First-Line Treatment Options for PD-L1–Negative Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Abstract

BackgroundFirst-line treatment strategies for programmed death-ligand 1 (PD-L1) negative non-small cell lung cancer (NSCLC) patients include chemotherapy and combination with anti-angiogenesis drugs and/or immune checkpoint inhibitor. We conducted a Bayesian network meta-analysis to evaluate the efficacy of these therapeutic options.MethodsWe included phase III randomized controlled trials comparing two or more treatments in the first-line setting for NSCLC, including data in PD-L1–negative patients. First-line strategies were compared and ranked based on the effectiveness in terms of overall survival (OS) and progression-free survival (PFS). A rank was assigned to each treatment after Markov Chain Monte Carlo analyses.ResultsFourteen trials involving 14 regimens matched our eligibility criteria. For OS, none of the treatment were significantly more effective than chemotherapy. Nivolumab plus ipilimumab plus chemotherapy was probably the best option based on analysis of the treatment ranking (probability = 30.1%). For PFS, nivolumab plus chemotherapy plus bevacizumab, atezolizumab plus chemotherapy plus bevacizumab, and atezolizumab plus chemotherapy were statistically superior to chemotherapy in pairwise comparison. Nivolumab plus chemotherapy plus bevacizumab was likely to be the preferred option based on the analysis of the treatment ranking (probability = 72.9%).ConclusionsNivolumab plus chemotherapy, in combination with angiogenesis inhibition or anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), had maximal benefits for NSCLC patient of PD-L1–negative expression. These findings may facilitate individualized treatment strategies. Safety at an individual patient level should be considered in decision making. Further validation is warranted.

Immune checkpoint inhibitors alone vs immune checkpoint inhibitors—combined chemotherapy for NSCLC patients with high PD-L1 expression: a network meta-analysis

“…Owing to the spatial and temporal heterogeneity in PD-L1 expression and the differences in detection mechanisms, PD-L1 was an imperfect biomarker [ 24 ]. However, PD-L1 expression in the tumour cells is currently the most widely applied biomarker for the stratification of patients [ 25 ]. Finally, data from head-to-head comparison of RCTs were lacking.…”

Role of sex and sex hormones in PD-L1 expression in NSCLC: clinical and therapeutic implications

“…Finally, patients with negative (<1%) PD-L1 are still candidates for combined immunotherapy with chemotherapy or targeted therapy and dual immunotherapy ( 25 , 30 , 31 ). PD-L1 blockade has significantly improved clinical outcomes mainly in patients with higher PD-L1 levels.…”

Toripalimab, a therapeutic monoclonal anti-PD-1 antibody with high binding affinity to PD-1 and enhanced potency to activate human T cells

“…For instance, pembrolizumab in combination with chemotherapy in PD-L1 high non-small cell lung cancer (NSCLC) patients (TPS > 1%) demonstrated better clinical activity compared to PD-L1 low NSCLC (TPS < 1%) (Keynote 189; PD-L1 screen: 22C3 pharmDx assay) though both PD-L1 groups benefitted from the combination treatment [ 9 ]. Similarly, the therapeutic efficacy of nivolumab correlated with the expression levels of PD-L1 in cancer patients (CheckMate: 037; PD-L1 screen: 28-8 pharmDx assay) [ 10 – 12 ]. Furthermore, based on the objective response rate, PD-L1 high NSCLC patients gain more benefits than PD-L1 low patients in response to treatment with cemiplimab in combination with chemotherapy (EMPOWER-Lung 3; PD-L1 screen: 22C3 pharmDx assay) [ 13 ].…”