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)

The primary objective of this study is to assess the anti-tumor activity of firmonertinib compared with investigator's choice of osimertinib or afatinib in participants with locally advanced or metastatic non-small-cell lung cancer harboring EGFR PACC mutations (P-Loop and Alpha C-Helix Compressing uncommon mutations). This objective addresses a clinically relevant unmet need in patients with EGFR uncommon mutations, a population for which optimal first-line therapeutic strategies remain incompletely defined. The study evaluates efficacy, safety, pharmacokinetics, and tolerability of the investigational agent in this specific molecular subgroup of advanced NSCLC.

The trial enrolled a total of **352 participants** diagnosed with **advanced or metastatic non-small-cell lung cancer** harboring **epidermal growth factor receptor P-loop and alpha C-helix compressing (PACC) uncommon mutations**. Both **male and female subjects** were included in the study population. The trial recruited **adults and elderly participants**. The study population comprised patients whose disease was not amenable to curative surgery or radiotherapy, with documented presence of EGFR PACC mutations confirmed through local testing of tumor tissue or blood. Participants were required to be treatment-naïve for their locally advanced or metastatic disease, with no prior exposure to systemic anticancer therapy or EGFR-targeting agents. Patients with a history of neo-adjuvant or adjuvant therapy for non-metastatic disease were eligible if they had maintained a treatment-free interval of at least 12 months. Individuals with asymptomatic **central nervous system metastases** were also considered eligible for enrollment. The trial included a vulnerable population as part of the study cohort.

This is a global, phase 3, randomized, multicenter, open-label clinical trial designed to evaluate the efficacy and safety of firmonertinib compared with investigator's choice of osimertinib or afatinib as first-line treatment in participants with locally advanced or metastatic non-small cell lung cancer harboring epidermal growth factor receptor P-Loop and Alpha C-Helix Compressing uncommon mutations. The trial employs a randomized design where participants are allocated to receive either the test product firmonertinib or one of the comparator products selected by the investigator. The study does not incorporate blinding for treatment assignment, reflecting an open-label methodology. The maximum treatment period for all study medications is 18 months, with maximum daily doses of 240 mg for firmonertinib, 80 mg for osimertinib, and 40 mg for afatinib. All investigational products are administered via the oral route in tablet or film-coated tablet formulations.

The primary endpoints of this trial are progression-free survival as determined by blinded independent central review and confirmed overall response rate as assessed by the same independent review process. The main objective is to assess the anti-tumor activity of firmonertinib compared with investigator's choice of osimertinib or afatinib in the target population. The trial is estimated to commence participant recruitment on March 15, 2026, with an estimated completion date of December 31, 2030, indicating an overall trial duration of approximately four years and nine months.

Eligible participants must have histologically or cytologically documented locally advanced or metastatic non-small cell lung cancer that is not amenable to curative surgery or radiotherapy. Documented presence of an epidermal growth factor receptor P-Loop and Alpha C-Helix Compressing mutation in tumor tissue or blood from local testing is required. Participants must not have received any prior systemic anticancer therapy regimens for locally advanced or metastatic disease, including prior treatment with any epidermal growth factor receptor-targeting agents such as tyrosine kinase inhibitors, monoclonal antibodies, or bispecific antibodies. Participants who have received prior neo-adjuvant or adjuvant chemotherapy, immunotherapy, or chemoradiotherapy for non-metastatic disease must have experienced a treatment-free interval of at least 12 months. Participants with asymptomatic central nervous system metastases are eligible for enrollment.

The study involves a series of visits throughout the participant's involvement in the trial. The screening visit serves to assess eligibility criteria and obtain baseline measurements. Following enrollment and randomization, participants attend regular follow-up visits for efficacy assessments, safety monitoring, and administration of study medication. These visits include clinical evaluations, laboratory assessments, and imaging studies to determine disease progression according to blinded independent central review criteria. The end-of-study visit occurs upon completion of the treatment period, disease progression, unacceptable toxicity, withdrawal of consent, or at the conclusion of the trial. Participant involvement extends for the duration of treatment, up to a maximum of 18 months, plus any additional follow-up period as specified in the protocol. Early termination from the study may occur due to disease progression, unacceptable adverse events, participant withdrawal of consent, investigator decision, protocol violation, or other circumstances that preclude continued participation.

The experimental medication under investigation in this clinical trial is furmonertinib, also known by alternative designations including firmonertinib, AST2818, AFU, alflutinib mesylate, and alflutinib. Furmonertinib is formulated as a tablet for oral administration. The active substance is N-[2-[2-(dimethylamino)ethyl-methylamino]-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-6-(2,2,2-trifluoroethoxy)pyridin-3-yl]prop-2-enamide, which is of chemical origin. The maximum daily dose is 240.00 mg, with a maximum total dose of 30240.00 mg over the treatment period. The maximum treatment duration is 18 months.

The comparator treatments consist of osimertinib or afatinib, selected at the investigator's discretion. Osimertinib is administered as a film-coated tablet via the oral route. The maximum daily dose of osimertinib is 80.00 mg, with a maximum total dose of 10080.00 mg. The maximum treatment period for osimertinib is 18 months. The active substance is osimertinib, which is of chemical origin.

Afatinib is also formulated as a film-coated tablet for oral administration. The maximum daily dose of afatinib is 40.00 mg, with a maximum total dose of 5040.00 mg. The maximum treatment period for afatinib is 18 months. The active substance is afatinib, which is of chemical origin.

Efficacy will be assessed using two primary endpoints in this clinical trial. The first primary endpoint is **Progression Free Survival** (PFS) as determined by blinded independent central review (BICR). The second primary endpoint is confirmed **overall response rate** (ORR) as determined by BICR. These endpoints will be used to evaluate the anti-tumor activity of furmonertinib compared with investigator's choice of osimertinib or afatinib in participants with locally advanced or metastatic **non-small-cell lung cancer** with EGFR PACC mutations.