Implications of HER2CLIMB Updates on Treating HER2+ MBC

Vijayakrishna Gadi, MD, PhD: Mylin, since you’ve got the floor, maybe you can update us on some of the new knowledge relating to the HER2CLIMB study and tucatinib [Tukysa] in particular.

Mylin A. Torres, MD: Sure. The HER2CLIMB study was first published in 2020. It was a groundbreaking study looking at the use of tucatinib, which is a tyrosine kinase inhibitor [TKI] and an oral agent. Essentially, it’s highly selective. It’s able to cross the cellular membrane and go into the cytosol and act on the intracellular portion of the HER2 [human epidermal growth factor receptor 2] receptor specifically, with very little interaction with HER1 or EGFR. With this drug, the thought is that it’s less toxic than other ones that are less specific.

The HER2CLIMB study was a randomized clinical trial in women with HER2-positive metastatic breast cancer who had seen the typical agents before—trastuzumab [Herceptin], pertuzumab [Perjeta], T-DM1 [trastuzumab emtansine]—and essentially had gone on to progress. What was very interesting about the HER2CLIMB study is they sought out women with brain metastasis, even those with active brain metastasis, which is a landmark study and concept.

As we all know, there were a number of women who were enrolled on that trial who had brain metastasis. About 22% had brain metastasis who weren’t even treated. Some had stable brain metastasis, and some had progressive brain metastasis. Among all the women enrolled with brain metastasis, a quarter had brain metastasis that hadn’t even received any treatment at all. And even among all those women, the randomization was basically a backbone of capecitabine [Xeloda] plus trastuzumab with or without tucatinib. The tucatinib arm was superior in all of its subgroups, whether a patient had active untreated brain metastases, progressive brain metastases, or treated brain metastases. As a radiation oncologist, it’s very interesting data.

One of the advantages of tucatinib is it’s a very small lightweight molecule, so it can cross the blood-brain barrier. And when you think about how to interlace radiation with an agent like that, the jury is still out on whether to do it concurrently. But it’s a very interesting thing. Could you hold SRS [stereotactic radiosurgery] and let the tucatinib do its job and only reserve SRS for later on when these brain metastases progress? Or do you need to do the SRS up front? That study didn’t answer that question, but importantly, it’s interesting that whether you had active progressive growing brain metastases or not, the drug was very effective.

It didn’t come without toxicity, as I mentioned earlier. It looks like the adverse effects were primarily due to the capecitabine. They were GI [gastrointestinal]–related, so diarrhea, nausea, vomiting, along with some fatigue and hand-foot syndrome. This regimen is very exciting, but it isn’t without cost. Neil, what do you think?

Neil M. Iyengar, MD: That was very comprehensive. Thanks for going through all of that, Mylin. I agree with all of the points that you made. I was really struck by the CNS [central nervous system] activity that was reported. And in the updated results, the continued prolongation of the survival-related end points are certainly reassuring that those curves continued to separate in a meaningful way.

In terms of the toxicity component of it, because that’s going to differentiate a lot of the agents that we have available to us, I was reassured by the low discontinuation rates due to toxicity in HER2CLIMB. Part of the difficulty with using that regimen is discerning whether the toxicity is from the capecitabine vs from the TKI. The patients in the tucatinib arm vs the control arm reported generally a greater percentage of adverse effects. But, of course, those patients were exposed to capecitabine for a longer time than the patients in the control arm as well. Trying to discern which ones are contributing can be tricky.

In my own practice, if it’s things we’re very familiar with in regard to capecitabine, like hand-foot syndrome or even some of the GI toxicity, which is difficult to delineate, I’ll try to dose reduce the capecitabine first if we’re needing a dose reduction before I reach for doing the same with the TKI. That’s because the dose reduction rates and discontinuation rates were fairly low in HER2CLIMB. I’m reassured by the ESMO [European Society for Medical Oncology Congress 2021] data. I’m reassured by the continued survival benefit and confirmation of safety.

Vijayakrishna Gadi, MD, PhD: Thanks, guys. And I’ll dovetail. In regard to the safety aspect and discontinuation rate, it was 6% in one arm and 3% in the other. If you think about it another way, that 3% difference means 1 out of every 30 patients is genuinely going to be discontinuing this combination because of a toxicity probably related to tucatinib. That’s actually a really low number for active oncolytic therapies, so that’s clearly something. And we’ll learn more. Over time, we’re going to get better at it.

Transcript edited for clarity.