Survival analysis and prognostic factors in advanced NSCLC harboring EGFR PACC mutations: A multicenter retrospective study.

[BACKGROUND] Epidermal growth factor receptor (EGFR) P-loop and αC-helix compression (PACC) mutations represent a distinct subset of uncommon EGFR mutations in non-small cell lung cancer (NSCLC). Although recent trials have explored the efficacy of high-dose furmonertinib and other EGFR tyrosine kinase inhibitors (TKIs) in this population, the real-world evidence regarding overall survival (OS) and prognostic factors remains limited.

[METHODS] We conducted a multicenter, retrospective study of 141 patients with advanced NSCLC harboring EGFR PACC mutations, identified from 6,842 screened cases between December 2018 and December 2023. The primary study endpoint was OS. Survival curves were generated using the Kaplan-Meier method, and prognostic factors were assessed using Cox regression.

[RESULTS] As of the cut-off date, June 20, 2024, the median follow-up period was 35.1 months (95%CI: 33.1-45.2 months). We identified that G719X (N = 72; 51.1%), S768I (N = 43; 30.5%), and E709X (N = 16; 11.3%) were the dominant subtypes, with compound mutations being frequently observed. The median OS in patients with NSCLC with EGFR PACC mutations was 27.6 months (95%CI: 25.2-30.7 months). Based on first-line therapy, the cohort was divided into patients who received chemo-based therapy (N = 33; 23.4%), EGFR-TKI (N = 87; 61.7%) and chemotherapy + TKIs (N = 21; 14.9%). Patients who had received chemotherapy + TKIs demonstrated superior OS than those who received only chemo-based treatments or TKI treatments (30.5 months vs. 24.1 months vs. 28.9 months, p = 0.022). Multivariate analyses identified lower Eastern Cooperative Oncology Group performance status scores, absence of brain metastasis, and receipt of chemotherapy combined with TKIs as independent, favorable prognostic factors (p < 0.05 for all).

[CONCLUSION] The G719X subtype was predominant, and compound mutations were frequently observed in patients with EGFR PACC-mutant NSCLC. The combination of chemotherapy and TKIs was associated with significant OS benefits, warranting future prospective clinical studies for confirmation.