ArriVent Initiates Pivotal Phase 3 ALPACCA Trial for Firmonertinib in EGFR PACC Mutant NSCLC
核心洞察
ArriVent BioPharma has dosed the first patient in the global pivotal Phase 3 ALPACCA trial evaluating firmonertinib (搜索) for first-line treatment of EGFR (搜索) PACC mutant non-small cell lung cancer.
The randomized study compares firmonertinib (搜索) 240 mg once daily against investigator's choice of osimertinib or afatinib, targeting an underserved population with limited treatment options.
PACC mutations represent approximately 12% of all EGFR (搜索) mutations and affect an estimated 42,000 patients globally and 6,200 patients annually in the US.
ArriVent BioPharma announced that the first patient has been dosed in the global pivotal Phase 3 ALPACCA study evaluating firmonertinib (搜索) monotherapy for first-line treatment of EGFR (搜索) PACC mutant non-small cell lung cancer (NSCLC). The milestone marks a significant step forward in addressing an underserved patient population with limited therapeutic options.
"Initiation of our pivotal Phase 3 ALPACCA trial marks an important milestone in our strategy to expand the global reach of firmonertinib (搜索)," said Bing Yao, Ph.D., Chairman and Chief Executive Officer of ArriVent. "Patients with EGFR (搜索) PACC mutant NSCLC currently have limited treatment options and represent a clear unmet medical need."
Trial Design and Endpoints
The ALPACCA (FURMO-006) randomized, global Phase 3 study is evaluating firmonertinib (搜索) 240 mg once daily versus investigator's choice of osimertinib or afatinib in first-line patients with EGFR (搜索) PACC mutant NSCLC. The primary endpoints are overall response rate (ORR) and progression-free survival (PFS) by blinded independent central review (BICR).
The 240 mg dose of firmonertinib (搜索) was selected for pivotal development based on compelling data showing a 16-month median PFS and a confirmed 68% ORR by BICR in the FURTHER trial. The ALPACCA study is designed to support potential global registration with endpoints for accelerated and full approval pathways.
Addressing an Unmet Medical Need
PACC mutations represent a distinct and underserved population of EGFR (搜索) mutant NSCLC, with limited approved first-line targeted therapies and historically poor outcomes. P-loop and αC-helix compressing (PACC) EGFR mutations are a distinct set of approximately 70 mostly missense activating mutations within the kinase domain of EGFR. They are similar to Exon 20 insertion mutations in narrowing the drug binding pocket to affect tyrosine kinase inhibitor activity.
PACC mutations represent approximately 12% of all EGFR (搜索) mutations. ArriVent estimates that the global ex-China annual incidence of NSCLC patients with EGFR PACC mutations to be approximately 42,000 patients and the US annual incidence to be approximately 6,200 patients. Patients with PACC mutations have limited treatment options, and there is no broadly utilized standard of care treatment for first-line PACC mutant patients.
Firmonertinib's Clinical Profile
Firmonertinib (搜索) is an oral, once daily, highly brain-penetrant and broadly active mutation-selective EGFR (搜索) inhibitor active against both classical and uncommon EGFR mutations, including PACC and exon 20 insertion mutations. In March 2021, firmonertinib was approved in China for first-line advanced non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletion or L858R mutations and for patients with previously treated locally advanced or metastatic NSCLC with EGFR T790M mutation.
The drug has received significant regulatory recognition in the United States. Firmonertinib (搜索) was granted U.S. Food and Drug Administration (FDA) Breakthrough Therapy Designation for the treatment of patients with previously untreated locally advanced or metastatic non-squamous NSCLC with EGFR (搜索) exon 20 insertion mutations. It also received U.S. FDA Orphan Drug Designation for the treatment of NSCLC with EGFR mutations or human epidermal growth factor receptor 2 (HER2 (搜索)) mutations or HER4 (搜索) mutations.
Broader Development Program
Firmonertinib (搜索) is currently being studied in multiple Phase 3 trials. In addition to ALPACCA, the drug is being evaluated in the global Phase 3 FURVENT trial for first-line NSCLC patients with EGFR (搜索) exon 20 insertion mutations. The FURVENT trial is a global, pivotal, 3-arm Phase 3 clinical trial assessing the safety and efficacy of firmonertinib administered at either 160 mg or 240 mg once-daily compared to platinum-based chemotherapy with pemetrexed. The study enrolled 398 patients globally, including from sites in the United States, Europe and certain Asian countries including Japan and China.
Disease Context
Globally, lung cancer is the leading cause of cancer-related deaths among men and women. NSCLC is the predominant subtype of lung cancer, accounting for approximately 85% of all cases. Mutational activation of the EGFR (搜索) is a frequent and early event in the development of NSCLC. EGFR mutations are divided into classical and uncommon, with EGFR exon 20 insertion mutations constituting approximately 9% of all EGFR mutations and PACC mutations representing approximately 12% of all EGFR mutations.
Patients with NSCLC whose tumors harbor uncommon EGFR (搜索) mutations have significantly lower life expectancy with available therapies and represent an area of unmet medical need. PACC mutations are diagnosed through commercially available NGS and most PCR tests.