Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 May;34(5):468-476.
doi: 10.1016/j.annonc.2023.02.012. Epub 2023 Feb 28.

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  1 , B Besse  1 , S Ponce Aix  2 , A Callejo  3 , K Al-Rabi  4 , R Bernabe  5 , L Greillier  6 , M Majem  7 , N Reguart  8 , I Monnet  9 , S Cousin  10 , P Garrido  11 , G Robinet  12 , R Garcia Campelo  13 , A Madroszyk  14 , J Mazières  15 , H Curcio  16 , B Wasąg  17 , Y Pretzenbacher  18 , B Fournier  18 , A-M C Dingemans  19 , R Dziadziuszko  20
Affiliations
Clinical Trial

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 et al. Ann Oncol. 2023 May.

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, treatment-naive 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.

Keywords: EGFR-mutant; advanced non-small-cell lung cancer; ctDNA; liquid biopsy; molecular progression; osimertinib.

PubMed Disclaimer

Conflict of interest statement

Disclosure JR: none directly related to this manuscript. Advisory/speaker: Merck Sharp & Dohme (MSD), Sanofi, Boehringer Ingelheim, Pfizer, Ose Immunotherapeutics, Janssen, and Takeda. Speaker at a company’s organized public event: MSD, Boehringer Ingelheim, Roche, and Janssen. Receipt of grants/research support: MSD (principal investigator in PECATI trial). BB: none directly related to this manuscript. Grant to institution: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chugai Pharmaceutical, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GlaxoSmithKline, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics. RD: honoraria for consultancy or lectures: AstraZeneca, Roche, Novartis, MSD, Takeda, Pfizer, Amgen, and Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Comment in

Publication types

MeSH terms

LinkOut - more resources