Dr. Pegram on the DESTINY-Breast01 Trial With Trastuzumab Deruxtecan in HER2+ Breast Cancer

Mark D. Pegram, MD, co-director of Stanford’s Molecular Therapeutics Program, and director of the Breast Cancer Oncology Program, at Stanford Women's Cancer Center, discusses the results of the phase 2 DESTINY-Breast01 study examining fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) in patients with HER2-positive breast cancer.

Trastuzumab deruxtecan is a HER2 antibody-drug conjugate (ADC) that is based on a backbone sequence of trastuzumab (Herceptin), which is covalently linked to a topoisomerase 1 inhibitor payload exatecan derivative by a tetrapeptide-based cleavable linker, says Pegram. This agent is unique, with many attributions that distinguish it from ado-trastuzumab emtansine (T-DM1; Kadcyla). For example, T-DM1 has about 3.5 molecules per payload per antibody backbone, whereas trastuzumab deruxtecan has a drug-to-antibody ratio of 8, adds Pegram.

The DESTINY-Breast01 study was a 2-part, open-label, single-group, multicenter, phase 2 study. In the first part of the study, 3 doses of trastuzumab deruxtecan were evaluated in order to identify a recommended phase 2 dose, which was determined to be 5.4 mg/kg given intravenously every 3 weeks. In the second part of the study, the efficacy and safety of the recommended dose was documented, says Pegram. Overall, 184 patients were enrolled and they had undergone a median of 6 previous treatments prior to study enrollment.

The overall response rate (ORR) in this heavily pretreated population was 60.9%; this is the highest ORR reported for a single-agent HER2-targeted therapy in such heavily pretreated patients, according to Pegram. The disease control rate was 97.3% at the time of data presentation, adds Pegram. The durability of response with the ADC was also impressive, according to Pegram, with a median progression-free survival (PFS) of 16.4 months.

Moreover, a subset analysis of the trial looked at 24 patients with central nervous system metastasis and showed that the ORR in that subset was approximately 58% with a median PFS of 18.1 months, which is very similar to what had been observed in the intention-to-treat populations. Once the ADC received regulatory approval from the FDA, it became a new practice standard, concludes Pegram.