LBA70 OSIRAM-1: A multicenter, open label, randomized phase II study of osimertinib plus ramucirumab versus osimertinib alone as initial chemotherapy for EGFR mutation-positive non-squamous non-small cell lung cancer (TORG1833)

Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram). Previously untreated patients with advanced NSCLC and EGFR mutations were randomized to receive Osi daily with or without Ram every 2 weeks. Eligibility included asymptomatic and/or treated brain metastases. Stratification was based on gender and mutation type (exon 19 del, L858R). The primary endpoint was progression free survival (PFS) assessed by central radiologic review. Between November 2018 and April 2020, 122 patients (Osi+Ram arm: 59, Osi arm: 63) were enrolled. With a median follow up of 36.0 months (m), median PFS was 20.0 m for Osi+Ram arm and 24.0 m for Osi arm, resulting in a hazard ratio of 1.054 (95% CI 0.674-1.648, p = 0.82). The overall response rate was 77.2% and 79.3%, with a median duration of response of 24.7 m and 25.1 m in the Osi+Ram and Osi arms respectively. Notable grade 3 or higher adverse events (≥10%) included CK elevation (13%) in Osi arm, neutropenia (10%) and hypertension (17%) in Osi+Ram arm. Pneumonitis of any grade occurred in 9% and 16% of Osi+Ram and Osi arms. Median treatment durations for Osi and Ram were 18.8 (0.5-49.7) and 4.6 (0.5-40.7) m in the Osi+Ram arm, and 17.4 m in the Osi arm. The treatment period of Ram was shorter compared to previous studies. In a post hoc analysis, PFS favored the Osi+Ram combination among patients with brain metastasis (n=34) with a hazard ratio of 0.655 (95% CI 0.296-1.451). While both treatment arms demonstrated long-term effects with acceptable toxicity, this study did not reveal an advantage of the Osi+Ram combination over Osi monotherapy in improving PFS. It’s noteworthy that conducted period during the COVID-19 pandemic, and the suboptimal administration of Ram may have influenced the outcome. jRCT2080224085