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.

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Mark D. Pegram, MD, discusses the results of the phase 2 DESTINY-Breast01 study examining fam-trastuzumab deruxtecan-nxki in patients with HER2-positive breast cancer.

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

Adam M. Brufsky, MD, PhD, a professor of medicine, associate chief in the Division of Hematology/Oncology, and co-director of Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine, discusses the treatment of early-stage, HER2-positive breast cancer.

Generally, patients with early-stage, metastatic HER2-positive breast cancer are treated depending on the size of their tumor, says Brufsky. If the tumor is greater than 2 cm, patients will receive neoadjuvant chemotherapy, usually with trastuzumab (Herceptin) and pertuzumab (Perjeta). If the patient achieves a pathologic complete response, they will then receive trastuzumab or pertuzumab for 1 year; if they do not, they will receive ado-trastuzumab emtansine (T-DM1; Kadcyla).

For patients with tumors of less than 1 cm, they will undergo surgery and then a decision will be made on next steps. If they have tumors that are less than 2 cm and are node negative, they will likely receive adjuvant paclitaxel and trastuzumab for 12 cycles or 12 weeks. Some will give T-DM1 for 1 year, but that decision is a little controversial right now, concludes Brufsky.

Adam M. Brufsky, MD, PhD, discusses the treatment of early-stage, HER2-positive breast cancer.

Dr. Brufsky on Treatment Approaches for Early-Stage HER2+ Breast Cancer

William J. Gradishar, MD, chief of hematology and oncology, Department of Medicine; Betsy Bramsen Professorship of Breast Oncology; and a professor of medicine (hematology and oncology) at Northwestern University Feinberg School of Medicine, discusses the benefit of fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) in patients with HER2-positive breast cancer and stable brain metastases.

In the phase 2 DESTINY-Breast01 trial, investigators evaluated trastuzumab deruxtecan in patients with HER2-positive breast cancer who received 2 or more prior HER2-directed therapies, including ado-trastuzumab emtansine (T-DM1; Kadcyla), says Gradishar. These patients had received standard treatments before enrolling on the trial. Importantly, patients could have stable brain metastases and still be included on the trial, adds Gradishar. The bulk of the trial was focused on the established dose, which was 5.4 mg/kg administered intravenously every 3 weeks.

The most compelling piece of evidence that came from the trial is the fraction of patients who responded, according to Gradishar. The data that were presented in a waterfall plot garnered a lot of attention. When looking at the forest plots, no subset of patients did not achieve benefit from trastuzumab deruxtecan.

More recently, additional data were presented at the ESMO Breast Cancer Virtual Meeting 2020, which focused on the population of patients who had stable brain metastases. While the duration of benefit was longer in patients who did not have brain metastases, it was clear patients who had stable brain metastases also benefitted from the ADC, concludes Gradishar.

William J. Gradishar, MD, discusses the benefit of fam-trastuzumab deruxtecan-nxki in patients with HER2-positive breast cancer and stable brain metastases.

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

Dr. Brufsky on Treatment Approaches for Early-Stage HER2+ Breast Cancer

Dr. Gradishar on the Benefit of Trastuzumab Deruxtecan in HER2+ Breast Cancer