Treating After T-DM1 in Relapsed/Refractory HER2+ MBC


Recommendations regarding how to best treat a patient with HER2-positive metastatic breast cancer who has previously received multiple lines of therapy, including T-DM1.

Vijayakrishna Gadi, MD, PhD: Neil, I’m going to hand it back to you. We have another case to talk about.

Neil M. Iyengar, MD: Thank you. This was the next case that we discussed on Twitter. This was a 44-year-old woman who presented with a 3.2 cm mass in her left breast, and she had 2 palpable axillary nodes. Biopsy of the breast mass yielded hormone receptor–negative, HER2 [human epidermal growth factor receptor 2]-positive invasive ductal carcinoma. Her staging workup revealed 2 lesions in the liver by CT scan, the largest being 3.1 cm. She had an MRI of the brain, which was negative for CNS [central nervous system] metastasis. In the first line, she went on to receive 6 cycles of THP [docetaxel, trastuzumab (Herceptin), pertuzumab (Perjeta)] followed by the antibodies alone, and she had a partial response in the primary breast mass and a complete response in the liver.

Seventeen months later, she had progression of disease in the liver with 2 lesions. The largest of those lesions measured 1.1 cm. In the second-line setting, she received T-DM1 [trastuzumab emtansine] and experienced a partial response that was noted in both the breast mass and the liver masses. Unfortunately, about a year later, she progressed again in the liver.

The question to the audience was: What’s the next best line of therapy? The answer choices were: trastuzumab deruxtecan [Enhertu], tucatinib [Tukysa]/capecitabine [Xeloda]/trastuzumab, neratinib [Nerlynx]/capecitabine, or other. We’re now essentially talking about third-line therapy. The responses were: 55.6% of respondents chose trastuzumab deruxtecan, 22% chose the tucatinib-based regimen, 11% chose the neratinib/capecitabine combination, and 11% chose other. That’s a very interesting spread of responses here. That’s what we’ll discuss now. This time I’ll ask Mylin first. What do you think of those answer choice responses? What are your opinions on this case?

Mylin A. Torres, MD: The data from DESTINY-Breast03 was so compelling. I can see why many people would support option A, the trastuzumab deruxtecan. This situation is supported very well by that study, where the patient had liver lesions, visceral metastases, and that’s in the context of the discussion we had previously on patients who have brain metastasis. It’s a different animal, so there’s every reason to believe that trastuzumab deruxtecan has activity in these visceral metastases when they’re outside of the brain. It seems to be a good option with very tolerable adverse effects. I agree with option A.

Neil M. Iyengar, MD: Great, thank you. VK, do you have anything to add to that?

Vijayakrishna Gadi, MD, PhD: Yes. I’m not surprised, especially now with not just DESTINY-Breast03, but DESTINY-Breast01 and the durability of what we’re seeing with the [trastuzumab] deruxtecan agent in this type of patient. This point may be opening up a new can of worms, but when I see a patient progress in this manner, I wouldn’t be happy with just my first MRI of the brain from several years ago. I’d want one pretty much each time this patient is progressing.

The underlying message there is brain metastases are super common in this disease. There’s a tropism for HER2-positive anything to getting into the central nervous system. I know that’s controversial, because we and a lot of colleagues, especially when we didn’t have drugs that did a great job for this, just didn’t look unless they were symptomatic. Now, even in the context of not being symptomatic, being able to control lesions before they become symptomatic rises in my priority list. If we have a combination like the tucatinib combination that’s been definitively proven to help in this setting, then it’s incumbent on us. That’s the 1 thing I’d pick apart about this case in the way it’s come together. But otherwise, the [trastuzumab] deruxtecan makes a lot of sense here.

Neil M. Iyengar, MD: Yes, I couldn’t agree more. I’ve also evolved my practice to continuously lower that threshold for CNS imaging. Let me twist this a little and go back to that second-line treatment option that she got, T-DM1. With DESTINY-Breast03, we now have the option of trastuzumab deruxtecan in the second-line setting. What are your thoughts with this case as a background in terms of your comfort level saving T-DM1 for a later line? Are you uncomfortable doing that? Would you rather continue using T-DM1 in the second line and reserve the other ADCs [antibody-drug conjugates] for later? VK, I’ll volley it back to you. What are your thoughts about second-line therapy here?

Vijayakrishna Gadi, MD, PhD: This is great. We don’t have a lot of data for TKI [tyrosine kinase inhibitor] after TKI, or in this case, ADC after ADC, so it’s going to be the efficacy of the chemotherapy backbone and resistance against that. The nice thing is the resistance mechanisms for [trastuzumab] deruxtecan are probably distinct from the resistance mechanisms for [trastuzumab] emtansine. There’s light here that these agents can be used in some order in each patient. However, we don’t have data for that right now and the stronger data lie with the tucatinib/capecitabine/trastuzumab combination, so I’d probably pick that in that type of patient. But there are a lot of patient factors. If for some reason oral therapies aren’t an option for a patient or there are copay problems or other issues, I could be influenced to think that the other ADC might be an option instead, which in this case is T-DM1.

Given that a lot of patients, especially the high-risk patients, may have seen trastuzumab emtansine in the adjuvant setting after incomplete responses to preoperative therapy, many of our patients may have already seen it, and that diminishes my enthusiasm to recycle it in the metastatic setting.

Neil M. Iyengar, MD: Mylin, let me ask you this question, because I’m sure you think about this a lot as a radiation oncologist. With this case as the backdrop, what if in addition to the progressive liver disease, she also had progressive brain metastasis? We talked a little about this in the first scenario, but that was a brain metastasis only progression. Here we have visceral and brain metastasis progression. What would you do in that situation?

Mylin A. Torres, MD: Clearly, if she’s symptomatic from either of those lesions, we’d have a very low threshold for intervening with radiation, whether it’s SBRT [stereotactic body radiation therapy] or SRS [stereotactic radiosurgery]. In that situation, there’s a clear indication of why we would give radiation at that point. What’s less clear is when you have these oligometastatic lesions—I’d be curious to see what you guys think about this—whether it was in someone without brain metastasis but someone who only has these liver metastasis, a few spots. Do you think about SBRT first and then continue them on the systemic regimen they’ve been on, do you switch it, or do you just not think about it at all? That’s an open question right now. There isn’t a clear answer in breast radiation oncology, so it’s an interesting thing to think about. If they have brain metastasis and concurrent visceral metastasis, I’d let systemic therapy go first, unless they were having symptoms.

Neil M. Iyengar, MD: I appreciate that point. I agree. If we’re witnessing a systemic progression, then that certainly calls for a change of systemic therapy. But if they’re symptomatic from a CNS standpoint and need more immediate control, that’s where I’m picking up the phone to call you. That makes a lot of sense. VK, do you have any comments on that?

Vijayakrishna Gadi, MD, PhD: Yes. I agree. That’s a conundrum. It’s going to be very patient specific. There’s a difference with a single metastasis that you’ve been tracking and starts to grow while you’re still getting good systemic coverage. I’m going to treat that situation differently than 5 small new metastases where we’re unsure how many more we’re missing that we can’t see yet. That’s going to alter how I approach patients as well. It’s easy enough to just say, “There are brain metastases,” but the characteristics of the patient and how those brain metastases developed are probably very important as well.

Transcript edited for clarity.

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