Double-Dose Firmonertinib Showing Promising Activity in First-Line EGFR L858R–Mutated NSCLC

Dual-dose firmonertinib was safe and active for the frontline treatment of patients with EGFR L858R–mutated non–small cell lung cancer (NSCLC), according to data from the phase 2 FIRM Study (ChiCTR2200060897) presented during the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.1

At the February 16, 2025, data cutoff, at a median follow-up of 18.1 months, the median progression-free survival (PFS) among patients who received firmonertinib was 21.1 months (95% CI, 17.5-not reached [NR]). The 18-month PFS rate was 59.7% (95%, 44.1%-80.8%).

“Double-dose firmonertinib exhibited promising efficacy and safety in this trial, supporting its use as a first-line option for patients with EGFR L858R–mutated [NSCLC],” Meiqi Shi, MD, of the Department of Medical Oncology at Jiangsu Cancer Hospital in Nanjing, China, and coauthors wrote in a poster presentation of the data.

What Were the Methods and Baseline Characteristics of the FIRM Study?

The FIRM Study was a prospective, multicenter, open-label, single-arm study that enrolled patients with EGFR L858R–mutated advanced NSCLC in China.1,2 Eligible patients needed to be at least 18 years of age, have received no prior systemic anti-tumor therapy, have an ECOG performance status of 0 or 1, and have a life expectancy of at least 12 weeks.2 Patients with asymptomatic brain metastases were allowed to be included in the study.

All patients received oral firmonertinib at 160 mg once daily. The primary end point was investigator-assessed PFS.1 Secondary end points included overall response rate (ORR), disease control rate (DCR), 18-month PFS rate, overall survival (OS), and safety. Dynamic changes of circulating tumor DNA (ctDNA) at baseline, day 1 of cycle 3, and disease progression were assessed as exploratory end points.

At baseline, the median age was 65 years (range, 47-80). Most patients were female (51.5%), had stage IV disease (90.9%), and were never smokers (66.7%). All patients had an ECOG performance status of 1 and adenocarcinoma.

What Were the Additional Efficacy and Safety Data?

Further efficacy data revealed that the ORR was 75.8% (95% CI, 57.7%-88.9%); all responses were partial. Patients achieved stable disease at a rate of 15.2% and 6.1% had disease progression. The DCR was 90.9% (95% CI, 75.7%-98.1%). The median OS was NR (95% CI, NR-NR), and the 12-month OS rate was 96.6% (95% CI, 90.1%-100%).

In terms of safety, 90.9% of patients experienced any-grade treatment-emergent adverse effects (TEAEs). The most common any-grade TEAEs included lymphopenia (39.4%), increased creatine phosphokinase levels (39.4%), diarrhea (36.4%), and increased creatinine levels (33.3%). Grade 3 or higher TEAEs were reported in 6.1% of patients. Notably, no patients had dose reductions, treatment discontinuations, or died.

Data from an exploratory analysis, which included 28 patients with available plasma samples, showed that ctDNA was detected in 92.9% of patients at baseline, fell to 32.0% (n = 8 of 25) at day 1 of cycle 3, and rose to 78.6% (n = 11 of 14) at the time of disease progression. The median variant allele frequency (VAF) fell from 1.1% to 0% at baseline to day 1 of cycle 3 (P < .001), then rose to 0.08% at disease progression.

Patients with ctDNA positivity at day 1 of cycle 3 (n = 17) had a median PFS of 23.4 months (95% CI, 18.9-NR) compared with 10.7 months (95% CI, 9.9-NR) among patients who were negative for ctDNA at the same time point (HR, 4.3; 95% CI, 1.4-13.1; P = .006).

“ctDNA analysis demonstrates its significant clinical value for efficacy monitoring and provides new insights for precise treatment strategies based on biomarker-driven stratification,” the study authors wrote in their conclusion.

References

1. Shi M, Shen B, Wang C, et al. Phase II trial of first-line double-dose firmonertinib in locally advanced or metastatic NSCLC with EGFR L858R (FIRM Study). Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract P3.12.01.
2. High dose Firmonertinib in treatment naive advanced non-small cell lung cancer patients harbouring EGFR Exon 21 L858R mutation: a prospective, multicenter, single arm, open label study. Chinese Clinical Trial Registry. Updated on April 15, 2025. Accessed September 9, 2025. https://www.chictr.org.cn/showproj.html?proj=171715