Tyrosine kinase inhibitors and survival in advanced or metastatic gastric cancer: a systematic review and meta-analysis.

Abstract

<h4>Background</h4>Small-molecule tyrosine kinase inhibitors (TKIs) have been extensively investigated in the management of advanced or metastatic gastric cancer (GC); however, their specific efficacy and optimal therapeutic role remain subjects of ongoing debate. Given the accumulation of new trial evidence and persistent uncertainty regarding patient subgroups most likely to benefit, we conducted an updated systematic review and meta-analysis to comprehensively evaluate the impact of TKIs on clinical outcomes in advanced GC.<h4>Methods</h4>We systematically searched PubMed, Web of Science, and Embase databases for articles published up to March 1, 2026, following PRISMA 2020 guidelines. Randomized controlled trials (RCTs) comparing TKI-containing regimens versus non-TKI regimens in patients with cytologically or pathologically confirmed advanced GC were eligible. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled for progression-free survival (PFS) and overall survival (OS) using random-effects models. Risk ratios (RRs) with 95% CIs were calculated for objective response rate (ORR) and disease control rate (DCR). Study quality was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, and evidence certainty was evaluated using the GRADE framework.<h4>Results</h4>Ten RCTs comprising 1810 patients (1169 experimental, 641 control) met inclusion criteria. TKI-containing regimens significantly improved OS (HR 0.76, 95% CI 0.63-0.92, P = 0.005; moderate certainty) and prolonged PFS (HR 0.51, 95% CI 0.35-0.73, P = 0.0003; low certainty) compared to non-TKI regimens. DCR was markedly improved (RR 3.98, 95% CI 2.08-7.58, P < 0.0001; moderate certainty), whereas ORR did not reach statistical significance (RR 2.03, 95% CI 0.83-5.01, P = 0.12; low certainty). Subgroup analyses revealed that TKI monotherapy significantly improved both OS and PFS, whereas combination with chemotherapy did not demonstrate additive survival benefits. Grade ≥3 adverse events, including hypertension (RR 31.5, 95% CI 11.71-84.73) and hand-foot syndrome (RR 55.0, 95% CI 7.65-395.32), were more frequent with TKIs but were largely predictable and clinically manageable.<h4>Conclusions</h4>This updated meta-analysis provides moderate-certainty evidence that TKI-containing regimens confer significant survival benefits in advanced GC, with a manageable safety profile. The differential efficacy observed between monotherapy and combination regimens underscores the need for biomarker-driven patient selection and optimization of treatment sequencing. These findings refine the current evidence base and support the continued role of TKIs in treatment algorithms for advanced GC, while highlighting critical knowledge gaps requiring further investigation.<h4>Registration</h4>https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024544568, identifier CRD42024544568.