Michael Shusterman, MD

Would you like a glimpse of the future? Where solid tumor oncology may be heading? Look no further. Agenus may have had some ups and downs in the past (BATMAN -> ROBBIN), but Bot Bal looks like it has the capacity to absolutely change how we manage MSS solid tumors. UNICORN, now in Nature Medicine. Phase 2, non-randomized, window-of-opportunity. Resectable rT3-4 colon cancer. One dose of botensilimab, two doses of balstilimab, surgery around day 30-40. Highlights: MPR 36% (5/14) in MSS disease, pCR 29%. Omg. (compare to FOLFOX in FOxTROT: 8%) Bot alone in MSS: 0%. The PD-1 matters. dMMR Bot Bal: MPR 100%, pCR 93% 😍12-month EFS 100% in both Bot Bal cohorts Yes there is tox. irAEs in 54%, mostly flu-like symptoms, and only one grade 3 (hyperthyroidism). No grade 3 diarrhea. Every MSS responder cleared ctDNA before surgery, that’s a helpful tool for predicting response in a disease that may fibrose and stay visible on imaging. The holy grail is almost here: melting the majority of rectal cancers away. In MSI-H we have AZUR-1. In MSS, perhaps we have this in the future. nature.com/articles/s41591-0… @OncoAlert @TheGutOncLab @Onco_Nexus

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

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