A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor-Naïve EGFR-Mutant Metastatic Non-Small Cell Lung Cancer (RAMOSE trial)

Abstract

Purpose: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS).

Methods: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis.

Results: At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug.

Conclusion: Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR-mutant NSCLC. The combination is safe and well tolerated.

FIG 1.

CONSORT diagram for the RAMOSE trial screening, randomization, allocation, treatment, and follow-up. AE, adverse event; EGFR, epidermal growth factor receptor; NSCLC, non–small cell lung cancer; PFS, progression-free survival.

FIG 2.

Clinical efficacy. Bold indicates P = .026 is statistically significant. (A) Kaplan-Meier curves for PFS in arm A (ramucirumab with osimertinib) and arm B (osimertinib); (B) waterfall plots for responses per RECIST from baseline two arms. CR, complete response; HR, hazard ratio; NE, not evaluable; NR, not reached; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

FIG 3.

Subgroup analysis for efficacy. EGFR, epidermal growth factor receptor; PH, proportional hazard.

FIG 4.

Treatment-emerged adverse events in the RAMOSE trial by treatment arms.