Comparison of the profiles of first-line PD-1/PD-L1 inhibitors for advanced NSCLC lacking driver gene mutations: a systematic review and Bayesian network meta-analysis

Numerous first-line immune checkpoint inhibitors (ICI) were developed for patients with advanced non-small cell lung cancer (NSCLC) lacking driver gene mutations. However, this group consists of a heterogeneous patient population, for whom the optimal therapeutic choice is yet to be confirmed.To identify the best first-line immunotherapy regimen for overall advanced NSCLC patients and different subgroups.Systematic review and Bayesian network meta-analysis (NMA).We searched several databases to retrieve relevant literature. We performed Bayesian NMA for the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (tr-AEs) with a grade equal or more than 3 (grade ⩾ 3 tr-AEs). Subgroup analysis was conducted according to programed death ligand 1 (PD-L1) levels, histologic type, central nervous system (CNS) metastases and tobacco use history.For the PD-L1 non-selective patients, sintilimab plus chemotherapy (sinti-chemo) provided the best OS [hazard ratio (HR) = 0.59, 95% confidence interval (CI):0.42-0.83]. Nivolumab plus bevacizumab plus chemotherapy (nivo-bev-chemo) was comparable to atezolizumab plus bevacizumab plus chemotherapy (atezo-bev-chemo) in prolonging PFS (HR = 0.99, 95% CI: 0.51-1.91). Atezo-bev-chemo remarkably elevated the ORR than chemotherapy (OR = 3.13, 95% CI: 1.51-6.59). Subgroup analysis showed pembrolizumab plus chemotherapy (pembro-chemo) ranked first in OS in subgroups of PD-L1 < 1%, non-squamous, no CNS metastases, with or without smoking history, and ranked second in OS in subgroups of PD-L1 ⩾ 1% and PD-L1 1-49%. Cemiplimab and sugemalimab plus chemotherapy ranked first in OS and PFS for squamous subgroup, respectively. For patients with CNS metastases, nivolumab plus ipilimumab plus chemotherapy (nivo-ipili-chemo) and camrelizumab plus chemotherapy provided the best OS and PFS, respectively.Sinti-chemo and nivo-bev-chemo were two effective first-line regimens ranked first in OS and PFS for overall patients, respectively. Pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 1-49%, non-squamous, no CNS metastases, with or without smoking history. Addition of bevacizumab consistently provided with favorable PFS results in patients of all PD-L1 levels. Cemiplimab was the best option in squamous subgroup and nivo-ipili-chemo in CNS metastases subgroup due to their advantages in OS.First-line PD-1/PD-L1 inhibitors for advanced NSCLC patients lacking driver gene mutations Patients with advance non-small cell lung cancer (NSCLC) lacking driver gene mutations are a group of heterogeneous people. Although numerous therapeutic regimens were developed, the optimal choice for advanced NSCLC patients and specific subgroups is yet to be identified.We conducted a Bayesian network meta-analysis with the currently available data, and performed subgroup analyses according to programed death ligand 1 (PD-L1) levels, histologic type, CNS metastases and tobacco use history.Our key findings were as follows: (1) in non-selective PD-L1 groups, sinti-chemo and pembro-chemo provided the best OS outcome; nivo-bev-chemo and atezo-bev-chemo resulted in the most prolonged PFS; atezo-bev-chemo and pembro-chemo yielded significantly improved ORR; (2) pembro-chemo was favorable for patients in subgroups of PD-L1 < 1%, PD-L1 ⩾ 1%, PD-L1 1–49%, non-squamous, no CNS metastases, with or without smoking history; (3) immunochemotherapies involving anti-PD-1 agents generally exhibited potential advantages over those with anti-PD-L1 drugs; (4) addition of anti-VEGF drugs to immunochemotherapies consistently provided with favorable PFS results in advanced NSCLC patients with or without PD-L1 selection; (5) in patients with squamous NSCLC, cemiplimab and suge-chemo were the optimal drugs for improving OS and PFS, respectively; in patients with non-squamous NSCLC, pembro-chemo provided the best OS, while nivo-bev-chemo, atezo-bev-chemo, sinti-chemo, and pembro-chemo showed comparable advantages in improving PFS; (6) for patients with CNS metastases, nivo-ipili-chemo and camre-chemo provided the best OS and PFS, respectively.Our findings provide evidence for a more precise selection of first-line immunotherapy regimen for advanced NSCLC patients.