Tucatinib and trastuzumab emtansine for patients with previously treated HER2-positive locally advanced and metastatic breast cancer: primary analysis of the randomized phase III trial HER2CLIMB-02

S A Hurvitz¹, S Loi², J O'Shaughnessy³, A F C Okines⁴, S M Tolaney⁵, J Sohn⁶, C Saura⁷, X Zhu⁸, D Cameron⁹, T Bachelot¹⁰, E Hamilton¹¹, G Curigliano¹², A C Wolff¹³, N Harbeck¹⁴, N Masuda¹⁵, L Vahdat¹⁶, K Zaman¹⁷, F Valdes-Albini¹⁸, M Block¹⁹, T Pluard²⁰, T J Tan²¹, C Gawryletz²², A Chan²³, P L Bedard²⁴, R Yerushalmi²⁵, B Xu²⁶, M Schmitt²⁷, D Xie²⁷, V F Borges²⁸; HER2CLIMB-02 study investigators

Affiliations

¹ Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
² Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
³ Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, USA.
⁴ The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
⁵ Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Yonsei Cancer Center, Seoul, South Korea.
⁷ Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁸ Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
⁹ Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
¹⁰ Centre Léon Bérard, Lyon, France.
¹¹ Sarah Cannon Research Institute, Nashville, TN, USA.
¹² European Institute of Oncology, Milan, Italy; Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy.
¹³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA.
¹⁴ Breast Center, Department of OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany.
¹⁵ Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁶ Dartmouth Health, Lebanon, NH, USA.
¹⁷ Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹⁸ Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL, USA.
¹⁹ Nebraska Cancer Specialists, Omaha, NE, USA.
²⁰ Saint Luke's Cancer Institute, Kansas City, MO, USA.
²¹ National Cancer Centre Singapore, Singapore.
²² University of Colorado Health, Fort Collins, CO, USA.
²³ Breast Cancer Research Centre, Nedlands, WA, Australia; Curtin University, Perth, WA, Australia.
²⁴ Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
²⁵ Rabin Medical Center, Petah Tikva, Israel; Tel Aviv University, Tel Aviv, Israel.
²⁶ Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.
²⁷ Pfizer Inc., Bothell, WA, USA.
²⁸ University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: virginia.borges@cuanschutz.edu.

PMID: 41260264
DOI: 10.1016/j.annonc.2025.11.005

Free article

Tucatinib and trastuzumab emtansine for patients with previously treated HER2-positive locally advanced and metastatic breast cancer: primary analysis of the randomized phase III trial HER2CLIMB-02

S A Hurvitz et al. Ann Oncol. 2025.

Free article

. 2025 Nov 17:S0923-7534(25)06263-5.

doi: 10.1016/j.annonc.2025.11.005. Online ahead of print.

Authors

Affiliations

¹ Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
² Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
³ Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, USA.
⁴ The Royal Marsden NHS Foundation Trust, London, UK; The Institute of Cancer Research, London, UK.
⁵ Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Yonsei Cancer Center, Seoul, South Korea.
⁷ Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁸ Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
⁹ Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
¹⁰ Centre Léon Bérard, Lyon, France.
¹¹ Sarah Cannon Research Institute, Nashville, TN, USA.
¹² European Institute of Oncology, Milan, Italy; Department of Oncology and Hematology-Oncology, University of Milan, Milan, Italy.
¹³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA.
¹⁴ Breast Center, Department of OB&GYN and CCC Munich, LMU University Hospital, Munich, Germany.
¹⁵ Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁶ Dartmouth Health, Lebanon, NH, USA.
¹⁷ Lausanne University Hospital (CHUV), Lausanne, Switzerland.
¹⁸ Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL, USA.
¹⁹ Nebraska Cancer Specialists, Omaha, NE, USA.
²⁰ Saint Luke's Cancer Institute, Kansas City, MO, USA.
²¹ National Cancer Centre Singapore, Singapore.
²² University of Colorado Health, Fort Collins, CO, USA.
²³ Breast Cancer Research Centre, Nedlands, WA, Australia; Curtin University, Perth, WA, Australia.
²⁴ Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
²⁵ Rabin Medical Center, Petah Tikva, Israel; Tel Aviv University, Tel Aviv, Israel.
²⁶ Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.
²⁷ Pfizer Inc., Bothell, WA, USA.
²⁸ University of Colorado Cancer Center, Aurora, CO, USA. Electronic address: virginia.borges@cuanschutz.edu.

PMID: 41260264
DOI: 10.1016/j.annonc.2025.11.005

Abstract

Background: Trastuzumab emtansine (T-DM1) is a standard treatment option in patients with previously treated human epidermal growth factor receptor 2-positive (HER2+) locally advanced or metastatic breast cancer (LA/MBC). Here, we report the efficacy and safety of tucatinib in combination with T-DM1 compared with T-DM1 alone from the phase III HER2CLIMB-02 study (NCT03975647).

Patients and methods: Eligible patients had HER2+ LA/MBC that had been previously treated with trastuzumab and a taxane in any setting; these included patients with brain metastases (BMs). Patients were randomly assigned 1:1 to receive T-DM1 (3.6 mg/kg intravenously every 21 days) combined with either tucatinib (300 mg orally twice daily) in the tucatinib arm or placebo (orally twice daily) in the control arm.

Results: In total, 463 patients were randomly assigned. After a median follow-up duration of 24.4 months, the median progression-free survival (PFS) was 9.5 months in the tucatinib arm and 7.4 months in the control arm (hazard ratio [HR]=0.76; 95% CI, 0.61-0.95; P=0.0163). A PFS benefit was observed across all prespecified subgroups, including in patients with BMs. Interim overall survival analysis results were immature. The median OS was not reached in the tucatinib arm and was 38.0 months in the control arm (HR=1.23; 95% CI, 0.87-1.74). The incidences of treatment-emergent adverse events (TEAEs) associated with any treatment discontinuation and of grade ≥3 TEAEs were higher in the tucatinib arm than in the control arm (22.1% versus 11.6% and 68.8% versus 41.2%, respectively). The most common grade ≥3 TEAEs in the tucatinib arm were elevated alanine aminotransferase (16.5%) and aspartate aminotransferase levels (16.5%) (versus 2.6% for both in the control arm).

Conclusion: The addition of tucatinib to T-DM1 improved PFS in patients with previously treated HER2+ LA/MBC, including patients with BMs, and exhibited a manageable safety profile.

Keywords: T-DM1; advanced/metastatic breast cancer; brain metastases; human epidermal growth factor receptor 2–positive; trastuzumab emtansine; tucatinib.

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Tucatinib and trastuzumab emtansine for patients with previously treated HER2-positive locally advanced and metastatic breast cancer: primary analysis of the randomized phase III trial HER2CLIMB-02

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Tucatinib and trastuzumab emtansine for patients with previously treated HER2-positive locally advanced and metastatic breast cancer: primary analysis of the randomized phase III trial HER2CLIMB-02

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Abstract

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Medical

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