Defining Value for the Treatment of Brain Metastases in Metastatic HER2-Positive Breast Cancer - Episode 10

Phase 2 DESTINY-Breast01 Trial

Kevin M. Kalinsky, MD, MS, and Sarah Sammons, MD, review the phase 2 single-arm trial DESTINY-Breast01, exploring the use of trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer.

Sarah Sammons, MD: DESTINY-Breast01 is a phase 2 single-arm clinical trial of trastuzumab deruxtecan, which is an antibody-drug conjugate, in patients with heavily pretreated HER2 [human epidermal growth factor receptor 2]–positive advanced breast cancer. Patients in this clinical trial had a median of 6 lines of prior therapy, which is heavily pretreated, and we saw an overall response rate in this population that we have really never seen before in such a heavily pretreated population. The overall response rate was above 60%. We also saw progression-free survival around 16 months, which is also nothing like we’ve seen before in a population like this, which was exciting. The adverse-effect profile was pretty well tolerated overall. There was some nausea and myelosuppression, which we’re certainly used to handling, but there was an adverse effect of interstitial lung disease [ILD] or pneumonitis in about 13% of patients. There were a few grade 5 toxicities or deaths with this agent. It is FDA approved at this point. We are all using it certainly beyond third-line treatment or beyond, and we still have some details to work out how to best identify patients who might be at risk for ILD.

Kevin M. Kalinsky, MD, MS: The first DESTINY study was a study of patients with pretreated HER2-positive disease. This was a single-arm study that was published in the New England Journal of Medicine in which patients received, as a single-agent, trastuzumab deruxtecan. This is a different antibody-drug conjugate compared with T-DM1 [trastuzumab emtansine], an antibody-drug conjugate that is linked to a microtubule inhibitor, and trastuzumab deruxtecan, which is linked to a topoisomerase 1 inhibitor.

We saw an incredibly impressive waterfall plot with significant responses, and arguably of the most significant response rates that we have seen in breast oncology. This single-arm study led to its approval in patients with metastatic HER2-positive disease.

There were data that were presented at ESMO [European Society for Medical Oncology] Breast [Cancer Virtual Meeting] in a small subgroup of patients that suggested that this may have some ability to keep CNS [central nervous system] disease under control, suggesting that the payload may be able to cross and treat CNS disease. We know with other disease subtypes that topoisomerase inhibitors, like irinotecan, for instance, can offer good CNS disease control. We’re awaiting the other phase 3 trials to see how this compares with other agents. It is also worth noting that there are ongoing studies that are looking at this particular agent in patients with HER2-low disease. One of the questions is about, if patients are HER2 nonamplified and are HER1-positive or HER2-positive, based on the initial studies, it looked as though there were similar response rates of trastuzumab deruxtecan, and we’re waiting for randomized studies to see whether they give benefit in those patients as well.