HER2-Positive mBC Emerging Treatment Landscape

Sara A. Hurvitz, MD: In 2020, we now have 7 FDA-approved HER2-targeted therapies in our toolbox for the treatment of HER2-positive metastatic breast cancer. It’s truly an embarrassment of riches, so deciding which therapy to use for which patient has become a bit tricky. There aren’t a lot of studies that have shown us how to properly sequence these agents, but I do think it’s important to highlight the 3 FDA approvals that we’ve had in the past 7 months for agents in this setting.

First of all, we have neratinib, which is FDA approved in combination with capecitabine based on the findings of the NALA study, in which neratinib and capecitabine were compared to lapatinib and capecitabine and was shown to have a 2-month better mean PFS (progression-free survival), as well as an improved time to progression of CNS (central nervous system) metastases.

This is a therapeutic combination that we now have available to use for patients who’ve progressed on multiple lines of therapy. Of course, one of the adverse effects that’s problematic with neratinib and lapatinib is diarrhea, so use of neratinib mandates that the capecitabine dose be 750 mg per meter squared BID (twice a day), and patients must start on an oral antidiarrheal agent with the first dose, the first cycle.

Another agent that’s shown great promise, which is also an oral tyrosine kinase inhibitor, is tucatinib. Tucatinib has been FDA approved this year in combination with capecitabine and trastuzumab for patients who at least had 1 prior line of therapy in the metastatic setting. And this approval came from the HER2CLIMB trial. Now the HER2CLIMB phase 3, randomized clinical trial only enrolled patients who’d had 2 lines of prior therapy in the metastatic setting, including trastuzumab and T-DM1 (trastuzumab emtansine). So the FDA approval a little bit earlier probably is due to the fact that this drug has shown such promising data for patients who have metastatic breast cancer involving the brain.

This study showed not only an improved progression-free survival, and progression-free survival in the patients who had CNS metastases, but also an improved overall survival. The use of this agent is quite exciting because 30% to 50% of patients with HER2-positive metastatic breast cancer will develop CNS metastases at some point in their lifetime.

Then there’s a third agent that’s been approved in the metastatic setting for patients who are third-line and beyond is T-DXd, or trastuzumab deruxtecan. This is an antibody drug conjugate, which is a HER2-targeted antibody stably linked to a deruxtecan topoisomerase-1 inhibitor cytotoxic payload.

This approval came off of a phase 2 single-arm trial in which patients with at least 2 prior lines of therapy—the median number of prior lines was 6 in this trial—received this agent every 3 weeks. The objective response rate was 61% with a median progression-free survival of around 16 months. These are very promising data, very exciting data, very good activity in heavily pretreated disease.

The one adverse effect we have to watch for is interstitial lung disease, which was grade 5 in this study in 2% of patients. That’s a toxicity that does need to be addressed when using this drug.

In summary, I think it’s a very exciting time for the treatment of HER2-positive metastatic breast cancer. The trick is figuring out how and when to use each of these agents.

Transcript edited for clarity.