HER2+ Breast Cancer: Special Challenges and Expert Insight - Episode 3

The Role of Prophylactic Therapy in HER2+ BC

Adam M. Brufsky, MD, PhD

Neil M. Iyengar, MD

Vijayakrishna K. Gadi, MD, PhD

Sara A. Hurvitz, MD

Key opinion leaders explore the appropriateness of prophylactic therapy for brain metastases and share their thoughts on best practices.

Adam Brufsky, MD, PhD: Before we get on to how we’re going to manage this particular case because we have about 5 minutes to do that, I want to ask a few more questions. Imagine a world where we had some sort of genomic predictor of who was going to get a brain metastasis and who wasn’t. Is there anything to be said for prophylaxis with a HER2 TKI [tyrosine kinase inhibitor]? I don’t know if we’d do it now. Let me throw out the predictor aspect. Would you do it now? Would you say, “This woman is going to potentially get a brain metastasis, and I want to give her a HER2 TKI now to prevent it from getting into the brain,” or would you not? We’re all familiar with the NEfERT-T data with neratinib in the first line, where the incidence of the first brain metastasis was cut in half by neratinib vs trastuzumab. We have no data that finding it early does anything. How do you guys think about prophylaxis? I’ll start with VK. Would you do prophylaxis?

Vijayakrishna Gadi, MD PhD: I would think more about prophylaxis in the nonmetastatic space. That would be my opportunity to prevent such an event in the metastatic disease setting from occurring. The tool for that would be neratinib in the extended adjuvant setting. My decision-making around how I would utilize that would have to do with patient-specific, cancer-specific factors at the time of diagnosis, lymph nodes, ER [estrogen receptor]-positive, etc. In the metastatic setting, the cat is out of the bag, and I don’t know how much at this point a brain metastasis changes the overall outcomes for patients. It’s part of the burden of disease that these patients can harbor. Using a variety of tools, whether it would be TKI, SRS [stereotactic radiosurgery] and so forth, we manage these on the go. I am not particularly focused on the concept of prophylaxis, at least in the metastatic space.

Adam Brufsky, MD, PhD: Sara, are you the same way? We’re all authors on this, but you’re the first author on one of these papers where 50% of people got brain metastases at some point. We know it’s going to happen in half of the patients. Would you use prophylaxis for it or not?

Sara A. Hurvitz, MD: No, I agree. I don’t actually do this. I am using tucatinib outside of the brain metastases setting. I am utilizing that regimen in the third-line setting and beyond. In a way, that’s prophylaxis for the brain and probably reducing the incidence of brain metastases, but I’m not doing it just for that. I’m doing it because it has good systemic control of disease as well. In the early stage setting, some people are turning to the use of neratinib in the highest-risk patients because it does have some CNS [central nervous system] penetration and is available to us based on the ExteNET trial. There is a lower rate of CNS recurrence, although it’s just numeric, just a trend, and highly exploratory. It’s a tough drug. I’m not doing it.

The patients I worry most about in the adjuvant setting are those with inflammatory breast cancer because they have such a high rate of CNS metastases. I might be compelled to do it if their tumors were hormone receptor-positive and inflammatory, thinking that might protect the brain a bit more, but I am not utilizing these agents for that. We need more trials to look at whether we should be using these types of drugs as upfront prophylaxis in the adjuvant setting.

Adam Brufsky, MD, PhD: Neil, what do you think? Everybody is interested in those data. It was a subset of a subset of ExteNET: the people who had residual disease after neoadjuvant chemotherapy and a trastuzumab, pertuzumab regimen, and then they got whatever—generally it was HP [trastuzumab, pertuzumab] because it was the pre–T-DM1 [trastuzumab emtansine] days. Then they were given neratinib for the following year. When you look at the neratinib vs the control arm of the trial, there were fewer brain metastases in the neratinib arm. The other thing is from KATHERINE, which is the T-DM1 [trastuzumab emtansine] trial, which had an 11% distant metastatic disease rate. Half of those were CNS recurrences. What do you think based on that? Are you a believer in this or no?

Neil Iyengar, MD: I was going to mention the KATHERINE data. If we look at the state of the data right now, we might all have this underlying feeling that as the data mature and we get more data, there might be a case in a certain subset of patients for CNS prophylaxis. But I don’t think we’re there yet. VK and Sara both mentioned neratinib in the extended adjuvant setting potentially having the prophylactic effect. We talked about the data. I’m not sure that our tools in the early stage setting are effective enough in the case of prophylaxis, and frankly, I haven’t been very successful in keeping my patients on neratinib in the extended adjuvant setting. I’m waiting for 2 things: the maturation of the data before I use prophylaxis, and data for tucatinib potential in the early stage setting.

Adam Brufsky, MD, PhD: I agree. Before we go on and talk about this case, have you used dose escalation as a neratinib strategy? Did you try starting at 120 or 160 mg and gradually escalating during the first month to help your patients get through that first month?

Neil Iyengar, MD: Yes, I did. That’s a great point. I have been more successful with dose escalation and the incorporation of colestipol for diarrhea prophylaxis. These things are helpful, but in my experience, when we are largely dealing with patients who are fatigued from quite a bit of therapy, and then you’re throwing in a fistful of pills for prophylaxis and treatment, it’s challenging.

Adam Brufsky, MD, PhD: I agree with you. Before we go on, let’s answer some of these questions. I’ll go around the room. VK, I’ll start with you. In this first polling question, what would you do if you didn’t know? This patient comes in and you’ve decided not to do an MRI [to screen for brain metastases]. Which 1 of the 4 would you choose?

Vijayakrishna Gadi, MD PhD: In the absence of other compelling evidence suggesting something else might be going on, I would choose T-DM1 [trastuzumab emtansine]. It’s supported by the data. It has classically performed and has been out there for a while. It’s well-validated with T-DM1 [trastuzumab emtansine] in that setting. That’s my choice, and I’m sticking with it.

Adam Brufsky, MD, PhD: Fair enough. Neil, do you feel the same way?

Neil Iyengar, MD: Are we avoiding the question of rechallenging with the taxane?

Adam Brufsky, MD, PhD: No, you can rechallenge, too. That’s fine. There’s nothing wrong with that.

Neil Iyengar, MD: I would rechallenge. I take the case point very well with regard to potential resistance, but I do tend to more often rechallenge with the taxane. That was our protocol operation in the Taxol, Herceptin, pertuzumab trial. In that study, we published the data in the subset of patients who were rechallenged with taxane, and it was quite successful. We didn’t have the statistical power to evaluate for things like site of recurrence and potential resistance, so I don’t have a very robust answer to the case point, but rechallenging tends to be my practice.

Adam Brufsky, MD, PhD: Sara, what do you think?

Sara A. Hurvitz, MD: I agree. I would use T-DM1 [trastuzumab emtansine] here. I’m interested in the fact that tucatinib doesn’t show up as an option here, because it is approved in the second-line setting, which this patient technically qualifies as. It would be a reasonable thing to do. I looked up the lines of therapy in HER2CLIMB. You were correct, VK. You had to have had trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine]. Even if you had trastuzumab and pertuzumab in the neoadjuvant setting, you could come on having had T-DM1 [trastuzumab emtansine] in the frontline setting. The median number of lines of therapy was 3 in the metastatic setting. The majority were third line and beyond, but there were some patients in there who had 1 prior line of therapy. That would be a reasonable option, but I agree, T-DM1 [trastuzumab emtansine] would be my choice. 

Transcript edited for clarity.