First-line pyrotinib plus apatinib in advanced non-small cell lung cancer harboring HER2 mutations or amplification: a phase II trial.

BACKGROUND: Although emerging agents have broadened the therapeutic landscape for non-small cell lung cancer (NSCLC) harboring HER2 alterations, effective and accessible first-line therapy remains limited. METHODS: In this single-arm, phase II trial, treatment-naïve patients with stage IIIB-IV NSCLC harboring de novo HER2 mutations or amplification were given oral pyrotinib (400 mg) in combination with apatinib (250 mg) once daily until disease progression, intolerable toxicity, or death. The primary endpoint was overall response rate (ORR). Secondary endpoints consisted of disease control rate (DCR), progression-free survival (PFS), and safety. RESULTS: Between November 2021 and March 2024, 22 eligible patients were enrolled. The ORR was 72.7 % (95 % CI, 49.8-89.3), and the DCR reached 95.5 % (95 % CI, 77.2-99.9). With a median follow-up of 37.0 months (95 % CI, 36.1-37.9), the median PFS was 10.7 months (95 % CI, 6.6-14.8). Both patients harboring HER2 amplification achieved PFS exceeding 10 months, while the patient harboring HER2 exon 19 L755P mutation achieved a PFS exceeding 24 months. Grade 3-4 treatment-related adverse events occurred in 27.3 % of subjects, with diarrhea being the most prevalent (18.2 %). In the propensity score-matched analysis, pyrotinib plus apatinib prolonged PFS compared with chemotherapy-based regimens (robust standard error HR 0.53, 95 % CI: 0.34-0.81, P = 0.003). Circulating tumor DNA analysis demonstrated decreased HER2 variant allele frequency in 93.3 % of patients with paired baseline and post-C1 samples. CONCLUSION: Pyrotinib combined with apatinib demonstrated promising first-line activity, rapid responses, and manageable toxicity in advanced HER2-altered NSCLC, supporting its potential as an accessible chemotherapy-sparing therapy, particularly in resource-constrained settings.