New Data and Guidelines Concerning HER2+ mBC Therapy Sequencing

Neil M. Iyengar, MD: So I think one of the great and exciting things about our recent days in HER2 positive metastatic breast cancer is we now have many treatment options and many of our patients will receive most of these treatment options. That being said, sequencing is an important question, and I think a lot of it depends on patient characteristics and the location of their disease. So of course, in the first line setting, I'm currently using the CLEOPATRA based regimen of taxane, Herceptin and pertuzumab. That may change with ongoing trials. In the second line setting, I'm currently using trastuzumab deruxtecan based on the DESTINY-Breast03 data. Now, the third line setting is really where we have some options. In that setting, I'm currently using the tucatinib based regiment, tucatinib, capecitabine and trastuzumab particularly for my patients that have brain metastasis, but also for my patients without brain metastasis. We often may forget that the tucatinib based regimen also has superior activity for visceral disease and for patients with systemic disease only, and no CNS disease. In that third line space, there are several other options as well, but I'm really compelled by the response data that we see with the tucatinib containing regimen. Where we sequence T-DM1 is starting to become a question now that we're starting to use trastuzumab deruxtecan in the second line space. I think that question may sort of resolve itself because we're using a lot of T-DM1 now in the adjuvant setting based on KATHERINE data. And certainly if a patient has received T-DM1 particularly recently in the adjuvant setting, I'll probably be sequencing trastuzumab deruxtecan first before T-DM1, followed by the tucatinib based regimen. And then perhaps reach to T-DM1. For those patients that have not seen T-DM1, I think it is certainly an option. I'm using it after the tucatinib based regimen, although we need sequencing data to guide us there. There are other options as well, including neratinib with capecitabine that also has some CNS activity. There is margetuximab, which is essentially an engineered version of trastuzumab, that also stimulates immune response and has more favorable binding to heterogeneous HER2 receptors in combination with chemotherapy, that is a later line option as well. And of course we have the classical lapatinib combinations with chemotherapy. So we do have several combination strategies that have different mechanisms of action. And my driving philosophy in the later lines is to try to alternate mechanisms of action either go ADC, TKI. Of course clinical trials are a good option in that setting as well. So we do see some heterogeneity after the third line. But if we generally stick with the CLEOPATRA regimen followed by trastuzumab deruxtecan, followed by the tucatinib based regimen, we still have options beyond that.

There are some patients in the second line setting who- for whom I may consider an agent other than trastuzumab deruxtecan. And these are patients, for example, who may have brain metastasis. We do see emerging data supporting the activity of trastuzumab deruxtecan in patients with brain metastasis. But particularly for my patients with active CNS disease or high burden CNS disease or predominantly CNS disease, I'm using the tucatinib based regiment in that setting, even if it's in the second line because we certainly have the most robust data prospectively from HER2CLIMB for that patient population. Now, if I have a patient who has a heavy burden of systemic disease and who may have a single asymptomatic brain metastasis that's been stable or treated, that patient is a patient I would probably use trastuzumab deruxtecan for, given their burden of heavy systemic disease in the second line setting. There are some patients in the second line setting who may also have contraindications due to pulmonary status. For example, if I have a patient who has a pulmonary disease that makes it difficult to diagnose or monitor for interstitial lung disease, that might be a patient for whom I'm using something different than trastuzumab deruxtecan. In addition to that, I do want to make the comment that interstitial lung disease is a very, very serious potential adverse effect of trastuzumab deruxtecan. And so asking our patients to be vigilant about symptoms, and for ourselves to be vigilant about radiographic findings on staging scans, follow up scans or imaging that's done to diagnose or to evaluate new symptoms like cough or shortness of breath. I'm quick to hold or pause trastuzumab deruxtecan if we're undergoing a workup for interstitial lung disease. That being said, the activity of trastuzumab deruxtecan is so impressive that if a patient has visceral disease and specifically pulmonary disease, these are patients for whom I wouldn't necessarily withhold trastuzumab deruxtecan. Because if we do see a favorable response in the lung, which we're likely to see, that can significantly alleviate the patient's pulmonary symptoms. So there are a lot of nuances in terms of deciding when or when not to use trastuzumab deruxtecan. But overall, the activity is quite favorable in the second line setting