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

J. Remon, Benjamin Besse, S. Ponce Aix, A. Callejo, K. Al-Rabi, R. Bernabe, L Greillier, Margarita Majem, N. Reguart, I. Monnet, S Cousin, Pilar Garrido, G. Robinet, R. Garcia Campelo, A. Madroszyk, Julien Mazieres, H. Curcio, B Wasag, Y. Pretzenbacher, B. FournierAnne-Marie Dingemans, R Dziadziuszko*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)

Abstract

Background:
The APPLE trial aimed to evaluate the feasibility of longitudinal plasma epidermal growth factor receptor (EGFR) T790M monitoring for the best sequencing strategy of gefitinib and osimertinib.

Methods:
APPLE is a randomized, non-comparative, phase II study in patients with common EGFR-mutant, treatmentnaive non-small-cell lung cancer including three arms: arm A (osimertinib upfront until RECIST progression, PD), arm B
[gefitinib until 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) after randomization in arm B (H0: PFSR-OSI-18 of 40%). Secondary endpoints include response rate, overall survival (OS), and brain PFS. We report the results of arms B and C.

Results:
From November 2017 to February 2020, 52 and 51 patients were randomized into arms B and C, respectively. Most patients were females (70%) and had EGFR Del19 (65%); one-third had baseline brain metastases. In arm B, 17%
of patients (8/47) switched to osimertinib based on the emergence of ctDNA T790M mutation before RECIST PD, with a median time to molecular PD of 266 days. The study met its primary endpoint of PFSR-OSI-18 of 67.2% (84% confidence interval 56.4% to 75.9%) in arm B versus 53.5% (84% confidence interval 42.3% to 63.5%) in arm C, with a median PFS of 22.0 months versus 20.2 months, respectively. The median OS was not reached in arm B versus 42.8 months in arm C. Median brain PFS in arms B and C was 24.4 and 21.4 months, respectively.

Conclusions:
The serial monitoring of ctDNA T790M status in advanced EGFR-mutant non-small-cell lung cancer during treatment with first-generation EGFR inhibitors was feasible, and a molecular progression before RECIST PD led to an
earlier switch to osimertinib in 17% of patients with satisfactory PFS and OS outcomes.
Original languageEnglish
Pages (from-to)468-476
Number of pages9
JournalAnnals of Oncology
Volume34
Issue number5
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
This work was supported by an educational grant from AstraZeneca (no grant number).

Publisher Copyright:
© 2023

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