Which is the optimal immunotherapy for advanced squamous non-small-cell lung cancer in combination with chemotherapy: anti-PD-1 or anti-PD-L1?

Recent randomized phase III trials (KEYNOTE-407 and IMpower131) reported that adding anti-programmed death (ligand) 1 (anti-PD-(L)1) antibodies in combination with taxane-platinum improve the therapeutic efficacy for advanced squamous non-small-cell lung cancer (NSCLC). However, there is no head-to-head comparison of pembrolizumab (anti-PD-1) plus chemotherapy vs. atezolizumab (anti-PD-L1) plus chemotherapy. Therefore, we performed an indirect comparison to explore the optimal choice of anti-PD-(L)1 treatment for advanced squamous NSCLC in combination with chemotherapy. The clinical outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and adverse event (AE). For overall patients, pembrolizumab had significantly superior OS (hazard ratio (HR) with 95% confidence interval, 0.67, 0.47-0.94; P=0.02) and numerically better PFS (HR, 0.79, 0.60-1.04; P=0.10) than atezolizumab, while they had similar ORR, all cause AE and grade 3-5 AE. For PD-L1 high patients, pembrolizumab and atezolizumab showed similar OS and PFS. However, for PD-L1 low/negative patients, pembrolizumab had superior OS (HR, 0.43, 0.24-0.76; P<0.01/ HR, 0.74, 0.40-1.38; P=0.35) and better PFS (HR, 0.80, 0.51-1.26; P=0.33/ HR, 0.46, 0.28-0.75; P<0.01) than atezolizumab. Our analysis raises the hypothesis that anti-PD-1 antibody therapy in combination with chemotherapy may have superior efficacy compared to anti-PD-L1 antibody combination for patients with PD-L1 low/negative advanced squamous NSCLC.