HER2CLIMB

HER2CLIMB is a phase III randomized clinical trial that evaluated the addition of tucatinib to the standard regimen of trastuzumab and capecitabine in adults with HER2-positive metastatic breast cancer. A key feature of the trial was the inclusion of patients with brain metastases, a subgroup historically difficult to treat, to assess whether the combination could improve outcomes in the central nervous system as well as systemically. Participants were assigned to tucatinib plus trastuzumab and capecitabine or placebo plus trastuzumab and capecitabine, with primary endpoints focused on progression-free survival and overall survival and secondary endpoints including intracranial response measures.

Results demonstrated that incorporating tucatinib significantly improved progression-free survival and overall survival versus the control regimen. The benefit extended to patients with brain metastases, showing reduced risk of intracranial progression and higher intracranial response rates. The safety profile was considered manageable and consistent with expectations for the combination, with higher rates of diarrhea and liver enzyme elevations related to the triplet therapy and standard capecitabine-associated effects such as hand-foot syndrome; most adverse events were not prohibitive and did not lead to disproportionate discontinuation compared with the control arm.

Impact and status: The findings from HER2CLIMB contributed to regulatory approval for tucatinib in combination with trastuzumab and capecitabine for adults with HER2-positive metastatic breast cancer, including those with brain metastases, and influenced clinical guidelines for this disease setting. Mechanism: Tucatinib is a selective HER2 tyrosine kinase inhibitor designed to target HER2-driven signaling while limiting off-target EGFR-related toxicities, and it is used in combination with trastuzumab and capecitabine to achieve comprehensive HER2 blockade in metastatic disease.