Firmonertinib Demonstrates Promise in EGFR+ Advanced/Metastatic NSCLC

Double-dose firmonertinib yielded promising efficacy and a manageable safety profile in a small cohort of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring EGFR L858R mutations, according to data from the phase 2 FIRM study (ChiCTR2200060897) published in Nature Communications.¹

After a median follow-up of 27.5 months (range, 5.5-35.3), the study therapy produced a median progression-free survival (PFS) of 21.1 months (95% CI, 17.6-31.6), with an 18-month rate of 63.1% (95% CI, 48.4%-82.1%). The median overall survival (OS) was not reached (NR), although data for this end point were immature at the time of analysis; the estimated OS rates were 90.0% (95% CI, 79.9%-100%) at 24 months and 76.5% (95% CI, 61.5%-95.3%) at 30 months.

Data showed an objective response rate (ORR) of 75.8% (95% CI, 57.7%-88.9%), which consisted entirely of partial responses (PRs). Firmonertinib also yielded a disease control rate (DCR) of 90.9% (95% CI, 75.7%-98.1%). Additionally, the median duration of response (DOR) was 21.6 months (95% CI, 18.3-NR), and the median maximum tumor shrinkage was –48.3% (IQR, –56.7% to –33.2%).

Regarding 6 patients with brain metastases, investigators noted a median systemic PFS of 27.3 months (95% CI, 12.9-NR). A systemic objective response occurred in 5 patients (83.3%), and all (100.0%) achieved disease control.

“While it remains unclear whether double-dose firmonertinib can provide long-term OS benefit, the systemic efficacy, manageable toxicity, and the availability of subsequent treatment options post-progression observed with double-dose firmonertinib are similar to the key factors that contributed to the phase 3 FLAURA2 [NCT04035486] success, suggesting a potentially positive trend for long-term outcomes as follow-up continues,” lead study author Bo Shen, from the Department of Medical Oncology at Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research in Nanjing, China, wrote with coauthors in the publication.^1,2 “In this phase 2 study, double-dose firmonertinib showed promising efficacy and a favorable safety profile in [patients with] locally advanced or metastatic NSCLC with EGFR L858R mutations, warranting further investigation in larger-scale phase 3 randomized trials.”

In the multi-center, single-arm, phase 2 FIRM study, a total of 33 patients received firmonertinib at 160 mg orally once daily in 21-day cycles until progressive disease, death, unacceptable toxicity, or withdrawal from the study.

The trial’s primary end point was PFS per investigator evaluation. Secondary end points included ORR, DCR, 18-month PFS rate, and OS.

Patients 18 years and older with histologically or cytologically confirmed locally advanced or metastatic NSCLC not amenable to surgery or other radical therapy were eligible for enrollment on the trial. Other eligibility criteria included having measurable disease per RECIST v1.1 guidelines, an ECOG performance status of 0 or 1, and a life expectancy of 12 weeks or longer.

The median age was 65 years (range, 47-80), and most patients were female (51.5%). Most of the population had an ECOG performance status of 1 (100.0%), stage IV disease (90.9%), no history of smoking (66.7%), TP53 mutations (63.6%), and at least 3 metastatic sites (54.4%).

According to exploratory analyses, patients who presented with positive circulating tumor DNA (ctDNA) status at day 1 of cycle 3 experienced a shorter median PFS at 10.7 months vs 24.3 months among those with ctDNA negativity (HR, 3.9; 95% CI, 1.4-10.6; P = .005). Additionally, baseline EGFR variant allele frequency (VAF) and ctDNA mean VAF correlated with ctDNA clearance based on an area under the curve of 68.3% (P = .146) and 72.5% (P = .042), respectively.

Treatment-emergent adverse effects (TEAEs) occurred in 90.9% of patients, with the most common including lymphopenia (39.4%), increased creatine phosphokinase (39.4%), diarrhea (36.4%), increased creatinine (33.3%), and rash (27.3%). Grade 3 or higher TEAEs affected 2 patients (6.1%), which included 1 patient (3.0%) with high-grade anemia.

Two patients (6.1%) required dose interruptions due to grade 2 anorexia and grade 3 anemia. Additionally, investigators reported no TEAEs associated with dose reduction, treatment discontinuation, or death.

References

1. Shen B, Wang C, Zhang L, et al. Double-dose firmonertinib as first-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer harboring EGFR L858R mutation: a prospective, multicenter, phase II study (FIRM). Nat Commun. Published online January 19, 2026. doi:10.1038/s41467-026-68554-6
2. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308