Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens.

Abstract

INTRODUCTION:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Sarah Waliany, Heather Wakelee, Kavitha Ramchandran, Millie Das, Jane Huang, Nathaniel Myall, Connie Li, Judy Pagtama, Alison Holmes Tisch, Joel W Neal
• Journal: Clinical lung cancer (Clin Lung Cancer) Vol. 23 Issue 6 Pg. 498-509 (09 2022) ISSN: 1938-0690 [Electronic] United States
• PMID: 35753988 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab
• Ado-Trastuzumab Emtansine

Topics

• Ado-Trastuzumab Emtansine
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Receptor, ErbB-2 (genetics)
• Retrospective Studies
• Trastuzumab (therapeutic use)