Key Updates in Gastrointestinal Oncology from ESMO 2025
The 2025 ESMO Congress brought several important updates across gastrointestinal (GI) cancers, highlighting the continued evolution of immunotherapy and targeted approaches in both curative and advanced disease settings. Several key studies were especially relevant and noteworthy.
MATTERHORN: Perioperative Durvalumab Plus FLOT in Resectable Gastric and GEJ Adenocarcinoma
The phase 3 MATTERHORN trial evaluated the addition of durvalumab to perioperative FLOT chemotherapy in patients with resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma. Patients were randomized 1:1 to durvalumab plus FLOT (D-FLOT) or placebo plus FLOT, followed by maintenance durvalumab or placebo after surgery.
At the 2025 ASCO Annual Meeting, MATTERHORN demonstrated a significant improvement in event-free survival (EFS), with a two-year EFS of 67.4% versus 58.5% and a hazard ratio (HR) for event or death of 0.71 (95% CI, 0.58–0.86; P < .001). The final overall survival (OS) analysis presented at ESMO 2025 confirmed a continued benefit, with an HR of 0.78 (95% CI, 0.63–0.96; P = .021).
The OS advantage appeared more pronounced in PD-L1 positive tumors (TAP ≥ 1%), where HR was 0.79 (95% CI, 0.63–0.99), compared with PD-L1 negative tumors (HR, 0.79; 95% CI, 0.41–1.50), which comprised about 10% of the population. While the magnitude of benefit may be smaller in PD-L1 negative disease, the limited numbers make it difficult to conclude that these patients derive no benefit.
Overall, D-FLOT demonstrated a statistically and clinically meaningful survival benefit, establishing a new standard of care for resectable gastric and GEJ adenocarcinoma. The regimen may be especially beneficial for patients with PD-L1 positive tumors.
FORTITUDE-101: Bemarituzumab Plus FOLFOX in FGFR2b-Positive Gastric Cancer
The phase 3 FORTITUDE-101 trial assessed bemarituzumab, a monoclonal antibody targeting FGFR2b, combined with FOLFOX chemotherapy, compared to placebo plus FOLFOX in FGFR2b-positive advanced gastric and GEJ adenocarcinoma (n = 547). The initial analysis showed a median OS of 17.5 versus 12.5 months (HR, 0.61, P = 0.005) and a clear progression-free survival benefit.
However, longer follow-up revealed attenuation of effect, with a median OS of 14.5 versus 13.2 months (HR, 0.82, 95% CI 0.62–1.08). Corneal adverse events (a known on-target effect) were frequent but manageable. FORTITUDE-101 is unlikely to change practice at this point. Ongoing FORTITUDE-102, which combines bemarituzumab with immunotherapy, will determine whether this combination can deliver more durable benefit.
CARES-009: Perioperative Camrelizumab Plus Rivoceranib in Resectable HCC
In resectable hepatocellular carcinoma (HCC), the CARES-009 phase 3 trial compared perioperative camrelizumab (PD-1 inhibitor) plus rivoceranib (VEGFR2 tyrosine kinase inhibitor [TKI]) versus surgery alone in patients with CNLC Ib–IIIa, Child-Pugh A disease. Combination therapy significantly improved EFS, with a median of 42.1 versus 19.4 months (HR, 0.59, 95% CI 0.41–0.85; P = .004).
A major pathological response (≤ 50% viable tumor cells) occurred in 35% of treated patients versus 7.5% in the control arm, and 10% achieved near-complete or complete tumor regression. No new safety signals were identified. These results highlight the promise of perioperative immunotherapy plus VEGF blockade in the potentially curative setting for patients with HCC. This also reinforces the direction in which the field appears to be moving in general–perioperative therapy helps improve outcomes in patients undergoing surgical resection.
STELLAR-303: Zanzalintinib Plus Atezolizumab in Refractory Colorectal Cancer
STELLAR-303 evaluated zanzalintinib, a multitargeted TKI (TAM, MET, VEGFR), plus atezolizumab versus regorafenib in 901 patients with refractory, microsatellite stable metastatic colorectal cancer. At a median follow-up of 18 months, the combination showed a median OS of 10.9 versus 9.4 months (HR, 0.80, P = .0045); the first immunotherapy-based regimen to demonstrate an OS benefit in this population. The benefit was greatest in patients without liver metastases (median OS 15.9 vs 12.7 months), consistent with the liver’s role in immune resistance.
Toxicity was a concern with grade 3 or higher events, occurring in 60% of patients on the combination versus 37% with regorafenib. Although the survival benefit is modest and the combination appears toxic, there is optimism that with appropriate dosing strategies in real world populations, tolerability will improve. This is welcome progress in the refractory disease setting and opens doors for more immunotherapy-based combinations in this tumor type that has historically been considered “cold.”
This year’s ESMO data reflect meaningful progress in GI oncology, with new therapeutic options emerging in both curative-intent and refractory settings. Immunotherapy combinations continue to expand their reach, while targeted agents are being refined to further advance the goal of personalized care. These developments represent truly encouraging progress for patients and the field. Heading into the ASCO GI 2026 symposium in San Francisco, there is strong optimism with these data, that will undoubtedly spark further discussion and exchange of knowledge among colleagues.