Tukysa (tucatinib) in combination with antibody-drug conjugate ado-trastuzumab emtansine improves progression-free survival in previously treated HER2-positive metastatic breast cancer

The combination showed a statistically significant improvement in progression-free survival (PFS), the study’s primary endpoint, in patients with unresectable locally advanced or metastatic human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer who had been previously treated with trastuzumab and a taxane, compared to those who received placebo plus ado-trastuzumab emtansine. Discontinuations due to adverse events were more common in the combination arm of the trial, but no new safety signals were observed for the combination.

“Combining HER2-directed therapies can improve outcomes for people with locally advanced or metastatic HER2-positive breast cancer,” said lead author Sara A. Hurvitz, M.D., Professor and 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. “Notably, the HER2CLIMB-02 trial is the second randomized study including patients with brain metastases demonstrating that TUKYSA delays disease progression in this population.”

Patients who received Tukysa in combination with ado-trastuzumab emtansine experienced : i. Median PFS of 9.5 months (95% Confidence Interval [CI]: 7.4, 10.9) by investigator assessment per RECIST v1.1 compared to 7.4 months (95% CI: 5.6, 8.1) in the placebo plus ado-trastuzumab emtansine arm (Hazard Ratio [HR], 0.76 [95% CI: 0.61, 0.95); P=0.0163)?. ii. In patients with brain metastases, median PFS of 7.8 months (95% CI: 6.7, 10.0) compared to 5.7 months (95% CI: 4.6, 7.5) in the placebo arm (HR, 0.64 [95% CI: 0.46, 0.89]). iii. Confirmed objective response rate (cORR) of 42.0% versus 36.1% in the placebo arm. iv. Overall survival (OS) data, a secondary endpoint, are not yet mature.

The most common (greater than 5%) Grade 3 or higher adverse events (AEs) were alanine transferase (ALT) increase (16.5% versus 2.6%), aspartate transferase (AST) increase (16.5% versus 2.6%), anemia (8.2% versus 4.7%), thrombocytopenia (7.4% versus 2.1%), and fatigue (6.1% versus 3.0%).

Tukysa in combination with trastuzumab and capecitabine is approved by the FDA based on the results of the HER2CLIMB trial and is the only Category 1 preferred recommendation by the National Comprehensive Cancer Network for third-line metastatic HER2-positive breast cancer.