LBA51 Osimertinib treatment based on plasma T790M monitoring in patients with EGFR-mutant non-small cell lung cancer (NSCLC): EORTC Lung Cancer Group 1613 APPLE phase II randomized clinical trial

APPLE is a randomized, non-comparative, open-label, 3-arm, phase II study in patients with common EGFR-mutant, treatment-naïve NSCLC, aimed to evaluate the feasibility of longitudinal plasma EGFR T790M monitoring and the best sequencing strategy from gefitinib to osimertinib. We report the results of arm B (gefitinib until the emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR Test v2 or progression (PD) by RECIST) and arm C (gefitinib until PD by RECIST), and then switch to osimertinib in both arms. Primary endpoint is Progression Free Survival rate (by RECIST 1.1) “on osimertinib” at 18 months (PFSR-OSI-18). The study was designed to reject a PFSR-OSI-18 of ≤40% in Arm B with 1-sided α = 0.08 and 92% power under a PFSR-OSI-18 of 60%. Arm C was an internal control arm. Secondary endpoints: response rate, overall survival (OS) and Brain PFS (BPFS). The primary analysis was performed in per-protocol (PP) population. From Nov 2017 to Feb 2020, 52 and 51 patients in 6 countries were randomized to Arm B and C. Most patients were females (75% and 65%), never smokers (71% and 59%) and had EGFR Del19 (64% and 65%), respectively. Median age was 69 and 61 years. One-third of patients had baseline brain metastases. In arm B, 17% of patients (8/47) switched to osimertinib based on ctDNA T790M-positive before RECIST PD. Median follow-up was 30 months. The study met its primary endpoint - PFSR-OSI-18 was 67.2% (84%CI 56.4-75.9%) in arm B vs. 53.5% (84% CI 42.3-63.5%) in arm C, with a median PFS of 22.0 months (95% CI 18.6-NR) vs. 20.2 months (95% CI 14.6-35.0), respectively. The median OS was not reached in arm B vs. 42.8 months (95%CI 27.0-NR) in arm C. Median BPFS in arm B and C were 24.4 months (95% CI 17.9-28.6) and 21.4 months (95% CI 14.5-42.8). Toxicity was as expected for both drugs. Serial monitoring of ctDNA T790M status in patients with advanced EGFR mutant-NSCLC by Cobas v2.0 PCR test treated with first-generation EGFR inhibitors is feasible, and a molecular progression before RECIST PD led to earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.