Emerging Treatment Strategies for R/R HER2+ mBC

Adam M. Brufsky, MD, PhD:There are a lot of drugs out there, there are a lot of novel agents in this space now. There’s margetuximab, which is basically a re-engineered trastuzumab to make it a little more immunogenic in the Fc [crystallizable fragment], which may have activity in third line and beyond metastaticHER2-positive breast cancer. There are a number of antibodies or conjugates that are available. They’re called SYD985 and DS8201, which could have activity in people who have progressive TDM1 [trastuzumab emtansine] and pertuzumab.

There potentially is immunotherapy. Checkpoint inhibitors are being combined with trastuzumab to see what happens, to see if we can boost the immune response. There is some immune response to this, the whole idea ofHER2-positive disease and the use of trastuzumab, pertuzumab antibodies. Part of us believe that they’re chemotherapy sensitizers and growth control inhibitors. Some people believe there is an immune reaction to these, and there are probably all 3. And so especially if margetuximab has benefit, it’s probably going to be things that boost the immune system to help a little bit more. We just don’t know yet.

In the initial trials, at least second-line breast cancer, combining immunotherapy with TDM1 [trastuzumab emtansine] didn’t work. But who knows. That’s maybe just one thing, maybe there will be other things where it may work. But there also are other HER2 tyrosine kinases, tucatinib, for example, which is a pure HER2 tyrosine kinase inhibitor that doesn’t have as much diarrhea as neratinib. There’s a trial called HER2CLIMB that should likely read out in the next year or so.

So we have a lot of stuff going on to try to really make this disease better. But again, and I’ve said this, monoclonal antibodies are good, ADCCs [antibody-dependent cellular cytotoxicity] are good. But where the biggest bang for the buck is going to be for the next several years are things that get into the CNS [central nervous system], and somehow either delay the onset or the progression of CNS disease inHER2-positive breast cancer. That’s what we need right now more than anything.

Transcript edited for clarity.