TOP Immunotherapy trials from ESMO GI 2025

At the ESMO GI 2025 Congress, three pivotal clinical trials provided new data that could shape the future of immunotherapy across gastrointestinal (GI) cancers. From perioperative treatment in resectable gastric cancer to expanded access in advanced hepatocellular carcinoma (HCC), and a novel approach in immunotherapy-resistant pancreatic cancer, the MATTERHORN, SIERRA, and EXPEL PANC trials each target an unmet clinical need using innovative immune-based strategies.

MATTERHORN Trial: Durvalumab + FLOT in Resectable Gastric/GEJ Adenocarcinoma

Presented by Dr. Salah-Eddin Al-Batran, the Phase 3 MATTERHORN trial (NCT04592913) evaluated the addition of durvalumab, an anti–PD-L1 antibody, to perioperative FLOT chemotherapy (fluorouracil, leucovorin, oxaliplatin, docetaxel) in patients with resectable gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

• Event-Free Survival (Primary Endpoint): Durvalumab + FLOT showed a significant improvement in EFS compared to FLOT alone (HR = 0.71; p < 0.001). Median EFS was not reached in the durvalumab arm vs. 32.8 months with placebo.

• Overall Survival (OS): Favored durvalumab (HR = 0.78; p = 0.025), though not statistically significant at interim analysis.

• Safety Profile: Comparable Grade 3/4 adverse event rates (~71%) between arms. Immune-related AEs were seen in 25.5% of the durvalumab arm.

• Quality of Life: No significant differences in patient-reported outcomes between the arms.

Conclusion: These results support durvalumab + FLOT as a potential new perioperative standard of care for resectable G/GEJ adenocarcinoma, improving EFS without compromising quality of life or safety.

You can read the full article here

SIERRA Study: Durvalumab + Tremelimumab (STRIDE) in Unresectable HCC with Poor Prognostic Features

The Phase 3b SIERRA trial (NCT05883644), presented by Dr. Stephen L. Chan, evaluated the STRIDE regimen—a combination of durvalumab and a single priming dose of tremelimumab (an anti–CTLA-4 antibody)—in patients with unresectable hepatocellular carcinoma (HCC) and poor prognostic characteristics, including Child-Pugh B7/B8, ECOG PS 2, or main portal vein thrombosis (Vp4).

• Patient Population: 98 patients, including 35 with CP B7/B8, 44 with ECOG 2, and 19 with Vp4.

• Adverse Events: Grade 3/4 treatment-related AEs occurred in 19.4% of patients. Serious AEs in 32.7%. Immune-mediated AEs reported in 25.5%.

• Safety by Subgroup:

  • CP B7/B8: Grade 3/4 PRAEs in 17.1%

  • ECOG PS 2: 18.2%

  • Vp4: 26.3%

Conclusion: The STRIDE regimen maintained a manageable safety profile, even in high-risk populations often excluded from trials. These data support STRIDE as a viable immunotherapy approach in broader real-world HCC populations, extending the impact beyond the HIMALAYA study.

You can read the full article here

EXPEL PANC: BXCL701 + Pembrolizumab in Second-Line Advanced PDAC

In a disease historically unresponsive to immunotherapy, Dr. Benjamin A. Weinberg presented interim results from the Phase 2 EXPEL PANC trial (NCT05558982) evaluating BXCL701—a first-in-class oral DPP4/8/9 and fibroblast activation protein (FAP) inhibitor—in combination with pembrolizumab, a PD-1 inhibitor, in second-line advanced pancreatic ductal adenocarcinoma (PDAC).

• Patient Cohort: 21 patients enrolled; 16 evaluable at 18 weeks.

• Disease Control Rate (DCR): 39%

  • Partial responses: 17%

  • Stable disease: 22%

• Median PFS: 2.3 months (95% CI: 1.6–5.3)

• Median OS: Not yet reached

• Safety: No new or unexpected toxicities observed.

Conclusion: These preliminary findings suggest that BXCL701, by targeting immunosuppressive mechanisms within the tumor microenvironment, may sensitize PDAC to checkpoint blockade. Ongoing biopsy and biomarker analysis may clarify predictors of response in this historically immune-resistant setting.

You can read the full article here

ABSK-011-201 Trial: Irpagratinib + Atezolizumab in Advanced FGF19+ HCC

Presented at ESMO GI 2025 (Abstract 149MO), updated results from the Phase 2 ABSK-011-201 trial evaluated the combination of irpagratinib, an FGFR4 inhibitor, and atezolizumab, a PD-L1 inhibitor, in patients with advanced hepatocellular carcinoma (HCC) and FGF19 overexpression.

• Objective Response Rate (ORR): Among 29 evaluable patients, the confirmed ORR was 51.7%, with responses observed in both first-line (50.0%) and previously treated (52.9%) subgroups. Most responses were ongoing at a median follow-up of 7.1 months, and the median duration of response (DOR) had not yet been reached.
• Progression-Free Survival (PFS): Median PFS was ≥7.0 months, and overall survival data were not yet mature.
• Safety Profile: Treatment-related adverse events (TRAEs) included liver function test elevations, with grade 3 ALT increase in 12.1% and AST increase in 9.1%. There were no grade 4/5 TRAEs and no treatment discontinuations due to toxicity.
• Patient Population: The trial was conducted in China; ~85% of patients were positive for hepatitis B virus (HBV). This highlights the need for further validation in broader global cohorts.
• Expert Commentary: Dr. Rachna Shroff (University of Arizona Cancer Center) noted,

“These are exciting data for patients with FGF19-positive tumours, which are associated with a poor prognosis… We have not reached the median DOR yet. However, additional details about the selection criteria, including how patients were screened for FGF19, would be of interest.”

Conclusion: This early-phase study demonstrates promising activity of irpagratinib + atezolizumab in a molecularly defined subset of HCC with limited therapeutic options. Longer follow-up and biomarker refinement will be key to confirming its potential.

Givastomig + Nivolumab + mFOLFOX6 in CLDN18.2+ Gastric, GEJ, and Esophageal Adenocarcinoma

Presented by Dr. Samuel Klempner at ESMO GI 2025, the phase 1b study (NCT04900818) evaluated givastomig—a bispecific antibody targeting CLDN18.2 and 4-1BB—in combination with nivolumab and mFOLFOX6 in patients with HER2-negative, CLDN18.2-positive advanced gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma.

• Objective Response Rate (Primary Efficacy): The combination achieved an ORR of 71% across all evaluable patients (n = 17). In PD-L1 CPS ≥5 patients, the ORR was 82%. High response rates were also observed across CLDN18.2 expression levels (67% for ≥75%; 80% for <75%).
• Progression-Free Survival (PFS): Median PFS and duration of response were not yet reached at 9-month follow-up. Six-month PFS rate was 72.9%.
• Safety Profile: Givastomig was well tolerated at all tested doses (5, 8, 12 mg/kg). Grade ≥3 treatment-emergent adverse events occurred in 65% of patients; 24% were related to givastomig. No dose-limiting toxicities were reported, and no treatment-related deaths occurred.
• Mechanism of Action: Givastomig binds CLDN18.2-positive tumor cells and conditionally activates 4-1BB signaling to stimulate T cells in the tumor microenvironment, while minimizing systemic immune toxicity.

Conclusion: Givastomig plus chemoimmunotherapy demonstrated promising efficacy and manageable safety in CLDN18.2+ upper GI cancers, including in patients with low PD-L1 expression. Expansion cohorts are ongoing.