IROCAS: PIII adjuvant mFOLFIRINOX vs mFOLFOX6 in high-risk stage III colon cancer, now in Annals of Oncology. TLDR: Adding irinotecan did nothing (because it has never worked in the adjuvant setting)📉 Key Points
• Adjuvant colon, pT4 and/or pN2
• mFOLFIRINOX vs mFOLFOX6, 12 cycles, n=795 Results
• 3-yr DFS 65.6% vs 66.3%, HR 1.07 
• 3-yr OS 91.2% vs 86.7%, HR 0.85
• Grade ≥3 AEs identical at 62% (little surprising, just more diarrhea and GCSF use) Importantly, the DFS curves sit on top of each other. Irinotecan doesn’t work in the adjuvant setting, which brings me to my next point, CIRCULATE-US 👀 The escalation arm is cooked. I wonder if there is still equipoise to enroll there? After this and DYNAMIC-III failed, do we have enough data? I guess OS is still immature here so there is a minuscule glimmer of hope? ctDNA keeps getting better at finding the patients who need better treatments, the problem is we didn’t have them until recently. My pitch? Let’s use the new meds, G12Xs, anti-HER2, ADCs with non-irinotecan payloads. We have to do better for our patients. No one should be reaching for Irinotecan as adjuvant in 2026. #ESMO26 
@OncoAlert @TheGutOncLab annalsofoncology.org/article…

For the final act of CheckMate 8HW, we finally have the significant OS data the doubters have been asking for. What happens when you have a great treatment and an even better one for a study (and almost everyone crosses over)? You have to wait a really, really long time for OS. Also, some thoughts on splitting the alpha I won’t get into here. Nivo/ipi vs nivo alone vs chemo, MSI-H/dMMR mCRC. Final OS analysis. Response rate 72% with nivo/ipi, 58% with nivo alone. 
Median OS still not reached. 
OS HR 0.66 for nivo/ipi over nivo, statistically significant. 
77% of nivo/ipi patients alive at 5 years. Three out of four patients alive at five years. In metastatic colorectal cancer. 🤯 Not even going to talk about the chemo arm. It's clearly worse, and there is never a time to give chemo in MSI-H unless someone has extreme, active autoimmune disease. “Debulking” is absolute nonsense. Bottom line: the doubters got their OS. Nivo/ipi is the first-line standard for MSI-H mCRC. Next steps: how do we decide length of therapy, and how do we manage oligometastatic progression? #ESMO26
@OncoAlert @TheGutOncLab @OncoAlert

HERIZON-GEA-01 second OS interim at #ESMO26, and I'm a triplet believer. In January I wondered if tislelizumab was necessary. With 35 months of follow-up, my answer is yes. 914 patients, 1L HER2+ GEA, randomized 1:1:1 to zani + chemo ± tislelizumab vs trastuzumab + chemo. Median OS
• Zani + chemo + tisle: 27.0 mo
• Zani + chemo: 22.9 mo
• Tras + chemo: 19.6 mo 3-year OS: 39.8% vs 31.5% vs 22.9% The doublet now has its own OS win over trastuzumab (HR 0.76, 95% CI 0.62–0.93, p=0.0088). The triplet vs trastuzumab got better with time (HR 0.72 at IA1, now 0.65). Triplet vs doublet: HR 0.81 (95% CI 0.65–1.00), p=0.0502. Yes, it technically misses. But 4 more months of median OS is clinically meaningful in metastatic gastric cancer. Patients also stayed on the triplet longer (~47 vs ~30 weeks), with no new safety signal. Takeaway: zani + chemo + tisle is my 1L default for HER2+ GEA. Bring on the bispecifics 🔥 @OncoAlert @TheGutOncLab @OncoAlert

ESMO 2026: GI abstracts I’m watching ESMO is a week away so time to post thoughts on studies that will either change practice, move the field forward or are thought provoking! Gut Onc Lab video next week once text is released. BELOW THE BELT AZUR-1: Dostarlimab for dMMR/MSI-H locally advanced rectal cancer (LBA87) When: Sun Oct 25, 11:00 CET. Lower GI Proffered Paper session. What: Stage II/III MSI-H rectal cancer (n=154) treated with dostarlimab alone. My take: This will be positive. Incredibly positive. This is already what I’m doing in clinical practice and is a massive step forward for the 5–10% of rectal cancer patients that are MSI-H. Yay. IROCAS: Adjuvant mFOLFIRINOX vs mFOLFOX6 in high-risk stage III colon cancer (LBA29) When: Sun Oct 25, 10:15 CET. Lower GI Proffered Paper session. What: Phase 3 of adjuvant mFOLFIRINOX vs mFOLFOX6 in T4 and/or N2 stage III colon cancer. My take: Important study, and honestly, it is going to predict if US-CIRCULATE will be positive. If this is negative, CIRCULATE will be a nail-biter. Encorafenib + cetuximab + FOLFIRI beyond progression in BRAF V600E mCRC (788RO) When: Sat Oct 24, 14:50 CEST. Lower GI Rapid Oral session. What: Continuing EC past progression, adding FOLFIRI, in BRAF V600E mCRC. My take: Already doing this in clinical practice with patients who have BRAF+ disease w/o resistance mechanism on ctDNA at progression. Data for its use is HUGELY welcome. CheckMate 8HW: Final overall survival (LBA32) When: Sat Oct 24, 15:42 CEST. Lower GI Rapid Oral session. What: Final OS for nivo/ipi vs nivo vs chemo in MSI-H metastatic CRC. My take: What happens when you do a trial with an agent that essentially cures a disease against another that cures most people? It is a really long damn trial. Excited for the final OS data. Will it be positive? TBD, but I certainly think the magnitude of benefit of dual IO makes it better than single agent, and this data could reinforce that practice. UNION: Short-course RT → camrelizumab + CAPOX in locally advanced rectal cancer (3530O) When: Sun Oct 25, 11:10 CET. Lower GI Proffered Paper session. What: Phase 3 of SCRT → camrelizumab + CAPOX vs long-course CRT → CAPOX in locally advanced rectal cancer. My take: pCR reported at ~40% in 2024, let’s see if more people were cured. Some criticism in changing radiation schedule and adding IO compared to standard, but will set the stage for future studies. EMT2: Omega-3 EPA after resection of colorectal liver metastases (LBA30) When: Sun Oct 25, 10:25 CET. Lower GI Proffered Paper session. What: Phase 3, double-blind, EPA vs placebo after CRLM resection. My take: It’s like fish oil but better. File this in the ALASCCA category of “costs nothing, helps people” if positive. ALASCCA + CHALLENGE ❤️ QTX3034 + cetuximab ± mFOLFOX6 in KRAS G12D CRC (790RO) When: Sat Oct 24, 15:15 CEST. Lower GI Rapid Oral session. What: Early data on an oral G12D-preferring KRAS inhibitor + cetuximab ± mFOLFOX6 in KRAS G12D mCRC. My take: Sick study. Moving us to molecularly driven treatments in earlier line settings for CRC. Where the field MUST move. If this isn’t positive I will eat a hat (a small one, preferably organic). BOT/BAL in the real world: refractory MSS mCRC and advanced sarcoma (905eP, 3771P) When: 905eP is an ePoster available throughout the meeting. 3771P is Mon Oct 26, 12:00 CET, sarcoma poster session. What: Real-world botensilimab + balstilimab in refractory MSS mCRC (AGEO, France) and advanced sarcoma (Spanish expanded access). My take: Gives us a look at Bot Bal in real world. Important data, multiple attempts to use CPI in advanced disease have provided mixed results, what happens when we use stronger agents? Runner-up: Biweekly vs conventional TAS-102 + bevacizumab in refractory mCRC (LBA31) When: Sat Oct 24, 15:37 CEST. Lower GI Rapid Oral session. What: Randomized comparison of biweekly vs standard-schedule TAS-102 + bev in refractory mCRC. My take: Runner up only because @cathyengmd already convincingly showed this is the dosing schedule we should be using. I already use this in clinical practice. Great to randomize but should be positive. UPPER GI CLARITY-Gastric01 + G-HOPE-001: CLDN18.2 ADCs in pretreated gastric/GEJ cancer (LBA7, LBA77) When: CLARITY-Gastric01 is Sun Oct 25, 17:18 CET, Presidential Symposium II. G-HOPE-001 is Fri Oct 23, 13:30 CEST, Upper GI Proffered Paper session. What: Two phase 3s of CLDN18.2 ADCs vs physician’s choice. Sone-Ve (CLARITY) was positive for OS, and arcotatug tavatecan (G-HOPE) was positive for PFS. My take: The next generation of CLDN18.2 is here. Expect less explosive emesis and improved outcomes. KEYNOTE-975: Pembrolizumab + definitive chemoradiotherapy in esophageal/GEJ cancer (2875O) When: Fri Oct 23, 13:50 CEST. Upper GI Proffered Paper session. What: Phase 3 of pembro vs placebo with definitive chemoradiation in esophageal/GEJ cancer. My take: Merck joins the D-FLOT era for patients still receiving definitive chemoRT. After the CROSS/FLOT study the impact of this is going to be less, but still important for patients receiving definitive chemoRT. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab in 1L HER2+ GEA, second interim (LBA79) When: Fri Oct 23, 16:15 CEST. Upper GI Rapid Oral session. What: Second interim of zanidatamab + chemo ± tislelizumab vs trastuzumab + chemo in 1L HER2+ GEA. My take: My practice in HER2+ upper GI/GEA has moved to Zani, will be helpful to see the longer-term outcomes here. SANO: Active surveillance vs surgery after neoadjuvant chemoradiotherapy for esophageal cancer, long-term results (LBA78) When: Fri Oct 23, 13:40 CEST. Upper GI Proffered Paper session. What: Long-term outcomes of active surveillance vs esophagectomy after nCRT in esophageal cancer. My take: People deserve to keep their organs. Our ability to offer this only improves when we layer in tools like ctDNA. Interested in what we can extrapolate to other organ systems (especially for MSI-H). PANCREAS RASolute 302: Daraxonrasib vs chemotherapy in previously treated mPDAC, subgroup analyses (LBA82) When: Fri Oct 23, 14:22 CEST. Upper GI Proffered Paper session. What: Additional subgroup analyses from the phase 3 of daraxonrasib vs chemo in 2L+ metastatic PDAC. My take: Everyone benefited. G12V more than others. Maybe there will be another standing ovation? Come for the science, stay for the clapping. AMPLIFY-7P: mKRAS vaccine ELI-002 7P vs observation in resected PDAC (LBA83) When: Fri Oct 23, 14:32 CEST. Upper GI Proffered Paper session. What: Randomized phase 2 of an off-the-shelf mKRAS vaccine vs observation after PDAC resection. It missed its DFS endpoint. My take: Vaccine therapies are the next frontier. Merck has pushed them forward in Melanoma where they are an amazing success, very interested in the randomized data here. Even if negative it will be critical data to learn from. HCC / BILIARY HARMONi-GI1: Ivonescimab vs durvalumab + GemCis in 1L biliary tract cancer (LBA8) When: Sun Oct 25, 17:42 CET. Presidential Symposium II. What: China-only phase 3 of a PD-1/VEGF bispecific vs durvalumab, both with GemCis. It was positive for OS. My take: PD-1/VEGF emerges in GI. Let’s see the benefit. China only. ACTICCA-1: Adjuvant gemcitabine + cisplatin after resected biliary tract cancer (LBA21) When: Sat Oct 24, 10:25 CEST. Upper GI Proffered Paper session. What: Phase 3 of adjuvant GemCis vs standard of care (capecitabine) after resection of cholangiocarcinoma or gallbladder cancer. My take: Might immediately change the standard of care for resected BTC. Worth tuning in for. @TheGutOncLab @Onco_Nexus @OncoAlert @oncodaily