Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens. Clinical lung cancer Waliany, S., Wakelee, H., Ramchandran, K., Das, M., Huang, J., Myall, N., Li, C., Pagtama, J., Tisch, A. H., Neal, J. W. 2022


About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC.This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1.We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations.In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.

View details for DOI 10.1016/j.cllc.2022.05.015

View details for PubMedID 35753988