Clinical Summary:

• Design/Population: The phase 2 FLAME study randomized patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who remained ctDNA-positive after 3 weeks of first-line osimertinib to receive either osimertinib plus carboplatin and pemetrexed or continued osimertinib monotherapy.
• Key Outcomes: Osimertinib plus chemotherapy significantly improved progression-free survival compared with osimertinib alone, with higher response rates and longer duration of response. Grade ≥3 treatment-related adverse events were more common with the combination, but no new safety signals were identified.
• Clinical Relevance: These findings support ctDNA-guided treatment escalation, suggesting that persistent early molecular disease may identify patients who benefit from adding chemotherapy to osimertinib.

According to results from the phase 2 FLAME study, osimertinib plus chemotherapy significantly improved progression-free survival (PFS) compared to osimertinib monotherapy among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) who have persistent plasma ctDNA EGFR mutations following first-line osimertinib. 

These results were presented by Zhijie Wang, MD, Cancer Hospital Chinese Academy of Medical Sciences, Langfang, Hebei, China, at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.

In this multicenter trial, 80 patients with locally advanced or metastatic EGFR mutated NSCLC with persistent ctDNA EGFR mutations following 3 weeks of first-line osimertinib were randomized 1:1 to receive either osimertinib plus carboplatin and pemetrexed (n = 40) or continue osimertinib monotherapy (n = 40). Stratification was based on central nervous system metastases and EGFR mutation subtype. 

The primary end point was investigator-assessed PFS. Key secondary end points were overall survival (OS) rate at 18 months, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), depth of response, safety, and resistance profile. 

At analysis, median PFS was 23.1 months in the osimertinib plus chemotherapy arm and 12.7 months in the osimertinib monotherapy arm (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.31 to 0.92; P = .024). The ORR was 50% and 35%, respectively. Median duration of response was 15.6 months in the osimertinib plus chemotherapy arm and 10.5 months in the osimertinib monotherapy arm. 

Grade ≥3 treatment-related adverse events were reported in 65% of patients in the osimertinib plus chemotherapy arm and 10% of patients in the osimertinib monotherapy arm. Toxicities were considered manageable and no new safety signals were identified.

“This is the first prospective randomized controlled trial showing osimertinib plus chemotherapy significantly prolongs PFS versus osimertinib,” concluded Dr Wang. “This study provides prospective evidence for individualized escalation combination therapy based on dynamic molecular detection.”

Source:

Wang Z, Zhong J, Duan J, et al.Osimertinib with/without chemotherapy in patients with persistent ctDNA EGFR mutant (EGFRm) NSCLC at 3 weeks after 1L osimertinib: A randomized phase II study (FLAME study). Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. LBA101.