Firmonertinib (AST2818; formerly furmonertinib), a novel EGFR inhibitor, has shown activity and tolerability in patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR P loop and aC-helix compressing (PACC) mutations, according to data presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer.¹

Results from the FURTHER trial (FURMO-002; ClinicalTrials.gov identifier NCT05364073), a global randomized study evaluating firmonertinib at two dose levels in tyrosine kinase inhibitor–naive patients with advanced NSCLC who had EGFR PACC mutations, demonstrated a confirmed objective response rate of 63.6% at the higher dose level of 240 mg once daily in first-line treatment.

David Planchard, MD, PhD

“Firmonertinib has shown strong, promising antitumor activity in a broad range of EGFR PACC mutations,” said study coauthor David Planchard, MD, PhD, a thoracic oncologist and Head of the Thoracic Pathology Committee at Gustave Roussy Institute of Oncology in France. “Clearly, these data support further investigation of firmonertinib as a first-line treatment in EGFR PACC–mutated non–small cell lung cancer.”

As Dr. Planchard reported, EGFR PACC mutations account for approximately 12.5% of EGFR mutations in NSCLC, primarily occurring in exon 18 to 20. These mutations are similar to exon 20 insertions in narrowing the drug-binding pocket, he explained, affecting tyrosine kinase inhibitor activity. Currently, there is no established standard of care for first-line treatment in this patient population.

Firmonertinib is a novel, central nervous system (CNS)-penetrant EGFR inhibitor with broad activity and selectivity across EGFR mutations. It has already been approved in China for first-line treatment of classical EGFR mutations and in previously treated patients with T790M mutations in NSCLC.

Study Methods

The FURTHER trial is a phase Ib, open-label, multicenter study. In the PACC cohort (cohort 4), 60 patients with tyrosine kinase inhibitor–naive, locally advanced or metastatic NSCLC with EGFR PACC mutations were randomly assigned 1:1 to receive firmonertinib at either 160 mg (n = 31) or 240 mg (n = 29) once daily until disease progression, intolerable toxicity, or death. The study enrolled patients across 40 sites in 10 countries. Baseline characteristics were comparable between the two dose cohorts, with a median age of 67 years, a slightly higher proportion of female patients, and approximately 30% of patients having brain metastases at baseline.

Activity and CNS Responses Across EGFR PACC Mutations

According to blinded independent central review, the best overall response rate with firmonertinib in the first-line setting for patients with NSCLC was 47.8% at 160 mg and 81.8% at 240 mg. The confirmed objective response rate in this group was 34.8% for the 160-mg dose compared with 63.6% for the 240-mg dose, consisting of partial responses for both dose levels. The disease control rate reached 91.3% with the lower dose and 100% with the higher dose.

“Confirmed partial responses were observed in a wide range of EGFR PACC mutations, including the most common ones, G719X or the S768I, as well as the less frequent ones,” said Dr. Planchard, who added that responses were observed in single and compound EGFR PACC mutations.

Although the median duration of response data were immature because of a short median follow-up of 4.2 months, 20 of 22 responding patients (90.9%) were still on treatment at the time of data cutoff. The majority of patients experienced a response at the first tumor assessment.

Firmonertinib also demonstrated encouraging intracranial activity. In patients with CNS disease, the confirmed CNS overall response rate was 55.6% at the lower dose level and 42.9% at the higher dose level. Of note, complete CNS responses were observed in both dose groups.

The safety profile of firmonertinib was reported to be manageable. Treatment-related adverse events of any grade occurred in 83.9% of patients at the 160-mg dose and 86.2% at the 240-mg dose. Grade 3 treatment-related adverse events were reported in 12.9% and 20.7% of patients in the 160-mg and 240-mg groups, respectively. The most common treatment-related adverse events of clinical interest were diarrhea, liver enzyme elevation, and rash. There were no grade 4 or 5 treatment-related adverse events reported.

Dose interruptions occurred in 19.4% (160 mg) vs 34.5% (240 mg) of patients, and dose reductions were seen in 12.9% vs 24.1% of patients. Of note, no treatment discontinuations were reported in either cohort, said Dr. Planchard. Ongoing studies are likely to provide more mature data on progression-free survival and overall survival, which were not yet available at the time of this presentation, he concluded.

EXPERT POINT OF VIEW

Alfredo Addeo, MD

Discussant of the study on firmonertinib in NSCLC, Alfredo Addeo, MD, Senior Oncologist, Geneva University Hospital, in Switzerland, commended the FURTHER trial for tackling a challenging area of research but advocated for a cautious approach in interpreting the results of firmonertinib in EGFR PACC–mutated NSCLC. Dr. Addeo also stressed the importance of balancing efficacy with toxicity while calling for more extensive data collection and sharing among researchers to better understand and treat these uncommon EGFR mutations.

Regarding the FURTHER trial results for firmonertinib in EGFR PACC–mutated NSCLC, Dr. Addeo called the efficacy data “promising,” particularly the 63.6% confirmed response rate at the 240-mg dose. He also noted the drug’s activity across various PACC mutations, including compound mutations, which comprised about 50% of the study population.

Although “intrigued by the intracranial activity of firmonertinib,” Dr. Addeo cautioned against drawing firm conclusions because of the small sample size and underscored the need for larger studies to confirm these findings. He also expressed concern about the drug’s toxicity profile, especially at the higher dose. “The increased gastrointestinal toxicity, particularly grade 3 diarrhea affecting 10% of patients, could significantly impact quality of life, and the need for dose reductions in about 25% of patients at the 240-mg dose is also a concern,” Dr. Addeo stated.

Questions for Future Research

In addition, Dr. Addeo raised several important questions for future research:

• Do compound PACC mutations differ significantly from single PACC mutations in terms of treatment resistance?
• Is the higher 240-mg dose necessary for all PACC mutations, or could some be effectively treated with lower doses?
• How does firmonertinib compare with other tyrosine kinase inhibitors for different uncommon EGFR mutations?
• What is the role of potential co-mutations, particularly with p53, in treatment outcomes?

“There is a strong need for real-world data and comprehensive registries to answer these questions, as traditional clinical trials may not provide sufficient insights into these rare and complex mutations,” Dr. Addeo concluded.

DISCLOSURE: Dr. Planchard reported financial relationships with AstraZeneca, Bristol Myers Squibb, Celgene, Merck, Novartis, Pfizer, Roche, Janssen, AbbVie, and Daiichi Sankyo. Dr. Addeo reported financial relationships with Bristol Myers Squibb, AstraZeneca, Roche, MSD, Pfizer, Eli Lilly, Astellas, Amgen, Novartis, and Merck; has conducted speakers bureau activities with Eli Lilly, AstraZeneca, and Amgen; and has received a grant from AstraZeneca.

REFERENCE

1. Le X L, 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. 2024 World Conference on Lung Cancer. Abstract PL04.07. Presented September 9, 2024.