A real-world study on the comparative effectiveness of first-line treatment regimens in advanced NSCLC patients with PACC mutations.

Background: P-loop and αC-helix compressing (PACC) mutations are a distinct structural subset of atypical epidermal growth factor receptor (EGFR) alterations in non-small-cell lung cancer (NSCLC), yet no standard first-line strategy has been established.

Objectives: This study aimed to evaluate first-line treatment outcomes in patients with PACC-mutant NSCLC.

Design: A real-world retrospective study.

Methods: This retrospective cohort study enrolled 100 patients with PACC-mutant NSCLC who were diagnosed between February 2015 and April 2025. The efficacy of different first-line treatment strategies in this population was evaluated.

Results: Among the 100 patients, compared with chemotherapy, treatment with tyrosine kinase inhibitors (TKIs) significantly prolonged progression-free survival (PFS; 14.2 vs 5.2 months, hazard ratio (HR) = 0.348, p = 0.005). The inverse probability of treatment weighting (IPTW)-weighted Cox analysis produced results consistent with the primary analysis (IPTW-adjusted HR = 0.487, p = 0.039). Among patients treated with TKIs, both second-generation (13.9 vs 13.1 months, HR = 0.338, p = 0.015) and third-generation TKIs (16.8 vs 13.9 months, HR = 0.239, p = 0.011) appeared to be associated with longer PFS compared with first-generation TKIs; however, given the relatively small subgroup sizes, these comparisons should be interpreted with caution. In patients with brain metastases, third-generation TKIs were associated with numerically longer PFS (28.0 vs 11.2 months, HR = 0.324, p = 0.132) and significantly longer overall survival (not reached vs 29.0 months, HR = 0.097, p = 0.030) compared with second-generation TKIs. In patients with a single PACC mutation, second-generation TKIs significantly prolonged PFS compared with non-second-generation TKIs (18.0 vs 11.0 months, HR = 0.347, p = 0.032). In addition, subgroup analyses indicated that, relative to the E709X subset, patients with S768I mutations had significantly prolonged PFS under TKI treatment (24.6 vs 10.6 months, HR = 0.263, p = 0.027).

Conclusion: TKIs may represent a promising first-line option for advanced NSCLC with PACC mutations. The choice of specific TKIs may depend on genomic characteristics and brain metastasis status.