Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer

Frontiers in Oncology

Oncology

Nick Freemantle¹  Josephine Louella Feliciano²  Dylan McLoone³  Keith Chan⁴  Sam Keeping⁴  Florence R. Wilson⁴  Giuseppe Gullo⁵  Yingxin Xu⁵  Jean-Francois Pouliot⁵  Andreas Kuznik⁵  Petra Rietschel⁵  Ruben G.W. Quek⁵  Patricia Guyot⁶  Gerasimos Konidaris⁷ 

[1] Institute of Clinical Trials and Methodology, University College London, London, United Kingdom;Johns Hopkins University, Baltimore, MD, United States;PRECISIONheor, Boston, MA, United States;PRECISIONheor, Vancouver, BC, Canada;Regeneron Pharmaceuticals, Inc., Tarrytown, NY, United States;Sanofi, Chilly-Mazarin, France;Sanofi, Reading, United Kingdom;

关键词: non-small cell lung cancer;    first-line treatment;    cemiplimab;    crossover design;    EMPOWER-lung 1;    chemotherapy;   

DOI  :  10.3389/fonc.2022.1081729

 received in 2022-10-27, accepted in 2022-12-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

ObjectivesIn randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression.MethodsPatients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring).ResultsIn the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction—the most suitable method based on published guidelines and trial characteristics—produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction.ConclusionsAfter adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.

【 授权许可】

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Copyright © 2023 Feliciano, McLoone, Xu, Quek, Kuznik, Pouliot, Gullo, Rietschel, Guyot, Konidaris, Chan, Keeping, Wilson and Freemantle