Multicenter phase 2 trial of first-line pyrotinib plus apatinib in advanced NSCLC harboring HER2 mutations or amplification

Although emerging agents have broadened the therapeutic landscape for non-small cell lung cancer (NSCLC) harboring HER2 alterations, effective and accessible first-line therapies remain limited. A multicenter phase 2 trial in China evaluated the first-line combination of pyrotinib and afatinib for patients with stage IIIB-IV NSCLC harboring de novo HER2 mutations or amplification. Patients received oral pyrotinib 400 mg plus apatinib 250 mg once daily until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR). Among 22 patients, the ORR was 72.7% (95% CI 52.5-92.9) and the disease control rate reached 95.5% (86.0-100). With a median follow-up of 37.0 months, the median progression-free survival (PFS) was 10.7 months (95% CI 6.6-14.8). The two patients harboring HER2 amplification achieved PFS exceeding 10 months, while the patient harboring HER2 exon 19 L755P mutation achieve PFS exceeding 24 months. Grade 3-4 treatment-related adverse events occurred in 27.3% of patients. In propensity score-matched analysis, pyrotinib plus apatinib prolonged PFS compared with chemotherapy-based regimens (robist standard error HR 0.53; p=0.003). The authors conclude that 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.