GI Oncology Daily Digest

On May 8, 2026, the FDA granted approval to zenocutuzumab-zbco (Bizengri, Merus) for adults with advanced unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy. Approval was based on the open-label, multicenter eNRGy trial (NCT02912949) with 22 evaluable cholangiocarcinoma patients, all of whom had received prior systemic therapy. Zenocutuzumab is a first-in-class bispecific antibody that engages both HER2 and HER3, blocking the heregulin-driven HER3 dimerization that NRG1 fusions exploit. Dose: 750 mg IV every 2 weeks until progression or unacceptable toxicity. This is the first targeted therapy approved specifically for NRG1+ cholangiocarcinoma — a molecularly defined subset estimated at <1% of biliary tract cancers but with no other tumor-agnostic options after gemcitabine/cisplatin failure. The approval was processed under the FDA's Commissioner's National Priority Voucher pilot program. Practical implication: NGS-based fusion testing should now be standard in any cholangiocarcinoma patient failing first-line chemotherapy, alongside FGFR2, IDH1, BRAF, HER2, and MSI testing.

Long-term follow-up of the Phase II KEYNOTE-224 study with median follow-up of 83 months in sorafenib-pretreated patients (Cohort 1, n=104) and 50.9 months in treatment-naïve patients (Cohort 2, n=51). Cohort 1: median OS 13.2 months, 24-month OS 31%, 48-month OS 17%. Cohort 2: median OS 16.9 months, 24-month OS 34%, 48-month OS 20%. Median PFS 4.9 and 4.3 months respectively. The most striking finding is durability — responses continued beyond 48 months despite the protocol-mandated 2-year cap on pembrolizumab. Grade 3–5 treatment-related adverse events occurred in 26% (C1) and 15.7% (C2), with no late-emerging safety signals. While combination IO/anti-VEGF and dual IO are now standard 1L in HCC, KEYNOTE-224 establishes pembrolizumab monotherapy as a viable option for patients who cannot tolerate combinations or VEGF-directed therapy, and defines the survival tail clinicians should counsel HCC patients about: roughly 1 in 5 advanced HCC patients on single-agent IO will be alive at 4 years.

MD Anderson clinicogenomic and outcomes analysis of 63 patients with supermassive intrahepatic cholangiocarcinoma (≥10 cm diameter), validated against a matched NCDB cohort. In the MDACC cohort, ablative-dose radiotherapy compared to chemotherapy alone produced a median OS of 28.7 vs 11.9 months (HR 0.4, p=0.02). Tumor-related liver failure — the typical driver of mortality in these patients — was dramatically reduced: 12.1% (RT) vs 47.1% (chemo alone, p=0.01). The NCDB-matched analysis confirmed the benefit at a national level: OS 37.6 vs 8.9 months (p<0.001). Mutational profiling revealed no unique signature distinguishing supermassive from standard ICC — these are large tumors of the same biology, not a separate disease entity. Practical implication: in unresectable supermassive ICC, ablative RT should be discussed as a standard-of-care option alongside systemic therapy, not as a salvage maneuver. The data argue that prioritizing local control with ablative dose preserves liver function long enough for systemic therapy to matter.

Multicenter Phase II RATIONALE-213 (n=70 resectable esophageal squamous cell carcinoma) tested a PET/CT-adaptive neoadjuvant strategy: after two cycles of tislelizumab + chemotherapy, PET responders continued chemotherapy + tislelizumab, while non-responders escalated to chemoradiation + tislelizumab. Pathologic complete response was 30.0% in PET responders and 34.4% in PET non-responders. One-year disease-free survival was 79.0% vs 74.2%; one-year event-free survival 87.1% vs 67.8%. Grade ≥3 treatment-related adverse events were notably lower in the chemo-only continuation arm (50.0% vs 82.5%) — the principal goal of imaging-adaptive escalation. Higher baseline PD-L1 TAP score correlated with pCR. This trial does not replace neoadjuvant CROSS-style chemoradiation as a global standard, but it offers a path to spare PET-responding ESCC patients the toxicity of radiation while maintaining pCR rates in the 30% range — a meaningful direction for de-escalation in a disease where post-operative morbidity remains substantial.

TIME-PRODIGE-28 correlative analysis (139 randomized, 104 with paired ctDNA samples) in RAS/BRAF wild-type metastatic colorectal cancer treated with FOLFIRI-cetuximab induction followed by randomized maintenance. ctDNA-negative patients at baseline who remained negative after induction had the longest median PFS at 9.6 months. Among baseline-positive patients, ≥80% ctDNA decrease yielded median PFS of 3.4 months versus 2.1 months for <80% decrease (p=0.013) — a clean dose-response between ctDNA dynamics and outcome. EGFR-MAPK pathway alterations detected in ctDNA at baseline or during treatment were associated with shorter PFS and OS. At progression, acquired resistance alterations were identified in 26.9% (17/63) of patients and were associated with worse OS after re-induction (14.9 vs 19.4 months, p=0.025). The data support a ctDNA-guided strategy: patients with sustained clearance after induction are candidates for active maintenance or treatment holiday, while those with persistent ctDNA likely need continued combination therapy or early treatment switch.