PD-L1 as a response biomarker to chemotherapy plus immune checkpoint inhibitors in operable gastroesophageal adenocarcinoma: a meta-analysis of neoadjuvant clinical trials

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 (R²). 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 (R² = 0.12) but improved in recent trials (R² = 0.51) and those with ChT–biological agents, including ICIs (R² = 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.