📬 GI Cancer Intelligence Digest — Week 2026-W31

FDA accepted the daraxonrasib NDA for previously treated metastatic pancreatic cancer under a 1-2 month priority voucher review, the first-in-human mutant KRAS interception vaccine drew wide comment, and phase III FIGHT-302 pemigatinib data published in JCO.

⚡ TL;DR

📄 Publications

Total Neoadjuvant Therapy With Long-Course Radiotherapy Versus Chemoradiotherapy in High-Risk Locally Advanced Rectal Cancer (TNTCRT): A Multicenter, Randomized, Phase III Trial. — 3-year DFS 74.8% vs 66.0% with doublet-LC TNT versus nCRT, HR 0.674
Short-Course Radiotherapy-Based Total Neoadjuvant Therapy plus Tislelizumab for Locally Advanced Rectal Cancer (Neo-STAR): Early Outcomes of a Randomized Phase II Trial. — pCR 45.3% with tislelizumab added versus 27.6% without (P = 0.052)
Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-Line Therapy for Advanced Colorectal Adenocarcinoma: the Phase II DeFianCe Trial. — Median PFS 9.2 vs 8.3 months, HR 0.84, primary endpoint not met

🐦 Twitter / 🦋 Bluesky

First-in-human mutant KRAS vaccine for pancreatic cancer interception draws wide clinician comment — This is described as the first study to demonstrate feasibility of a mutant KRAS targeted vaccine in high-risk individuals, with persistent T cells about 2 years
Narrative review on optimizing multimodality sequencing in HCC circulates widely — The review argues HCC management is shifting toward a personalized, multimodal continuum
NEJM editorial "Breaking the RAS Barrier in Pancreatic Cancer" frames the RASolute 302 moment — An NEJM editorial titled "Breaking the RAS Barrier in Pancreatic Cancer" accompanied the RAS data
Review of cancer-associated thrombosis in GI cancers shared across GI oncology accounts — A review of cancer-associated thrombosis in GI cancers was circulated to the GI oncology community
FDA accepts daraxonrasib NDA for previously treated metastatic pancreatic cancer, with review possible in 1-2 months — Revolution Medicines' NDA for daraxonrasib was accepted for review by the U.S. FDA for previously treated metastatic pancreatic cancer

Full details below ↓

📄 What's Being Published

Manuscripts:

Non-Armored GCC-targeting CAR-T cell therapy demonstrates significant efficacy in patients with advanced colorectal cancer. — Zhang Qianyu et al., Clin Cancer Res

In heavily pretreated metastatic colorectal cancer, the overall response rate (ORR) and disease control rate (DCR) reached 33% and 63%, respectively. Median progression-free survival was 57 days and median overall survival was 190 days. All patients experienced grade 3 or higher hematologic toxicity, 75% developed cytokine release syndrome, and two treatment-related deaths occurred.

Clinical bottom line: The full Clinical Cancer Research report confirms GCC-targeted CAR-T produces genuine but short-lived responses in refractory colorectal cancer, and the toxicity profile means dose and eligibility must be re-engineered before further development.

Read full article →

Total Neoadjuvant Therapy With Long-Course Radiotherapy Versus Chemoradiotherapy in High-Risk Locally Advanced Rectal Cancer (TNTCRT): A Multicenter, Randomized, Phase III Trial. — Wang Xin et al., J Clin Oncol

Doublet-LC TNT improved 3-year DFS (74.8% vs 66.0%; HR 0.674 [95% CI, 0.489 to 0.929]; P = .016) and metastasis-free survival (77.7% vs 67.6%; HR 0.655 [95% CI, 0.469 to 0.915]) compared with neoadjuvant chemoradiotherapy, alongside a substantially higher pathologic complete response rate (26.37% vs 9.80%; P < .001). Grade ≥3 adverse events during the neoadjuvant phase were more frequent with doublet-LC TNT (27.59% vs 8.56%; P < .001), though severe toxicities across the entire treatment course were comparable (28.02% vs 24.32%; P = .371).

Clinical bottom line: Doublet chemotherapy delivered uninterrupted around long-course radiotherapy should now be considered a standard TNT option for high-risk locally advanced rectal cancer, buying disease-free and metastasis-free survival without a net toxicity penalty.

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Short-Course Radiotherapy-Based Total Neoadjuvant Therapy plus Tislelizumab for Locally Advanced Rectal Cancer (Neo-STAR): Early Outcomes of a Randomized Phase II Trial. — Wu Fengpeng et al., Cancer Commun (Lond)

The pCR rate was 45.3% (95% CI, 31.5% to 59.8%) in the SCRT-TNT-ICI group compared to 27.6% (95% CI, 16.6% to 40.8%) in the SCRT-TNT group (odds ratio 2.17; 95% CI, 0.99 to 4.79; P = 0.052), missing conventional statistical significance. Major pathological response rates were 50.9% (95% CI, 36.6% to 65.2%) versus 31.0% (95% CI, 19.5% to 44.6%; odds ratio 2.31; 95% CI, 1.06 to 5.01; P = 0.033), a difference that did reach significance.

Clinical bottom line: Adding tislelizumab to short-course radiotherapy-based TNT missed statistical significance on pCR by a hair while significantly increasing major pathological response, making the combination a phase III question rather than a practice change.

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Sirexatamab in Combination with Bevacizumab and Chemotherapy as Second-Line Therapy for Advanced Colorectal Adenocarcinoma: the Phase II DeFianCe Trial. — Wainberg Zev A et al., Clin Cancer Res

Median PFS was 9.2 months with sirexatamab versus 8.3 months with control (HR 0.84; 95% CI, 0.58–1.21; one-sided p = 0.1712), and the primary endpoint was not met; ORR was 35.1% versus 26.6% (one-sided p = 0.1009). In patients with baseline plasma DKK1 above the median, PFS HR was 0.61 (95% CI, 0.37–1.00) and OS HR was 0.42 (95% CI, 0.19–0.91), with ORR 38.0% vs 23.7% in that subgroup.

Clinical bottom line: DeFianCe is a negative trial in all comers, and any future development of DKK1-directed therapy in colorectal cancer must be run in a plasma DKK1-selected population.

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Multikinase Inhibition with Tinengotinib in Advanced Solid Tumors: Results from a Multicenter Phase Ib/II Trial. — Piha-Paul Sarina A et al., Clin Cancer Res

The objective response rate in cholangiocarcinoma (n = 23) was 13.0%. Among 197 patients receiving tinengotinib across tumor types, treatment-related treatment-emergent adverse events occurred in 160 (81.2%) patients, most commonly hypertension; hyperphosphatemia and ocular toxicities were uncommon.

Clinical bottom line: Tinengotinib delivers modest but real activity in cholangiocarcinoma with FGFR2 fusions among responders, and its low rate of hyperphosphatemia and ocular toxicity distinguishes it from selective FGFR inhibitors.

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Impact on survival of severe immuno-related adverse events in deficient mismatch repair/microsatellite instable-high digestive cancers treated with immunotherapy. — Tougeron David et al., J Immunother Cancer

Across 1,175 patients from 34 centers, 382 (32.5%) had an irAE and 117 (10.0%) had a severe irAE (irSAE); irSAE was associated with a better ORR (48.6% vs 34.6%, p < 0.0001) but was not associated with better PFS (HR 1.280 [95% CI, 0.898 to 1.824], p = 0.172) or OS (HR 1.043 [95% CI, 0.712 to 1.528], p = 0.828). ICIs were resumed in 26.9% of patients following irSAEs, with an irAE recurrence rate of 57.1%.

Clinical bottom line: Clinicians should stop treating a severe immune-related adverse event as a favourable prognostic sign in dMMR/MSI-H digestive cancers: response rates are higher but survival is not, and rechallenge carries a majority chance of recurrence.

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A phase 2 multicenter trial of rucaparib and nivolumab as maintenance therapy in patients with advanced biliary tract cancer: BilT-02. — Mohan Arathi et al., Clin Cancer Res

The 4-month PFS rate was 54.8% (95% CI, 36.0–72.7) in all patients, missing the primary endpoint, but reached 83.3% and 100% in the DDR and IDH1 cohorts, respectively. Median PFS1 was 4.6 months (95% CI, 3.7–6.2) and median OS1 was 15.9 months (95% CI, 9.8–24.1).

Clinical bottom line: Rucaparib plus nivolumab maintenance failed in unselected advanced biliary tract cancer and should only be pursued in DDR- or IDH1-altered patients, where the 4-month PFS rates were far above expectation.

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Safety and efficacy of fecal microbiota transplantation in solid cancers resistant to immune checkpoint inhibitors: results of the MITRIC trial. — Ullern Andreas et al., J Immunother Cancer

No objective responses were observed among 12 patients, while 5/12 recorded stable disease; median PFS was 1.5 months and median OS was 10.1 months. FMT was well tolerated, though immune-related toxicity occurred in 6/12 patients.

Clinical bottom line: Fecal microbiota transplantation from checkpoint inhibitor responders is feasible and safe but produced no objective responses in this basket trial, so donor selection and patient selection criteria must be defined before further trials are justified.

Read full article →

🗣️ What People Were Discussing This Week

How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).

First-in-human mutant KRAS vaccine for pancreatic cancer interception draws wide clinician comment

This first-in-human study demonstrated the feasibility of a mutant KRAS-targeted vaccine administered not to patients with established disease but to high-risk individuals: 20 participants received the investigational vaccine, 90% achieved an immune response, none developed the malignancy, and responses remained detectable for as long as 2 years. Published in Cancer Discovery, the study reported T cell responses in 90% of patients with hereditary pancreatic ductal adenocarcinoma predisposition, classified as immune responders, with persistence up to 2 years and no participants developing PDAC. The central question for clinicians is whether a durable T cell response in high-risk individuals is a sufficient basis to launch an incidence-reduction trial, or whether interception studies must wait for lesion-level endpoints.

Discussed by: @EladSharonMD, @EladSharonMD, @Gio_Marchegiani, @CyHusain, @HemOncToday, @CancerNetwrk

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Narrative review on optimizing multimodality sequencing in HCC circulates widely

A narrative review framed as expanding the path to cure through optimized multimodality sequencing in HCC circulated widely among GI oncologists this week, with contributors characterizing HCC management as shifting toward a personalized, multimodal continuum. The review was shared both as a Canadian perspective on the therapeutic continuum and, separately, as a practical guide to sequencing decisions. The underlying debate is where in the HCC continuum sequencing choice actually changes cure rates, rather than merely reordering the same agents.

Discussed by: @ArndtVogel, @Erman_Akkus, @OncoAlert

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NEJM editorial "Breaking the RAS Barrier in Pancreatic Cancer" frames the RASolute 302 moment

An NEJM editorial by @ShivanSivakumar titled "Breaking the RAS Barrier in Pancreatic Cancer" accompanied the RASolute 302 data, with clinicians describing back-to-back pioneering breakthroughs in the same issue of NEJM with targeted therapy doubling OS in advanced pancreatic cancer. The agent — taken as a pill once a day — doubled the survival time of those enrolled in a 500-person trial, with fewer side effects compared to traditional chemotherapy. The open question now is which combination or line of therapy should be prioritized to build on a single-agent survival doubling.

Discussed by: @Aiims1742, @BalazsHalmosMD, @aliya_Hshah

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Review of cancer-associated thrombosis in GI cancers shared across GI oncology accounts

A review of cancer-associated thrombosis in GI cancers was circulated broadly to the GI oncology community this week. The same accounts also shared a phase II trial — the ACT-GI trial — of avatrombopag versus placebo for persistent chemotherapy-induced thrombocytopenia in GI cancers, published in the Journal of Clinical Oncology. The practical question circulating alongside both pieces is how thromboprophylaxis and platelet support decisions should be integrated into routine GI cancer treatment plans.

Discussed by: @Erman_Akkus, @EladSharonMD

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FDA accepts daraxonrasib NDA for previously treated metastatic pancreatic cancer, with review possible in 1–2 months

Revolution Medicines' NDA for daraxonrasib was accepted for review by the U.S. FDA for previously treated metastatic pancreatic cancer, supported by the phase 3 RASolute 302 trial. Under the FDA Commissioner's National Priority Voucher pilot program, review of the NDA could be completed in 1 to 2 months. Clinicians framed the acceptance as the start of the regulatory clock, noting that an oral RAS inhibitor with phase 3 PFS and OS benefit is the basis for the submission, and the operative question is how quickly pancreatic cancer practices can transition patients off expanded access and onto commercial supply if approval follows within that window.

Discussed by: @GIMedOnc, @CathyEngMD, @pashtoonkasi, @BHuffmanMD, @jgong15, @OncLive

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Review of therapeutic developments in MSS colorectal cancer circulates among GI oncologists

A review article summarizing therapeutic developments for MSS colorectal cancer was shared this week as an excellent overview of the field, and a separate review on next-generation precision oncology in MSS colorectal cancer was published the same week. Both pieces circulated among GI oncologists, sharpening the debate over which MSS colorectal strategies now described in review articles — bispecifics, neoadjuvant immunotherapy, or targeted combinations — deserves the next phase III trial.

Discussed by: @DaisukeKotani, @AlgazeMD

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FIGHT-302 phase III pemigatinib published in JCO for FGFR2-rearranged cholangiocarcinoma

The phase 3 FIGHT-302 trial of pemigatinib was published in the Journal of Clinical Oncology this week, with frontline pemigatinib cutting the risk of progression or death by 42% versus gemcitabine/cisplatin in FGFR2-rearranged cholangiocarcinoma. Investigators described PFS rate, response rate, and duration of response as all significantly improved, characterizing FIGHT-302 as the largest study ever to report first-line activity for an FGFR inhibitor in cholangiocarcinoma. The central clinical debate is whether a first-line FGFR inhibitor now displaces gemcitabine/cisplatin-based chemotherapy in this molecularly selected population, or whether chemo-immunotherapy should still come first.

Discussed by: @VivekSubbiah, @OncLive, @OncLive, @JCO_ASCO

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CHALLENGE cost-utility analysis: structured exercise after adjuvant chemotherapy for colon cancer is cheaper and more effective

A prespecified economic evaluation of the phase III CHALLENGE trial found that a 3-year structured exercise program for patients with stage II/III colon cancer was both more effective and less costly than standard health education, improving life-years and quality-adjusted life-years while reducing overall healthcare expenses, largely by lowering recurrence-related costs. Some clinicians pushed back on the framing, noting that new oncology drugs are not expected to be cost-saving to become standard of care in the U.S. and that exercise is being held to a higher economic bar than drugs. The debate turns on whether a survivorship intervention that is both cost-saving and survival-improving should be held to a stricter economic standard than a new drug.

Discussed by: @NiuSanford, @OncoAlert, @JCO_ASCO

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Modified perioperative FLOT in resectable gastric/GEJ adenocarcinoma reports favorable real-world outcomes

In 29 patients treated with modified perioperative FLOT for resectable gastric or GEJ adenocarcinoma, curative-intent resection was achieved in 86%, R0 resection in 88%, and pCR in 16%; at a median follow-up of 30.3 months, median OS was 53.6 months (3-year OS 75.3%) and median RFS was 46.1 months (3-year RFS 52.4%), with grade ≥3 neutropenia in 34%, infections in 10%, and no treatment-related deaths. Separately, an analysis of 522 patients with advanced gastric cancer found that HER2-low versus HER2-null status was associated with more liver metastases, higher CEA, and worse ECOG performance status, but was not independently prognostic. The operative question is whether predefined dose modification is a better strategy than switching regimens when standard-dose FLOT is likely to be undeliverable.

Discussed by: @sonbol_bassam, @BbaharK

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🔥 Top Ranked Tweets

Oncology Learning Network @OncLearnNetwork

Phase 3 #EMERALD3 results show #STRIDE-based #immunotherapy plus #TACE, with or without #lenvatinib, significantly improved PFS versus TACE alone in embolization-eligible #HCC. Learn more: https://t.co/nG1RErCClj https://t.co/rwXNogWqra

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