Understanding the HER2CLIMB Trial

Rita Nanda, MD: Similar to lapatinib and neratinib, tucatinib is an oral tyrosine kinase inhibitor. It inhibits the tyrosine kinase domain, which is the intercellular domain of HER2. Unlike lapatinib and neratinib, however, tucatinib is very selective for HER2, so there’s very little effect on EGFR. Because of that, it has a much more favorable toxicity profile. Certainly, we can see diarrhea with tucatinib, but nowhere near what we see with those agents that more strongly inhibit EGFR. There is very minimal diarrhea, and there’s no rash associated with tucatinib. Overall, it is very well tolerated, and because of how little it affects EGFR, it’s actually been able to be a very potent inhibitor of HER2, leading, I believe, to the increased efficacy that we have seen as part of the HER2CLIMB trial.

As part of HER2CLIMB, diarrhea and LFT [liver function test] elevations were seen with tucatinib. But for the most part, these were pretty low-grade toxicities and didn’t necessarily require dose interruption or dose reduction, but rather antidiarrheal agents or monitoring of LFTs.

HER2CLIMB was a randomized phase 3 trial, patients were randomized in a 2:1 fashion to receiving tucatinib versus a placebo in conjunction with trastuzumab and capecitabine. The trial was stratified based on whether patients had brain metastases, and 48% of patients who participated in HER2CLIMB did have brain metastases. Patients were allowed on whether these brain metastases had been treated or untreated, as long as they didn’t require urgent local management with radiation therapy. The primary end point of the trial was progression-free survival for the overall intent-to-treat population, and secondary end points included overall survival in the intent-to-treat population, as well as progression-free survival in those patients who had brain metastases at the time of study entry.

I think as you all know, brain metastases can be a real challenge when we’re taking care of patients with metastatic HER2-positive breast cancer. Up to 50% of patients experience brain metastases over the course of their journey. For the most part, brain metastases are treated with whole brain radiation or SRS [stereotactic radiosurgery], and brain metastases and radiation are associated with a decrease in the quality of life for patients who have CNS [central nervous system] disease. Having a therapy that’s very well tolerated and oral that can actually help to control CNS metastases has been a real breakthrough for those of us who treat patients with HER2-positive metastatic breast cancer and brain metastases. It’s a well-tolerated therapy and can delay the need for radiation. It is also offering our patients a great option to help control their disease.

Transcript Edited for Clarity