RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small cell lung cancer: exposure–response relationship
| Autor: | Kazuhiko Nakagawa, Edward B. Garon, Ling Gao, Sophie Callies, Annamaria Zimmermann, Richard Walgren, Carla Visseren-Grul, Martin Reck |
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| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Lung Neoplasms Clinical Trials and Supportive Activities Antibodies Monoclonal Humanized Toxicology Antibodies Ramucirumab Erlotinib Hydrochloride Non-small cell lung cancer Clinical Research Carcinoma Non-Small-Cell Lung Monoclonal Antineoplastic Combined Chemotherapy Protocols Humans Pharmacokinetics Pharmacology (medical) Oncology & Carcinogenesis Non-Small-Cell Lung Humanized Lung Cancer Pharmacology Exposure-response Carcinoma Lung Cancer Evaluation of treatments and therapeutic interventions Pharmacology and Pharmaceutical Sciences Exposure–response ErbB Receptors Oncology 6.1 Pharmaceuticals Hypertension Mutation Digestive Diseases |
| Zdroj: | Cancer chemotherapy and pharmacology, vol 90, iss 2 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-022-04447-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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