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.

Abstract

9076 Background: PD-L1 has emerged as a potential biomarker for predicting responses to immunotherapy and as a prognostic factor in non-small cell lung cancer (NSCLC). In this network meta-analysis, we aimed to evaluate the efficacy of first-line PD-(L)1 monotherapy in advanced NSCLC patients with high PD-L1 expression. Methods: We conducted a systematic search in PubMed to identify all eligible trials from inception until 1 November 2020, with no start date limit applied. Only phase III trials evaluating the efficacy of first-line (1L) PD-(L)1 monotherapy in patients with stage IIIB/stage IV NSCLC and high PD-L1 expression were included. Results: Six clinical trials (KEYNOTE-024, KEYNOTE-042, EMPOWER Lung-01, IMpower110, MYSTIC and CheckMate-026) with 2,111 patients were included. In head-to-head comparisons, immunotherapy showed a significant improvement in progression-free survival (PFS: HRpooled = 0.69, 95% CI: 0.52-0.90, p = 0.007), overall survival (OS: HRpooled = 0.69, 95% CI: 0.61-0.78; p < 0.001) and overall response rate (ORR) (Risk ratio [RR]pooled = 1.354, 95% CI: 1.04-1.762, p = 0.024) compared to chemotherapy (CT). In the assessment of relative efficacy for PFS through indirect comparisons, pembrolizumab (results from KEYNOTE-024) ranked highest followed by cemiplimab and atezolizumab, with statistical significance determined across some of the drugs. In terms of OS, cemiplimab ranked highest followed by atezolizumab and pembrolizumab, although non-significant OS was determined across these drugs. Overall, 1L PD-(L)1 monotherapy improved OS in almost all subgroups, reaching statistical significance in men (HRpooled = 0.624, 95% CI: 0.51-0.72, p < 0.001), non-Asian patients (HRpooled = 0.66, 95% CI: 0.55-0.79, p < 0.001), all patients regardless of age ( < 65 years [HRpooled = 0.72, 95% CI: 0.57-0.90, p = 0.005]; ≥65 years [HRpooled = 0.61, 95% CI: 0.48-0.77, p < 0.001]), ECOG PS status (ECOG PS = 0 [HRpooled = 0.68, 95% CI: 0.56-0.82, p < 0.001; ECOG PS = 1 [HRpooled = 0.59, 95% CI: 0.43-0.82, p = 0.001) and histological tumour type (Squamous [HRpooled = 0.49, 95% CI: 0.37-0.67, p < 0.001; Non-squamous [HRpooled = 0.67, 95% CI: 0.52-0.87, p = 0.003). In the case of smokers and NSCLC stage, only current/former smokers (HRpooled = 0.623, 95% CI: 0.47-0.83, p = 0.001) and patients with stage IV disease* (HRpooled = 0.687, 95% CI: 0.59-0.81, p < 0.001) benefited from single PD-(L)1 monotherapy over CT. Conclusions: PD-(L)1 inhibitor monotherapy improves efficacy outcomes in the 1L setting of advanced NSCLC patients with high PD-L1 expression. Current/former smokers ≥65 years, with ECOG PS = 1 and squamous NSCLC benefited most from this therapy. *KEYNOTE-042 was the only study including patients with stage IIIB NSCLC.

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%

“…An indirect comparison of immunotherapies among patients with locally advanced or metastatic NSCLC with PD-L1 expression ⩾50% who had not received prior systemic therapy for their locally advanced or metastatic disease was recently published. 76 Majem et al assessed OS and PFS with a constant HR NMA using generalized pairwise modeling framework with the Bucher method, which ignored the nonproportionality observed in the survival data. For OS, results of cemiplimab versus pembrolizumab and atezolizumab were generally consistent with the constant HR NMA reported in the Supplemental material.…”

“…An indirect comparison of immunotherapies among patients with locally advanced or metastatic NSCLC with PD-L1 expression ⩾50% who had not received prior systemic therapy for their locally advanced or metastatic disease was recently published. 76 76 The main strength of the current analysis was the use of robust statistical models for time-varying HRs. NMAs for survival outcomes based on constant HRs relied on the proportional hazard assumption, which was implausible given that this assumption was shown to be violated in several trials for OS and PFS.…”

Cemiplimab (Libtayo)

“…The objective of the ITC by Majem et al ( 2021) 31 was to evaluate the efficacy of available PD-L1 and PD-1 inhibitor monotherapies for the first-line treatment of patients with high PD-L1 expression (≥ 50%) and locally advanced or metastatic NSCLC compared to chemotherapy.…”

Cost-effectiveness of atezolizumab versus pembrolizumab as first-line treatment in PD-L1-positive advanced non-small-cell lung cancer in Spain

“…The use of chemotherapy has been the only systemic therapeutic strategy for decades with five-year survival rates of 0-5% in advanced NSCLC patients [8]. Fortunately, the better understanding of the biology of this cancer and the emergence of immunotherapy has expanded treatment options for advanced NSCLC with improvements in survival, in security and with reduced overall toxicity compared to chemotherapy and other classic cancer therapies [9][10][11][12]. 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 with locally advanced disease and metastatic NSCLC [13][14][15][16][17][18].…”

“…The first-line immunotherapy anti-PD-(L)1 monotherapy strategy has become the new standard of care in locally advanced and metastatic NSCLC patients with high PD-L1 expression (Tumor Proportion Score [TPS] ≥ 50%) and no targetable mutations (EGFR mutation or ALK translocations wild-type [WT]) [11,20,21]. Until now, pembrolizumab monotherapy was the only first-line treatment option for this subgroup of NSCLC patients [17,20,21].…”