Case 3: Treatment for HER2+ Breast Cancer Progression in Viscera


The panel of experts in breast cancer discusses the treatment options for a patient with systemic progression of HER2+ disease on T-DM1 and no CNS metastases.

Sara Tolaney, MD, MPH: In this particular case, we had a scenario where the patient developed CNS [central nervous system] progression but had controlled systemic disease. We decided we’d radiate that lesion and continue our systemic treatment. Whereas we did note that if the patient had both CNS and systemic progression, we potentially would’ve radiated those 2 spots and moved on to tucatinib-based therapy, given a survival benefit in patients with brain metastases. But how about if we switch the scenario a bit, and we said that the patient had systemic progression on T-DM1 [trastuzumab emtansine] with no CNS metastases? So now this is a patient who had first-line THP [docetaxel, trastuzumab, and pertuzumab] second-line T-DM1, developed progression let’s say in their liver, and had no brain metastases. Let’s pretend they were Ingrid’s patient and even had a screening brain MRI, and had nothing seen. What would you do in this case in terms of treatment recommendations? This is where there’s a bit of debate in terms of selection of treatment. Andy, we’ll start with you. What would you pick?

Andrew Seidman, MD: We have 2 worthy contenders here. If this was a medical oncology board examination, it wouldn’t be a fair question or would have to be more than one. The ADC [antibody-drug conjugate] trastuzumab deruxtecan has activity in this setting, and the HER2CLIMB regimen of capecitabine, trastuzumab, and tucatinib also has efficacy. There are no comparative data. For this patient, either would be acceptable, correct oncology board exam answers.

Ingrid A. Mayer, MD, MSCI: But I do confess that right or wrong, because both are acceptable, how I’ve been allocating people to one or the other, is based on if you have somebody with visceral disease, symptomatic or at risk of having visceral crisis, which technically would be this patient with lung and liver lesions, one of them was like 6 cm in size, I would probably be more inclined to use trastuzumab deruxtecan before I committed that patient to tucatinib if CNS is not what’s going to kill her. Whereas if I have somebody with low burden of disease, asymptomatic, I may favor using tucatinib even in the absence of brain metastasis, just in the spirit of it’s a regimen that has an overall survival advantage. And it’s a regimen that would probably work well and has potentially, I wouldn’t say necessarily less day-to-day toxicity. But then again, going back to that interstitial lung disease [ILD] risk, I wouldn’t want to expose somebody to a drug that has 13% [risk] of ILD if I could use a regimen that has an overall survival advantage and I’m trying to prevent CNS metastases as one of the goals of treatment. I’m using my trastuzumab deruxtecan when I’m worried about the visceral disease, and using tucatinib when I’m dealing with brain metastases or lower-burden asymptomatic disease, whatnot. And again, there’s no right or wrong here, just a preference that I thought made sense.

Sara Tolaney, MD, MPH: How about you, Carey? Where would you fall in terms of your third line?

Carey Anders, MD: I tend to echo Ingrid’s thoughts here. Based on the available data that we have, we have better data in the randomized phase 3 setting for patients with brain metastasis. I tend to use the HER2CLIMB regimen there. When we are in the absence of brain metastasis, particularly with high-burden disease, I will turn to trastuzumab deruxtecan based on the response rate that we saw in the DESTINY study. It was impressive. When you talk to the patients when we’re having this discussion about whether they are in a place where one IV [intravenous] therapy vs IV therapy plus managing pills at home, that does come into account because it can be a little tricky to manage the capecitabine and the tucatinib. And we worry about the ILD with trastuzumab deruxtecan, but we also have been managing GI [gastrointestinal] toxicity with the HER2CLIMB regimen. It can be very individualized, but if I’m looking for a robust response, like we really need a response now, I will usually choose the trastuzumab deruxtecan compound.

Andrew Seidman, MD: If I could circle back, this is usually the point where I try to insert my “use capecitabine 7 days on and 7 days off.”

Ingrid A. Mayer, MD, MSCI: I always do, Andy.

Andrew Seidman, MD: Anyway, I’ll just throw that out there as art and not science.

Ingrid A. Mayer, MD, MSCI: Actually, the only people for whom I use capecitabine 14 days on, 7 days off, it’s adjuvant triple-negative disease.

Carey Anders, MD: Triple negative. We call that the Memorial [Sloan Kettering Cancer Center] regimen.

Andrew Seidman, MD: Even though I called it a tie, and there’s no right answer on the board exam, I do agree with both of you that I lean in the direction of trastuzumab deruxtecan, partly because the randomized trial data impress me with respect to the control arm in HER2CLIMB. The regimen of cape [capecitabine] and tras [trastuzumab], some of you are old enough to remember, where did that come from? That was simply better than cape [capecitabine] alone in HER2-positivemetastatic breast cancer. In a sense it was a bit of a straw man control arm, and I think less so for the DESTINY study.

Carey Anders, MD: Interesting. I certainly have patients for whom even with the 7-on 7-off [regimen], we have backed down to tucatinib, trastuzumab as a dual agent if we haven’t had tolerability to capecitabine. I don’t know if that’s been the experience of your team.

Ingrid A. Mayer, MD, MSCI: Same here.

Carey Anders, MD: But I’d much rather have that dual HER2-targeted blockade than the capecitabine and the trastuzumab, which of course was the control arm. I just wanted to insert that, yes.

Sara Tolaney, MD, MPH: I know. It’s so nice to have so many choices of highly effective therapies. We’re lucky to have a unique trial with HER2CLIMB, which was the first registration trial to allow patients on who could’ve had progressive CNS disease. This is a paradigm-shifting in the way we’re going to see development of HER2-directed therapies for our metastatic patients, which is tremendous. And we’re hoping to see phase 3 data from T-DXd [trastuzumab deruxtecan] in the near future, which will allow us to have more robust comparison data. We’d also love to see what the toxicity profile is in the larger numbers of patients in a phase 3 trial, to balance that tremendous efficacy. I’ve never seen a waterfall plot like that with T-DXd before. It’s unbelievable to see a disease control rate of almost 98% of people, which is unreal.

Transcript edited for clarity.

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