FLAME: Osimertinib Plus Chemotherapy Improves PFS in ctDNA-Persistent NSCLC

The combination of osimertinib (Tagrisso) plus carboplatin/pemetrexed significantly imporved progression-free survival (PFS) vs vs osimertinib monotherapy in patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC) who had persistent plasma ctDNA EGFR mutation at 3 weeks after first-line osimertinib initiation, according to results from the phase 2 FLAME study (NCT04769388) presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

At the June 25, 2025, data cutoff, with a PFS maturity of 68.8%, the combination arm met the primary end point with a statistically significant and clinically meaningful PFS improvement. Median PFS was 23.1 months (95% CI, 12.65-29.24) in the osimertinib plus chemotherapy arm vs 12.7 months (95% CI, 12.45-18.07) in the osimertinib monotherapy arm (HR, 0.54; 96% CI, 0.34-0.86; P = .028). A consistent PFS benefit favoring the combination was observed across all prespecified subgroups, regardless of sex, age, EGFR mutation type, or presence of brain metastases.

Response data similarly favored the combination. The ORR was 50% (95% CI, 34%-66%) with osimertinib plus chemotherapy vs 35% (95% CI, 20%-50%) with osimertinib alone; the median duration of response (DOR) was 15.6 months (95% CI, 5.9–not evaluable [NE]) vs 10.5 months (95% CI, 4.3-19.5), respectively. The disease control rate (DCR) was 93% (95% CI, 84%-100%) in the combination arm vs 98% (95% CI, 93%-100%) in the monotherapy arm.

OS data remained immature at 37.5% maturity. The 18-month OS rate was 76.3% (95% CI, 59.4%-86.9%) with the combination vs 74.6% (95% CI, 58.0%-85.5%) with the monotherapy (HR, 0.62; 95% CI, 0.29-1.30); median OS had not been reached in either arm.

Exploratory analyses revealed that persistent EGFR ctDNA at week 3 was associated with higher intratumor heterogeneity, more frequent co-alterations, and numerically higher plasma ctDNA concentration after initial osimertinib exposure — biological features that may underlie this poor-prognosis population’s benefit from early treatment intensification.

The rationale for FLAME builds on exploratory analyses from the phase 3 FLAURA2 trial (NCT04035486), in which persistence of EGFR-mutant ctDNA at 3 weeks was associated with shorter median PFS, and on retrospective analyses from FLAURA2, which showed improved PFS with osimertinib plus chemotherapy in patients with persistent EGFR-mutant ctDNA at 3 weeks. FLAME is the first prospective, randomized trial designed to validate ctDNA dynamics as a tool for guiding early treatment intensification in this population.

A total of 80 patients were randomly assigned 1:1 after demonstrating persistent plasma ctDNA EGFR mutation (L858R) at 3 weeks following first-line osimertinib initiation. Patients in the experimental arm received osimertinib 80 mg once daily plus pemetrexed 500 mg/m² and carboplatin AUC5 every 3 weeks for 4 to 6 cycles, followed by maintenance osimertinib 80 mg once daily plus pemetrexed; patients in the control arm received osimertinib 80 mg once daily as monotherapy. The primary end point was investigator-assessed PFS per RECIST 1.1; secondary end points included OS, ORR, DCR, DOR, and safety.

The median patient age was 58 years in the osimertinib/chemotherapy arm vs 60.5 years in the monotherapy arm with 60% vs 55% being female, 90% vs 85% having an ECOG performance status of 1, and 53% vs 50% having exon 19 deletions. Additionally, 98% vs 100% of patients had stage IV disease, 35% vs 35 had brain metastases, 13% vs 30% had liver metastases, 88% vs 85% had extrathoracic metastases, and the median baseline tumor size was 45.5 mm vs 42.2 mm.

The safety profile was consistent with the established profiles of osimertinib and platinum/pemetrexed chemotherapy and was broadly comparable with that reported in the FLAURA2 trial, with no new safety signals identified. Cancer Network^® has previously reported on osimertinib-combination strategies in EGFR-mutant advanced NSCLC.

Investigators concluded that FLAME is the first prospective proof-of-concept study demonstrating that ctDNA-guided early intensification with osimertinib plus carboplatin-pemetrexed significantly improves PFS in patients with persistent ctDNA EGFR mutation at 3 weeks after first-line osimertinib monotherapy initiation. The findings provide prospective evidence supporting the emerging framework of ctDNA-guided treatment escalation and point toward further investigation of molecular feature-based strategies in advanced EGFR-mutant NSCLC.

Reference

Zhong J, Wang J, et al. Osimertinib monotherapy versus osimertinib plus chemotherapy in advanced EGFR-mutant NSCLC with persistent ctDNA EGFR mutation at three weeks after first-line osimertinib monotherapy initiation: a multicenter randomized trial (FLAME study). Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 30–June 3, 2026; Chicago, IL.