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

• Published in: Cancer chemotherapy and pharmacology 2022-08, Vol.90 (2), p.137-148
• Main Authors: Nakagawa, Kazuhiko, Garon, Edward B., Gao, Ling, Callies, Sophie, Zimmermann, Annamaria, Walgren, Richard, Visseren-Grul, Carla, Reck, Martin
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Confidence intervals; Dermatitis; Diarrhea; Epidermal growth factor receptors; ErbB Receptors - genetics; Erlotinib Hydrochloride; Evaluation; Exposure; Humans; Hypertension; Immunotherapy; Liver; Liver diseases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medicine; Medicine & Public Health; Metastases; Metastasis; Monoclonal antibodies; Mutation; Non-small cell lung carcinoma; Oncology; Original; Original Article; Patients; Pharmacokinetics; Pharmacology/Toxicology; Placebos; Proteinuria; Quartiles; Ramucirumab; Safety; Small cell lung carcinoma; Statistical analysis; Targeted cancer therapy
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-022-04447-x

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 ( C min,1 ), and at steady state ( C min, 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 C min,1 quartile. Exposure–safety was evaluated by assessing incidence rates for safety parameters by C min, 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 C min,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.