Defining Value for the Treatment of Brain Metastases in Metastatic HER2-Positive Breast Cancer - Episode 12

Sequencing HER2-targeted Agents in mBC

Comparing and contrasting the safety and efficacy of agents when approaching treatment of brain metastases in HER2-positive mBC.

Sarah Sammons, MD: One of the major questions of 2020 is about how we are now sequencing these HER2 [human epidermal growth factor receptor 2]–targeted regimens. There’s no question that a taxane, trastuzumab, and pertuzumab is still first-line treatment for a vast majority of patients with metastatic HER2-positive breast cancer. When we get into the second-line setting, a majority of patients will still receive T-DM1 [trastuzumab emtansine]. The HER2CLIMB regimen, which is tucatinib added to trastuzumab and capecitabine, was approved by the FDA after 1 line of HER2-targeted therapy, so it could technically be considered in the second-line setting. The only patients to whom I would consider giving the HER2CLIMB regimen before T-DM1 [trastuzumab emtansine] are those who have either treated progressive brain metastasis or for some reason untreated brain metastasis that we did not want to give local therapy to. In that select population, I would consider the HER2CLIMB regimen in the second-line setting. Otherwise, I would still give T-DM1 [trastuzumab emtansine].

In the third-line setting and beyond, we have the HER2CLIMB regimen, we have trastuzumab deruxtecan, we still have neratinib and lapatinib, and we have chemotherapies added to trastuzumab. In the third- and fourth-line settings, I’m choosing either the HER2CLIMB regimen or trastuzumab deruxtecan. For patients with underlying brain metastases, a history of brain metastases, or those with treated or untreated progressive brain metastases, I prefer the HER2CLIMB regimen in the third-line setting. For patients without a history of brain metastases who have rapid visceral progression or a large disease burden, I would certainly consider trastuzumab deruxtecan as a third-line therapy. In the fourth- or fifth-line setting and beyond, 1 of the questions we need to answer at this point is whether the HER2-targeted tyrosine kinase inhibitors have activity after subsequent use. Would neratinib or lapatinib have activity after tucatinib? That remains unclear. I would consider utilizing those regimens after tucatinib in select cases. Otherwise, I would move on to chemotherapy-based regimens with trastuzumab.

Kevin M. Kalinsky, MD, MS: One of the good things in HER2-positive metastatic breast cancer is that we have a number of agents in our arsenal, and that’s only increasing. With that, it becomes increasingly complicated, so at this moment, giving your first- and second-line treatments haven’t necessarily changed in the absence of CNS [central nervous system] metastases, where we give trastuzumab and pertuzumab, often with chemotherapy, followed by T-DM1 [trastuzumab emtansine] as a second-line agent.

It somewhat depends on what’s going on with the patient at the time. That’s a general statement, but in patients with CNS metastases, given the overall survival advantage that we see and given the significant activity in the brain, if I had a patient who I had seen with metastasis, I would consider utilizing a tucatinib-based regimen, possibly earlier on.

If I have a patient who has significant systemic disease for whom I need to get a response, in those patients I would consider something like trastuzumab deruxtecan. The main concern about trastuzumab deruxtecan is that even though we can see some great responses, it has some significant but rare toxicities. In particular, the interstitial lung disease. They saw it in about 2% of patients, and there were some fatalities. We don’t have great predictors for who developed that toxicity.

When I speak with a patient about the kinds of therapy you would consider, the thing I think about is asking for CNS metastasis. Tucatinib is now the first tyrosine kinase inhibitor of choice among the options we have. In terms of the volume of disease, comorbidities, and what our goals of therapy are, that’s what is leading me to consider something like tucatinib vs trastuzumab deruxtecan in patients who have previously received T-DM1 [trastuzumab emtansine] or trastuzumab pertuzumab.