RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small cell lung cancer: exposure-response relationship

Kazuhiko Nakagawa, Edward B Garon, Ling Gao, Sophie Callies, Annamaria Zimmermann, Richard Walgren, Carla Visseren-Grul, Martin Reck, Kazuhiko Nakagawa, Edward B Garon, Ling Gao, Sophie Callies, Annamaria Zimmermann, Richard Walgren, Carla Visseren-Grul, Martin Reck

Abstract

Purpose: In RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure-response relationship of RAM from RELAY.

Methods: Patients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan-Meier method and Cox regression analyses were utilized to evaluate exposure-efficacy by Cmin,1 quartile. Exposure-safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only.

Results: Analyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure-efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45-0.99), 0.77 (0.53-1.12), 0.57 (0.38-0.84), and 0.50 (0.33-0.76). No apparent exposure-safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury.

Conclusions: No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC.

Trial registration: ClinicalTrials.gov, NCT02411448.

Keywords: Exposure–response; Non-small cell lung cancer; Pharmacokinetics; Ramucirumab.

Conflict of interest statement

This work was supported by Eli Lilly and Company. S. Callies, A. Zimmermann, R. Walgren, and C. Visseren-Grul are full-time employees of Eli Lilly and Company. S. Callies, A. Zimmermann, and R. Walgren are minor stockholders in Eli Lilly and Company. L. Gao owned stock in Eli Lilly and Company at the time of this work. K. Nakagawa has received funding or grants from Takeda, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, ICON, Kissei Pharmaceutical, Parexel, EPS, Syneos Health, Pfizer, A2 Healthcare, Eisai, CMIC Shift Zero, Kyowa Kirin, Bayer Yakuhin, Otsuka Pharmaceutical, PRA Health Sciences, Covance, Medical Research Support, Sanofi, PPD-SNBL, Japan Clinical Research Operations, Sysmex Corporation, AbbVie, Mochida Pharmaceutical, and GlaxoSmithKline, consulting fees from Astellas Pharmaceuticals, Pfizer, KYORIN, Takeda, Eli Lilly and Company, Ono Pharmaceutical, and speaker’s bereaus from AstraZeneca, Chugai Pharmaceutical, Takeda, Roche Diagnostics, MSD, Eli Lilly and Company, Nippon Kayaku, Astellas Pharma, Bayer Yakuhin, Merck, Nanzando, Daiichi Sankyo, Novartis, Kyowa Kirin, Medical Mobile Communications, Yomiuri Telecasting Corporation, Nikkei Business Publications, Nippon Boehringer Ingelheim, MEDICUS SHUPPAN, Taiho Pharmaceutical, AbbVie, Bristol Myers Squibb, Care Net, Amgen, Medical Review, Yodosha, 3H Clinical Trial Inc., Thermo Fisher Scientific, Hisamitsu Pharmaceutical, Nichi-Iko Pharmaceutical, KYORIN Pharmaceutical, Pfizer, and Ono Pharmaceutical. E. B. Garon received grants from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly and Company, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis, and consulting fees from ABL-Bio, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, Eli Lilly and Company, EMD Serono, Eisai, GlaxoSmithKline, Merck, Natera, Novartis, Regeneron, Sanofi, Shionogi, and Xilio. M. Reck received consulting fees and honoraria for speaker’s bureaus from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly and Company, Merck, MSD, Mirati, Novartis, Pfizer, Roche, and Sanofi. M. Reck has also participated on the data safety monitoring or advisory board from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly and Company, Merck, MSD, Mirati, Novartis, Pfizer, Roche, and Sanofi.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
RELAY predicted ramucirumab concentration–time profiles following 10 mg/kg Q2W in RELAY compared with 10 mg/kg Q3W in REVEL. Shaded regions represent the 5th and 95th percentile ramucirumab concentrations calculated from 500 simulation iterations. The dashed horizontal line indicates ramucirumab Cmin,ss of 50 ug/mL. Q2W, on Day 1 of each 2-week cycle; Q3W, on Day 1 of each 3-week cycle
Fig. 2
Fig. 2
RELAY Progression free survival predicted by Cmin,1 quartile. Predicted Cmin,1 exposure quartiles: RAM Q1 Cmin,1 4.13–31.6 μg/mL (< 25%); RAM Q2, Cmin,1 31.8–37.6 μg/mL (25–< 50%); RAM Q3, Cmin,1 37.7–42.9 μg/mL (50–< 75%); RAM Q4, Cmin,1 43.0–59.9 μg/mL (≥ 75%). Cmin,1, minimum concentration after first dose; Q, quartile; RAM + ERL, ramucirumab plus erlotinib; PBO + ERL, placebo plus erlotinib; N, number of patients in group

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