Ado-trastuzumab emtansine (T-DM1) in patients with HER2-amplified tumors excluding breast and gastric/gastroesophageal junction (GEJ) adenocarcinomas: results from the NCI-MATCH trial (EAY131) subprotocol Q
Open accessAbstract
BACKGROUND: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors. METHODS: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed. RESULTS: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay. CONCLUSION: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials.
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The majority of clinical trials testing antibody-drug conjugates targeting CEACAM5, EGFR and TROP2 with various cytotoxic payloads showed either insufficiency to overcome therapy resistance or high toxicity.
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From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [71]
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Current and emerging concepts for systemic treatment of metastatic colorectal cancer
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- Authors
- Jhaveri, K. L., Wang, X. V., Makker, V., Luoh, S.-W., Mitchell, E. P., Zwiebel, J. A., Sharon, E., Gray, R. J., Li, S., McShane, L. M., Rubinstein, L. V., Patton, D., Williams, P. M., Hamilton, S. R., Conley, B. A., Arteaga, C. L., Harris, L. N., O’Dwyer, P. J., Chen, A. P., & Flaherty, K. T.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Oregon Health & Science University (US)
- Thomas Jefferson University (US)
- National Cancer Institute (US)
- Dana-Farber Cancer Institute (US)
- National Institutes of Health (US)
- Frederick National Laboratory for Cancer Research (US)
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Southwestern Medical Center (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Jhaveri, K.L.
- ORCID
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 30
- Issue
- 11
- Pages
- 1821-1830
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC6927318
- OpenAlex
- W2971230454
- Cited by
- 151
- References
- 53
- Citations by year
- 2026: 13 · 2025: 15 · 2024: 25 · 2023: 29 · 2022: 22 · 2021: 21 · 2020: 25 · 2019: 1
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-08-01)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- ECOG-ACRIN Cancer Research Group
- Memorial Sloan Kettering Cancer Center Support (P30 CA008748)
- National Cancer Institute of the National Institutes of Health (U10CA180820, U10CA180794, UG1CA233302, UG1CA233290, UG1CA233341, UG1CA233329, UG1CA233180, NCI P30 CA142543)
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- trastuzumab emtansine, HER2 amplification, NCI-MATCH trial, mucoepidermoid carcinoma, ovarian carcinoma, uterine carcinoma, HER2 copy number, objective response rate, progression-free survival, PTEN loss, targeted therapy
- MeSH terms
- Antineoplastic Agents, Immunological, Progression-Free Survival, Ado-Trastuzumab Emtansine, Adult, Aged, Aged, 80 and over, Female, Gene Amplification, Humans, Middle Aged, Neoplasms, Biomarkers, Tumor, United States, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, National Cancer Institute (U.S.), Precision Medicine
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