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

Ann Oncol. 2023 May;34(5):468-476. doi: 10.1016/j.annonc.2023.02.012. Epub 2023 Feb 28.

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.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Antineoplastic Agents* / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • ErbB Receptors / genetics
  • Female
  • Gefitinib / therapeutic use
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use

Substances

  • osimertinib
  • Gefitinib
  • ErbB Receptors
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Aniline Compounds
  • EGFR protein, human