Firmonertinib Shows Efficacy, CNS Activity in EGFR+ NSCLC

Firmonertinib (Ivesa; formerly furmonertinib), a highly central nervous system (CNS)-penetrant EGFR inhibitor, led to notable antitumor activity across a range of patients with EGFR PACC–mutated non–small cell lung cancer (NSCLC), according to updated findings from the PACC cohort of the phase 2 FURTHER trial (FURMO-002; NCT05364073) presented during the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer.¹

At a median follow-up of 16.5 months (95% CI, 14.6–16.6), firmonertinib produced a best objective response rate (ORR) of 81.8% (95% CI, 59.7%–94.8%) and a confirmed ORR (cORR) of 68.2% (95% CI, 45.1%–86.1%) at a dose of 240 mg once daily (n = 22) among patients in the first-line PACC cohort. The stable disease (SD) rate was 31.8%; no complete response (CRs) or instances of disease progression (PD) were observed. The median duration of response (DOR) was 14.6 months, the disease control rate (DCR) was 100% (95% CI, 84.6%–100%), and the median progression-free survival (PFS) was 16.0 months (95% CI, 11.0–not reached [NR]).

When administered at a dose of 160 mg daily (n = 23), the best ORR with firmonertinib was 52.2% (95% CI, 30.6%–73.2%), and the cORR was 43.5% (95% CI, 23.2%–65.5%). The CR, partial response (PR), SD, and PD rates were 4.3%, 39.1%, 47.8%, and 8.7%, respectively. The median DOR was NR, the DCR was 91.3% (95% CI, 72.0%–98.9%), and the median PFS was 11.1 months (95% CI, 6.6–NR).

“Firmonertinib continues to show promising antitumor activity in a broad range of [patients with] EGFR PACC-mutated NSCLC,” Xiuning Le, MD, PhD, an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, and colleagues wrote in a poster presentation of the data.

“Encouraging CNS antitumor activity [was] observed, including CNS CRs…and firmonertinib showed an acceptable and manageable safety profile at both dose levels.”

Why Was the FURTHER Trial Conducted?

EGFR PACC mutations encompass approximately 70 different missense mutations in exons 18 through 20. These mutations can exist as single or compound mutations, affecting TKI binding by narrowing the drug-binding pocket, similar to exon 20 insertions. Early CNS spread is also common in this patient population, highlighting a significant unmet medical need for new treatment options.

Firmonertinib is an oral, highly CNS-penetrant EGFR inhibitor with broad activity and selectivity across EGFR mutations, including PACC. The agent has been previously studied across a range of doses up to 240 mg once daily and is approved in China at a dose of 80 mg once daily for patients with NSCLC expressing classical and T790M EGFR mutations.

Results from the phase 1b FAVOUR trial (NCT04858958) provided proof of concept for FURTHER, showing firmonertinib’s efficacy and safety in patients with EGFR exon 20 insertion–positive NSCLC.² Among treatment-naive patients (n = 28), the cORR was 78.6% (95% CI, 59.05%–91.70%), with a median DOR of 15.2 months (95% CI, 8.74–24.84). In previously treated patients, firmonertinib showed antitumor activity at both the 160-mg (n = 26) and 240-mg (n = 26) doses; respective cORRs were 38.5% (95% CI, 20.23%–59.43%) and 46.2% (95% CI, 26.59%–66.63%). Furthermore, firmonertinib was found to be well tolerated, with no new safety signals observed and a safety profile similar to that of the approved dose in China.

How Was the PACC Cohort in FURTHER Designed?

The FURTHER trial was a global dose escalation/expansion study conducted across 40 sites in 10 countries.¹ Stage 1 of the study included patients with locally advanced or metastatic EGFR-mutated NSCLC displaying HER2 exon 20 insertion mutations or EGFR-activating mutations. Stage 2 included pretreated patients with EGFR exon 20 insertion mutations (cohort 1); those with EGFR-mutated NSCLC with HER2 exon 20 insertion mutations (cohort 2); those with EGFR mutations other than exon 20 insertions and PACC mutations (cohort 3); and patients harboring EGFR PACC mutations (cohort 4; PACC cohort).

Patients were not permitted to have received prior treatment with an EGFR TKI, though patients with asymptomatic brain metastases who had not received prior radiation therapy were allowed to enroll. Upon enrollment, patients were stratified by prior treatment (yes vs no) and whether they expressed EGFR G719X or S768I mutations (yes vs no).

In total, 60 patients were randomly assigned 1:1 to receive firmonertinib at 160 mg daily or 240 mg daily. Tumor assessments were conducted every 6 weeks, and treatment continued until progression, intolerable toxicity, or death.

The study’s primary end point was ORR by blinded independent central review, with key secondary end points including DOR, CNS ORR, PFS, and OS.

Patient demographics for the first-line PACC cohort were generally balanced between the 160-mg (n = 25) and 240-mg (n = 22) arms. The median age was 67 years (range, 48–86) for 160 mg and 67.5 years (range, 50–83) for 240 mg. Male patients constituted 40.0% and 36.4% of the populations in these respective arms, with female patients making up 60.0% and 63.6% of the study populations, respectively. The majority of patients were Asian (80.0%; 77.3%), followed by White patients (20.0%; 13.6%). Most patients had an ECOG performance status of 1 (68.0%; 72.7%).

Brain metastases were present at baseline in 28.0% of patients in the 160-mg arm and 31.8% of those in the 240-mg arm. Nonsmokers comprised 76.0% and 86.4% of these respective groups; former or current smokers made up 24.0% and 13.6% of patients. Only 1 patient (4.5%) in the 240-mg arm had received prior immunotherapy, with 4.0% of those in the 160-mg arm having received prior chemotherapy.

How Did Responses With Firmonertinib Differ According to PACC Mutation Frequency or Mutation Type?

Confirmed PRs were observed across a wide range of EGFR PACC mutations. For patients with frequently observed PACC mutations, including those in G719X and S768I, the cORR was 41.2% (n = 7/17) at the 160-mg dose and 72.2% (n = 13/18) at the 240-mg dose. For those with less frequent PACC mutations, including mutations in E709X or V774M, the cORR was 50% (n = 3/6) at 160 mg and 50% (n = 2/4) at 240 mg.

When evaluated by mutation type, the cORR for single EGFR PACC mutations was 25% (n = 3/12) at 160 mg and 60% (n = 6/10) at 240 mg. For compound EGFR PACC mutations, the cORR was 63.6% (n = 7/11) at 160 mg and 75% (n = 9/12) at 240 mg

What CNS Activity and ctDNA Responses Were Reported?

In the response-evaluable CNS population, which comprised patients with EGFR PACC mutations in the first line as well as the second-line and beyond, firmonertinib also demonstrated antitumor activity.

At the 160 mg dose (n = 9), the confirmed ORR was 55.6% (95% CI, 21.2%–86.3%), with best overall responses including a CR rate of 44.4% and PR rate of 11.1%. SD and PD were experienced by 11.1% of patients, respectively, and the DCR was 88.9% (95% CI, 51.8%–99.7%). In the 240 mg cohort (n = 8), the confirmed ORR was 37.5% (95% CI, 8.5%–75.5%), comprising a with CR rate of 37.5% and no PRs. SD and PD were experienced by 12.5% of patients, respectively. The DCR was 87.5% (95% CI, 47.3%–99.7%).

In the first-line CNS population (n = 14), which combined both dose levels, the confirmed ORR was 42.9% (95% CI, 17.7%–71.1%), including a CR rate of 35.7% and PR rate of 7.1%. SD and PD were experienced by 14.3% of patients, respectively. The DCR for this group was 85.7% (95% CI, 57.2%–98.2%).

Rapid molecular circulating tumor DNA (ctDNA) responses, defined as EGFR PACC ctDNA clearance, were observed in the first-line PACC cohort. Among patients with evaluable ctDNA results, the ctDNA response rate was 79% (n = 11/14) for the 160-mg cohort and 82% (n = 9/11) for the 240-mg cohort. Consistent changes in PACC variant allele frequency from baseline to cycle 3 day 1 were observed across all variants for compound mutations.

What Was the Agent’s Safety Profile in the EGFR PACC Cohort?

Firmonertinib demonstrated an acceptable and manageable safety profile across both dose levels (n = 60) in the first-line PACC cohort. Any-grade treatment-related adverse effects (TRAEs) occurred in 90.3% of patients in the 160-mg cohort (n = 31) and 96.6% in the 240-mg cohort (n = 29). Grade 3 or higher TRAEs were reported in 25.8% and 20.7% of patients, respectively. No grade 4 to 5 TRAEs were observed. Treatment-related serious AEs (SAEs) occurred in 6.5% and 3.4% of patients, respectively.

Dose interruptions were required for 29.0% and 37.9% of patients in the 160-mg and 240-mg arms, respectively; dose reductions occurred in 19.4% and 24.1% of patients, respectively. Treatment discontinuation due to TRAEs was observed in 3.2% of patients at the 160-mg dose, with no discontinuations in the 240-mg arm.

Among all patients enrolled in the FURTHER trial (n = 158), any-grade TRAEs were reported in 85.7% (160 mg; n = 42) and 87.1% (240 mg; n = 116) of patients. Grade 3 or higher TRAEs occurred in 21.4% and 21.6% of patients in these respective arms. Treatment-related SAEs affected 7.1% and 9.5% of patients, respectively. Dose interruptions were necessary for 31.0% and 38.8% of patients, respectively; dose reductions were required for 16.7% and 20.7%, respectively. Treatment discontinuation due to TRAEs occurred in 4.8% and 6.9% of patients, respectively.

What’s Next for Firmonertinib?

These data support the continued investigation of firmonertinib as first-line therapy in patients with EGFR PACC–mutated NSCLC in the randomized, global phase 3 ALPACCA (FURMO-006) study (NCT06203210).

This study will enroll approximately 480 patients; patients who received prior therapy for metastatic disease and or a prior EGFR TKI are ineligible. Notably, those with untreated brain metastases are permitted to enroll if clinically stable. The study will compare firmonertinib at 240 mg daily with investigator’s choice of 80 mg of osimertinib (Tagrisso) or 40 mg of afatinib (Gilotrif). The study’s primary end points will be ORR by BICR for the interim analysis, and PFS by BICR for the final analysis.

Firmonertinib is also being evaluated at 160 mg and 240 mg daily in the ongoing phase 3 FURVENT study (NCT05607550) for patients with NSCLC displaying EGFR exon 20 insertion mutations.

REFERENCES:

1. Le X, Yan Y, Zhou Y, et al. Updated clinical results from FURTHER: a study of firmonertinib in TKI-naive, advanced NSCLC with EGFR PACC mutations. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Poster P3.12.38

2. Han B, Zhou C, Zheng Wei, et al. FAVOUR, a phase 1b study of furmonertinib, an oral, brain penetrant, selective EGFR inhibitor, in patients with advanced NSCLC with EGFR exon 20 insertions. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA03.04.