HER2+ mBC Trials in Progress and Other Exciting Prospects on the Horizon

Neil M. Iyengar, MD: There are a lot of new and more exciting agents coming out in HER2-positive metastatic breast cancer. I think that in the next few years, we're still going to see a rapid change in the way that we treat this disease. One of the class of drugs that are particularly interesting are bispecific antibodies. For example, ZW25 is a bispecific antibody, and we saw phase 1 data presented in combination with docetaxel in the first-line setting at ASCO this year. The activity of ZW25 was favorable and the tolerability in combination with docetaxel was also favorable. Here at ESMO, we saw the antibody-drug conjugate ZW49, the bispecific antibody-drug conjugate, also showing a favorable tolerability profile and an objective response rate of about 30% across solid tumors. Those are a class of drugs that I'm watching closely as they move on to later phase trials.

Biosimilars for trastuzumab are useful in terms of clinical practice, particularly in areas where cost is a concern. We have seen real-world data specifically at ESMO this year showing that the use of biosimilars is on the rise and the toxicity profile of biosimilars is very similar to what we would expect with trastuzumab. Fortunately, a lot of ongoing trials also allow for the use of biosimilars. For example, HER2CLIMB allowed for the use of a trastuzumab biosimilar so it's nice to be able to have that option when combining with some of our newer agents as well.

There are three ongoing trials that I'm particularly interested in, in the metastatic space. Of course, there are many more than that but three that I would particularly focus on, HER2CLIMB-05 is an ongoing phase 3 trial which is testing tucatinib in the maintenance setting with trastuzumab and pertuzumab after the classical CLEOPATRA taxane-based approach. I think this is very interesting because as many of us experience with our patients, this is a very good time for our patients when they're on just the dual antibody therapy. Many of my patients will tell me that they're starting to feel normal again during this maintenance phase so anything we can do to prolong that maintenance phase, I think is going to be very clinically useful. The combination of tucatinib with trastuzumab and Perjeta, I think is an attractive approach. Although we await the efficacy data from HER2CLIMB-05. HER2CLIMB-04 is an ongoing phase 2 trial which is testing tucatinib in combination with trastuzumab deruxtecan in the third-line setting or beyond. This is particularly exciting because now we're taking two of our most effective agents in HER2-positive metastatic breast cancer and combining them. This trial will specifically look at a cohort of patients with brain metastasis and a cohort of patients without brain metastasis, so we'll get some interesting subgroup analysis data from that trial as well. Finally, I would want to mention DESTINY-Breast09 which is an ongoing phase 3 trial testing trastuzumab deruxtecan with or without pertuzumab versus the classic CLEOPATRA-based regiment, taxane plus trastuzumab and pertuzumab. I think this is a highly awaited trial because of the known activity of trastuzumab deruxtecan, the overall favorable tolerability profile, and moving this to the first-line setting may be attractive, though it's got a very high bar to beat with CLEOPATRA. Overall, I think this is a very exciting time for our patients and their families who have to deal with this disease every single day as we start to see newer, better-tolerated agents with overall survival benefit.