Toxicity Management When Using HER2CLIMB Regimen

Julie R. Gralow, MD: Mark, let’s talk about the adverse effects of the HER2CLIMB regimen with tucatinib, capecitabine, and trastuzumab. What did we see in these studies, and what should we be looking out for?

Mark Pegram, MD: In the pivotal trial of HER2CLIMB, which won FDA approval, the most common adverse reactions occurring in at least 20% of the population or more were diarrhea, palmar-plantar erythrodysesthesia, from the capecitabine component obviously. Nausea, fatigue. There’s some hepatotoxicity. Stomatitis, anorexia, headache, anemia, and cutaneous rash were the most frequently reported.

Fortunately you know most of the time these can be mitigated by either dose modification or pill medication or both. You can also consider in some patients who may be, let’s say, more heavily pretreated in the metastatic setting or who aren’t able to tolerate capecitabine as well. In practice I’ve already considered the 1 week on, 1 week off schedule of capecitabine. That’s also another possibility to think about in case you’re getting any untoward toxicities with the FDA-prescribed

dose and schedules.

Using the combination of adjustment and schedule, adjustment and dose, or dose of either component drug and/or comedication will usually get you through this regimen safely and with a good tolerability. Therapeutic index with this regimen I judge to be quite high for a regimen in this setting in such heavily pretreated patients.

Julie R. Gralow, MD: What we saw in HER2CLIMB with the diarrhea was, a lot of it, undoubtedly also related to capecitabine because it occurred in the other arm as well. Knowing the pure toxicity of tucatinib is not evident from this trial. But I agree with you: It appears to be well tolerated. The diarrhea seems less than with both lapatinib and neratinib. Who are you going to give this regimen to now that it’s FDA approved?

Mark Pegram, MD: It’s an interesting question. The key question that keeps coming up in my practice are patients who have, let’s say, 1 or 2 new CNS [central nervous system] metastasis on whatever regimen they’re already on. In the old days, we would simply treat those with perhaps a cyber knife and then continue the systemic therapy if the extracranial disease had been under control. But given the extraordinary efficacy signals from the HER2CLIMB study, particularly in the HER2 [human epidermal growth factor receptor 2]–positive brain metastasis subset, which was almost half the patients, and many of those patients had active brain metastasis or even untreated brain metastasis. I’ve been considering switching those patients to a tucatinib-based regimen just because we have evidence from a randomized phase 3 trial of a survival benefit.

Julie R. Gralow, MD: Actually switching them before a progression.

Mark Pegram, MD: You could even do it before radiation and use it as a buffer to prolong the time needed prior to intervention with local control measures like neurosurgery radiation; that is also correct. For small occult metastasis in particular, treating them with the tucatinib-based regimen, our priority is a good strategy as long as you follow them closely, with serial MRI [magnetic resonance imaging], of course. That could also be an enhancement in quality of life metrics by postponing the need for radiation. Because even stereotactic approaches can be associated ultimately with cognitive decline, especially if you have to use it multiple times serially.

Julie R. Gralow, MD: One thing I’ve done in a couple of cases, since you’ve got 2 oral drugs in this regimen—capecitabine and tucatinib—and then you have the intravenous trastuzumab, is I’ve offered patients subcutaneous trastuzumab just to keep their time in the infusion room as short as possible. We have a separate injection clinic where they can go. That also can add to the patient’s quality of life in terms of receiving this regimen; so minimize the time they need to spend in clinics.

Mark Pegram, MD: Absolutely. We made the same decision in our group at the beginning of the COVID-19 [coronavirus disease 2019] pandemic, that we would prefer subcutaneous routes of administration for HER2 antibodies. We even started a trial of the fixed-dose combination of pertuzumab plus trastuzumab as a subcutaneous regimen, and that can be given at home by home-visiting nurses on that study protocol. That completely takes out of the loop their need to travel to a medical center, which would otherwise be considered a high-risk zone for a viral transmission.

Transcript edited for clarity.