Addressing Resistance to HER2-Targeted Therapy in Metastatic Breast Cancer

Transcript:

Virginia Kaklamani, MD, DSc: Resistance in breast cancer, and in general, in cancer, is extremely important and it happens with every single drug that we use. When we look at resistance to T-DM1 [trastuzumab emtansine] or trastuzumab, some of the mechanisms of resistance have to do with the binding. So, with the HER2 receptor, there could be mutations there and those mutations may not allow the antibody to bind the receptor. It can also be the destruction of HER2 and therefore, if there is no HER2, then neither trastuzumab nor TDM-1 can bind. There can also be, especially in the in the case of T-DM1, resistance to the payload; so, resistance to emtansine, the toxin. This is something that might end up being specific for T-DM1, and if we use a different antibody drug conjugate, that antibody drug conjugate can be active or not depending again on the payload that that ADC [antibody drug conjugate] uses. There is resistance to T-DXd [trastuzumab deruxtecan], we see this in practice all the time. We may not have the preclinical data yet, but we know that patients who are on T-DXd for a certain amount of time, at some point, the cancer grows and progresses, and how does it progress? It progresses because that cancer cell has become resistant to T-DXd and that's the same case with TKIs [tyrosine kinase inhibitors]. It's the same case with tucatinib, neratinib, and so forth. The resistance mechanism for tucatinib neratinib is a little different because they bind the tyrosine kinase domain of HER2, so resistance to those agents is going to be even more likely in the tyrosine kinase domain, whereas resistance to T-DXd may have to do with the binding ability of T-DXd to the HER2 receptor.

One of the things that we all are trying to understand is how to better navigate resistance of one agent and whether that resistance means resistance to another agent. We now have T-DXd and T-DM1, which are both antibody drug conjugates, and we have to understand how resistance happens. Both of those antibodies are trastuzumab-based antibodies, and if there is resistance in the sense that there is a change in conformation of HER2, and therefore doesn't allow the binding of the antibody, then we could envision there to be resistance to T-DM1 but also resistance to T-DXd. But if the resistance is to the payload, the payload that those 2 antibody drug conjugates use is different; one uses emtansine and the other one uses deruxtecan. One is a microtubule inhibitor, the other is a topoisomerase-1 inhibitor. You would assume that if there is resistance in that sort of mechanism with T-DM1, then T-DXd would be active. It would be wonderful if at some point, we get to where we can see this resistance in real time, and therefore make educated decisions as to whether to give T-DXd after T-DM1 or whether to move to tucatinib or so forth. The data, especially from [the] DESTINY-Breast02 [trial], suggest that T-DXd is active after T-DM1, and therefore, I have no issue giving these agents sequentially.

There are several agents that are now being looked at in phase 1, 2, and 3 trials in that HER2 arena and it's hard to get into this arena because of how crowded the field is. The agent that's closest to being approved by the FDA is SYD895, and this is another antibody drug conjugate trastuzumab duocarmycin. The TULIP trial was a phase 3 clinical trial that showed a significant improvement in benefit with SYD895, so we're going to look at the FDA to potentially approve this medication. There's also another target that will hopefully find its way into clinic, and that is YES1. This is a way that cells become resistant to T-DM1, and there’s preclinical data suggesting that if we pair T-DM1 with a CRC inhibitor, such as ... we may overcome the resistance mechanism and therefore benefit our patients. We'll see this a little early in the development, but it may be important. There's HER3 developed antibody bodies as well, that might be paired with anti-HER2 antibodies. There’s a lot of excitement here, and in the next few years we'll have more approvals that will help our patients even more.

Transcript edited for clarity.