Tucatinib for HER2-Positive Metastatic Breast Cancer

Sara A. Hurvitz, MD: HER2CLIMB was a large, randomized, placebo-controlled clinical trial evaluating trastuzumab combined with capecitabine, in combination with either tucatinib, the HER2-selective tyrosine kinase Inhibitor, or placebo. In this study, patients with heavily pretreated HER2-positive metastatic breast cancer were assigned to 1 of these treatment arms and followed for efficacy. The important key feature of this clinical trial, in terms of the eligibility criteria, is that patients who had a history of brain metastases—either stable, previously treated brain mets [metastases], or newly diagnosed brain metastases, or progressing brain metastases after treatment for the brain metastases—were allowed on the clinical trial. Oftentimes in studies for metastatic breast cancer, those patients would be excluded. Knowing that tucatinib can cross the blood-brain barrier, investigators designed this study to include these patients. Close to 50% of patients enrolled in this study did have a history of brain metastasis. In this study, the median progression-free survival in the intent-to-treat population was significantly prolonged. Also, the progression-free survival in the subset of patients with brain metastases was prolonged. Moreover, the overall survival in the intent-to-treat population was significantly prolonged, with a hazard ratio of 0.66, which is highly statistically significant. The overall survival was also prolonged in patients who had brain metastases. The percentage of patients who had an intracranial objective response in their brain metastases was about 50%, which was about double that seen in the control arm.

These very exciting data led to the FDA approval of this agent. When the data came out sayingthe overall survival improved significantly in the tucatinib-treated patients, a decision was made to unblind patients and allow those receiving the placebo to cross over to the tucatinib arm. Unblinding and crossover can affect long-term overall survival analysis because if patients move to the arm that is associated with better survival, this can certainly impact the readout of the intent-to-treat analysis for overall survival later. However, it’s an ethical thing to do when you know that a particular agent is so active that it’s improving survival. I applaud the sponsor of the study for deciding to do that.

Transcript Edited for Clarity