PD-1 inhibitor plus VEGFR-2 inhibitor and chemotherapy versus chemotherapy alone for locally advanced gastric cancer: A systematic review and meta-analysis.

Abstract

e16125 Background: Despite multimodality treatment, pathological response rates remain suboptimal in patients with locally advanced gastric cancer (LAGC). Perioperative chemotherapy combined with immune checkpoint inhibition, such as FLOT plus durvalumab, has recently demonstrated clinically meaningful benefit and is emerging as a new standard of care. However, a substantial proportion of patients fail to achieve deep pathological responses. Evidence suggests that anti-angiogenic therapy potentiate the activity of immune checkpoint inhibition and chemotherapy. Several recent studies have evaluated this triplet strategy; however, the magnitude of pathological benefit and safety profile remain incompletely defined. We conducted a pooled analysis to assess efficacy and toxicity of PD-1/PD-L1 inhibitor plus VEGFR-2 inhibitor and chemotherapy compared with chemotherapy alone in LAGC. Methods: A comprehensive search of PubMed, Cochrane library,and clinicaltrials.gov was conducted from inception until December 2025. We pooled aggregate data from three comparative studies, including DRAGON IV and CAP-05, evaluating neoadjuvant/perioperative PD-1/PD-L1 inhibitor + VEGFR-2 inhibitor + chemotherapy versus chemotherapy alone. Primary endpoints were pathological complete response (pCR) and major pathological response (MPR). Selected hematologic and nonhematologic adverse events (AEs) were assessed. Risk ratios (RR) with 95% confidence intervals (CI) were estimated using random-effects models. Results: A total of 590 patients with locally advanced gastric cancer were included, including 286 who received PD-1/PD-L1 inhibitor plus VEGFR-2 inhibitor and chemotherapy and 304 who received chemotherapy alone. Combination therapy significantly improved pathological outcomes compared with chemotherapy alone: pCR (RR 3.45, 95% CI 2.05–5.78) and MPR (RR 1.39, 95% CI 1.15–1.66). For safety, most hematologic toxicities were numerically higher but not statistically significant, including anemia (any grade RR 1.06, 95% CI 0.77–1.45) and leukopenia (any grade RR 1.26, 95% CI 0.87–1.82). Grade ≥3 leukopenia was increased (RR 2.14, 95% CI 1.17–3.90). Any-grade diarrhea occurred more frequently with combination therapy (RR 1.49, 95% CI 1.02–2.16), while grade ≥3 diarrhea was not increased. Grade ≥3 hypertension was significantly higher with triplet therapy (RR 10.78, 95% CI 1.36–85.42). Conclusions: Across included studies, adding PD-1/PD-L1 and VEGFR-2 inhibition to chemotherapy substantially improved pathological response rates in LAGC, supporting a biologically synergistic strategy. Increased risks of grade ≥3 leukopenia and hypertension highlight the importance of careful toxicity monitoring. Larger randomized trials with survival endpoints are warranted to define the long-term benefit–risk balance of this approach.