Emerging Therapies for HER2-Positive Metastatic Breast Cancer - Episode 4

Unmet Needs in Relapsed/Refractory HER2+ Breast Cancer

December 24, 2019

Ian Krop, MD, PhD:The biggest unmet medical need right now in HER2-positive advanced breast cancer is 2-fold. One is that while there are a number of different options that we discussed in the previous part of the talk for treating patients in third- and later-line combinations of chemotherapy and HER2-directed therapy, none of them has been shown to have high rates of efficacy. In general studies suggest response rates in the 20% range with progression-free survival in the 5-month range for patients who are heavily pretreated HER2+ disease. Clearly more efficacious regimens would be helpful for such patients.

The other unmet medical need is brain metastases, which unfortunately is a common occurrence in HER2+ metastatic disease. Some studies have shown up to 50% of patients with HER2+ advanced disease will eventually develop brain metastases. These brain metastases typically respond well to radiation, but in some patients continued recurrence happens after radiation or eventually radiation options become limited and at that point really don’t have good treatment for such patients.

To identify and develop new treatments for patients with treatment-refractory HER2+ breast cancer, a number of different options have been looked at. One is antibody-drug conjugates. We already have an approved antibody-drug conjugate for this disease, which is T-DM1 [ado-trastuzumab emtansine]. What is an antibody-drug conjugate? Basically, it’s a monoclonal antibody, in this case typically a HER2-specific monoclonal antibody. But rather than give a free drug, as we do with trastuzumab or pertuzumab, we link it via a chemical linker to some cytotoxic agent.

With T-DM1 [ado-trastuzumab emtansine] it consists of basically trastuzumab linked to a cytotoxic agent that’s a microtubular inhibitor. That’s the DM1 component. And the idea is that we take advantage of the specificity of these antibodies. When you inject T-DM1 [ado-trastuzumab emtansine] into the bloodstream, the trastuzumab component of it brings the molecule directly to the HER2+ cancer cells, but now it’s bringing along with it the microtubule inhibitor cytotoxic payload. The idea here is that you’re able to selectively deliver this cytotoxic agent directly to the cancer cell. Because it’s linked to antibody, you minimize the amount of toxicity that happens when the payload interacts with normal tissues, as would happen if you were using a free chemotherapy. It’s essentially a way of giving trastuzumab plus chemotherapy in 1 package, to minimize the toxicity and improve the therapeutic index of your cytotoxic agent.

T-DM1 [ado-trastuzumab emtansine] provided the first proof of concept in a solid cancer that is antibody-drug conjugate approach can be effective. Basically, it does exactly what it was designed to do, which is effectively kill HER2+ cancers and have a relatively manageable safety profile.

Transcript edited for clarity.