Front-Line vs Sequential Use of Osimertinib in EGFR-Mutant NSCLC: Potential Impact of Liquid Biopsies

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Using liquid biopsies to detect circulating tumor DNA (ctDNA) may soon transform treatment strategies for patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC), according to data presented during the European Lung Cancer Congress 2023 by lead study author Jordi Remon, MD, PhD, of Gustave Roussy, France.1 Authors of the study underscored the potential impact of using liquid biopsies to monitor T790M mutation status and identify a subpopulation of patients with EGFR-mutant NSCLC who may benefit from escalating treatment strategies.

Jordi Remon, MD, PhD

Jordi Remon, MD, PhD

Findings from the phase II APPLE study, which evaluates osimertinib upfront vs a sequential approach in patients with advanced EGFR-mutant NSCLC, showed that 17% of patients initially treated with gefitinib experienced molecular disease progression prior to disease progression. Although patients treated with osimertinib upfront had a significant reduction in the risk of brain progressive disease, overall survival results were comparable between osimertinib upfront and the sequential treatment approach.

“The APPLE trial is the first prospective trial to report that it is completely feasible to perform liquid biopsies in daily clinical practice for monitoring the status of the T790M mutation in patients initially treated with gefitinib,” said Dr. Remon. “The results of this trial may have significant implications for the treatment and management of patients with EGFR-mutant NSCLC.”

As Dr. Remon reported, the discovery that approximately 60% of EGFR-mutant NSCLC tumors initially treated with first- or second-generation EGFR tyrosine kinase inhibitors might develop an acquired EGFR T790M mutation in exon 20 led to a shift in the treatment paradigm for this population, as osimertinib has been shown to effectively overcome this mutation.2 However, tissue biopsies are not always feasible at the time of progressive disease, leading to the exploration of liquid biopsies as an alternative tool for genomic profiling and guiding treatment decisions.

APPLE Trial Details

The EORTC Lung Cancer Group 1613 APPLE trial is a phase II noncomparative clinical trial that enrolled 156 patients with common sensitizing EGFR-mutant advanced NSCLC. Patients were randomly assigned to one of three arms: arm A received osimertinib upfront, and arms B and C explored the sequential treatment approach. Patients in arm B started with gefitinib and switched to osimertinib upon molecular or pathologic disease progression. Patients in arm C received gefitinib and switched to osimertinib upon radiologic disease progression. The primary endpoint of the trial was 18-month progression-free survival with osimertinib.

After a median follow-up of 50 months, the study showed comparable overall survival rates between both strategy arms, with a median overall survival not reached for patients initially randomly assigned to osimertinib and 43 months for those receiving a sequential treatment approach (hazard ratio = 1.01; 90% confidence interval = 0.61–1.68). More than 80% of patients were alive at 18 months, regardless of treatment strategy.

“In an exploratory subgroup analysis, no patient characteristics were identified to suggest that one strategy is better than the other, even when evaluating overall survival based on the stratification criteria, the EGFR mutation subtype, and brain metastasis status at baseline,” said Dr. Remon.

However, the trial observed 68 disease progression events in the brain. The median time to brain progression was 34.3 months for patients initially randomized to osimertinib vs 22.3 months for those receiving a sequential treatment approach. This corresponds to a significant 46% reduction in the risk of progressive disease in the brain for patients receiving osimertinib upfront.

The safety profile was similar between osimertinib upfront and sequential treatment, with 7% of patients reporting grade 3 treatment-related adverse events, primarily gastrointestinal events.

Dr. Remon and colleagues also found that clearance of ctDNA at 4 or 8 weeks after treatment initiation correlated with longer progression-free survival. This finding supported ctDNA as an early prognostic marker for poor prognosis in this population. “The lack of ctDNA clearance may identify a subpopulation of patients with EGFR-mutant NSCLC who have a poor prognosis, highlighting the potential of personalized treatment strategies based on an individual patient’s molecular and radiologic disease progression,” Dr. Remon concluded. 

DISCLOSURE: Dr. Remon reported financial relationships with MSD, BMS, Pfizer, Ose Immunotherapeutics, Boehringer Ingelheim, Sanofi, Janssen, Takeda, Roche, Merck, and AstraZeneca.


1. Masip JR, Aix SP, Perez AC, et al: Osimertinib versus gefitinib followed by osimertinib in patients with EGFR-mutant non-small cell lung cancer : EORTC Lung Cancer Group 1613 APPLE trial. European Lung Cancer Congress 2023. Abstract 10. Presented March 29, 2023.

2. Soria JC, Wu YL, Nakagawa K, et al: Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS). Lancet Oncol 16:990-998, 2015.

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