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Results from the Phase III GEMSTONE-303 trial (NCT03802591) show that sugemalimab combined with chemotherapy produced a significant improvement in overall survival (OS) and progression-free survival (PFS) compared to chemotherapy alone in patients with previously untreated locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS 5 or greater.1,2 According to the trial investigators, these findings, along with a manageable safety profile, support sugemalimab as a potential first-line treatment option for the disease.
“GEMSTONE-303 is the first randomized, phase 3 study of a PD-L1 inhibitor in combination with chemotherapy showing significantly prolonged survival benefit in the first-line setting compared with chemotherapy alone in patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, for which PD-1 inhibitors have demonstrated efficacy,” the study authors wrote. “This is also the first to restrict enrollment to patients with CPS 5 or greater. The Kaplan-Meier curves of overall survival and progression-free survival illustrated an early separation that persisted throughout the evaluation period, suggesting sustained benefits.”1
Sugemalimab is a novel monoclonal antibody that targets PD-L1. The investigational therapy is being evaluated in multiple clinical trials, including a Phase II trial in relapsed/refractory extranodal natural killer/T cell lymphoma and four Phase III trials in stage III non-small cell lung cancer (NSCLC), stage IV NSCLC, gastric cancer, and esophageal cancer.3
“Sugemalimab is a full-length, fully human immunoglobulin G4 (s228p) monoclonal antibody targeting PD-L1 that retains FcγRI (a receptor for the Fc region of IgG) binding, enabling antibody-dependent cellular phagocytosis via crosslinking of PD-L1–expressing tumor cells with macrophages,” the study authors wrote. “In the GEMSTONE-101 phase 1b study, sugemalimab with capecitabine plus oxaliplatin (CAPOX) demonstrated good tolerability and encouraging efficacy in 29 patients with gastric or gastroesophageal junction adenocarcinoma, achieving an objective response rate (ORR) of 62.1%, median progression-free survival of 8.3 months, and median overall survival of 17.0 months.”1
Trial Design
The randomized, double-blind, placebo-controlled GEMSTONE 303 trial was conducted at 54 sites across China. Investigators enrolled 479 eligible patients aged 18 to 79 years with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who were not previously administered systemic therapy. Patients were randomly assigned in a 1:1 ratio to receive either sugemalimab or placebo plus CAPOX chemotherapy.
Sugemalimab was administered intravenously (IV) at a dose of 1200 mg every 21 days for up to 24 months, along with CAPOX comprised of oral capecitabine at a dose of 1000 mg/m2/d twice daily on days one to 14 and IV oxaliplatin at a dose of 130 mg/m2 on day one every 21 days for up to six cycles. Patients continued on the regimen until disease progression, unacceptable toxicity, consent withdrawal, or other protocol-specified reasons.
Eligibility criteria included having unresectable, locally advanced or metastatic gastric or gastroesophageal junction cancer with histologically confirmed adenocarcinoma; having adequate tumor tissue for PD-L1 assessment; PD-L1 CPS 5 or greater at baseline; and having at least one measurable or evaluable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
The trial’s primary endpoints were OS and investigator-assessed PFS, with key secondary endpoints that included PFS assessed by blinded independent central review committee, ORR, and duration of response.
At a median follow-up of 25.1 months in the sugemalimab cohort and 26.3 months in the placebo cohort, patients administered sugemalimab had a median OS of 15.6 months (95% CI, 13.3-17.8) compared to 12.6 months in the placebo cohort (95% CI, 10.6-14.1; hazard ratio, 0.75 [95% CI, 0.61-0.92]; P = .006). Median PFS was 7.6 months in the sugemalimab cohort (95% CI, 6.4-7.9) compared to 6.1 months in the placebo cohort (95% CI, 5.1-6.4; hazard ratio, 0.66 [95% CI, 0.54-0.81]; P < .001).
In terms of safety, grade 3 or higher treatment-related adverse events were reported by 53.9% of patients in the sugemalimab cohort compared to 50.6% in the placebo cohort.
“Sugemalimab is the first PD-L1 inhibitor demonstrating superior overall survival and progression-free survival and a manageable safety profile in combination with chemotherapy vs chemotherapy alone in patients with previously untreated locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma,” the study authors concluded. “The results support sugemalimab plus chemotherapy as a new standard first-line treatment option for patients with PD-L1 CPS 5 or greater.”1
References
1. Zhang X, Wang J, Wang G, et al. First-Line Sugemalimab Plus Chemotherapy for Advanced Gastric Cancer: The GEMSTONE-303 Randomized Clinical Trial. JAMA. Published online February 24, 2025. doi:10.1001/jama.2024.28463.
2. A Study of CS1001 in Subjects With Gastric Adenocarcinoma or Gastro-Esophageal Junction Adenocarcinoma. ClinicalTrials.gov. Updated November 29, 2023. Accessed February 25, 2025. https://www.clinicaltrials.gov/study/NCT03802591?id=NCT03802591&rank=1