Combination therapy of tucatinib and T-DM1 significantly improves progression-free survival in patie

Primary analysis data from the randomized, double-blind, placebo-controlled phase III HER2CLIMB-02 study showed that for patients with HER2-positive locally advanced or metastatic breast cancer who had previously received trastuzumab and taxane treatment, the regimen of tucatinib combined with trastuzumab emtansine (T-DM1) significantly reduced the risk of disease progression or death and prolonged progression-free survival (PFS) by 2.1 months compared with placebo combined with T-DM1. PFS benefits were consistently observed across all prespecified subgroups, including in patients with brain metastases.

About Tucatinib

Tucatinib is an oral tyrosine kinase inhibitor (TKI) with high selectivity for HER2. In the HER2CLIMB study, compared with trastuzumab and capecitabine used alone, the addition of tucatinib to the trastuzumab plus capecitabine regimen improved PFS and overall survival (OS) in patients with unresectable locally advanced or metastatic breast cancer, including those with brain metastases. These results led to the regulatory approval of the tucatinib-trastuzumab-capecitabine combination for the treatment of previously treated HER2-positive locally advanced or metastatic breast cancer.

About T-DM1

T-DM1 is a HER2-targeted antibody-drug conjugate (ADC), also approved for the treatment of previously treated patients with HER2-positive metastatic breast cancer. It demonstrated intracranial activity and efficacy in the TH3RESA and KAMILLE studies. Preclinical findings in breast cancer models indicated that the combination of tucatinib and T-DM1 enhanced the antitumor activity of either agent alone. In a phase Ib study, tucatinib combined with T-DM1 showed encouraging antitumor activity (including intracranial responses) and manageable toxicity in heavily pretreated patients with HER2-positive metastatic breast cancer.

About the HER2CLIMB-02 Study

Based on these findings, the HER2CLIMB-02 study was designed to evaluate the efficacy and safety of tucatinib combined with T-DM1 in patients with HER2-positive locally advanced or metastatic breast cancer who had experienced disease progression after treatment with trastuzumab and taxanes (in any setting). Patients were randomly assigned in a 1:1 ratio to two groups: the tucatinib group received T-DM1 (intravenous infusion of 3.6 mg/kg every 21 days) combined with tucatinib (300 mg orally twice daily), and the control group received T-DM1 combined with placebo (orally twice daily).

A total of 463 patients were randomly assigned. After a median follow-up of 24.4 months, the median PFS was 9.5 months in the tucatinib group versus 7.4 months in the control group (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.61–0.95; p=0.0163). PFS benefits were observed across all prespecified subgroups, including in patients with brain metastases.

Results from the interim OS analysis were immature. The median OS was not reached in the tucatinib group, compared with 38.0 months in the control group (HR 1.23, 95% CI 0.87–1.74).

The incidence of any treatment discontinuation due to treatment-related adverse events (TEAEs) and the incidence of grade ≥3 TEAEs were both higher in the tucatinib group than in the control group, at 22.1% versus 11.6% and 68.8% versus 41.2%, respectively. The most common grade ≥3 TEAEs in the tucatinib group were elevated alanine aminotransferase and aspartate aminotransferase levels, with incidences of 16.5% each, compared with 2.6% for both in the control group.