Case 2: Third-Line Therapy and Beyond in HER2+ Metastatic Breast Cancer


Focusing on the HER2CLIMB regimen, experts consider appropriate treatment options for patients with HER2+ metastatic breast cancer in the third-line setting and beyond.


Sara A. Hurvitz, MD: Bill, I’m hoping you can take us through a discussion on how to sort through the next line of therapy for this patient when her disease progresses on T-DXd [trastuzumab deruxtecan] based on what we have available. Can you take us through the data? Particularly as it relates to tucatinib, trastuzumab, and capecitabine? Of course, we don’t have data to support the use of T-DM1 [trastuzumab emtansine] after T-DXd [trastuzumab deruxtecan], but we still have this drug available. Can you talk us through the HER2CLIMB study and how you would approach a patient after T-DXd [trastuzumab deruxtecan] and THP [docetaxel, trastuzumab, pertuzumab]?

William J. Gradishar, MD: The reality is that we have a lot of options. That’s the luxury in this space for HER2 [human epidermal growth factor receptor 2]–positive disease. On the flip side, what we don’t have is a lot of data substantiating a particular sequence as being optimal. That said, after T-DXd [trastuzumab deruxtecan] progression, for most patients we typically think about the tucatinib-based regimen—a regimen that has a survival advantage that has been demonstrated. Data in those with CNS [central nervous system] disease were also enhanced, not only as PFS [progression-free survival] but also CNS [central nervous system] PFS. That would be an attractive next option for patients. It has been clearly demonstrated in that trial that with the addition of tucatinib, trastuzumab, and capecitabine, you improve median overall survival in the population as a whole. It didn’t matter whether you had visceral metastases or no visceral metastases: there’s a substantial clinically meaningful improvement and outcome.

When you think about all the other options, we have some old-school options, including things like an alternative TKI [tyrosine kinase inhibitor] like lapatinib, which I probably wouldn’t opt for. We have a variety of chemotherapy drugs that can be partnered with trastuzumab. These are options that will be exercised further down the line. We even have drugs like newer anti-HER2-directed agents, like margetuximab, which may have a role in later lines of therapy. For most patients, I’d probably opt for tucatinib after T-DXd [trastuzumab deruxtecan]. As you pointed out, 1 strategy that folks like us might say is, “I’d like to come at the tumor with some other drug that has a different mechanism of action.” In other words, T-DM1 [trastuzumab emtansine] is another antibody-drug conjugate [ADC]. It might have the same level of efficacy or be muted after having T-DXd [trastuzumab deruxtecan]. I don’t think we know the answer to that, but my inclination is to try tucatinib before T-DM1 [trastuzumab emtansine].

Sara A. Hurvitz, MD: Absolutely. What about you, Sara? Do you think tucatinib is the next go-to regimen outside enrolling the patient in a clinical trial, of which there are many? What would be your standard option after T-DXd [trastuzumab deruxtecan]?

Sara M. Tolaney, MD, MPH: We’re torn between the tucatinib-based regimen or T-DM1 [trastuzumab emtansine] because we don’t have data for anything after T-DXd [trastuzumab deruxtecan] to know what the efficacy of anything is. I was disappointed by the performance of T-DM1 [trastuzumab emtansine] as the control arm in DB03 [DESTINY-Breast03 trial]. The PFS wasn’t what I was hoping it would be, so I’d probably go a bit more toward tucatinib-based treatment. I’m also very curious to better understand how these ADCs perform 1 after the other. They have different payloads, so it’s not that you necessarily expect cross resistance, but I wonder if using an ADC could potentially downregulate HER2 expression. It makes you wonder if another ADC will sequentially work right away. Our group [at Dana-Farber Cancer Institute] has an ongoing biopsy study trying to understand how ADCs function after one another because that’s a big question ; it could go either way. If they had brain metastases, you’d probably prefer giving tucatinib. If they didn’t, you could choose between T-DM1 [trastuzumab emtansine] and tucatinib-based treatment. We’re without data to guide us.

Sara A. Hurvitz, MD: We have several ongoing studies looking at T-DXd [trastuzumab deruxtecan] or T-DM1 [trastuzumab emtansine] in combination with tucatinib, so we’ll have more evidence in the coming months and years on how to best partner tucatinib. It could be that the combination with trastuzumab and capecitabine isn’t the ideal partner, but we’ll have to see the toxicity. What’s your experience with the toxicity of this regimen with tucatinib, Bill? Are you seeing a lot of diarrhea in your patients, hand-foot syndrome?

William J. Gradishar, MD: Not so much hand-foot [syndrome], but diarrhea is what we’ve seen more of. The recommendation should be to tweak the capecitabine dose rather than the tucatinib dose. With that done, most patients are able to stay on it, but diarrhea is something we’ve seen, particularly at the outset.

Sara A. Hurvitz, MD: Sara, has the COVID-19 era changed how you’re preferentially sequencing drugs? Are you choosing oral regimens preferentially over IV [intravenous] formulations? Of course, the HER2CLIMB regimen does involve IV, but you can now get subcutaneous trastuzumab and make the visits quick. How has that affected your treatment recommendations?

Sara M. Tolaney, MD, MPH: I’ll be honest: it hasn’t influenced it. The patients are still coming in every 3 weeks. If it were T-DM1 [trastuzumab emtansine] or capecitabine-tucatinib-trastuzumab, the frequency of visits to clinic would be the same. It’s nice when you use the subcutaneous receptor formulation, which is what we typically do when someone is getting, for example, capecitabine-based therapy or something oral. In addition, it’s nice for them to pop in for their subcutaneous and be able to get it as an infusion, but it’s not changing that they need a visit, so I haven’t made decisions based on that.

Sara A. Hurvitz, MD: Last question on this patient: is there any patient for whom you’d choose tucatinib- capecitabine-trastuzumab before T-DXd [trastuzumab deruxtecan]? The FDA has approved tucatinib in the second-line setting for select patients. Is there a patient for whom you’d change the order and use T-DXd [trastuzumab deruxtecan] after tucatinib, Bill?

William J. Gradishar, MD: The patient who has dominant CNS disease—that’s the big issue. For that patient, based on the data we have, I’m more convinced about the efficacy of the HER2CLIMB regimen with tucatinib. Our whole way of thinking about big molecules getting into the CNS is probably changing. We may find that for patients even with active CNS disease, T-DXd [trastuzumab deruxtecan] may work fine. We don’t have sufficient data at this point to make that claim. It would be that kind of patient. For somebody who clearly has underlying contraindications to getting T-DXd [trastuzumab deruxtecan] with preexisting pneumonitis of some sort, that would be the patient for whom I’d avoid it.

Sara A. Hurvitz, MD: Do you agree, Sara?

Sara M. Tolaney, MD, MPH: Very much. I like the way you describe it, Bill: dominant disease. That’s good. It’s a little tricky because you could think of someone who had treated stable brain metastases. You could go to T-DXd [trastuzumab deruxtecan] because certainly in DB03, that group of people did very well. Let’s say you had someone who had multiple brain metastases and who couldn’t get SRS [stereotactic radiosurgery]. I had this come up, and I chose not to give whole-brain radiation. I gave them capecitabine-tucatinib-trastuzumab as their second-line approach to try to avoid whole-brain radiation, knowing that this population has very nice CNS response. As you pointed out, there are good survival benefits. This is mostly for the brain-dominant patient. That’s a good way to describe it.

Transcript edited for clarity.

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