ALPACCA: Phase 3 trial of firmonertinib vs investigator’s choice of EGFR inhibitor as first-line treatment for locally advanced or metastatic NSCLC with EGFR P-loop and alpha c-helix compressing (PACC) uncommon mutations (FURMO-006).

Abstract

TPS8675 Background: Despite advances in treatment of NSCLC with EGFR classical mutations, no universally accepted standard-of-care treatment exists for patients with EGFR uncommon mutations including PACC mutations. Treatment options include EGFR tyrosine kinase inhibitors (TKIs) (osimertinib, afatinib), chemotherapy, or other targeted therapies (amivantamab for exon 20 insertion mutations). EGFR PACC mutations comprise approximately 12.5% of all NSCLC EGFR mutations (Robichaux et al 2021, Nilsson et al 2024). Firmonertinib is a once daily oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets classical and uncommon mutations (Musib et al., NACLC 2022). In the phase 1b FURMO-002 study (FURTHER), first-line locally advanced or metastatic EGFR PACC mutation NSCLC patients treated with firmonertinib 240 mg daily achieved a confirmed ORR of 68.2%, best ORR of 81.8%, disease control rate (DCR) of 100%, and median progression-free survival (mPFS) of 16.5 months by blinded independent central review (BICR) (Le et al., WCLC 2025). Firmonertinib was generally well-tolerated with manageable EGFR TKI-associated adverse events. Methods: ALPACCA (FURMO-006; NCT07185997) is a global, phase 3, randomized, open-label study investigating firmonertinib vs investigator’s choice of osimertinib or afatinib. Eligible patients have locally advanced or metastatic NSCLC with EGFR PACC mutations. Key inclusion criteria include documented presence of EGFR PACC mutation and measurable disease per RECIST v1.1. Patients with asymptomatic CNS metastases are allowed. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastatic setting or any prior EGFR TKI therapy. Approximately 480 patients will be randomized 1:1 to receive firmonertinib 240 mg daily or investigator’s choice of osimertinib 80 mg daily or afatinib 40 mg daily. Primary endpoints are PFS and ORR per RECIST v1.1 by BICR. Key secondary endpoints include OS, investigator assessed PFS and ORR, and safety and tolerability. Enrollment is ongoing. Clinical trial information: NCT07185997 .