Investigating the synergistic effects of immunochemotherapy in esophageal squamous cell carcinoma

Background: Although combinations of immune-checkpoint inhibitors (ICI) with chemotherapy have been approved for esophageal squamous cell carcinoma (ESCC), it remains unclear whether immunochemotherapy (ICT) offers advantages over the simple addition of individual monotherapies. This study aimed to investigate whether ICT exhibits a synergistic effect in patients with advanced ESCC. Methods: Reconstructed individual patient data of 3330 patients were electronically extracted from the Kaplan–Meier (KM) curves of eight randomized-controlled trials (ATTRACTION-3, CheckMate648, KEYNOTE-181, KEYNOTE-590, RATIONALE-302, RATIONALE-306, ESCORT, and ESCORT-1st). The observed progression-free survival (PFS) curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than the simulated curve, the combination of ICI and chemotherapy may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy. Results: The 1-year, 2-year, and median PFS of the observed and simulated KM curves were 26.3% vs. 24.8%, 14.6% vs. 12.0%, and 6.9 vs. 6.4 months, respectively. The one-sample log-rank test showed no significant differences between the observed and simulated KM curves (p = 0.073). Conclusions: The observed PFS with ICT was comparable to the simulated PFS estimated from the data for each monotherapy. Although it is unclear whether potential synergies exist for ICT, these findings suggest that the benefits of ICI and chemotherapy do not interfere with each other, thereby providing theoretical support for the efficacy of ICT.