Abstract
BACKGROUND: There have been no comprehensive large-scale studies that have evaluated the benefits of chemotherapy-based regimens in addressing HER2-altered advanced non-small-cell lung cancer (NSCLC) in a first-line setting. Data on HER2 alteration subtypes and concomitant alterations are also limited. Accordingly, our retrospective, real-world POLISH study assesses the efficacy of first-line chemotherapy alone (C) as well as combinations with immune checkpoint inhibitors (C + I) or angiogenesis inhibitors (C + A) for HER2-altered NSCLC; molecular features are also reported. METHODS: HER2-altered NSCLC patients who received a first-line treatment between November 2015 and September 2021 were screened. Patients treated with C, C + I, or C + A were included in our final efficacy analysis. Progression-free survival (PFS) was compared between the subgroups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed to evaluate concomitant alterations. RESULTS: A total of 293 patients were screened, with an identification of HER2 amplification and 37 distinct HER2 mutations, and 210 cases treated with C, C + I, or C + A were ultimately included. C + A achieved longer PFS than C (5.63 vs 4.03 months, hazard ratio: 0.64, 95% confidence interval [CI]: 0.46-0.88, p = 0.006). C + I did not improve median PFS compared to C + A or C (both p > 0.05), despite the programmed cell death ligand-1 (PD-L1) expression or tumor mutational burden. KEGG analysis revealed that concomitant upregulation of PI3 K/AKT pathway signaling was common in HER2-altered NSCLC. CONCLUSION: Chemotherapy plus angiogenesis inhibitors may yield a greater survival benefit than chemotherapy alone in a first-line setting for HER2-altered NSCLC, whereas an immune-based combination therapy may not be superior to a sole chemotherapy regimen. Activation of PI3 K/AKT signaling may mediate immunosuppression in HER2-altered NSCLC.