A total of 22 patients with HER2 alterations were enrolled, including 15 with HER2 mutations, 5 with HER2 amplifications, and 2 with both. The overall objective response rate (ORR) was 45.5% (10/22), disease control rate (DCR) was 90.9% (20/22), and median progression-free survival (mPFS) stood at 7.5 months (95% CI 6.6-8.4 months). 95.5% of patients (21/22) underwent combination therapy, yielding an ORR of 47.6% (10/21)....The mPFS was notably prolonged in HER2-amplified patients and anti-HER2 naïve patients....For HER2-altered NSCLC patients, RC48 combined therapies are applicable treatment options, particularly with platinum agents.