Abstract
BACKGROUND: Perioperative chemoimmunotherapy [i.e. chemotherapy plus immune checkpoint inhibitor (ICI) (ChT-ICI)] is an investigational treatment for operable gastroesophageal adenocarcinoma (GEA) with unclear outcomes in an unselected population. We aimed to assess the cumulative treatment effect of ChT-ICI on pathological response rates, the surrogacy of pathological response rates on overall survival (OS), and the value of programmed death-ligand 1 (PD-L1) as a biomarker of response to ICIs in operable GEA. METHODS: We conducted a systematic review and meta-analysis of randomised clinical trials (RCTs) of ChT with or without ICIs with the primary outcome being pathological response rates [pathological complete response (pCR) and similar metrics]. A weighted linear regression model quantified the relationship between pathological response rates and OS using a determination coefficient (R (2)). A second meta-regression analysed the predictive effect of PD-L1 on pCR in trials of ICIs with ChT or chemoradiotherapy (CRT). RESULTS: A total of 18 records from 15 RCTs were included. Of 6624 patients, 5291 received ChT and 1333 ChT-ICI. ChT-ICI significantly improved pathological response rates [pooled odds ratio 3.18, 95% confidence interval (CI) 2.42-4.18, P < 0.0001] compared with ChT (pooled odds ratio 1.66, 95% CI 1.33-2.07, P < 0.0001). The correlation between pathological response and OS was low (R (2) = 0.12) but improved in recent trials (R (2) = 0.51) and those with ChT-biological agents, including ICIs (R (2) = 0.79). In the second analysis (11 studies, 633 patients), PD-L1 ≥5 was a significant predictor of response both individually (estimate: 0.73, 95% CI 0.28-1.18, P = 0.001) and after accounting for the backbone treatment (estimate: 0.80, 95% CI 0.28-1.33, P = 0.003). CONCLUSIONS: Perioperative ChT-ICI improves pathological response rates in operable GEA and PD-L1 ≥5 is a significant biomarker of pCR, supporting stratification by PD-L1 and the design of biomarker-selected trials.