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. 2023 Apr 4:12:1081729.
doi: 10.3389/fonc.2022.1081729. eCollection 2022.

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

Josephine Louella Feliciano  1 , Dylan McLoone  2 , Yingxin Xu  3 , Ruben G W Quek  3 , Andreas Kuznik  3 , Jean-Francois Pouliot  3 , Giuseppe Gullo  3 , Petra Rietschel  3 , Patricia Guyot  4 , Gerasimos Konidaris  5 , Keith Chan  6 , Sam Keeping  6 , Florence R Wilson  6 , Nick Freemantle  7
Affiliations

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

Josephine Louella Feliciano et al. Front Oncol. .

Abstract

Objectives: In 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.

Methods: Patients 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).

Results: In 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.

Conclusions: After 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.

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

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Conflict of interest statement

NF declares consulting services for Abbott Singapore, ALK, Allergan, Aimmune, AstraZeneca, Galderma, Ipsen, Novartis, Novo Nordisk, Regeneron, Sanofi Aventis, Thea, and Vertex; and a leadership or fiduciary role for the European Association of Cardiothoracic Surgery. JF has received grants or contracts from Bristol-Myers Squibb, AstraZeneca and Pfizer; consulting fees from AstraZeneca, Coherus, Eli Lilly, Genentech, Merck, Pfizer, Regeneron, and Takeda; honoraria from Janssen; and meeting attendance support from Regeneron. YX, RQ, AK, J-FP, GG, and PR are employees of Regeneron Pharmaceuticals. PG and GK are employees of Sanofi. DL, KC, SK, and FW are employees of PRECISIONheor and received funding from Regeneron Pharmaceuticals and Sanofi to produce this work.

Figures

Figure 1
Figure 1
EMPOWER-Lung 1 treatment crossover trial design. Conditions for crossover or continued treatment in both trial arms included independent review committee–assessed RECIST 1.1–defined disease progression. IV, intravenous; Q3W, every 3 weeks; R, randomized; RECIST 1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.
Figure 2
Figure 2
Overall survival Kaplan-Meier curves for the unadjusted and crossover-adjusted results from the EMPOWER-Lung 1 PD-L1 ≥50% population based on simplified two-stage correction. Values under the figure represent number of patients at risk. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; PD-L1, programmed cell death-ligand 1.
See this image and copyright information in PMC

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