Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer: a systematic review and meta-analysis

Abstract

Background: Frontline immune checkpoint inhibitors (ICI)-based regimens in non-oncogene-addicted non-small-cell lung cancer (NSCLC) have been deeply investigated. To rank the available therapeutic options, we carried out a systematic review and Bayesian meta-analysis.

Methods: A comprehensive search for randomized controlled trials (RCTs) of ICI regimens, and a pairwise and a network meta-analysis (NMA) with an all-comers and a stratified strategy were conducted. Endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (TRAEs).

Results: Nineteen RCTs involving 17 treatment regimens were included. For the all-comers population, pembrolizumab/chemotherapy (CT) and cemiplimab were most likely the best treatments. For programmed death-ligand 1 (PD-L1) <1% nivolumab/ipilimumab with/without CT, for PD-L1 >1% and 1%-49% pembrolizumab/CT and for PD-L1 >50% cemiplimab ranked first for OS. In non-squamous (NSQ), pembrolizumab with/without CT ranked first for OS; cemiplimab ranked worse than the unselected population. In squamous (SQ), pooled hazard ratio (HR) showed a better chance in improving efficacy for combination strategy, while monotherapy did not, except for cemiplimab that ranked second. Atezolizumab/CT/bevacizumab ranked first in most subgroups for PFS. Direct comparison showed a non-statistically significant benefit of ICI regimens for the liver metastases cohort in OS, with a good ranking for pembrolizumab/CT and atezolizumab/bevacizumab/CT. Regarding brain metastases, all ICI regimens demonstrated an improvement in OS and PFS compared to CT. Nivolumab/ipilimumab/CT ranked better in this subset.

Conclusions: Our meta-analysis updated on the most recent findings demonstrates that different ICI treatments rank differently in specific NSCLC settings (histology, biomarker and clinical presentation) offering a novel challenging scenario for clinical decision making and research planning.

Keywords: checkpoints inhibitors; frontline therapy; network meta-analysis; non-small-cell lung cancer; systematic review.

Figure 1

Pooled HR for OS (A) and PFS (B) on head-to-head comparison in unselected cohorts. Immune checkpoint inhibitor-based regimen represents the experimental group. Subgroups have been created according to the type of drug. CI, confidence interval; HR, hazard ratio; IV, instrumental variables; OS, overall survival; PFS, progression-free survival; SE, standard error.

Figure 1

Pooled HR for OS (A) and PFS (B) on head-to-head comparison in unselected cohorts. Immune checkpoint inhibitor-based regimen represents the experimental group. Subgroups have been created according to the type of drug. CI, confidence interval; HR, hazard ratio; IV, instrumental variables; OS, overall survival; PFS, progression-free survival; SE, standard error.

Figure 2

Ranking of treatments based on NMA. All of the SUCRA values for each regimen with regard to PFS, OS, ORR and G3 or higher AEs. An average SUCRA and the average ranking are provided. AE, adverse event; atezo, atezolizumab; beva, bevacizumab; camre, camrelizumab; cemi, cemiplimab; CT, chemotherapy; durva, durvalumab; ipi, ipilimumab; nivo, nivolumab; NMA, network meta-analysis; ORR, overall response rate; OS, overall survival; pembro, pembrolizumab; PFS, progression-free survival; SUCRA, surface under the cumulative ranking curve; tisle, tislelizumab; treme, tremelimumab.

Figure 3

Pooled HR for OS (A) and PFS (B) on head-to-head comparison in NSQ histology cohort. Network plot of direct (lower) and indirect (upper) comparison of the studies included in the analysis for OS (C) and PFS (D) in the NSQ cohort. Each circular node represents a treatment type. The thickness of the lines is proportional to the number of patients in head-to-head comparisons. atezo, atezolizumab; beva, bevacizumab; camre, camrelizumab; cemi, cemiplimab; CI, confidence interval; CT, chemotherapy; durva, durvalumab; HR, hazard ratio; ipi, ipilimumab; IV, instrumental variables; nivo, nivolumab; NSQ, non-squamous; OS, overall survival; pembro, pembrolizumab; PFS, progression-free survival; SE, standard error; tisle, tislelizumab; treme, tremelimumab.

Figure 3

Pooled HR for OS (A) and PFS (B) on head-to-head comparison in NSQ histology cohort. Network plot of direct (lower) and indirect (upper) comparison of the studies included in the analysis for OS (C) and PFS (D) in the NSQ cohort. Each circular node represents a treatment type. The thickness of the lines is proportional to the number of patients in head-to-head comparisons. atezo, atezolizumab; beva, bevacizumab; camre, camrelizumab; cemi, cemiplimab; CI, confidence interval; CT, chemotherapy; durva, durvalumab; HR, hazard ratio; ipi, ipilimumab; IV, instrumental variables; nivo, nivolumab; NSQ, non-squamous; OS, overall survival; pembro, pembrolizumab; PFS, progression-free survival; SE, standard error; tisle, tislelizumab; treme, tremelimumab.

Figure 4

Pooled HR for OS (A) and PFS (B) on head-to-head comparison in SQ histology cohort. CI, confidence interval; HR, hazard ratio; IV, instrumental variables; OS, overall survival; PFS, progression-free survival; SE, standard error; SQ, squamous.

Figure 5

Hazard ratios and 95% CrI for OS and PFS of the NMA in the PD-L1 >50% cohort. The results are presented as column-defined treatment versus row-defined treatment. atezo, atezolizumab; beva, bevacizumab; camre, camrelizumab; cemi, cemiplimab; CI, confidence interval; CrI, credible interval; CT, chemotherapy; durva, durvalumab; HR, hazard ratio; ipi, ipilimumab; nivo, nivolumab; NMA, network meta-analysis; NSQ, non-squamous; OS, overall survival; PD-L1, programmed death-ligand 1; pembro, pembrolizumab; PFS, progression-free survival; tisle, tislelizumab; treme, tremelimumab.