The following is a summary of “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,” published in the May 2023 issue of the Oncology by Remon et al.
The objective of the APPLE trial was to assess the viability of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring to determine the optimal sequencing strategy for gefitinib and osimertinib. Arm A (osimertinib upfront until RECIST progression, PD), arm B [gefitinib until the emergence of circulating tumor DNA (ctDNA) EGFR T790M mutation by cobas EGFR test v2 or RECIST PD], and arm C [gefitinib until RECIST PD], and then switch to osimertinib in both arms.
The primary endpoint is the progression-free survival (PFS) rate ‘on osimertinib’ at 18 months (PFSR-OSI-18) in arm B (H0: PFSR-OSI-18 40%). The secondary endpoints are the response rate, overall survival (OS), and brain PFS. The researchers will discuss the outcomes of arms B and C. From November 2017 to February 2020, 52 and 51 patients, respectively, were randomly assigned to arms B and C. Most patients were female (70%) and had EGFR Del19 (65%); one-third had cerebral metastases at baseline. In arm B, 17% (8/47) of patients switched to osimertinib based on the appearance of the ctDNA T790M mutation before RECIST PD, with a median latency to molecular PD of 266 days.
The primary endpoint of PFSR-OSI-18 was met in arm B with 67.2% (84% confidence interval 56.4% to 75.9%) versus arm C with 53.5% (84% confidence interval 42.3% to 63.5%), with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B, compared to 42.8 months in arm C. In limbs B and C, the median brain PFS was 24.4 and 21.4 months, respectively. The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer was feasible, and molecular progression before RECIST PD led to an earlier switch to osimertinib in 17% of patients with favorable PFS and OS outcomes.