The combination of domvanalimab, zimberelimab, and FOLFOX elicited responses in patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, irrespective of PD-L1 status.
Treatment with the combination of the anti-TIGIT therapy domvanalimab, zimberelimab (Sepalizumab), and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) led to responses in patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma, irrespective of PD-L1 status, according to data from a preliminary analysis of arm A1 of the phase 2 EDGE-Gastric trial (NCT05329766).
Findings presented during the November ASCO Plenary Series showed that at a minimum follow-up of 6 months, evaluable patients in the overall population (n = 41) experienced an overall response rate (ORR) of 59% (95% CI, 42%-74%) and a confirmed ORR of 56% (95% CI, 40%-72%). The confirmed complete response (CR), confirmed partial response (PR), and unconfirmed PR rates were 5%, 51%, and 2%, respectively. Additionally, 34% of patients had stable disease (SD), 5% had progressive disease (PD), and 2% had no post-baseline scan.
Patients with PD-L1–high disease (n = 15), defined as a tumor activity positivity (TAP) score of at least 5%, achieved an ORR of 80% (95% CI, 52%-96%) and a confirmed ORR of 73% (95% CI, 45%-92%). The confirmed CR, confirmed PR, and unconfirmed PR rates were 7%, 67%, and 7%, respectively. All non-responders (20%) had SD.
In the PD-L1–low population (n = 24), defined as a PD-L1 TAP score of less than 5%, the ORR and confirmed ORR were both 46% (95% CI, 26%-67%). All responders achieved confirmed PRs, and the rates of SD and PD were 42% and 8%, respectively. One patient (4%) did not have a post-baseline scan.
Notably, 2 patients had unknown PD-L1 TAP scores.
“Most of the patients derived benefit and disease control from this regimen of dual PD-1 and TIGIT [inhibition with zimberelimab and domvanalimab, respectively] and FOLFOX, irrespective of PD-L1 status,” lead study author Yelena Y. Janjigian, MD, said in a presentation of the data. Janjigian is the chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York.
Arm A1 of EDGE-Gastric enrolled patients with first-line locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma irrespective of PD-L1 status. Patients were required to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Those with HER2-positive tumors were not allowed to enroll.
All patients received 1600 mg of domvanalimab once every 4 weeks, 480 mg of zimberelimab once every 4 weeks, and FOLFOX once every 2 weeks. FOLFOX consisted of 85 mg/m2 of oxaliplatin, 400 mg/m2 of leucovorin, 400 mg/m2 of bolus fluorouracil, and 2400 mg/m2 of continuous fluorouracil. Patients were scanned once every 6 weeks during the first year, then once every 12 weeks thereafter.
Safety and investigator-assessed ORR served as the trial’s primary end point. Secondary end points consisted of efficacy by PD-L1 status, including overall survival, progression-free survival (PFS), disease control rate, and duration of response, as well as pharmacokinetics and biomarker data.
As of the September 4, 2023, data cutoff, 41 patients received study treatment and were included in the efficacy and safety populations.
The median age of enrolled patients was 61 years (range, 30-82). The majority of patients were male (59%), from the United States or France (54%), had an ECOG performance status of 1 (59%), and had the stomach as the primary tumor location (63%). Additionally, 32% of patients had liver metastases, and 34% had peritoneal metastases. Two percent of patients had microsatellite instability (MSI)–high disease, and 59% had microsatellite stable/MSI-low disease. MSI status was unknown or missing for 39% of patients.
At data cutoff, 41% of patients discontinued all study treatment. Reasons for discontinuation included disease progression (29%), the start of a new anticancer therapy (5%), patient withdrawal (5%), and other (2%). Additionally, 17% of patients (n = 7) discontinued from the study due to death (n = 2), patient withdrawal (n = 4), and other protocol-defined disease progression at the physician’s discretion (n = 1).
Additional data showed the median time on treatment was 33 weeks (range, <1-53).
At a median follow-up of 8 months (95% CI, 7-8), the overall population achieved a 6-month PFS rate of 77% (95% CI, 64%-90%). The median PFS was not evaluable (NE; 95% CI, 8-NE). In the PD-L1–high population, the 6-month PFS rate was 93% (95% CI, 81%-100%), and the median PFS was NE (95% CI, 8-NE). PFS data were not disclosed for the PD-L1–low population.
Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients, and 98% had any-grade TEAEs deemed related to treatment. Grade 3 or higher TEAEs were reported in 68% of patients, including 56% who had grade 3 or higher treatment-related TEAEs. The rates of serious TEAEs and serious TEAEs related to treatment were 24% and 5%, respectively. TEAEs led to permanent withdrawal of any study drug in 49% of patients and dose interruptions or modifications of any study drug in 81% of patients; however, TEAEs did not lead to any deaths.
The most common TEAEs reported in at least 20% of patients included neutropenia (grade 1/2, 10%; grade ≥3, 49%), nausea (54%; 0%), anemia (15%; 12%), fatigue (27%; 0%), increased alanine aminotransferase (ALT; 20%; 5%), increased aspartate aminotransferase (AST; 22%; 2%), peripheral neuropathy (22%; 2%), peripheral sensory neuropathy (22%; 2%), constipation (20%; 2%), decreased appetite (22%; 0%), diarrhea (22%; 0%), decreased platelet count (15%; 5%), asthenia (18%; 2%), and paranesthesia (20%; 0%).
Twenty percent of patients experienced any-grade infusion-related reactions, including 17% who had infusion-related reactions associated with FOLFOX.
The rates of any-grade and grade 3 or higher immune-related AEs were 12% and 2%, respectively. No serious immune-related AEs were reported. The most common any-grade immune-related AEs were increased ALT (n = 2), increased AST (n = 2), arthralgia (n = 1), asthenia (n = 1), hyperthyroidism (n = 1), and pneumonitis (n = 1).
The combination of domvanalimab, zimberelimab, and FOLFOX is under further investigation in the ongoing phase 3 STAR-221 trial (NCT05568095), which is evaluating the triplet vs nivolumab (Opdivo) plus chemotherapy in the first-line setting for patients with locally advanced unresectable or metastatic gastric, GEJ, or esophageal adenocarcinoma.
“The study is underway. We hope to get your help with accrual,” Janjigian concluded.
Janjigian YY, Oh DY, Pelster M, et al. EDGE-Gastric arm A1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer. J Clin Oncol. 2023;41(suppl 36):433248. doi:10.1200/JCO.2023.