Successful Rechallenge of Trastuzumab Deruxtecan After Drug-Induced Interstitial Lung Disease in a NSCLC With HER2 Mutation: A Case Report

Trastuzumab deruxtecan, an antibody-drug conjugate targetingHER2-expressing tumor cells, was found to have promising results in treatment-refractory, metastatic NSCLC harboring HER2 mutations. Nevertheless, drug-induced interstitial lung disease (ILD)/pneumonitis is a concern that limits treatment response in this subset of patients. For grade 2 or more ILD/pneumonitis, permanent discontinuation is warranted with vigorous treatment with high-dose steroid. We report a case of successful rechallenge of trastuzumab deruxtecan after recovery of grade 3 ILD/pneumonitis in treatment-refractory NSCLC harboring ERBB2 Y772-A775dup

Brief Report: Heterogeneity of Acquired Resistance Mechanisms to Osimertinib and Savolitinib

Introduction: MET amplification is a frequently observed mechanism of resistance to osimertinib, and coinhibition strategy of MET and EGFR revealed promising results in recent clinical trials. Nevertheless, acquired resistance mechanisms to combined EGFR and MET inhibition are poorly understood. In this study, we investigated the mechanisms of acquired resistance to osimertinib and savolitinib by using pretreatment and post-treatment tissue analysis. Methods: Whole-exome sequencing was performed in EGFR-mutant, MET-amplified patients who received osimertinib and savolitinib using tissues obtained both before and after therapy. All patients achieved partial response or durable stable disease to osimertinib and savolitinib before developing acquired resistance. Results: After progression on osimertinib and savolitinib, whole-exome analysis revealed MET-dependent mechanisms of resistance, such as acquired MET p.D1246H mutation, MET p.Y1230C mutation, and MET copy number gain. As for MET-independent mechanisms, development of ERBB2 mutation and amplification and copy number gains in amplifications in CCNE, CCND1, CDK6, and EGFR were observed. Patient 2 harbored an acquired PIK3CA p.H1047R mutation in which resistance could be overcome with combination of PI3K inhibitor and osimertinib in the patient-derived xenograft model. Conclusions: Our study reveals that acquired resistance to savolitinib plus osimertinib can occur from both MET-dependent and MET-independent mechanisms