Relapsed/Refractory HER2+ Metastatic Breast Cancer - Episode 5

Case 2: 61-Year-Old Patient With R/R HER2+ MBC

Adam M. Brufsky, MD, PhD: Let’s look at this last case and see how everyone would manage it. Maybe we’ll have time at the end for a few questions.

This is a 61-year-old woman, diagnosed 2 years ago with a left-sided invasive ductal carcinoma. She had a grade 3 ER+ [estrogen receptor-positive]/PR+ [progesterone receptor-positive] , HER2 [human epidermal growth factor receptor 2]-positive. She’s BRCA wild type. She received neoadjuvant TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] with a pCR [pathologic complete response], which is about half the time, and then received adjuvant HP [trastuzumab, pertuzumab] to complete a year.

Eight months later, she had rapid disease progression, and she initiated treatment with T-DM1 [trastuzumab emtansine]. With the T-DM1, she had stable disease for about 24 months. Now she has progression in her liver and left lung.

Here is the polling question. What would you recommend for this patient: tucatinib, trastuzumab, and capecitabine; trastuzumab deruxtecan; neratinib/capecitabine; clinical trial; or other?

What would you guys give this woman? She doesn’t have brain metastases. That’s part of the confusion here. What would you do? She has now progressed fairly quickly, which is kind of unusual for triple-positive breast cancer, but let’s assume that it happened. She had TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab], 8 months later had progression or new disease, got T-DM1 and it held her for quite a while, but now has progression—but nothing above the neck. Sara, what would you do?

Sara A. Hurvitz, MD, FACP: I like the tucatinib option because of tolerability and the fact that she hasn’t had a TKI [tyrosine kinase inhibitor], a different mechanism of action here. That’s a very reasonable option. As was mentioned just a few moments ago, that ILD [interstitial lung disease] risk in the COVID-19 [coronavirus disease 2019] era is something to consider. We don’t yet have randomized data supporting the use of trastuzumab deruxtecan, so I like the tucatinib idea, hoping that it will postpone, delay, or mitigate the risk of progression in the brain. Trastuzumab deruxtecan is a fine option. It’s certainly FDA-approved here. Given how quickly her disease recurred, she would have qualified for the DESTINY study, but tucatinib would probably be my go-to here.

Adam M. Brufsky, MD, PhD: VK, what do you think?

VK Gadi, MD, PhD: I agree with tucatinib. It is a randomized controlled trial that’s established the quality of the evidence, just to bring that out. When you look at the waterfall plot from tucatinib, it’s not that different from the deruxtecan waterfall plot. There are a lot of downward arrows. The other thing is that I know it’s exploratory analysis, but we now know that even in patients who don’t have brain metastases, who just have even stable disease in their body or responses in non-CNS [central nervous system] disease, they have an overall survival [OS] advantage that you can demonstrate in that study. You have a drug with a proven OS benefit in this context vs a phase 2 study. I don’t fault anybody for picking the deruxtecan here because it is such an active agent in somebody with rapid progression. I can see the reason for doing that, but I like the option of tucatinib here as well.

Adam M. Brufsky, MD, PhD: Neil, would you like to add anything different?

Neil M. Iyengar, MD: No, I agree with what everyone has said. I would like to highlight the point that VK made about the systemic activity of tucatinib. I believe a prespecified secondary end point was to look at disease progression in patients without brain metastases. It was a robust data set to support the use of tucatinib in patients who don’t have brain metastases. The other thing I find interesting I believe Sara mentioned. We saw at ESMO [the European Society for Medical Oncology annual meeting] that the hazard ratio for the development of new brain metastases or death was around 0.5 for patients treated with a tucatinib-based regimen. That’s a pretty significant risk reduction in terms of developing new brain metastases. That is why I would favor tucatinib in this setting as well.

Adam M. Brufsky, MD, PhD: I agree. All of these are reasonable data. The question I have, though, is if DESTINY-Breast03 comes out and is wildly positive, in a phase 3 trial, will that change your mind? You’re going to have a survival benefit now for another agent. Would that change any of your minds? I’ll start with VK.

VK Gadi, MD, PhD: I don’t know that it would because there’s the toxicity issue that we’ve talked about, and efficacy is always weighed against that. The nice thing is we have both drugs, and we’re going to be able to sequence them. The 1 other concern I have with deruxtecan is how fit patients will be to try another line of therapy after it. We don’t have a lot of that kind of data because they are on it for a long time. The study did have an average of 6 lines of prior therapy in the phase 2 setting. How fit are these patients going to be to try something else? If we know the drug is going to work after other stuff has worked, I might try the other stuff first and then have this still available to me in that third-line or so setting.

Adam M. Brufsky, MD, PhD: Here’s the last question to you guys. Is the site of disease the problem with trastuzumab deruxtecan? In other words, are you concerned about giving this to someone with lung disease, either limited spread or parenchymal metastases? Sara, would you have concern doing that?

Sara A. Hurvitz, MD, FACP: No. They actually did a fairly big analysis presented at the San Antonio [Breast Cancer Symposium] in 2018 of all the patients treated with this drug. There were over 600 patients, and when they looked at factors that would predict ILD, it was number of prior lines of therapy, Asian ancestry, and higher dose of the drug that were associated with the development of ILD. Pulmonary metastases had no predictive effect. It was sitting right on the null point in the forest plot, so I don’t think this is something we see more frequently in those with lung metastases.

Adam M. Brufsky, MD, PhD: Got it. Any other comments from either of you guys about this? Would you treat someone with lung metastases with this drug? Neil?

Neil M. Iyengar, MD: The only caveat that I would add to that is that I agree with what Sara just said. We don’t have data to support that there’s any concern there. My only concern there is that, again, this is a case-by-case basis. If we have someone who has sort of a lymphangitic pattern to their lung metastases and presents with PFTs [pulmonary function tests] that are supportive of a restrictive pattern, then I might be a little concerned. That’s just clinical gestalt and not data-based, but that’s the only exception I would make. Otherwise, in terms of your standard parenchymal lung lesions, there are no data to support that we should be concerned about deruxtecan in that setting.

Adam M. Brufsky, MD, PhD: Got it. I’m sorry to the audience. We had 3 questions; I have time for 1 because we have to wrap it up. It’s the top of the hour. Here’s a clinical question for you guys. This is a good one. If you have stable brain metastases and progression in the lungs, would you use tucatinib or trastuzumab deruxtecan? Let’s start with Sara.

Sara A. Hurvitz, MD, FACP: It’s similar to our patient we just discussed who had just liver lesions, and so I would echo what Neil said. As long as we feel the patient is healthy enough from a pulmonary standpoint, either of those would be perfectly appropriate. My choice, based on the phase 3 evidence we have today, would be tucatinib first. That’s based on the safety data that we have and the efficacy.

Adam M. Brufsky, MD, PhD: Great. Any other comments from either of you on this? Same thing?

VK Gadi, MD, PhD: I agree 100%.

Neil M. Iyengar, MD: I agree.

Adam M. Brufsky, MD, PhD: Got it. Guys, this has been a great hour. I want to thank all of you, Dr Iyengar, Dr Hurvitz, and Dr Gadi, for joining us in a lively discussion on HER2+ metastatic breast cancer, brought to you by the Cancer Network®. We want to thank our viewing audience and hope you found this interactive discussion to be informative and beneficial to your clinical practice. Thank you very much and have a good night.

Transcript edited for clarity.