Understanding HER2CLIMB Clinical Trial

Mark Pegram, MD: Julie, what is the HER2CLIMB regimen, and what have we learned about it so far in terms of its role in the treatment of HER2 [human epidermal growth factor receptor 2]–positive metastatic breast cancer?

Julie R. Gralow, MD: Tucatinib is the new agent just approved by the FDA in April 2020 that was used in the HER2CLIMB study. It’s yet another oral small molecule tyrosine kinase inhibitor. But this one is really highly selective for the kinase domain of HER2, and it has a very minimal inhibition of EGFR, HER1.

The adverse effects are going to be different, and the diarrhea in particular is markedly less. The HER2CLIMB trial was a study in patients with HER2-positive metastatic breast cancer who had prior trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine]. That was required. A very fascinating addition was that active brain mets [metastases] were allowed. This trial specifically stated, as a lot of trials do, that treated and in-control brain mets could be included. But they also allowed the addition of patients with either treated brain mets that were progressing or untreated brain mets with any local treatment. That was about half—47% of the patients enrolled in the trial had a presence or a history of brain mets.

They disallowed any prior capecitabine or any recent lapatinib. In 600-some patients everybody got capecitabine and trastuzumab, and then patients were randomized to tucatinib or a placebo. The results were published in the New England Journal of Medicine just this year for the primary end point, which was progression-free survival. We saw a difference of 7.8 versus 5.6 months for the intent-to-treat population, both the population with brain mets and without.

At the time of its publication it already had a positive overall survival benefit with a median overall survival for the intent-to-treat group of 21.9 months with tucatinib and 17.4 months without tucatinib. Two-year overall survival at the time of publication was 45% if you had tucatinib added to trastuzumab and capecitabine and 27% without the tucatinib, for a pretty powerful result.

We’ve separately looked at the brain mets cohort, both with the original publication, and then just updated it at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting with respect to survival in the brain mets cohort. That looked very powerful and very promising, and this is great news for our patients with HER2-positive brain mets.

Taking that 47% who had a history of either treated or active brain mets, the median progression-free survival was 7.6 versus 5.4 months. One-year progression-free survival in this brain mets group was 25%. A quarter had not progressed if they had tucatinib added. In the group that didn’t get tucatinib, 100% had actually progressed; so 0% had 1-year progression-free survival without the tucatinib. It’s updated at ASCO 2020. We saw that in the brain mets cohort the median overall survival was 18.1 months versus 12 months, with and without tucatinib with a P value of .005. These patients are living longer as well with the brain mets. The ASCO presentation looked at CNS [central nervous system] progression-free survival, which was also superior in the tucatinib arm, 9.9 versus 4.2 months. So there are really powerful data overall for managing disease unrelated to the brain but also within the brain; very exciting.

Mark Pegram, MD: The presentation as ASCO by Dr Nancy Lin was just extraordinary. I’ve never seen that kind of efficacy data before for HER2-positive brain metastasis. Is there any situation in HER2-positive brain metastasis where you wouldn’t consider this regimen or actually just use it?

Julie R. Gralow, MD: I can’t think of 1, although a question I would like to have answered with future trials is, do we really need to give tucatinib in this setting in combination with capecitabine and trastuzumab? There were early data that showed benefit and synergy, etc, that led to this being the regimen that was tested. Especially if our patient has seen a lot of prior trastuzumab or prior capecitabine. You know, what do we do? Would single-agent tucatinib work here? Do we need to add another HER2 agent, such as trastuzumab? Are there other chemotherapy agents we could use in synergy? This is where future trials are going to help. You’ve already mentioned the T-DM1 [trastuzumab emtansine] trial with tucatinib that’s ongoing; that’s very interesting as well. But tucatinib, especially in the patients with brain metastases, is powerful, and here to stay, and it’s going to be a first-line choice, I think.

Transcript edited for clarity.