Firmonertinib Demonstrates Response in NSCLC With EGFR PACC Mutation

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Overall and central nervous system (CNS) responses were shown with firmonertinib (AST2818; formerly furmonertinib) in patients with non–small cell lung cancer (NSCLC) and EGFR P-loop and αC-helix compressing (PACC) mutations, according to a presentation at the 2024 World Conference on Lung Cancer.¹

“Firmonertinib has shown promising antitumor activity in a broad range of EGFR PACC-mutant NSCLC,” David Planchard, MD, PhD, thoracic oncologist and head of the Thoracic Pathology Committee at Gustave Roussy in Villejuif, France, and president of the International Center for Thoracic Cancers, said in his presentation. “At 240 mg, firmonertinib showed a confirmed overall response rate [ORR] of 63.6% with encouraging CNS antitumor activity in this PACC mutation–[positive population].”

In the phase 1b, open-label, multicenter FURTHER trial (FURMO-002; NCT05364073), patients received firmonertinib, an oral EGFR inhibitor, in stage 1 cohort 1 for dose escalation and backfill or stage 2 cohort 2, 3, or 4 for dose expansion.

Planchard discussed stage 2 cohort 4, also called the PACC cohort, of 60 patients with EGFR tyrosine kinase inhibitor (TKI) naive, locally advanced or metastatic NSCLC with EGFR PACC mutations. Those in the PACC cohort were randomly assigned 1:1 to receive firmonertinib at 160 mg once a day (n = 31) vs 240 mg once a day (n = 29) until progression, intolerable toxicity, or death.

The median age was 65 years in the 160-mg arm and 68 years in the 240-mg arm. Most patients had ECOG performance status of 1, were nonsmokers, and were Asian. Prior metastatic therapies included chemotherapy in 12.9% and 17.2% of the 160-mg and 240-mg groups, respectively, and other therapies were used in 6.5% and 6.9% of the respective groups.

ORR by blinded independent central review (BICR) was the primary end point, and secondary end points included duration of response (DOR), CNS ORR, progression-free survival (PFS), and overall survival (OS). Patients were stratified by whether they had received prior treatment and if they had EGFR PACC G719X and S768I mutations.

Efficacy of Firmonertinib

The best ORR by BICR in the PACC cohort for only first-line NSCLC was 47.8% in patients given 160 mg of firmonertinib (n = 23) vs 81.8% in patients given 240 mg (n = 22). The confirmed ORR in this group was 34.8% for the 160-mg dose compared with 63.6% for the 240-mg dose, consisting of partial responses (PRs) for both dose levels.

Firmonertinib at 160 mg had 2 instances of progressive disease (PD) in the first-line patients, while the 240-mg dose had none. All other patients in this group had stable disease (SD) in both groups. Therefore, the disease control rate was 91.3% with the lower dose vs 100% with the higher dose.

“Confirmed PRs were observed in a wide range of EGFR PACC mutation including the most common PACC mutations, G719X or the S768I, as well as the less frequent PACC mutations. Responses have been observed in single and compound EGFR PACC mutations,” Planchard explained.

In the PACC cohort, there was a median follow-up for DOR of 4.2 months. A majority of response were seen at the first tumor assessment and the median DOR has not been reached at the time of the presentation. Twenty out of 22 responders (90.9%) are still receiving treatment. Currently, the PFS and OS data are immature.

Patients with asymptomatic brain metastases who had not received prior radiation were allowed on the trial. From the combined first- and second-line population, there were 9 patients with CNS disease who were evaluable for response in the 160-mg arm and 7 evaluable in the 240-mg arm. The confirmed CNS ORR was 55.6% vs 42.9% in the 160-mg and 240-mg dose groups, respectively.

The best CNS responses in the patients receiving 160 mg of firmonertinib included 4 complete responses (CRs), 1 PR, 1 SD, 1 PD, and 2 non-measurable responses for a DCR of 88.9%. For patients receiving 240 mg of firmonertinib, there were 3 CRs, no PRs or SD, 1 PD, and 3 non-measurable responses with a DCR of 85.7%. In first-line only patients (n = 13) on either dose, the confirmed ORR was 46.2% with 5 CRs, 1 PR, 1 SD, 2 PD, 4 non-measurable responses, and a DCR rate of 84.6%.

Safety With Firmonertinib

In terms of safety for the entirety of the PACC cohort, there were treatment-related adverse events (TRAEs) of any grade in 26 patients (83.9%) given 160 mg of firmonertinib vs 25 patients (86.2%) given 240 mg. Grade 3 TRAEs were observed in 4 (12.9%) vs 6 (20.7%) for the 160-mg and 240-mg groups, respectively. One patient in each group had a serious TRAE. The most common TRAEs of clinical interest were diarrhea, liver enzyme elevation, and rash. There were no grade 4 or 5 TRAEs.

There were dose interruptions for 6 patients (19.4%) in the 160-mg arm compared with 10 (34.5%) in the 240-mg arm, dose reductions were needed in 4 (12.9%) vs 7 (24.1%) patients, and there were no dose discontinuations.

Firmonertinib in Other EGFR Mutations

Previously, firmonertinib was investigated vs gefitinib (Iressa) in the phase 3 FURLONG trial (NCT03787992) in China and subsequently approved in the first line for patients with advanced NSCLC and EGFR exon 19 deletion or L858R mutations.

The phase 1b FAVOUR trial (NCT04858958) also looked at firmonertinib in patients with NSCLC and EGFR exon 20 insertion mutations. In this trial, there was a confirmed ORR of 78.6% and median DOR of 15.2 months in treatment naive patients receiving 240 mg once a day. It received breakthrough therapy designation in the first line for patients with advanced NSCLC with an EGFR exon 20 insertion mutation and is being investigated in the ongoing global phase 3 FURVENT study (NCT05607550) for this population.

EGFR PACC mutations make up approximately 12.5% of all EGFR mutations and present similarly to exon 20 insertions by narrowing the drug-binding pocket to affect TKI activity.

“The PACC mutation can exist as a single PACC mutation or compound mutation in association with other PACC mutation or EGFR mutation. Currently, the real-world data show us that we don't have any standard of care in first line in this population with a PACC mutation,” Planchard said. He concluded that “clearly these data support for the investigation of firmonertinib once daily in EGFR PACC-mutant NSCLC.”

REFERENCE:

Le X, Yu Y, Zhao Y, et al. FURTHER: a global, randomized study of firmonertinib at two dose levels in TKI-naive, advanced NSCLC with EGFR PACC mutations. Presented at: 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA and virtual. Accessed September 9, 2024.