Compare the efficacy and safety of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors for advanced non-small cell lung cancer: a Bayesian analysis

Abstract

Background: Inhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have represented a novel approach for the management of advanced non-small cell lung cancer (NSCLC). In this study, we aimed to estimate five anti-PD-1/L1 agents (nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab) using network meta-analyses (NMAs) and the Bayesian method to provide suggestions for advanced NSCLC treatments.Methods: We searched PubMed, Web of Science, Embase, and the Wiley Online Library for eligible studies published up to March 2020. Both pairwise analyses and NMAs were conducted with clinical outcomes, including overall survival (OS), progression-free survival (PFS), objective response rate, and the incidences of adverse events. Results were presented in several patient populations according to treatment lines and PD-L1 status.Results: Nineteen randomized clinical trials (RCTs) involving 11,456 patients were included in our study.PD-1/L1 inhibitors showed significant benefits over chemotherapies in OS regardless of tumor PD-L1 status [first-line settings: OS =0.85, 95% CI (0.77, 0.94), I 2 =37%; second-or further-line settings: OS =0.77, 95% CI (0.71, 0.84), I 2 =37%]. The combined regimen of pembrolizumab and chemotherapy stood out to be the most effective and safest for patients in the first-line settings. Pembrolizumab monotherapy was showed to be the best especially for patients with PD-L1 ≥50%. In the subsequent-line settings, nivolumab ranked the best in improving the survival of patients, and durvalumab had the greatest effect in tumor shrinkage.Atezolizumab, followed by nivolumab, ranked the safest in reducing adverse events, whereas durvalumab was showed with the largest side effects among the five inhibitors. Conclusions:The combination of pembrolizumab with chemotherapy is suitable for advanced NSCLC patients who have not received any systematic treatments before, and pembrolizumab monotherapy should also be considered, especially for patients with highly-expressed PD-L1 (≥50%). Nivolumab is the best option for patients with advanced NSCLC whose tumors have progressed following chemotherapies or combined modalities of treatments including chemotherapy. However, our results need to be further validated in future head-to-head clinical trials.

Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis

“…Some authors found no benefit with nivolumab in terms of OS, PFS, or overall response rate, but for a lower percentage of grades 3 or 4 AEs [ 56 ], nivolumab has been associated with significantly longer overall survival, and has a good safety profile in both squamous [ 5 ] and non-squamous NSCLC [ 7 ]. Compared with other PD-1 inhibitors (pembrolizumab and atezolizumab), nivolumab has been estimated as the best option in terms of anti-tumor efficacy, while atezolizumab is better at reducing adverse events, and pembrolizumab monotherapy was shown to be the best especially for patients with PD-L1 ≥ 50% [ 57 ].…”

PD-(L)1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer Patients with High PD-L1 Expression: A Network Meta-Analysis

“…Since then, the understanding of the biology of this cancer has rapidly increased and the use of targeted therapy with tyrosine kinase inhibitors (TKIs) improve the management of patients with oncogenic driven cancers and their survival rates. Major progress was made with the emergence of the immunotherapy with reduced overall toxicity and almost complete absence of non-specific side effects compared to chemotherapy and other classic cancer therapies, but with specific toxicity profiles depending on the mechanisms of action [ 5 , 6 , 7 ]. In this regard, immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has markedly improved the overall survival (OS) of patients, not only in those with metastatic NSCLC, but also in patients with locally advanced disease and extensive-stage small-cell lung cancer [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

PD-L1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer in PD-L1 Positive Patients: A Safety Data Network Meta-Analysis

“…Specifically, the use of targeted therapy with tyrosine kinase inhibitors improved patient management and their survival rates [ 6 ]. In turn, the emergence of immunotherapy, with reduced overall toxicity and non-specific side effects compared to chemotherapy and other classic cancer therapies, has been a great leap forward [ 7 , 8 ]. As a matter of fact, current evidence indicates that immunotherapy’s efficacy (overall survival, objective response rate and progression free survival) is superior to traditional standard chemotherapy in first line treatment for some types of cancer [ 8 , 9 , 10 ].…”

“…Moreover, treatment of advanced solid-organ malignancies with immunotherapy compared with traditional chemotherapy is associated with a lower risk of adverse events (AEs) [ 11 ]. However, immunotherapy presents specific toxicity profiles depending on its mechanisms of action [ 7 , 8 , 12 , 13 ].…”

“…In this study, anti-PD-L1 monotherapy resulted in significantly longer overall survival and progression free survival in advanced NSCLC patients with high PD-L1 expression compared to chemotherapy alone, thus supporting the potential of this therapeutic option as a first-line strategy for this subgroup of patients [ 9 ]. In the past few years, several studies have focused on the efficacy and safety of PD-1/PD-L1 inhibitor agent immunotherapies [ 7 , 8 , 9 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. However, no safety comparisons evaluating first-line monotherapy with anti-PD-L1 agents in NSCLC patients with a PD-L1 positive expression enriched design have been published to date.…”