Tucatinib for the Treatment of HER2+ Breast Cancer

Ian Krop, MD, PhD:At the San Antonio Breast Cancer Symposium in 2019, we saw data from 3 promising agents in patients who have pretreated HER2-positive advanced breast cancer. Trastuzumab-deruxtecan was 1 that we’ve already discussed. The 2 others were also interesting. One is called tucatinib. This is a tyrosine kinase inhibitor that blocks HER2 kinase. It’s in some ways similar to lapatinib and neratinib. But unlike those 2 drugs, tucatinib blocks only HER2, whereas the other 2 agents also block EGFR. And EGFR inhibition is what causes the diarrhea and rash that are common adverse effects of those other kinase inhibitors. With tucatinib, because it’s so specific to HER2, there’s much less of those 2 adverse effects of diarrhea and rash.

The other interesting thing about tucatinib was that it crosses the blood-brain barrier quite well, as does lapatinib and neratinib, so there are early studies to suggest that it could have efficacy in preventing progression of HER2-positive brain metastases. These questions were all addressed in a randomized phase III trial called HER2CLIMB. This was a trial that randomized patients with HER2-positive breast cancer. All the patients on the study had already had trastuzumab, pertuzumab, and T-DM1 [ado-trastuzumab emtansine].

Interestingly, because of the ability of tucatinib to cross the blood-brain barrier in this trial, patients who had either treated brain metastases or actually progressive brain metastases were allowed on studies. It’s probably the first large randomized trial that allowed patients with progressive brain metastases. Again, this was to take advantage of the fact that we you thought that tucatinib could have efficacy in this population.

The results of the trial, which were presented at San Antonio this year, measured the addition of tucatinib. All patients on the trial got a combination of capecitabine and trastuzumab. The trial compared trastuzumab-capecitabine with either tucatinib or placebo. What the results showed was that in those patients who received tucatinib over placebo, there was substantial superiority. In terms of the primary objective, which was progression-free survival in the entire population, there was essentially a 46% reduction in progression-free-survival events with the use of tucatinib. There was a hazard ratio of 0.54, which is a pretty impressive improvement.

Interestingly, they also had an interim overall survival analysis in the presentation, and tucatinib was superior in terms of overall survival as well, with a 36% reduction overall in deaths because of the use of tucatinib. So there was a really impressive improvement in overall survival with the use of tucatinib.

As I mentioned, some patients on the trial also had had treated or progressive brain metastases, and in that subgroup of patients, specifically tucatinib also was very effective with a hazard ratio of 0.48, so a 52% reduction in death or progression in that subgroup as well. I think those are very encouraging data given the prevalence of HER2-positive brain metastases.

In terms of adverse effects with tucatinib, there was somewhat of an increase in diarrhea with the use of tucatinib compared with placebo, but the difference was not dramatic. The general sense was that these were manageable toxicities. Weighed against the substantial improvement in progression-free survival and overall survival, I think it’s a clear win for patients, and hopefully this will lead to the approval of this agent in combination with trastuzumab and capecitabine.

Transcript edited for clarity.