ESMO 2025 TIGIT and PD-1 blockade shows ‘encouraging’ survival rates in gastroesophageal cancer

medwireNews: The monoclonal antibodies domvanalimab and zimberelimab show survival benefits when combined with chemotherapy in patients with advanced gastric cancer (GC), gastroesophageal junction cancer (GEJC), or esophageal cancer (EAC), indicates the phase 2 EDGE-Gastric study.

“These findings provide the rationale for continued investigation of domvanalimab, zimberelimab and chemotherapy in advanced GC/GEJC/EAC in the ongoing phase 3 STAR-221 trial,” write Yelena Janjigian (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues in Nature Medicine.

Blockers of the T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) including domvanalimab are designed to boost T-cell activation, potentially enhancing the immune-cell activation achieved with PD-1 inhibitors such as zimberelimab for more durable benefits, the authors write.

The results reported are for adults enrolled in a nonrandomized arm of one of two first-line setting cohorts from the study and included 41 patients aged 30–82 years with previously untreated advanced HER2-negative GC (63%), EAC (24%), or GEJC (12%). They were a median of 62 years old, 59% were men, and 51% were Asian.

Seventy-one percent had a clinical tumor stage of IVB, with 95% of tumors being metastatic. A total of 29% and 44% of patients had liver and peritoneal metastases, respectively.

Every 4 weeks, the patients received intravenous domvanalimab (1600 mg) and zimberelimab (480 mg), alongside FOLFOX chemotherapy.

After a median follow-up of 26.4 months and a median treatment exposure of 49.4 weeks, the investigators reported “encouraging” outcomes in the cohort, with an objective response rate (ORR) of 58.5%, including complete (CR) and partial (PR) response rates of 7.3% and 51.2%, respectively.

The median duration of response (DOR) was 12.4 months, and 34% had stable disease, giving a disease control rate of 93%.

Median progression-free survival (PFS) was 12.9 months, and median overall survival (OS) was 26.7 months, with corresponding 24-month rates of 26% and 50%. The results suggest that “dual TIGIT and PD-1 blockade may extend the benefit of immunotherapy beyond current standards,” write Janjigian et al.

PD-L1 positivity improves treatment response

The researchers point out that the ORR was higher among the 16 patients who had a high level of PD-L1 expression (tumor area positivity score [TAP] ≥5%) and the 29 patients who were PD-L1-positive (TAP score ≥1%), at a respective 69% and 62%. However, they had similar CR to those of the whole cohort.

By contrast, the 11 patients with low PD-L1 expression (TAP <1%) had a lower ORR than the whole cohort, at 46%, with no CRs.

A similar pattern of clinical activity according to PD-L1-high, positive, and low status was also seen for disease control rates (100 and 97 vs 82%) and median DOR (15.4 and 12.4 vs 4.4 months). And was reflected in the median PFS (14.5 and 13.2 vs 6.8 months), the median OS (not reached and 26.7 vs 18.4 months), and the 24-month PFS (31 and 25 vs 20%) and OS (56 and 54 vs 33%) rates.

“Together, these data suggest that patients who are PD-L1 high may derive particular benefit from TIGIT inhibition added to PD-1 blockade,” write Janjigian and colleagues.

Is the dual blockade strategy well tolerated?

The safety profile of the treatment was “consistent with that reported for anti-PD-1 plus platinum-based chemotherapy,” with all patients having treatment-related adverse events (AEs), 78% of which were related to the study drugs, primarily nausea (73%), a decrease in neutrophil count (37%), anemia (17%), and neutropenia (15%). Serious AEs occurred in 37% of patients, none of which were deemed related to the study drugs.

Immune-related adverse events were reported in 27% of patients, with 22% related to the study drugs. The most common included hypothyroidism (12%), adrenal insufficiency (5%), and pneumonitis (5%).

Meanwhile, the most common infusion reactions, which occurred in 29% of patients (7% related to the study drugs), included pyrexia (17%) and infusion-related reactions (7%).

The researchers observe that domvanalimab has an Fc-silent design that, unlike Fc-enabled designs, “preserves peripheral [regulatory T cells] critical for maintaining immune homeostasis and is not associated with increased [antibody-dependent cellular cytotoxicity], which may mitigate autoimmune toxicities and provide durable antitumor activity when combined with PD-1 inhibition.”

The research was also presented at the EMSO congress 2025, held in Berlin, Germany.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature

Nat Med 2025; doi:10.1038/s41591-025-04022-w
ESMO Congress 2025; Berlin, Germany: 17–21 October