Sara A. Hurvitz, MD: Data from HER2CLIMB were indeed practice-changing and deserve a little bit more attention. Tucatinib, when combined with capecitabine plus trastuzumab, demonstrated not only an improvement in the progression-free survival for the overall population, but also for the patients with CNS (central nervous system) metastases. It also showed an improved overall survival. The design of this study was unique in that they allowed patients who had active, untreated, progressing brain metastases on the study. We almost never see that in a study design for a large phase 3 randomized clinical trial. Tucatinib is relatively unique because it is a HER2-targeted tyrosine kinase inhibitor that is selective for HER2. Thus, there is less of that EGFR inhibition that can cause diarrhea and rash. Indeed, the triplet combination is quite well tolerated.

At ASCO [American Society of Clinical Oncology annual meeting] 2020, data relating to the central nervous system outcomes for patients who had CNS metastases in this study were presented. And it’s really exciting to know that those patients who had active CNS metastases had an objective response rate in the brain of close to 50%, and it was about double that of patients treated with capecitabine plus trastuzumab.

These are truly practice-changing data because right now as we watch the way that HER2-positive metastatic breast cancer progresses for patients, it’s clear that CNS metastases are becoming quite a common problem, with nearly 50% of patients developing them in their lifetime.

It’s also important to note that this drug combination is relatively well tolerated in quality of life. In my own patients who I have treated with this regimen, it’s relatively good. I’m looking forward to using tucatinib in earlier-line settings. There are ongoing clinical trials looking at whether you can combine tucatinib with T-DM1 (trastuzumab emtansine) in the second-line setting, and I think this is promising because my hope would be rather than just treating patients with CNS metastases with this drug, can we prevent them from developing?

Although the data relating to tucatinib, capecitabine, and trastuzumab are very exciting and indeed practice-changing, we also have the FDA approval of trastuzumab deruxtecan, which is also incredibly effective for patients. With an objective response rate of over 60% in patients who had a median of 6 prior lines of therapy, this is not only practice-changing but very novel findings that we’re seeing in the metastatic setting.

It often is coming up in my own clinical practice and in my discussion with other oncologists: how do we sequence tucatinib and DS-8201, or trastuzumab deruxtecan? Because they’re approved essentially in the same patient population. The correct answer is we don’t know right now because there hasn’t been a trial to help us understand how to sequence them. I think both are equally appropriate to utilize for patients. Some people would prefer to utilize tucatinib-based therapy for those patients who have CNS metastases, given its activity in the central nervous system.

I would like to underscore that tucatinib has a lot of efficacy even in those patients without CNS metastases, so I think it’s really a discussion between the patients and clinicians. Tucatinib is based on a phase 3 randomized clinical trial. It met its overall survival endpoint as well as its PFS (progression-free survival) endpoints, and central nervous system objective response rate improvement. DS-8201 ([fam]- trastuzumab deruxtecan) was approved based on a single-arm phase 2 study but did show phenomenal data in terms of activity.

If a patient is very symptomatic from visceral metastases, for example, and does not have brain metastases, I might be more inclined to use trastuzumab deruxtecan and save tucatinib for later. On the other hand, if a patient has CNS metastases or is very concerned about quality of life and trying to mitigate adverse effects and risks from drugs, I would probably choose tucatinib.

The drug toxicity associated with trastuzumab deruxtecan of note is interstitial lung disease, or pneumonitis, so if the patient has underlying lung disease or fibrosis, I would not select that drug for them. However, the presence of lung metastases does not appear to place patients at higher risk of that outcome.

In all, I think both drugs are ultimately going to be utilized in most patients since we are treating patients for such a long time. With so many lines of therapy for HER2-positive metastatic breast cancer, hopefully we’ll see data looking at the combination of these agents in the future because that may be a real winner.

Transcript edited for clarity.

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