The HER2 CLIMB-02 trial of tucatinib/tucatinib in HER2+ breast cancer

The HER2 CLIMB-02 study aims to further investigate the potential role of existing drugs. Tucatinib was approved by the U.S. Food and Drug Administration (FDA) for patients with HER2-positive breast cancer based on findings from the Phase 2 HER2 CLIMB study (NCT02614794), which showed that when the drug is added to carboside When capecitabine plus trastuzumab was used, progression-free survival (PFS) was better than capecitabine plus trastuzumab alone.

Tucatinib is particularly beneficial for patients with brain metastases. Subsequently, various studies explored different combinations of tucatinib. HER2 CLIMB-02 was studied for use in combination with T-DM1 beyond first-line use. Patients were randomly assigned to receive T-DM1 plus placebo or tucatinib, with PFS as the primary and secondary endpoints, including overall survival (OS) and PFS in patients with brain metastases.

In the tucatinib arm, a substantial proportion of patients had brain metastases (43.4%) or de novo metastatic disease (45.2%), and patients had received a median of 1 prior first-line therapy (range, 0-8), suggesting relatively few treatments, primarily in the second-line metastatic setting. Across the entire population, tucatinib resulted in a modest improvement in PFS compared with placebo, 9.5 months (95% CI, 7.4-10.9) versus 7.4 months (95% CI, 5.6-8.1), although this improvement in PFS was statistically significant, with a HR of 0.76 (95% CI, 0.61-0.95; p=0.0163). Similar PFS trends were observed in patients with brain metastases, suggesting potential benefit of combination therapy in this subgroup. Although OS data are still immature, preliminary OS indications favored the tucatinib arm, with median OS not reached (NR) (HR, 1.23; 95% CI, 0.87-1.74) compared with 38.0 months (95% CI, 31.5-NR) in the placebo arm.

However,the rapidly evolving treatment paradigm for HER2-positive breast cancer requires consideration. By the time HER2 CLIMB-02 was completed, the antibody-drug conjugates (ADCs) of choice in second-line metastatic breast cancer had changed. Although the HER2 CLIMB-02 findings are clinically relevant, their direct applicability to clinical practice may vary. Phase 3 DESTINY-Breast03 trial (NCT03529110) identifies trastuzumab (T-DXd; Enhertu) as a significantly more potent ADC than T-DM1. Therefore, T-DXd has become the preferred second-line ADC for metastatic HER2-positive breast cancer.