Study Results Indicate Combined Therapy of Tucatinib, T-DM1, Extended PFS in Patients With Breast Cancer


Although PFS was improved in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, OS data were immature, requiring further research.

Results from the HER2CLIMB02 trial demonstrate that, compared to trastuzumab emtansine (T-DM1; Kadcyla, Genentech USA) alone, a combination of tucatinib (Tukysa; Seagen Inc) and T-DM1, 2 HER2-targeted drugs, extended progression-free survival (PFS) among patients with unresectable locally advanced or metastatic HER2-positive breast cancer. The trial results were presented at the San Antonio Breast Cancer Symposium, held December 5 through December 9, 2023.

Physician overseeing a mammography

Image credit: okrasiuk |

T-DM1, an antibody-drug conjugate, is made up of trastuzumab and the cytotoxic drug emtansine. It was approved in 2013 for use as a monotherapy for patients with late-stage HER2-positive breast cancer, and in 2019 for patients with early-stage HER2-positive breast cancer; however, not all patients have durable responses to T-DM1, and a combination approach can potentially boost the efficacy of the drug.

Unlike other HER2-targeted drugs, tucatinib, a small-molecule inhibitor of HER2, has been shown to delay disease progression in the central nervous system. For patients who have brain metastases, tucatinib can make a significant difference.

“HER2-positive breast cancer has a predilection to spread to the brain, and when this occurs, prognosis is poor,” said Sara A. Hurvitz, MD, professor, head of the division of hematology and oncology at the University of Washington Department of Medicine, and senior vice president and director of the clinical research division at Fred Hutchinson Cancer Center, in a press release. “Few options exist for the successful management of breast cancer brain metastases, making this an area of unmet need.”

HER2CLIMB, a previous trial, had found that the addition of tucatinib to a regimen that contains the HER2-targeted antibody trastuzumab and the chemotherapy capecitabine had significantly improved PFS and overall survival (OS) in patients—including those with brain metastases—who received previous treatment. This trial led to the FDA approval of tucatinib, trastuzumab, and capecitabine in 2020; however, advances in HER2-targeting therapies prompted the current study authors to investigate additional tucatinib-based combinations.

The phase 3 trial, HER2CLIMB-02, examined 463 patients with unresectable locally advanced or metastatic HER2-positive breast cancer who were randomly assigned to receive tucatinib plus T-DM1 (n = 228) or placebo plus T-DM1 (n = 235 patients), of which approximately 44.1% had brain metastases at baseline. The median time to disease progression or death was 9.5 months for those in the tucatinib arm, and 7.4 months for patients in the placebo arm, with tucatinib plus T-DM1 reducing the risk of disease progression or death by 24.1%. Among those with brain metastases at baseline, the median time to disease progression or death was 7.8 months for those in the tucatinib arm, and 5.7 months for those treated in the placebo arm, with tucatinib plus T-DM1 reducing the risk of disease progression or death by 36.1%.

After a median follow-up of 24.4 months, the OS data were immature—a limitation of the study—and require further investigation. In addition, another limitation was the study’s design, as it was not meant to compare tucatinib plus T-DM1 to tucatinib plus trastuzumab and capecitabine, or any regimens that contained the antibody-drug conjugate trastuzumab deruxtecan.

According to Hurvitz, the rate of certain treatment-related adverse effects (AEs)—particularly those related to liver and gastrointestinal function—was higher among patients treated with tucatinib than those treated with placebo. This resulted in a higher rate of dose adjustments and treatment discontinuation in the tucatinib arm; however, the AEs were primarily manageable with clinical intervention and monitoring.

“This study is one of very few large breast cancer studies prospectively designed to evaluate novel systemic therapies in patients with brain metastases,” said Hurvitz in the press release. “While there is much interest in improving outcomes for patients with HER2-positive breast cancer brain metastases, most studies evaluating systemic agents have been limited by a small size, a retrospective design, or an exploratory analysis of a larger study.”


American Association for Cancer Research. Tucatinib plus trastuzumab emtansine may benefit patients with advanced or metastatic HER2-positive breast cancer. News release. December 6, 2023. Accessed December 4, 2023.

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