A Global, Phase 3, Randomized, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Firmonertinib Compared With Investigator's Choice of Osimertinib or Afatinib as First-Line Treatment in Participants Who Have Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With Epidermal Growth Factor Receptor P-Loop and Alpha C-Helix Compressing (PACC) Uncommon Mutations (ALPACCA)

Global, Phase 3, randomized, multicenter, open-label study evaluating the efficacy and safety of firmonertinib at a dose level of 240 mg QD compared to investigator's choice of osimertinib (80 mg QD) or afatinib (40 mg QD) in participants who have locally advanced or metastatic NSCLC with EGFR PACC mutations, and who have not received any prior therapy for advanced disease. Participants will be randomized in a 1:1 ratio to treatment with firmonertinib or osimertinib or afatinib and will take the assigned dose daily.

Overview

Firmonertinib (also known as furmonertinib, alflutinib; development codes AST‑2818/ASK‑120067) is an oral, irreversible, third‑generation EGFR tyrosine‑kinase inhibitor (EGFR‑TKI). It is approved in China for EGFR‑mutant NSCLC and is being investigated globally, including for EGFR exon 20 insertion (ex20ins)–mutated disease. Key randomized and single‑arm trials have reported activity in treatment‑naïve “classical” EGFR mutations and in T790M‑positive disease; multiple studies are evaluating higher doses (160–240 mg QD) for ex20ins. (cancer.gov)

Mechanism of action

Firmonertinib is a mutant‑selective, covalent EGFR‑TKI that targets sensitizing EGFR mutations and the resistance mutation T790M, with relative sparing of wild‑type EGFR. Preclinical work identified ASK‑120067 (firmonertinib) as an irreversible inhibitor that suppresses EGFR signaling and tumor growth in EGFR‑mutant models; Ack1 activation was described as a potential resistance mechanism and a rationale for combination approaches. (molecular-cancer.biomedcentral.com)

Efficacy

• First‑line, classical EGFR mutations (ex19del/L858R): In the randomized, double‑blind phase 3 FURLONG trial (N=358), firmonertinib 80 mg QD significantly prolonged progression‑free survival (PFS) versus gefitinib: median PFS 20.8 vs 11.1 months (HR 0.44, 95% CI 0.34–0.58; p<0.0001). A preplanned CNS subgroup analysis showed superior CNS PFS (20.8 vs 9.8 months; HR 0.40) and higher CNS objective response rate (91% vs 65%) with firmonertinib. (pubmed.ncbi.nlm.nih.gov)

• Post‑EGFR‑TKI, T790M‑positive disease: A multicenter, single‑arm phase 2b study of limertinib/ASK‑120067 (synonymous with firmonertinib) in 301 patients reported an objective response rate (ORR) of 68.8% (95% CI 63.2–74.0) and median PFS of 11.0 months (95% CI 9.7–12.4); among those with CNS metastases, ORR was 64.6% and median PFS 9.7 months. (pubmed.ncbi.nlm.nih.gov)

• EGFR exon 20 insertions: Early clinical datasets suggest activity, particularly at higher doses. Real‑world and retrospective series reported ORRs of 37–67% and median PFS around 6–10 months with 160–240 mg QD dosing; CNS activity has been observed. Prospective development includes the global, randomized phase 3 FURVENT trial (first line ex20ins; 160 mg or 240 mg QD vs platinum‑pemetrexed), which completed enrollment in Q1 2025, with topline results projected in early 2026. (pubmed.ncbi.nlm.nih.gov)

Safety

• In FURLONG (first‑line), grade ≥3 treatment‑related adverse events occurred in 11% with firmonertinib vs 18% with gefitinib; no new safety signals were identified. (pubmed.ncbi.nlm.nih.gov)

• In the phase 2b T790M‑positive study (ASK‑120067), treatment‑related AEs occurred in 96% of patients; the most common were diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 34.6% (notably diarrhea 13.0%); discontinuation due to TRAEs was 2%, with no treatment‑related deaths. (pubmed.ncbi.nlm.nih.gov)

• Exon 20 insertion cohorts/series generally report manageable toxicity, with low rates of grade ≥3 TRAEs at higher doses (160–240 mg QD) and common events including diarrhea and rash. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Discovery and resistance biology of ASK‑120067 (firmonertinib): Molecular Cancer, 2020. (molecular-cancer.biomedcentral.com)
• FURLONG phase 3 primary results (first‑line vs gefitinib): Lancet Respir Med (PubMed). (pubmed.ncbi.nlm.nih.gov)
• FURLONG CNS subgroup analysis: J Thorac Oncol (PubMed). (pubmed.ncbi.nlm.nih.gov)
• Phase 2b, post‑TKI T790M cohort (ASK‑120067): J Thorac Oncol (PubMed). (pubmed.ncbi.nlm.nih.gov)
• Exon 20 insertion studies (real‑world/retrospective) and dosing: Frontiers in Oncology/Pharmacology reviews and observational series. (pubmed.ncbi.nlm.nih.gov)
• Ongoing phase 3 FURVENT (first‑line ex20ins) trial listing (NCI). (cancer.gov)

Notes on names: firmonertinib is synonymous with furmonertinib/alflutinib; development codes include AST‑2818 and ASK‑120067. (cancer.gov)

Last updated: Nov 2025

Key Eligibility Criteria:

* Histologically or cytologically documented, locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy.

* Documented results of the presence of an Epidermal Growth Factor Receptor (EGFR) PACC mutation in tumor tissue or blood from local testing.

* No prior systemic anticancer therapy regimens received for locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) including prior treatment with any Epidermal Growth Factor Receptor (EGFR)-targeting agents (e.g., previous (EGFR) TKIs, monoclonal antibodies, or bispecific antibodies).

* Patients who have received prior neo-adjuvant and/or adjuvant chemotherapy, immunotherapy, or chemo radiotherapy for non-metastatic disease must have experienced a treatment free interval of at least 12 months.

* Patients with asymptomatic CNS metastases are eligible.