Nivolumab plus ipilimumab versus pembrolizumab as chemotherapy-free, first-line treatment for PD-L1-positive non-small cell lung cancer

Abstract

Background: Nivolumab plus ipilimumab (N-I) or pembrolizumab (PEM) is associated with survival improvement as chemotherapy-free, first-line treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and positive programmed cell death ligand 1 (PD-L1). However, no direct comparison data exist between these two regimens to inform clinical decisions. Therefore, we performed indirect comparison for N-I versus PEM using frequentist methods.

Results: Three randomized trials (KEYNOTE-024, KEYNOTE-042, and CheckMate 227) involving 2372 patients were included. For patients with tumor PD-L1 level of ≥1%, pooled meta-analyses showed that both N-I and PEM improved overall survival (OS) relative to chemotherapy (N-I: hazard ratio [HR] 0.82, 95% CI 0.69-0.97; PEM: HR 0.81, 95% CI 0.71-0.93); whereas only N-I significantly improved progression-free survival (PFS) (N-I: HR 0.79, 95% CI 0.65-0.96; PEM: HR 1.07, 95% CI 0.94-1.21). Neither N-I nor PEM was associated with improved objective response rate (ORR) compared with chemotherapy (N-I: relative risk [RR] 1.20, 95% CI 0.98-1.46; PEM: RR 1.03, 95% CI 0.86-1.23). Indirect comparisons showed that N-I was associated with longer PFS than PEM (HR 0.77, 95% CI 0.62-0.95). However, N-I was not superior to PEM in terms of OS (HR 0.98, 95% CI 0.77-1.24) and ORR (RR 1.17, 95% CI 0.89-1.52). N-I showed a less favorable toxicity profile relative to PEM (all grade adverse events: RR 1.28, 95% CI 1.17-1.40).

Conclusions: N-I and PEM provide comparable OS benefit for PD-L1-positive NSCLC. N-I further improves PFS relative to PEM but at meaningful cost of toxicities.

Keywords: ipilimumab; nivolumab; non-small cell lung cancer; pembrolizumab; programmed cell death-ligand 1.

FIGURE 1

Flow diagram of trial selection

FIGURE 2

Direct comparisons between pembrolizumab (PEM) with chemotherapy (Chemo) for patients with PD‐L1 level greater than 50%. A‐C, Forest plot of hazard ratios (HRs) and risk ratio (RR) comparing overall survival (OS) (A), progression‐free survival (PFS) (B), and objective response rate (ORR) (C) between PEM with Chemo. The size of the data markers (squares) corresponds to the weight of the study in the meta‐analysis. The horizontal line crossing the square represents the 95% CI. The diamonds represent the estimated overall effect based on the meta‐analysis

FIGURE 3

Indirect comparisons of efficacy and safety between nivolumab plus ipilimumab (N‐I) versus pembrolizumab (PEM) for patients with positive programmed cell death‐ligand 1 (PD‐L1) expression. A, Results of indirect analysis for overall survival (OS), progression‐free survival (PFS) and objective response rate (ORR) between N‐I and PEM. The solid lines represent the existence of direct comparisons between the treatments, whereas the dashed line represents the indirect comparison between N‐I versus PEM. The size of the circle corresponds to the number of enrolled patients. B, Forest plot of hazard ratios (HRs) for OS in all subgroups between N‐I and PEM. P‐value with a marker^a demonstrates the significance of differences between the subgroups. C, Forest plot of risk ratios (RRs) for treatment‐related adverse events (TRAEs) between N‐I and PEM. The horizontal line crossing the square represents the 95% confidence interval (CI) in (B) and (C). The diamonds represent the estimated overall effect based on the meta‐analysis. All statistical tests were two‐sided. Abbreviations: chemo, chemotherapy