📬 GI Cancer Intelligence Digest — Week 2026-W39

TROP2 expression mapped across gastric/GEJ cancer, including tumors without established actionable biomarkers, ahead of phase 3 sac-TMT data

TROP2 was widely expressed in gastric/GEJ cancer, including in tumors lacking established actionable biomarkers, with phase 3 sac-TMT results still awaited. Separately, a bispecific antibody-drug conjugate binding EGFR and HER3 is approved in China for nasopharyngeal carcinoma and esophageal squamous-cell carcinoma, with BMS holding rest-of-world rights and now taking it global. The parallel activity of these two ADC strategies in GI cancers sharpens a practical question: if TROP2 is broadly expressed in biomarker-negative gastric tumors, does antibody-drug conjugate selection there need any biomarker threshold at all?

Discussed by: @OncoAlert, @GlopesMd

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Daraxonrasib gets FDA breakthrough therapy designation in first-line metastatic pancreatic cancer, and a new cost-effectiveness preprint puts it at ~$500,000 per QALY

The FDA granted breakthrough therapy designation to daraxonrasib combined with gemcitabine/nab-paclitaxel for treatment-naive metastatic pancreatic adenocarcinoma, based on phase 1/2 RMC-GI-102 data. Daraxonrasib nearly doubled median overall survival in previously treated metastatic pancreatic adenocarcinoma, a setting where median survival with standard chemotherapy was about 7 months. A cost-effectiveness analysis placed daraxonrasib at approximately $500,000 per QALY at wholesale acquisition cost, with threshold list prices consistent with $150,000–$200,000/QALY set at $14,060–$17,730 per 30 days — a 55%–65% reduction from WAC; even doubling overall survival adds only 0.65 life-years, and at approximately $40,000 per month, longer treatment keeps the cost per QALY high, raising the question of whether first-line use — with its longer treatment duration — makes the value problem worse rather than better.

Discussed by: @Larvol, @GlopesMd, @NiuSanford, @OncoAlert, @Latinamd, @JCO_ASCO, @OncUpdates

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Sources cited: medRxiv · Daraxonrasib in Pancreatic Cancer: From Second-Line Breakthrough to First-Line Evidence (Journal of Clinical Oncology, 2026)

Bispecific EGFR/HER3 antibody-drug conjugate approved in China for esophageal squamous-cell carcinoma goes global

The world's first bispecific antibody-drug conjugate binds both EGFR and HER3, which are often co-expressed on the cell surface; the bispecific design improves avidity, promotes receptor clustering, and enhances payload delivery, with cells expressing low EGFR also captured through HER3. The agent is approved in China for nasopharyngeal carcinoma and esophageal squamous-cell carcinoma, with positive readouts in triple negative breast cancer and lung cancer, and BMS holds rest-of-world rights. In a separate report, EMB-01, an anti-EGFR/c-MET bispecific antibody, was studied in heavily pretreated metastatic colorectal cancer in a phase Ib/II open-label multicenter study, extending bispecific EGFR-directed strategies into additional GI tumor types and raising the question of whether improved avidity through bispecific design gives oncologists a route back into EGFR-directed therapy in tumors with low receptor expression.

Discussed by: @GlopesMd, @EladSharonMD

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Sources cited: EMB-01, an Anti-EGFR/c-MET Bispecific Antibody, in Patients with Heavily Pretreated Metas… (Clinical Cancer Research, 2026)

NEJM review of esophageal cancer: survival still rarely exceeds 20% at 5 years as adenocarcinoma and squamous-cell incidence diverge

A new NEJM review by Shao-Hua Xie, Elizabeth Smyth, and Jesper Lagergren confirms that esophageal cancer is the thirteenth most common cancer and seventh leading cause of cancer-related death worldwide, causing approximately 500,000 deaths annually, with 5-year survival having improved in recent decades but rarely exceeding 20%. On the perioperative side, ESOPEC — comparing perioperative FLOT versus neoadjuvant CROSS in resectable esophageal/GEJ adenocarcinoma — was published in NEJM and described as practice-changing, with an overall survival HR of 0.70 in favor of FLOT; the benefit was noted as not yet clear for squamous-cell carcinoma or low-stage adenocarcinoma. With survival capped near 20% at five years, clinicians are debating where the bigger return lies — earlier detection in high-risk groups, or further intensification of perioperative regimens.

Discussed by: @EladSharonMD, @GillSharlene, @cmpabon

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Sources cited: Esophageal Cancer. (N Engl J Med) · Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer (New England Journal of Medicine, 2025)

CLDN18.2 discordance meta-analysis: 35.8% intratumoral and 20.3% primary-metastasis disagreement means one biopsy can misclassify zolbetuximab eligibility

A systematic review and meta-analysis published in ESMO Gastrointestinal Oncology, covering 13 studies and 3,097 patients with gastric/GEJ cancer, found pooled intratumoral CLDN18.2 discordance of 35.8% (95% CI 20.5–54.7) and primary-to-metastasis discordance of 20.3% (95% CI 17.3–23.7). At that level of intratumoral heterogeneity, a single specimen can misclassify treatment eligibility, with multi-region or multi-lesion testing recommended when feasible. The degree of discordance directly frames whether declaring a gastric tumor zolbetuximab-ineligible on the basis of one biopsy can be considered reliable.

Discussed by: @OncoAlert, @K_Yadavir, @ronanhsieh

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Sources cited: Elsevier

PEGASUS published in Nature Cancer: ctDNA-guided adjuvant de-escalation misses its primary endpoint but confirms ctDNA as a powerful prognostic split in stage II/III colon cancer

PEGASUS enrolled 135 patients with high-risk stage II/III colon cancer; 26% (n=35) were ctDNA-positive at the postsurgery landmark, with 3-year DFS 58% for ctDNA-positive versus 83% for ctDNA-negative (HR 2.71; 95% CI 1.35–5.45; P=0.0036). The primary aim — determining whether oxaliplatin could be safely omitted in ctDNA-negative patients — was not met: the observed 2-year relapse-free rate was 88% (90% CI 81–93%), below the predefined threshold of ≥92%. Neurotoxicity was reduced 43% versus the historic TOSCA control, and FOLFIRI cleared 11 of 24 ctDNA converters with no relapses in that subgroup, yet 54% remained positive; ctDNA is a strong prognostic marker, but the trial does not establish that oxaliplatin can be safely omitted solely on the basis of a negative result, leaving the question of whether single-arm feasibility is sufficient or randomized confirmation is required.

Discussed by: @ronanhsieh, @OncoAlert, @jgong15

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Sources cited: Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk… (Nat Cancer)

NCCN adds daraxonrasib as preferred Category 1 in pancreatic cancer and zanidatamab-based therapy as preferred first line in HER2+ GEA, with MATTERHORN upgraded for PD-L1<1 and diffuse type

Daraxonrasib enters the NCCN pancreatic cancer guidelines as Preferred, Category 1, on the basis of RASolute-302 data showing OS 13.2 versus 6.6 months (HR 0.40) and PFS 7.3 versus 3.5 months (HR 0.45) in previously treated metastatic PDAC. For HER2-positive gastroesophageal adenocarcinoma, NCCN now lists zanidatamab-based therapy as Preferred first-line treatment at Category 2A, with zanidatamab plus tislelizumab plus chemotherapy versus trastuzumab plus chemotherapy showing PFS 12.4 versus 8.1 months (HR 0.63) and OS 26.4 versus 19.2 months (HR 0.72) in HERIZON-GEA-01; NCCN specifically recommends antidiarrheal prophylaxis and avoiding bolus 5-FU given grade ≥3 diarrhea of 24.8% with the quadruplet. FLOT plus durvalumab (MATTERHORN) was upgraded from Category 2B to 2A for PD-L1 <1 and diffuse-type EGJ adenocarcinoma, with overall 2-year EFS 67.4% versus 58.5% (HR 0.71) and pCR 19.2% versus 7.2%; whether zanidatamab-based therapy should be Category 1 rather than 2A given a positive phase III, or whether the absence of a PD-1 comparator arm justifies the lower grade, remains an open debate.

Discussed by: @GIMedOnc, @OncLive

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Sources cited: OncLive

Adjuvant therapy in biliary malignancies: new paper argues current benefit is inadequate and asks whether immunotherapy or a move to neoadjuvant is the answer

A new paper on adjuvant treatment in biliary malignancies concludes that improvement is much needed and asks whether immunotherapy is the answer or whether treatment should move to the neoadjuvant setting. In HER2-positive biliary tract cancer, the HERBOT trial of first-line trastuzumab with nivolumab, gemcitabine, and cisplatin met its primary endpoint, improving ORR and DCR with a manageable safety profile. A marketing authorization application for lirafugratinib in previously treated FGFR2-altered metastatic cholangiocarcinoma has been submitted to the EMA, and clinicians are pressing for hybrid-capture NGS — particularly in intrahepatic cholangiocarcinoma — to ensure FGFR2 fusions are not missed before treatment decisions are made.

Discussed by: @DrAngelaLamarca, @DrAngelaLamarca, @VJOncology, @OncLive

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Sources cited: Taylor & Francis · OncLive

KRAS G12D inhibitors report phase 1 activity in pancreatic cancer: GFH375 in Nature Medicine and HRS-4642 plus adebrelimab in Cancer Cell

GFH375, a dual ON/OFF-state KRAS G12D inhibitor, enrolled 74 patients (PDAC 43, NSCLC 16, CRC 10) at an RP2D of 600 mg once daily with no dose-limiting toxicities and grade ≥3 TRAEs in 36.5%; PDAC confirmed ORR was 35.1% (13/37) with median PFS 5.5 months and median OS 9.9 months, and NSCLC ORR was 35.7%. HRS-4642 plus adebrelimab in the RP2D cohort (n=37) produced a confirmed ORR of 43.2% (95% CI 27.1–60.5), DCR 81.1% (95% CI 64.8–92.0), median PFS 5.7 months (95% CI 4.0–7.5), and median OS 11.5 months (95% CI 9.2–16.9) in pretreated KRAS G12D-mutant metastatic PDAC. A separate phase 1 program in heavily pretreated pancreatic cancer with INCB161734 reported a 37% ORR described as significant in a typically refractory third-line population; new allele-specific combinations are also emerging, including G12D plus anti-PD-L1 with ORR 48.5% and G12C plus a farnesyltransferase inhibitor with ORR 60%, prompting debate over which agent or combination should move first into randomized first-line testing.

Discussed by: @HHorinouchi, @Gio_Marchegiani, @hongjaechon, @OncLive, @DrJashDatta

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Sources cited: Oral KRAS G12D inhibitor GFH375 for previously treated advanced solid tumors with KRASG12… (Nat Med) · Conference abstract · OncLive

Indirect comparison of first-line HCC combinations from reconstructed KM data ranks camrelizumab plus rivoceranib best against sorafenib

In a reconstructed individual-patient analysis of 8 phase III RCTs, camrelizumab plus rivoceranib had the best hazard ratio versus sorafenib (0.61), while cabozantinib plus atezolizumab showed no benefit; versus lenvatinib, nivolumab plus ipilimumab and pembrolizumab plus lenvatinib showed modest, similar gains, and the authors note that comparator choice shapes the results in a descriptive, not causal, ranking. Real-world data from the STAR-HCC multicenter Chinese cohort (n=4,250) showed transarterial plus systemic therapy beat systemic therapy alone with median OS 21.2 versus 16.1 months (HR 0.76; p<0.001), and ICI-based combinations reached median OS up to 22.4 versus 17.0 months against TKI monotherapy, with grade ≥3 adverse events in 28.3%. Early hepatic decompensation occurred in 31% of cohorts on immune checkpoint inhibitor therapy and nearly halved median OS — atezolizumab-bevacizumab 5.5 versus 16.2 months; STRIDE 5.2 versus 13.6 months — remaining significant after adjusting for baseline liver function, a finding that complicates any ranking derived from reconstructed indirect comparisons alone.

Discussed by: @hongjaechon, @hongjaechon, @LorenzaRimassa

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Sources cited: Elsevier · Elsevier

KEYNOTE-859 4.5-year follow-up: pembrolizumab plus chemotherapy keeps OS curves separated in first-line HER2-negative advanced gastric/GEJ cancer, with the clearest benefit at CPS ≥10

With 4.5-year follow-up, KEYNOTE-859 ITT OS was 12.9 versus 11.5 months (HR 0.78), with 4-year OS 14% versus 8%; in the PD-L1 CPS ≥10 subgroup, OS was 15.8 versus 11.8 months (HR 0.64), 4-year OS 26% versus 10%, PFS 7.8 versus 5.6 months (HR 0.62), and ORR 60.4% versus 43.2%. A network meta-analysis in first-line HER2-negative CLDN18.2-positive gastroesophageal cancer found similar or numerically favorable OS/PFS with zolbetuximab plus chemotherapy at CPS 1–<10 and a numerical advantage for immune checkpoint inhibitors at CPS ≥10, though these were indirect comparisons. The sustained OS separation largely confined to CPS ≥10 puts pressure on whether PD-L1 CPS and CLDN18.2 status should be read together to individualize first-line selection between checkpoint inhibition and zolbetuximab.

Discussed by: @OncoAlert, @OncoAlert

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HARMONi-2 overall survival lands for ivonescimab versus pembrolizumab, and GI oncologists are watching because HARMONi-GI3 is already testing the same bispecific in first-line mCRC

HARMONi-2 showed ivonescimab versus pembrolizumab PFS of 11.1 versus 5.8 months (HR 0.51) and OS of 30.8 versus 22.6 months (HR 0.73); in PD-L1 ≥50% the HR was 0.58 and in PD-L1 1–49% it was 0.85. The same PD-1 × VEGF bispecific is being tested in first-line mCRC in HARMONi-GI3, comparing mFOLFOX6 plus ivonescimab against mFOLFOX6 plus bevacizumab; a phase 2 of first-line ivonescimab 20 mg/kg plus mFOLFOX6 in colon cancer reported PR 71% and DCR 100% in a predominantly KRAS/BRAF-mutant cohort with liver metastases, with grade 3 TRAEs in 44% and only 4% discontinuation. The debate for GI oncologists is whether an 8-month OS gain over pembrolizumab in a lung cancer study justifies confidence in a PD-1 × VEGF bispecific added to FOLFOX in microsatellite-stable colorectal cancer.

Discussed by: @GIMedOnc, @TapiaJC1

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Fecal microbiota transplant as first-line therapy for checkpoint inhibitor colitis: 10 of 13 patients responded, with median improvement in 1.5 days

In 13 patients with ICI-induced diarrhea/colitis given fecal microbiota transplant as first-line treatment, 10/13 had a clinical response, median time to improvement was 1.5 days, and 8/10 responders remained in remission during follow-up; only patients who failed fecal microbiota transplant went on to standard immunosuppression, avoiding upfront steroids and biologics. A parallel question in the field concerns whether microbiome signatures can become a reliable biomarker for immunotherapy response — microbial signatures vary across studies, leaving the gut–liver–immune axis as a suggestive but not yet validated predictor. Clinicians are weighing whether a 10/13 response rate with 1.5-day median improvement is sufficient to attempt fecal transplant before steroids, or whether it should remain reserved for patients in whom standard immunosuppression has failed.

Discussed by: @GIMedOnc, @HepatomaRes

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Sources cited: Cell Press