APPLE is a 3 arms phase II non-comparative trial exploring the sequential treatment approach of gefitinib followed by osimertinib or osimertinib frontline in patients with advanced EGFR-mutant NSCLC. Here we report the exploratory analysis of the outcome with osimertinib frontline compared to a sequential approach.
Patients were randomized to: arm A (osimertinib until RECIST progression -PD-), arm B (gefitinib until the emergence of circulating tumor DNA EGFR T790M mutation or RECIST PD) or arm C (gefitinib until RECIST PD), and then switch to osimertinib in both arms B and C. In this analysis, arms B and C were pooled. Primary endpoint: Progression Free Survival rate “on osimertinib” at 18 months (PFSR-OSI-18) in arm B (H0: PFSR-OSI-18 of ≤40%). Secondary endpoints: overall survival (OS) and Brain PFS (BPFS). Primary analyses were performed in per-protocol population (PPP). In all arms, contrast-enhanced brain CT-scan was performed every 8 weeks.
From 11/2017 to 02/2020, 156 patients were randomized (arm A:53, arm B/ C:103), and 136 were included in the PPP. Most patients were females (56.6% and 69.9%), with EGFR Del19 (66% and 64%). Baseline brain metastases: 19% and 29.1%, respectively. In pooled arms B/C, 70% of patients received osimertinib at PD. In arm A, PFS on osimertinib was 19.5 months. The PFSR-OSI-18 was 51.1% in Arm A and 61% in pooled arms B/C. The median OS was NR in arm A vs 42.8 (95% CI: 28.6-NR) months (mo) in pooled arm B/C, with 18-months OS of 84.4% and 82.3%, respectively. In all arms, 68 brain progression events were observed. Median time to brain PD in arm A and B/C were 34.3 mo (95% confidence interval, CI:26.9-NR) and 22.3 mo (95%CI:18.6-22.3), and corresponding hazard ratio was 0.54 (90% CI: 0.34-0.86) with 18-months BPFS of 82.2% and 63.5%, respectively.
In advanced EGFR mutant-NSCLC, upfront treatment with osimertinib shows a significant reduction in the risk of brain progression, with comparable OS versus the sequential treatment approach.
NCT02856893