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

Sarah Waliany; Heather Wakelee; Kavitha Ramchandran; Millie Das; Jane Huang; Nathaniel Myall; Connie Li; Judy Pagtama; Alison Holmes Tisch; Joel W Neal

doi:10.1016/j.cllc.2022.05.015

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

Clin Lung Cancer. 2022 Sep;23(6):498-509. doi: 10.1016/j.cllc.2022.05.015. Epub 2022 Jun 3.

Authors

Affiliations

¹ Department of Medicine, Stanford University School of Medicine, Stanford, CA.
² Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA.
³ Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA; Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA.
⁴ Stanford Cancer Institute, Stanford, CA.
⁵ Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA. Electronic address: jwneal@stanford.edu.

PMID: 35753988
DOI: 10.1016/j.cllc.2022.05.015

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.

Keywords: ERBB2-mutant/EGFR-wildtype mNSCLC; NSCLC; Precision oncology; Trastuzumab deruxtecan.

MeSH terms

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

Substances

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