HER2-mutated lung squamous cell carcinoma responding to trastuzumab deruxtecan followed by pyrotinib: a Case Report.

Introduction: HER2 (ERBB2) alterations are recognized oncogenic drivers in non-small cell lung cancer, but they are uncommon and poorly characterized in lung squamous cell carcinoma (LSCC). Case Presentation: We report a patient with initially resected stage IA2 LSCC who subsequently developed metastatic pulmonary recurrence. Molecular profiling of the resected tumor revealed an ERBB2 exon 20 p. G776V (p.Gly776Val) mutation, MET amplification, and copy-number deletions involving CDKN2A/B, MTAP, and TERT. Postoperative systemic therapy was administered as an individualized off-guideline strategy after multidisciplinary discussion. Following pulmonary recurrence and subsequent progression on platinum-based therapy, trastuzumab deruxtecan (T-DXd) achieved clinically meaningful disease control but was discontinued because of suspected drug-associated interstitial lung disease/pneumonitis complicated by pulmonary infection. Pyrotinib was subsequently administered and achieved disease control despite gastrointestinal intolerance. After further disease progression and clinical improvement of the prior pulmonary event, reduced-dose T-DXd was cautiously reintroduced, resulting in an additional radiologic response and approximately 7 months of disease control. The later clinical course was complicated by suspected treatment-associated cardiac dysfunction and terminal respiratory deterioration related to progressive pulmonary disease and infection. Conclusion: This case suggests that ERBB2 activating mutations may represent potentially actionable alterations in selected patients with recurrent LSCC. Comprehensive genomic profiling may identify rare therapeutic opportunities in this histologic subtype. However, individualized off-guideline treatment, HER2-directed therapy sequencing, and T-DXd rechallenge after pulmonary toxicity require cautious multidisciplinary risk-benefit assessment.