Network meta-analysis of immune-oncology monotherapy as first-line treatment for advanced non-small-cell lung cancer in patients with PD-L1 expression ⩾50

Abstract

Background: For patients with advanced non-small-cell lung cancer (NSCLC) and high (⩾50%) programmed cell death-ligand 1 (PD-L1) expression, effective first-line immune-oncology monotherapies with significant survival benefits are approved, cemiplimab being the most recent. In a phase III trial, cemiplimab demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced NSCLC and PD-L1 ⩾50%. A systematic literature review and network meta-analysis (NMA) was conducted to identify/compare the efficacy/safety of cemiplimab versus pembrolizumab or other immune-oncology monotherapies from randomized-controlled trials (RCTs) published in November 2010-2020.

Methods: Relevant RCTs were identified by searching databases and conference proceedings as per ISPOR, NICE, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. NMA with time-varying hazard ratios (HRs) was performed for OS and PFS. Analyses were conducted for objective response rate (ORR) and safety/tolerability. Fixed-effect models were used due to limited evidence. Various sensitivity analyses were conducted to validate the base case analyses.

Results: The feasibility assessment determined that EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 trials were eligible. IMpower110 was excluded because an incompatible PD-L1 assay (SP142) was used for patient selection. For first-line advanced NSCLC with PD-L1 ⩾50%, cemiplimab was associated with statistically significant improvements in PFS [HR (95% credible interval [CrI]): 0.65 (0.50-0.86), 1-12 months] and ORR [odds ratio (OR) (95% CrI): 1.64 (1.04-2.62)], and comparable OS [HR (95% CrI): 0.77 (0.54-1.10), 1-12 months] versus pembrolizumab. There was no evidence of differences between cemiplimab and pembrolizumab for Grade 3-5 adverse events (AEs) [OR (95% CrI): 1.47 (0.83-2.60)], immune-mediated AEs [1.75 (0.33-7.49)], and all-cause discontinuation due to AEs [1.21 (0.58-2.61)].

Conclusions: Considering the limitations of indirect treatment comparisons, in patients with advanced NSCLC and PD-L1 ⩾50%, cemiplimab monotherapy demonstrated significant improvements in PFS and ORR, comparable OS, and no evidence of differences in safety/tolerability versus pembrolizumab.

Keywords: IO monotherapy; PD-L1 expression; cemiplimab; cemiplimab monotherapy; network meta-analysis; non-small-cell lung cancer; systematic literature review.

Figure 1.

PRISMA flow diagram. NMA, network meta-analysis; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SLR, systematic literature review.

Figure 2.

(a) Full evidence network of included and ongoing trials from the SLR and (b) network of base case and sensitivity analysis.* *EMPOWER-Lung 1, KEYNOTE-024, and KEYNOTE-042 were used for the base case while IMpower110 was used for the sensitivity analysis. ext., extension; IC, investigator’s choice; IHC, immunohistochemistry; IO, immune-oncology; NMA, network meta-analysis; NSCLC, non-small-cell lung cancer; PD-L1, programmed cell death-ligand 1; SLR, systematic literature review; TPS, tumor proportion score.

Figure 3.

(a) Estimated OS time-varying HRs for cemiplimab versus pembrolizumab and chemotherapy, and (b) estimated OS curves for cemiplimab, chemotherapy, and pembrolizumab. Numbers in figures are estimates (95% CrIs). An FE fractional polynomial model NMA was performed as the base case analysis to assess OS for cemiplimab monotherapy versus competing interventions. According to the model selection process, the best-fitting model for the base case OS analysis was the FE second-order fractional polynomial with p1 = 1 and p2 = −0.5 (scale and second shape). The estimated time-varying HRs were applied to a pooled reference modeled survival function (IC chemotherapy) to generate the OS proportions over time. CrI, credible interval; FE, fixed effect; HR, hazard ratio; IC, investigator’s choice; NMA, network meta-analysis; OS, overall survival.

Figure 4.

(a) Estimated PFS time-varying HRs for cemiplimab versus pembrolizumab and chemotherapy, and (b) estimated PFS curves for cemiplimab, chemotherapy, and pembrolizumab. Numbers in figures are estimates (95% CrI); dashed lines indicate estimates based on model extrapolations. An FE fractional polynomial model NMA was performed as the base case analysis to assess PFS for cemiplimab monotherapy versus competing interventions. According to the model selection process, the best-fitting model for the base case PFS analysis was the FE second-order fractional polynomial with p1 = 0 and p2 = −1 (scale and first shape). The estimated time-varying HRs were applied to a pooled reference modeled survival function (IC chemotherapy) to generate the PFS proportions over time. CrI, credible interval; FE, fixed effect; HR, hazard ratio; IC, investigator’s choice; NMA, network meta-analysis; PFS, progression-free survival.