Esophagus to Small Intestine
J Clin Oncol. 2022;40(4):392–402
Low programmed death-ligand 1-expressing subgroup outcomes of first-line immune checkpoint inhibitors in gastric or esophageal adenocarcinoma
Purpose: The US Food and Drug Administration has granted regulatory approval for the use of nivolumab – an immune checkpoint inhibitor (ICI) – in the first-line treatment of advanced gastric or esophageal adenocarcinoma (GEAC), regardless of programmed death-ligand 1 (PD-L1) expression. However, the efficacy of ICIs in low PD-L1-expressing tumors remains unclear.
Materials and methods: This study aims to reconstruct unreported Kaplan-Meier (KM) plots of PD-L1 combined positive score (CPS) subgroups of randomized phase 3 trials comparing the addition of ICIs with conventional chemotherapy in the first-line treatment of GEAC. A graphical reconstructive algorithm was adopted to estimate time-to-event outcomes from reported overall survival and progression-free survival (OS and PFS) KM plots describing overall or subgroup cohorts. Using reconstructed time-to-event outcomes, KM Subtraction conducts bipartite matching of patients from the reported subgroup among the overall cohort. By excluding matched patients, KM plots and survival analyses of the unreported subgroups were retrieved.
Results: CheckMate-649, KEYNOTE-062, and KEYNOTE-590 were included. Two PD-L1 subgroups were identified with data unreported in the primary manuscripts: PD-L1 CPS 1–4 from CheckMate-649 and PD-L1 CPS 1–9 from KEYNOTE-062. No significant differences in OS and PFS were demonstrated in ICI-chemotherapy combinations when compared with chemotherapy among CheckMate-649 PD-L1 CPS 1–4 (OS: hazard ratio [HR] = 0.950, 95% confidence interval [CI]: 0.747–1.209, p = 0.678; PFS: HR = 0.958, 95% CI: 0.743–1.236, p = 0.743) and KEYNOTE-062 PD-L1 CPS 1–9 subgroups. In the KEYNOTE-062 PD-L1 CPS 1–9 subgroup, patients treated with pembrolizumab had an increased hazard of tumor progression (HR = 2.092, 95% CI: 1.661–2.635, p < 0.001).
Conclusion: Using Kaplan-Meier Subtraction, data of programmed death-ligand 1 (PD-L1) subgroups previously unreported by primary manuscripts of pivotal clinical trials were retrieved. These data suggest the lack of benefit in the addition of immune checkpoint inhibitors to chemotherapy in low PD-L1-expressing tumors in gastric or esophageal adenocarcinoma.