KEY TAKEAWAYS
- The FURTHER phase 1b trial aimed to evaluate the efficacy and safety of firmonertinib in TKI-naive patients with advanced EGFR PACC-mutant NSCLC.
- The primary endpoint was confirmed ORR.
- Firmonertinib demonstrated promising efficacy and acceptable safety in this patient population. Further investigation is warranted.
P-loop and αC-helix compressing (PACC) mutations constitute approximately 12% of EGFR mutations in non-small cell lung cancer (NSCLC). These mutations, similar to ex20ins mutations, narrow the drug-binding pocket of ATP competitive EGFR inhibitors, posing a challenge for treatment. Firmonertinib, an oral, highly brain-penetrant EGFR inhibitor, has shown activity and selectivity across EGFR mutations, including PACC and ex20ins mutations.
Xiuning Le and the team aimed to evaluate the efficacy and safety of firmonertinib in patients with EGFR PACC-mutated NSCLC.
The global Phase 1b FURTHER study (FURMO-002; NCT05364073) involved 2 stages: a dose-escalation/backfill Stage 1 and a dose-expansion Stage 2. In Stage 2, Cohort 4 (PACC cohort), TKI-naive patients with EGFR PACC-mutant NSCLC were randomized to receive firmonertinib at either 160 mg or 240 mg once daily.
Key eligibility criteria included documented EGFR PACC mutation, measurable disease as defined by RECIST 1.1, and no prior EGFR TKI therapy. The primary endpoint was confirmed objective response rate (ORR) per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR) and CNS ORR.
As of July 5, 2024, 60 patients were enrolled in the PACC cohort with a median age of 67 years. Of these, 66.7% were female, 71.7% were Asian, 33.3% had brain metastases, 28.3%/71.7% had ECOG scores of 0/1, and 78.3% had no prior metastatic systemic therapy. The BICR cutoff date was June 20, 2024. In first-line metastatic NSCLC patients with EGFR PACC mutations, the ORR by BICR was 81.8% (n=22; 95% CI, 59.7%-94.8%) at 240 mg QD and 47.8% (n=23; 95% CI, 26.8%-69.4%) at 160 mg QD. Confirmed ORR by BICR was 63.6% (n=22; 95% CI, 40.7%-82.8%; 1 uPR pending confirmation) at 240 mg QD and 34.8% (n=23; 95% CI, 16.4%-57.3%; 1 uPR pending confirmation) at 160 mg QD.
Responses were seen across a wide range of PACC mutations. Median DoR was not reached, as 90.9% (n=20 of 22) of patients with confirmed responses remain on treatment (median follow-up 4.2 months).
Among first-line metastatic patients with brain metastases, CNS confirmed ORR by BICR was 46.2% (n=6 of 13) per modified RECIST. The safety profile in the PACC cohort was consistent with previous firmonertinib studies, with the most frequent treatment-related adverse events (TRAEs) being diarrhea, rash, stomatitis, and hepatic enzyme elevation.
Most TRAEs were Grade 1-2, with Grade 3 events occurring in 20.7% and 12.9% of patients at the 240 mg and 160 mg dose levels, respectively. No Grade ≥4 TRAEs or treatment discontinuations due to TRAEs were reported.
FURTHER is the first clinical trial to assess firmonertinib in patients with NSCLC who had EGFR PACC mutations. The study showed promising efficacy in the first-line metastatic setting, especially at the 240 mg dose, with notable CNS antitumor activity and a manageable safety profile. These findings support the need for further investigation of firmonertinib in this patient population.
The trial was sponsored by ArriVent BioPharma, Inc.
Source: https://cattendee.abstractsonline.com/meeting/20598/presentation/3203
Clinical Trial: https://clinicaltrials.gov/study/NCT05364073
Le X, Yu Y, Zhao Y, et al. (2024). “FURTHER: a global, randomized study of firmonertinib at two dose levels in TKI-naive, advanced NSCLC with EGFR PACC mutations.” Presented at: World Conference on Lung Cancer (WCLC); September 8, 2024; Singapore.
