Updated Clinical Results From FURTHER: A Study of Firmonertinib in TKI-Naive, Advanced NSCLC With EGFR PACC Mutations

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

J Thorac Oncol

Keywords

epidermal growth factor receptor, firmonertinib, aged, antineoplastic activity, brain metastasis, cancer inhibition, clinical trial, cohort analysis, conference abstract, controlled study, drug dose reduction, drug therapy, female, follow up, Food and Drug Administration, human, human tissue, major clinical study, multicenter study, non small cell lung cancer, phase 3 clinical trial, response evaluation criteria in solid tumors, special situation for pharmacovigilance

Abstract

Introduction: Firmonertinib (also known as furmonertinib) is a oncedaily oral, highly brain-penetrant EGFR inhibitor with broad activity and selectivity across EGFR mutations. Firmonertinib has FDA breakthrough therapy designation and is being tested in a global, Phase 3 study in first-line (1L) EGFR ex20ins mutant NSCLC. P-loop and aC-helix compressing (PACC) mutations represent approximately 12% of EGFR mutations and are similar to ex20ins mutations in narrowing the drug-binding pocket of ATP competitive EGFR in- hibitors. We report updated FURTHER trial clinical and translational results. Methods: FURTHER (FURMO-002; NCT05364073) is a global, Phase 1b study. Stage 2, Cohort 4 (PACC cohort) enrolled NSCLC pa- tients with EGFR PACC mutations randomized to two dose levels of firmonertinib (160 mg or 240 mg, QD). Key eligibility criteria include documented EGFR PACC mutation, measurable disease per RECIST 1.1, and no prior EGFR TKI. Patients with untreated but clinically stable brain metastases were eligible. Primary endpoint is confirmed ORR per RECIST 1.1 by BICR. Key secondary endpoints include PFS and duration of response (DoR). Results: Updated efficacy results for 1L NSCLC patients (n=45 patients) with EGFR PACC mutations include ORR by BICR which was 81.8% (18/22; 95% CI, 59.7% - 94.8%) at 240 mg, and 52.2% (12/23; 95% CI, 30.6% - 73.2%) at 160 mg. Confirmed ORR by BICR were 68.2% (15/22; 95% CI, 45.1% - 86.1%) at 240 mg, and 43.5% (10/23; 95% CI, 23.2% - 65.5%) at 160 mg, and median DoR was 14.6 months at 240 mg and not reached (NR) at 160 mg. Median PFS by BICR was 16.0 months (95% CI, 12.5, NR) at 240 mg QD and 11.1 months at 160 mg (95% CI, 6.6, NR) with a hazard ratio of 0.728 (95% CI, 0.305, 1.736) and a median follow-up of 12.5 months for both dose levels. Antitumor activity was observed in both single PACC mutation (confirmed ORR by BICR of 60% [6/10; 95% CI, 26.2% - 87.8%] at 240 mg and 25% [3/12; 95% CI, 5.5% - 57.2%] at 160 mg) and compound PACC mutation (confirmed ORR by BICR of 75% [9/12; 95% CI, 42.8% - 94.5%] at 240 mg and 63.6% [7/11; 95% CI, 30.8% - 89.1%] at 160 mg) subgroups. In patients with brain metastases, CNS confirmed ORR by BICR was 50% (7/14) per modified RECIST. A rapid decrease in EGFR mutation variant frequency in ctDNA was overall consistent with radiographic responses. The adverse event profile was consistent with prior firmonertinib studies with dose reductions due to TRAEs occurring at 22.7% and 12.0% at 240 mg and 160 mg dose levels, respectively. Treatment discontinu- ation due to TRAE occurred at 0% and 4.0% at the 240 mg and 160 mg dose levels, respectively. Additional updated efficacy and safety data will be presented at the conference. Conclusions: Updated FURTHER trial results demonstrate promising antitumor activity in 1L EGFR PACC mutant NSCLC patients treated with firmonertinib including prolonged DoR and PFS with a tolerable and manageable safety pro- file. Further investigation of firmonertinib in this patient population is planned, including future registrational studies.

Volume

20

Issue

10

First Page

S482

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