Tucatinib, Trastuzumab Combination Improves Progression-Free Survival in HER2+, Locally Advanced or Metastatic Breast Cancer

Adding tucatinib (Tukysa; Seagen) to trastuzumab emtansine (T-DM1) resulted in a median progression-free survival (PFS) of 9.5 months vs 7.4 months with placebo among patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive, locally advanced or metastatic breast cancer, according to new data from the HER2CLIMB-02 trial. Importantly, improvements in PFS were also seen among patients with brain metastases. These data were presented at the 2023 San Antonio Breast Cancer Symposium (SABCS) in Texas.

Tucatinib is a highly selected HER2-directed tyrosine kinase inhibitor that has been FDA-approved in combination with trastuzumab and capecitabine for previously treated HER2-positive locally advanced or metastatic breast cancer. T-DM1 is a HER2-directed antibody-drug conjugate approved for the same patient population who were previously treated with trastuzumab and a taxane.

Tucatinib is a highly selected HER2-directed tyrosine kinase inhibitor that has been FDA-approved in combination with trastuzumab and capecitabine for previously treated HER2-positive locally advanced or metastatic breast cancer. Image Credit: © annamaria - stock.adobe.com

Presenter Sara Hurvitz, MD, senior vice president of the Clinical Research Division at Fred Hutch and head of the Division of Hematology and Oncology at the University of Washington Department of Medicine in Seattle, said the incidence of brain metastases among patients with HER2-positive advanced disease is quite high. Previous data have suggested that combining HER2-directed therapies could improve outcomes in this setting, with preclinical and phase 1 and 2 clinical data showing promising activity with the combination of T-DM1 and tucatinib.

“About 44% of patients enrolled in this study had brain metastases, and roughly half of them had active brain metastases,” Hurvitz said during the presentation. “Over 40% of patients enrolled had de novo metastatic breast cancer at the time of enrollment.”

Patients were randomly assigned 1:1 to receive 21-day cycles of either tucatinib (300 mg orally twice a day) or placebo, combined with T-DM1 (3.6 mg/kg intravenously every 3 weeks). The primary endpoint was PFS. Alpha-controlled secondary endpoints included overall survival (OS) and objective response rate (ORR) for the overall population, and PFS and OS for the subset of patients with brain metastases at baseline. Safety was also analyzed as a secondary endpoint.

Between October 8, 2019, and June 16, 2022, 463 patients were randomly assigned, with 228 in the tucatinib arm and 235 in the control arm. The median duration of follow-up was 24.4 months for the overall population.

At the data cutoff of June 29, 2023, the study met its primary endpoint with a statistically significant improvement in PFS in the tucatinib arm vs the control arm. The risk of disease progression or death decreased by 24.1% in the tucatinib arm (HR=0.759). Median PFS was 9.5 months in the tucatinib arm and 7.4 months in the control arm. Hazard ratios (HRs) for PFS across all prespecified subgroups were consistent with the HR of the overall population, including patients with brain metastases at baseline.

“The combination of tucatinib and T-DM1 was associated with a strong trend in improvement for PFS,” Hurvitz said.

The interim OS results were immature, with 134 of 253 total required events (53%) and did not meet the prespecified crossing boundary. The confirmed ORR was numerically higher in the tucatinib arm vs the control arm (42% and 36.1%, respectively). The most common treatment-emergent adverse events (TEAEs) included nausea (65.4% vs 49.4% for tucatinib and control arms, respectively), diarrhea (56.7% vs 26.6%, respectively), and fatigue (48.9% vs 37.3%, respectively). The most common grade 3 or higher TEAEs in the tucatinib arm were alanine and aspartate aminotransferase elevations, each reported in 38 patients (16.5%) in the tucatinib arm and 6 patients (2.6%) in the control arm.

“Following HER2CLIMB, HER2CLIMB-02 is the second-largest randomized study of systemic therapy for breast cancer that included patients with active or progressing brain metastases,” Hurvitz said during the presentation. She then added that a large majority of patients received anti-cancer therapy in a subsequent setting, and about half went on to receive trastuzumab deruxtecan.

“In conclusion, adding tucatinib to T-DM1 significantly improved PFS in patients with previously treated HER2-positive advanced disease,” Hurvitz said. “The median PFS was 9.5 months vs 7.4 months with a HR of .76 and strong trends in favor of PFS for patients with brain metastases.”

Reference

Hurvitz S. HER2CLIMB-02: Randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium. December 5-9, 2023.