Journal article
Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial
Nature medicine, Vol.31(3), pp.909-916
03/2025
DOI: 10.1038/s41591-024-03462-0
PMCID: PMC11922774
PMID: 39825152
Abstract
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .
Details
- Title: Subtitle
- Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial
- Creators
- Alicia F C OkinesGiuseppe Curigliano - University of MilanNobumasa Mizuno - Aichi Cancer CenterDo-Youn OhAndree Rorive - University of LiègeHatem Soliman - Moffitt Cancer CenterShunji Takahashi - The Cancer Institute HospitalTanios Bekaii-Saab - Mayo Clinic in ArizonaMark E Burkard - University of Wisconsin Carbone Cancer CenterKi Y Chung - Prisma HealthPhilip R Debruyne - AZ GroeningeJenny R Fox - Rocky Mountain Cancer CentersValentina Gambardella - Hospital Clínico Universitario de ValenciaMarta Gil-Martin - Institut Català d'OncologiaErika P Hamilton - Sarah CannonBradley J Monk - Florida Cancer Specialists & Research InstituteYoshiaki Nakamura - National Cancer Center Hospital EastDanny Nguyen - City Of Hope National Medical CenterDavid M O'MalleyAlexander B Olawaiye - University of Pittsburgh Medical CenterBhavana Pothuri - NYU Langone HealthMartin Reck - German Center for Lung ResearchKazuki SudoYu Sunakawa - St. Marianna University School of MedicineCedric Van Marcke - Cliniques Universitaires Saint-LucEvan Y Yu - University of WashingtonJorge Ramos - PfizerSherry Tan - PfizerMark Bieda - PfizerThomas E Stinchcombe - Duke Cancer InstitutePaula R Pohlmann - The University of Texas MD Anderson Cancer Center
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.31(3), pp.909-916
- DOI
- 10.1038/s41591-024-03462-0
- PMID
- 39825152
- PMCID
- PMC11922774
- NLM abbreviation
- Nat Med
- ISSN
- 1546-170X
- eISSN
- 1546-170X
- Publisher
- NATURE PORTFOLIO
- Grant note
- Pfizer (Pfizer Inc.): SGNTUC-019 Merck Sharp Dohme LLCF. Hoffmann-La Roche
We thank the patients who participated in this study, their families, and the investigators and staff at the SGNTUC-019 clinical sites. We also thank A. Drees, K. Earley and S. Lonning of Pfizer for critical review of the data and the paper and K. Garton of Pfizer for critical review of the paper. Finally, we thank the entire SGNTUC-019 study team for support. H. Brignull of Populus Group, supported by Pfizer, provided medical writing and editorial support in accordance with Good Publication Practice guidelines. This study was sponsored by Seagen, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Seagen was acquired by Pfizer in December 2023. F. Hoffmann-La Roche provided trastuzumab for the study. The sponsor had final responsibility for the design of the trial, protocol, database maintenance, trial conduct, data analyses and confirmation of the accuracy of the data. We prepared and approved the paper and made the decision to submit it for publication.
- Language
- English
- Electronic publication date
- 01/17/2025
- Date published
- 03/2025
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984773412402771
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