Defining Value for the Treatment of Brain Metastases in Metastatic HER2-Positive Breast Cancer - Episode 5

Treatment Beyond Second-line Therapy in HER2+ mBC

Exploring current advances in treatment options beyond the second-line setting for progressive HER2-positive metastatic breast cancer.

Kevin M. Kalinsky, MD, MS: There have been some real advances in HER2 [human epidermal growth factor receptor 2]–positive metastatic disease. For a long time, our first- and second-line therapy included treating with monoclonal antibodies like Herceptin [trastuzumab] and pertuzumab, as well as T-DM1 [trastuzumab emtansine] as a second-line therapy and an antibody drug conjugate. It’s been an open space for what to treat for patients after second-line treatment. Within this year, we’ve seen some real advances in treating patients, including patients with CNS [central nervous system] metastases.

In our armamentarium, we had agents that included things like the tyrosine kinase inhibitors lapatinib and neratinib. In the last year, we also had an approval of tucatinib, for which we saw an overall survival advantage. There was also an impressive response rate with the antibody drug conjugate trastuzumab deruxtecan. This added additional active agents for our patients with HER2-positive metastatic disease.

Sarah Sammons, MD: The treatment options for patients with progressive HER2-positive metastatic breast cancer beyond the second-line setting have drastically improved in the year 2020. It’s been an exciting year for HER2-positive metastatic breast cancer. We know in the first-line setting that the optimal treatment is still a taxane plus pertuzumab and trastuzumab. The optimal second-line option for most patients will still be trastuzumab emtansine, or T-DM1. Beyond the second-line setting, there’s no standard approach. However, we do have many options, and we have 2 new highly appealing options in 2020.

We now have what I refer to as the HER2CLIMB regimen, which is tucatinib, which is a tyrosine kinase inhibitor that is very specific to HER2 added to chemotherapy: capecitabine and trastuzumab. This regimen was found to be highly effective in patients with brain metastases and is a very good optimal third-line regimen for a patient with or without brain metastases. We also have trastuzumab deruxtecan, which is a newer antibody drug conjugate that was approved by the FDA this year and has an extremely impressive overall response rate and unclear activity in patients with brain metastases. This is also a very good third- or fourth-line option for patients, and I’ll discuss that trial a little later.

Beyond those 2 highly appealing options, the HER2CLIMB regimen or trastuzumab deruxtecan, we also have neratinib, which is a pan-HER tyrosine kinase inhibitor added to capecitabine. We know that neratinib has fairly robust intracranial activity as well. We still have lapatinib, which is an EGFR- and HER2-targeted tyrosine kinase inhibitor with either trastuzumab or capecitabine. What’s unknown is if HER2-targeted tyrosine kinase inhibitors will have any added efficacy after you’ve already received 1. That’s unclear, and you have to think about that sequencing. Beyond the tyrosine kinase inhibitors and antibody drug conjugates, we recommend continuing trastuzumab into further lines of therapy with alternative chemotherapy backbones. Navelbine [vinorelbine] with trastuzumab is an active regimen. Eribulin, platinum, and a variety of chemotherapies with trastuzumab can be used in the later-line setting.