Phase 1b study of ramucirumab in combination with erlotinib or osimertinib for untreated EGFR-mutated non–small cell lung cancer patients with asymptomatic brain metastases

Abstract

Objectives: The study was designed to investigate the safety and tolerability of ramucirumab administered in combination with erlotinib or osimertinib for patients with untreated EGFR-mutated nonsmall cell lung cancer (NSCLC) and asymptomatic brain metastases, a patient subgroup in which these regimens have remained untested.Materials and methods: This multicenter phase 1b study (RELAY-Brain) consisted of two cohorts with three patients each. The two cohorts were assessed independently of one another and were not compared. Patients whose asymptomatic brain metastases had or had not undergone prior local therapy received ramucirumab (10 mg/kg) every 2 weeks plus either erlotinib (150 mg/day) or osimertinib (80 mg/day) until disease progression or intolerable toxicity. The primary objective of the study was to assess dose-limiting toxicity (DLT), de ned as central nervous system (CNS) hemorrhage of grade ³2.Secondary end points included safety pro le, objective response (systemic and intracranial), and disease control rate.Results: Six patients were enrolled in the study. Neither DLT nor serious or unexpected adverse events were observed. At the time of this analysis, discontinuation of the study drugs had also not occurred. One treatment-related adverse event of grade ³3 (hypertension of grade 3) was apparent. Common adverse events were generally manageable. The median number of ramucirumab administrations was 18.5 (range, 13 to 31), and there were no detected episodes of CNS hemorrhage. Four patients experienced at least one dose delay for ramucirumab, but there were no dose reductions or omissions for this drug. Five of the six patients showed an objective systemic response. Although only one patient had a measurable CNS lesion at baseline, a con rmed intracranial partial response was observed.Conclusion: Ramucirumab in combination with erlotinib or osimertinib showed promising safety and e cacy for EGFR-mutated NSCLC with brain metastases.Clinical trial registration: Japan Registry of Clinical Trials (jRCTs2051190027)

Rationale and design of phase II clinical trial of dual inhibition with ramucirumab and erlotinib in EGFR exon 19 deletion-positive treatment-naïve non-small cell lung cancer with high PD-L1 expression (SPIRAL-3D study)

“…Based on the safety results of a phase I study examining the combination therapy of ramucirumab with erlotinib for EGFR mutation-positive NSCLC patients with asymptomatic brain metastases, these patients are eligible for this study. 21 Interventions Eligible patients will be administered erlotinib 150 mg/day orally and ramucirumab 10 mg/kg intravenously biweekly until disease progression, withdrawal of consent, death, or unacceptable toxicity, whichever occurs first. Efficacy assessment will be conducted first at 6 weeks ± 1 week, and at 6 weeks ± 2 weeks thereafter.…”

“…Based on the safety results of a phase I study examining the combination therapy of ramucirumab with erlotinib for EGFR mutation-positive NSCLC patients with asymptomatic brain metastases, these patients are eligible for this study. 21…”