This may be the most consequential oncology study of 2026. Yes, on par with daraxonrasib. At #ASCO26# we highlighted the 5-year KEYNOTE-942 data for the individualized mRNA cancer vaccine intismeran + pembrolizumab in resected high-risk melanoma. And the numbers were 👀 RFS HR 0.51 5-year RFS: 68.8% vs 49.1% DMFS HR 0.41 OS HR 0.47 (still immature) Amazing data. But 157 patients. Phase IIb. The big question: does it hold up in phase III? Apparently, yes. 🔥 INTerpath-001 randomized 1,137 patients with resected stage IIB-IV melanoma to intismeran + pembrolizumab vs pembrolizumab alone. At the prespecified interim analysis: ✅ RFS met ✅ DMFS met ✅ Statistically significant AND ✅ No new safety signals We don’t have the HRs yet. So some restraint until we see the actual data (also this is a press release, so grain of salt) But why is this such a big deal? Because this isn’t really about melanoma. 🧬 Sequence YOUR tumor 🎯 Identify YOUR neoantigens 💉 Manufacture a vaccine specifically for YOUR cancer 🦠 Train YOUR immune system to recognize it And now that approach has succeeded in a randomized phase III trial. This is actually personalized. And if this platform works across tumor types, the implications are enormous. Daraxonrasib may change how we treat RAS-driven cancers. INTerpath-001 may change how we think about cancer vaccines altogether. 2026 has been an amazing year for oncology advances. 🔥 @OncoAlert @Onco_Nexus @TheGutOncLab

A randomized phase III rectal cancer trial out of China just reported some great results for Locally Advanced Rectal Cancer (and confirms our modern TNT practice). TNTCRT randomized 458 patients with high-risk LARC to conventional long-course CRT → surgery → adjuvant chemotherapy versus CAPOX before, during, and after long-course radiation. Yep. Doublet chemo, all the way through. 3-year DFS: 74.8% vs 66.0% HR 0.67 MFS: 77.7% vs 67.6% HR 0.66 pCR: 26.4% vs 9.8% Big numbers, much win. But the criticism is the comparator. The control arm is not how we treat high-risk rectal cancer in the US. We already know TNT is better than CRT → surgery → adjuvant chemotherapy based on OPRA's modern benchmark. With CRT followed by consolidation FOLFOX/CAPOX, 3-year DFS was 76%, essentially the same as the 74.8% seen here. But OPRA also comes with the added benefit of TME-free survival of 54%. I think what is still impressive is the scale and speed of this trial. The Chinese trial infrastructure is fully operational and anyone in drug development should take note. @TheGutOncLab @OncoAlert