Favorable Safety Profile of Tucatinib for Metastatic HER2+ BC

Thomas Bachelot, MD, PhD: Regarding the safety profile of tucatinib, I feel that it is very good. It is not complicated to use this molecule. Actually, it is easier to use tucatinib than other HER2 [human epidermal growth factor receptor 2] tyrosine kinase inhibitors, like lapatinib and neratinib. At this time, it is more toxic with HER1; inhibition gives cutaneous toxicities and digestive toxicities like diarrhea. Tucatinib has some of those toxicities too, but they tend to be very mild.

I was an investigator on the HER2CLIMB study. Patients were randomized and given tucatinib, trastuzumab, and capecitabine or trastuzumab-capecitabine alone. I could not discern which patients were on the placebo or the experimental drug because there were not many differences in digestive toxicities, particularly diarrhea, which is the main toxicity that results from this combination. It was not much worse than the treatment we have with capecitabine alone. The management is quite simple. You have to give medication to prevent diarrhea if patients experience that; you can then adapt to the dosage of tucatinib. This toxicity occurred in only a few patients. In most patients, you could manage them very easily with some alimentary modifications. It is not a large problem to manage this agent.

Volkmar Mueller, MD: One important point to consider when considering every new compound is the safety profile. When adding an additional compound to a regimen, we expect some additional toxicity. In the context of the HER2CLIMB study, patients were at an increased risk of diarrhea and also elevated liver enzymes. However, I must say that I was impressed by the low rate of treatment discontinuation due to adverse events: 7% in the tucatinib arm and approximately 4% in the placebo arm. Going off my impression, patient management with the 3-drug arm is driven by the good management of capecitabine, which we have a lot of experience with. In my opinion, this is causing the diarrhea more often than tucatinib.

I do not feel that routine loperamide is required, so we do not use that. In the context of adverse effects, it is also important to know that there are a great deal of data concerning the quality-of-life data of patients in the trial. Actually, the first set of data was presented at ESMO [European Society for Medical Oncology Congress] 2020. These data indicated that the quality of life of patients was not impaired by adding tucatinib. Patients were able to maintain a good quality of life. Because patients had received treatment for a longer time, they had a longer period in which they experience good quality of life. However, because of the progression of disease, quality of life was also eventually worsening.

At the San Antonio Breast Cancer Symposium in December 2020, there were additional data sets available for patients with brain metastases. The quality of life for patients was also maintained for a longer time with an addition of tucatinib. There is a positive trial outcome but also a positive outcome in regard to quality of life.

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