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. 2023 Oct 11:14:20406223231189224.
doi: 10.1177/20406223231189224. eCollection 2023.

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

Fu Wenfan  1   2   3 , Xu Manman  4 , Shi Xingyuan  5 , Jiang Zeyong  1 , Zhao Jian  1 , Dai Lu  6
Affiliations

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

Fu Wenfan et al. Ther Adv Chronic Dis. .

Abstract

Background: 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.

Objective: To identify the best first-line immunotherapy regimen for overall advanced NSCLC patients and different subgroups.

Design: Systematic review and Bayesian network meta-analysis (NMA).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: PD-1/PD-L1 inhibitors; bevacizumab; immunotherapy; network meta-analysis; non-small cell lung cancer.

Plain language summary

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.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1.
Figure 1.
Flowchart of study selection.
Figure 2.
Figure 2.
Comparative network plots on OS, PFS, ORR, tr-AEs, and grade ⩾ 3 tr-AEs of reported treatment regimens in advanced NSCLC patients according to PD-L1 levels. (a) OS, PFS, and ORR in PD-L1 non-selective patients; (b) tr-AEs and grade ⩾ 3 tr-AEs in PD-L1 non-selective patients; (c) OS, PFS, and ORR in PD-L1 < 1% patients; (d) OS, PFS, and ORR in PD-L1 ⩾ 1% patients; (e) OS, PFS, and ORR in PD-L1 1–49% patients; (f) OS, PFS, and ORR in PD-L1 ⩾ 50% patients. The size of the node and the width of the line are proportional to the number of RCTs and comparisons, respectively. NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PD-L1, programed death ligand 1; PFS, progression-free survival; RCT, randomized controlled trial; tr-AE, treatment-related adverse event.
Figure 3.
Figure 3.
Efficacy and safety profiles for OS, PFS, ORR, and grade ⩾ 3 tr-AEs in PD-L1 non-selective patients based on network consistency model. (a) HRs and 95% CIs for OS (lower triangle in blue) and PFS (upper triangle in orange). HR < 1 indicates better efficacy. (b) ORs and 95% CIs for ORR (lower triangle in blue) and grade ⩾ 3 tr-AEs (upper triangle in orange). OR > 1 indicates better efficacy, while OR < 1 implies better safety. CI, confidence interval; HR, hazard ratio; OR, odds ratio; ORR, objective response rate; OS, overall survival; PD-L1, programed death ligand 1; PFS, progression-free survival; tr-AE, treatment-related adverse event.
Figure 4.
Figure 4.
Efficacy and safety profiles for OS, PFS, and ORR in PD-L1<1% patients based on network consistency model. (a) HRs and 95% CIs for OS (lower triangle in blue) and PFS (upper triangle in orange). HR < 1 indicates better efficacy. (b) ORs and 95% CIs for ORR (lower triangle in blue). OR > 1 indicates better efficacy. CI, confidence interval; HR, hazard ratio; OR, odds ratio; ORR, objective response rate; OS, overall survival; PD-L1, programed death ligand 1; PFS, progression-free survival; tr-AE, treatment-related adverse event.
Figure 5.
Figure 5.
Efficacy and safety profiles for OS, PFS, and ORR in PD-L1 ⩾ 1% patients based on network consistency model. (a) HRs and 95% CIs for OS (lower triangle in blue) and PFS (upper triangle in orange). HR < 1 indicates better efficacy. (b) ORs and 95% CIs for ORR (lower triangle in blue). OR > 1 indicates better efficacy. CI, confidence interval; HR, hazard ratio; OR, odds ratio; ORR, objective response rate; OS, overall survival; PD-L1, programed death ligand 1; PFS, progression-free survival; tr-AE, treatment-related adverse event.
Figure 6.
Figure 6.
Efficacy and safety profiles for OS, PFS, and ORR in PD-L1 1–49% patients based on network consistency model. (a) HRs and 95% CIs for OS (lower triangle in blue) and PFS (upper triangle in orange). HR < 1 indicates better efficacy. (b) ORs and 95% CIs for ORR (lower triangle in blue). OR > 1 indicates better efficacy. CI, confidence interval; HR, hazard ratio; OR, odds ratio; ORR, objective response rate; OS, overall survival; PD-L1, programed death ligand 1; PFS, progression-free survival; tr-AE, treatment-related adverse event.
Figure 7.
Figure 7.
Efficacy and safety profiles for OS, PFS, and ORR in PD-L1 ⩾ 50% patients based on network consistency model. (a) HRs and 95% CIs for OS (lower triangle in blue) and PFS (upper triangle in orange). HR < 1 indicates better efficacy. (b) ORs and 95% CIs for ORR (lower triangle in blue). OR > 1 indicates better efficacy. CI, confidence interval; HR, hazard ratio; OR, odds ratio; ORR, objective response rate; OS, overall survival; PD-L1, programed death ligand 1; PFS, progression-free survival; tr-AE, treatment-related adverse event.
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