Press Release
Sep 09, 2024
(San Diego, Calif.--September 9, 2024, 10:05 a.m.) — The tyrosine kinase inhibitor firmonertinib showed promising efficacy in patients with non-small cell lung cancer across a broad range of EGFR PACC mutations in the first-line metastatic setting with CNS antitumor activity, according to research presented today at the International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer.
Firmonertinib is an oral, highly brain-penetrant EGFR inhibitor with broad activity and selectivity across EGFR mutations. It is approved in China for first-line, advanced NSCLC with EGFR Ex19del/L858R and previously treated advanced NSCLC with EGFR T790M and has received FDA Breakthrough Therapy Designation for first-line, advanced NSCLC with EGFR ex20ins mutations.
The FURTHER Trial is a global, Phase 1b study with Stage 1 (dose escalation/backfill) and Stage 2 (dose expansion). Stage 2, Cohort 4 (PACC cohort) enrolled NSCLC patients with EGFR PACC mutations randomized to one of two dose levels of firmonertinib (160 mg or 240 mg once daily). P-loop and ⍺C-helix compressing (PACC) mutations are primarily missense mutations located in exons 18-20 and account for ∼12.5% of all EGFR mutations, which is larger than Exon 20 insertion mutations. Key eligibility criteria include documented EGFR PACC mutation, measurable disease per RECIST 1.1, and no prior EGFR TKI. Primary endpoint is confirmed overall response rate per RECIST 1.1 by BICR. Key secondary endpoints include the duration of response and the central nervous system's overall response rate.
Dr. Jie Wang, an investigator from Cancer Hospital Chinese Academy of Medical Sciences, and her fellow global investigators across 10 countries enrolled 60 patients in the FURTHER Trial PACC cohort. The patients had a median age of 67.0 years-- 66.7% were female, 71.7% were Asian and 33.3% had brain metastases, 28.3%/71.7% ECOG 0/1, and 78.3% with no prior metastatic systemic therapy.
In first-line metastatic NSCLC patients with EGFR PACC mutations, the overall response rate by blinded independent central review was 81.8% (n=22; 95% CI, 59.7%-94.8%) for those receiving the 240 mg daily dose. For patients at the 160 mg daily dose level, the overall response rate was 47.8% (n=23; 95% CI, 26.8%-69.4%). The confirmed overall response rates were 63.6% (n=22; 95% CI, 40.7%-82.8%; with 1 unconfirmed partial response pending confirmation) at the 240 mg dose and 34.8% (n=23; 95% CI, 16.4%-57.3%; with 1 unconfirmed partial response pending confirmation) at the 160 mg dose levels, respectively.
Responses to firmonertinib were observed across a broad range of PACC mutations, with a median duration of response not yet reached, as 90.9% (n=20 of 22) of patients with confirmed responses remain on treatment, with a median follow-up of 4.2 months.
For patients with brain metastases, the confirmed central nervous system overall response was 46.2% (n=6 of 13) based on modified RECIST criteria. This result underscores firmonertinib's potential effectiveness in treating brain metastases in this patient cohort.
Firmonertinib showed promising efficacy in NSCLC patients across a broad range of EGFR PACC mutations in the first-line metastatic setting with central nervous system antitumor activity and acceptable safety.
"Based on the results from the FURTHER Trial, firmonertinib merits continuing investigation for patients with NSCLC with EGFR PACC mutations," said Dr. Wang.
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About the IASLC:
The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated solely to the study of lung cancer and other thoracic malignancies. Founded in 1974, the association's membership includes more than 10,000 lung cancer specialists across all disciplines in over 100 countries, forming a global network working together to conquer lung and thoracic cancers worldwide. The association also publishes the Journal of Thoracic Oncology, the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies. Visit www.iaslc.org for more information.
About the WCLC:
The World Conference on Lung Cancer (WCLC) is the world's largest meeting dedicated to lung cancer and other thoracic malignancies, attracting nearly 7,000 researchers, physicians and specialists from more than 100 countries. The goal is to increase awareness, collaboration and understanding of lung cancer, and to help participants implement the latest developments across the globe. The conference will cover a wide range of disciplines and unveil several research studies and clinical trial results. For more information, visit https://wclc2024.iaslc.org.
Abstract Control Number:
1358
Abstract Type:
Late-Breaking Abstract
Track:
12. Metastatic Non-small Cell Lung Cancer - Targeted Therapy
Title:
FURTHER: A Global, Randomized Study of Firmonertinib at Two Dose Levels in TKI-Naive, Advanced NSCLC with EGFR PACC Mutations
Sections:
Introduction:
Firmonertinib (also known as furmonertinib) is an oral, highly brain-penetrant EGFR inhibitor with broad activity and selectivity across EGFR mutations, according to data presented today from the FURTHER Trial at the International Association for the Study of Lung Cancer 2024 World Conference on Lung Cancer.
Firmonertinib is approved in China for first-line, advanced NSCLC with EGFR Ex19del/L858R and previously treated advanced NSCLC with EGFR T790M. Firmonertinib has received FDA Breakthrough Therapy Designation for first-line, advanced NSCLC with EGFR ex20ins mutations. P-loop and αC-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 inhibitors (Robichaux et al., 2021). Firmonertinib is potent in cell lines harboring EGFR PACC and ex20ins mutations and inhibits tumor growth at doses in PDX models that are clinically relevant (Musib et al., 2022; Nilsson et al., 2024).
Methods:
The FURTHER Trial is a global, Phase 1b study with Stage 1 (dose escalation/backfill) and Stage 2 (dose expansion). Stage 2, Cohort 4 (PACC cohort) enrolled NSCLC patients with EGFR PACC mutations randomized to one of two dose levels of firmonertinib (160 mg or 240 mg once daily). Key eligibility criteria include documented EGFR PACC mutation, measurable disease per RECIST 1.1, and no prior EGFR TKI. Primary endpoint is confirmed ORR per RECIST 1.1 by BICR. Key secondary endpoints include DoR and CNS ORR.
Results:
Funding Source:
ArriVent Biopharma, Inc. and Shanghai Allist Pharmaceuticals Co.
LBA Reason:
This is the first presentation of clinical data for an EGFR inhibitor being evaluated in EGFR TKI-naive, advanced NSCLC patients with EGFR P-loop and αC-helix Compressing (PACC) missense mutations, a subset of uncommon EGFR activating mutations that share some structural similarities with exon 20 insertion mutations (Robichaux et al., 2021). There is no clear standard of care for patients with EGFR PACC mutations. Sixty patients have already been randomized to two different dose levels of firmonertinib for optimal dose selection based upon efficacy and safety. This clinical data could provide proof of concept for a novel EGFR inhibitor in EGFR PACC mutant NSCLC patients and provide further rationale for clinically evaluating PACC mutations as a distinct subgroup of activating EGFR mutations.
Results are anticipated on July 15th, 2024.
The measured endpoints will be ORR by RECIST v1.1, DOR, DCR, PFS, Depth of Response, and CNS ORR and CNS DOR by modified RECIST. Safety endpoints including the frequency of adverse events (AEs), Grade >=3 AEs, and dose modifications. Endpoints will be described by firmonertinib dose level and by furmonertinib line of therapy.
LBA Type of Analysis and Data:
Baseline demographics, clinical safety, and efficacy data will be reported from patients enrolled. Anticipated efficacy data include confirmed ORR, median DoR, disease control rate (DCR), and progression-free survival (PFS) by firmonertinib dose level, by line of firmonertinib therapy, and by the history or presence of CNS metastases at baseline, and CNS ORR. Safety data will include frequency of adverse events (treatment-emergent adverse events, treatment-related adverse events, serious adverse events), frequency of Grade >=3 adverse events, and frequency of dose modifications.
Confirmed ORR is defined as the percentage of patients with a confirmed CR or PR relative to the total number of patients. Confirmation of the response is based on a subsequent assessment at least 28 days later using the criteria in RECIST v1.1.
The observed ORR and the Clopper-Pearson 95% confidence interval (CI) will be provided. DoR for patients with confirmed ORR is defined as the time from first documented evidence of confirmed CR or PR until the first documented evidence of disease progression or death, whichever occurs earlier. The Kaplan-Meier curve and the Kaplan-Meier estimates of the quartiles (with 95% CI) of DoR will be provided. Patients who do not progress or die will be censored at the last tumor assessment at the analysis time. DCR is defined as CR or PR or achieving SD lasting at least 6 weeks post first dose using RECIST v1.1. DCR will be analyzed similarly to confirmed ORR. The efficacy endpoint, PFS, is defined as the time from the first dose date to the first occurrence of disease progression according to RECIST v1.1 or death from any cause, whichever comes first. The Kaplan Meier curve and the Kaplan Meier estimates of the quartiles (with 95% CI) will be provided. Best objective CNS response will be calculated by modified RECIST.
Presenter:
Jie Wang, Cancer Hospital Chinese Academy of Medical Sciences, China