Patient Profile 1: Sequencing Therapies in HER2+ mBC

Shared insights on the use of therapies as a patient progresses with HER2+ metastatic breast cancer, which includes sequencing through T-DM1 [trastuzumab emtansine], tucatinib/capecitabine/trastuzumab, and trastuzumab deruxtecan.


Neil Iyengar, MD:But it sounds like you went on in the third line to T-DM1, is that what happened?

Milana Dolezal, MD, MSci: Yeah, that's what happened. We played around a little bit with Xeloda [capecitabine] dosing as well, because we know that the concomitant GI [gastrointestinal] side effects of neratinib [Nerlynx] in addition to Xeloda can be GI-based. But that didn't go too well. Then we transitioned to T-DM1 and based on her baseline, hepatitis B and D, we did do a lower 3 dose of T-DM1 in terms of managing side effects and LFTs [live function tests]. There is rare nodular hyperplasia that can happen with T-DM1 so that is a concern in a patient who already has stage 4 cirrhosis. She did well on T-DM1 for a while and interestingly, her liver enzymes stayed stable but it was the brain that kept coming back in terms of metastases. It really wasn't her systemic disease in terms of liver medications and all the adenopathy.

Neil Iyengar, MD: I think you raise a great point certainly about T-DM1 having activity in the later lines as well, I think we think of it classically as a second-line agent. Your case nicely illustrates how the location of disease, particularly CNS [central nervous system] involvement, may influence our sequencing of therapies. What came next after T-DM1?

Milana Dolezal, MD, MSci: She did fine on T-DM1 but unfortunately, she developed another brain metastasis. That was managed with a gamma knife. Then we were at the point where we had the neurosurgeon and the radiation oncologist working together but no resections, more just in terms of side effects of multiple attempts of gamma knife. Then the HER2CLIMB data came out and tucatinib [Tukysa] was approved in April of 2020, so I was able to transition her. She was pretty reluctant at first in terms of, “Oh, you're going to put me on these pills again?” But we worked it all out and what's nice is with the Herceptin [trastuzumab] in the HER2CLIMB regimen being every 3 weeks, I was able to really keep close tabs on her in terms of how she was doing from a toxicity standpoint as were our nurse navigators and our nurse practitioners in our practice to make sure that she was on target with her calendar. She actually tolerated it very well. It's interesting that the difference between having HER2-targeted kinome like tucatinib vs neratinib [Nerlynx], which is hitting one of these dirty kinase inhibitors that's hitting EGFR [epidermal growth factor receptor]/HER1 [homologous EGF receptor kinase] as well. Because as far as side effects go, she really didn't have diarrhea. We were able to manage her side effects. It was really making sure she was taking her pills appropriately. We even started with a bit of a dose reduction of the Xeloda, too, and then tucatinib dosing based on the package insert because of her stage IV cirrhosis. She tolerated it very well. We were doing well in terms of her systemic disease and not having a lot of systemic disease. She maintained that for a while.

Neil Iyengar, MD: That's fantastic. I think it's interesting because we are not just seeing your thought process with the sequencing, but also the practical sequencing as data emerged over the years. Did you have any concerns about using a TKI [tyrosine kinase inhibitors] like tucatinib again after prior neratinib or even after T-DM1?

Milana Dolezal, MD, MSci: That's an interesting question. She didn't have the Xeloda with the neratinib for very long. I think we got through just a few months, maybe about 4 or 5 months of that. I think we worry and certainly, we see this in the lung cancer world, because I'm a community oncologist, so I see all types of patients, but subspecialize in the breast. There can be selective pressure that happens in terms of mutations. Certainly, in lung cancer, we see this a lot with the EGFR inhibitors. I didn't think that she had a long enough course of the neratinib to claim her a TKI failure per se. And we didn't have the DESTINY-03 data yet in terms of up to 60% intracranial response rates. I'll segue to that in a bit with her future history, but I wasn't worried about revisiting a TKI and Xeloda with Herceptin. It is a nice idea in terms of the HER2CLIMB regimen because it's this inside-and-outside type of approach. You have the Herceptin that's targeting the extracellular receptor on HER2 positive cells. Then you've got your generic Xeloda chemotherapy that's cytotoxic, and then you've got your TKI that's acting on the inside of the cells. It's this idea of this inside-and-out blockade, which I think is important to explain to patients in terms of fully targeting therapy. We know that HER2 mechanisms of escape can happen as well. This idea of let's suppress both inside and out and deal with any clones that could be developing that might be HER resistant by a different mechanism, mTOR [mammalian target of rapamycin] PI3 [phosphatidylinositide 3]kinase, some of the things that we're familiar with in terms of mechanisms of resistance. I wasn't concerned about that.

Neil Iyengar, MD: Great point. I think this is a great opportunity to remind folks that in HER2CLIMB, essentially everyone had received treatment with T-DM1 before coming (into the) study.I think the range of prior therapies was between 1 and up to something like 19. Certainly, we know that the drug has activity, tucatinib has activity after multiple prior lines of therapy, as well as early on in treatment. What happened after? How long was she on the tucatinib-based regimen and what happened next?

Milana Dolezal, MD, MSci: She remained on that regimen basically from…some time in spring 2020 to pretty recently, [around November/December of 2021]

That's when we saw the ESMO [European Society For Medical Oncology annual meeting] data, which was presented in September on HER2 deruxtecan. I know we should use generic names. We had seen that data in September and then at San Antonio, [Breast Cancer Symposium] Sarah Hurwitz presented the intracranial response rates as well. We had been having a “What's next?” discussion for a while, so then we transitioned her.I do wonder a little bit, too, we did have to do dose reductions based on her stage IV cirrhosis in terms of the tucatinib and even the Xeloda a bit.I do wonder how much intracranial efficacy was she getting there with some of the dose reductions of the TKI. That was always in the back of my head. That's the last part of the story about continuing to have brain metastases even on TKI regimens. It's interesting because Nancy Lynn has presented data in terms of time to next brain Met [metastases] based on HER2CLIMB too and we know that there's a protection base. It’s not necessarily only treating the brain Mets that's there but it’s prevention for the next one. We can certainly do better in some ways. It's exciting seeing the response rates of a large monoclonal antibody, an antibody-drug conjugate that is upwards of 60%. You always worry about those patients, are the therapies getting up into the brain? With a lot of radiation therapy, we do know that we disrupt that blood-brain barrier and we have sensitive imaging techniques to actually even look at the brain in terms of being able to see the HER agents potentially getting up in there. That’s a bit of a summary of a complicated patient.

Neil Iyengar, MD: What a wonderful outcome. Thank you for taking us through that case and again, I think it was very interesting to see you rapidly implement the data as it was reported to your clinical practice. So very, very interesting.

Transcript edited for clarity.

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