HER2CLIMB: Role of Tucatinib in Treating HER2+ mBC With CNS Disease

A panel of expert oncologists highlight the use of the tucatinib, trastuzumab and capecitabine regimen that was investigated in the HER2CLIMB trial to manage patients with HER2+ breast cancer and brain metastases.


Sara Tolaney, MD: One thing you mentioned when making these decisions is who really needs radiation, and who could do well with systemic therapy? Certainly, as Ada pointed out, one of the largest sources of data we have for benefits of treatment in the CNS comes from HER2CLIMB [NCT02614794]. Nancy, you’ve been instrumental in developing systemic therapies that benefit patients with CNS disease and were very involved in HER2CLIMB. So maybe you could share with us the data that came out from HER2CLIMB in terms of the benefits overall from the regimen but also specifically what those benefits looked like in those patients who had active vs stable brain metastases.

Nancy Lin, MD: The HER2CLIMB study randomized about 600 patients. [Approximately] half of the patients, so 300 patients, had known brain metastases at study entry. They were known because in the trial, patients were required to have a brain MRI as part of their screening study. So, the brain metastases status on HER2CLIMB is actually very well characterized. The study included not only patients with stable treated brain [metastases], which are now, fortunately, included in most studies, but also included patients with active brain metastases, including previously treated ones that have subsequently progressed as well as patients with newly diagnosed brain metastases where they didn’t receive any radiation therapy and went straight on to the trial. What was seen in the brain met population was that there was an improvement in overall survival, and the absolute delta was about 9 months, going from about a year to about 21 months. This was a really impressive improvement in overall survival in these patients.

There’s improvement in overall progression-free survival, taking into account both the brain and extracranial sites. There’s also a prolongation of time to progression in the CNS [central nervous system] or death, which was characterized as or called CNS progression-free survival in the study. There was also an improvement in the objective response rate both systemically and in the CNS.

When it comes to this question of whether we should or can offer up-front systemic therapy vs radiation, 1 of the important metrics in the study was actually looking at the rate of disease control at that first restaging time point. This was actually done in the trial 6 weeks after patients started therapy, which was after 2 cycles. Very few patients, fewer than 10%, came off the study at that point for CNS progression. I think that the data is also reassuring in that a HER2CLIMB-type of regimen can be a safe alternative to offer to patients. This being they are appropriately counselled, obviously, about the alternative of radiation to consider instead of whole brain radiation. This is particularly important in our HER2-positive patients because these are the patients who tend to live the longest after brain met diagnosis.

There’s this very big effort that Paul Sperduto, [MD, Duke University] has put together that is through an academic consortium. Basically, what he found was that over time in the current era, the median survival after brain met diagnosis in HER2-positive patients is about 3 years for those who have good performance status, and about 25% of patients are alive 5 years or longer. Those are the patients who are going to develop long-term whole-brain radiation toxicity. Especially in this setting where it’s pretty early for your disease course, I really would want as much as possible to push out the need for whole brain.

Sara Tolaney, MD: That’s super helpful. Honestly, it’s pretty amazing to see these data because we’ve never had a randomized trial that included active brain metastases in a registration study. Again, amazing to see the benefits that come from it. While we do use this regimen now not infrequently, Ada, when you’re treating a patient with this regimen, what are some of the [adverse] effects that you see, and how do you manage those?

Adrienne Waks, MD: One that I would not say is the most common but was highlighted by our case here is that you can see some transaminitis associated with the regimen. In some cases, like in this patient’s case, you can see the transaminase is reasonably high pretty early on in therapy. Though, the good news is that it’s typically manageable by doing a brief hold so that you can get the transaminases back down to normal and then dose reducing and resuming. I wouldn’t say that’s the most common toxicity, but it’s a good one to highlight and to be aware of since it can be seen with other HER2 TKIs [tyrosine kinase inhibitors] as well, so that’s a good one to highlight.

I would say in terms of more general, typical, and sort of lower-level [adverse] effects, I definitely see some GI [gastrointestinal] toxicity with the regimen, which you can see with capecitabine by itself to a small extent. I would say it definitely looks a little bit more frequent and a little bit more severe with the addition of tucatinib to the capecitabine. Generally, though, I don’t tell patients they’ll experience sort of frank nausea or frequent emesis or something like that, but it’s just sort of low level, like dyspepsia or food aversion or maybe a little bit of diarrhea. This patient had a little low-level nausea. I find that sort of GI symptom profile can absolutely come up on this regimen.

Then of course we know, because we’re using it in combination with capecitabine, that we can see hand-foot syndrome, which we manage just as you would on the absence of the tucatinib. I do always think it’s interesting that on HER2CLIMB, there was more hand-foot syndrome in the tucatinib-containing arm, even though we basically know that it comes from the capecitabine. Nonetheless, you just manage it expectantly with aggressive moisturization and dose reduction of, probably, the capecitabine in that case if you need to. That’s generally what I feel like I run into.

Sara Tolaney, MD: It is tricky though isn’t it when you have 2 oral agents and then either IV or subcutaneous trastuzumab. Then you have some overlapping toxicity like the GI toxicity and you’re trying to figure out which one do you tinker with to manage, for example, diarrhea or something like that. Sometimes that does become a little tricky but as you point out, most people do tolerate this well which is fortunate.

Transcript edited for clarity.

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