Trastuzumab Deruxtecan Shows Superior PFS Versus T-DM1 in HER2+ Unresectable/Metastatic Breast Cancer

A highly statistically significant improvement in progression-free survival (PFS) has been observed with the HER2 monoclonal antibody trastuzumab deruxtecan (Enhertu) treatment compared with trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable or metastatic breast cancer, meeting the primary end point of the phase 3 DESTINY-Breast03 trial.¹

Findings announced in a press release from AstraZeneca and Daiichi Sankyo Company, Limited also revealed a trend toward overall survival (OS) improvement with trastuzumab deruxtecan versus T-DM1, signaling a potential positive result for the secondary end point. The OS data remain immature, however. Safety results from the study showed consistency with prior clinical trials. No new safety signals were observed. Treatment-related interstitial lung disease events that were grade 4 or 5 in severity did not occur.

“DESTINY-Breast03 is the first global phase 3 head-to-head trial of Enhertu against an active control and supports the potential of this medicine to become the new standard of care for patients with HER2-positive metastatic breast cancer following initial treatment with trastuzumab and a taxane, said Ken Takeshita, global head, Research and Development at Daiichi Sankyo, in the press release. We believe this highly sophisticated and specifically engineered ADC is fulfilling its promise to reshape the treatment of HER2-positive metastatic breast cancer, with the goal to move into earlier lines of treatment for HER2-positive breast cancer and many other HER2-expressing tumor types across our broad clinical trial program.”

Roughly 500 patients with HER2-positive unresectable or metastatic breast cancer were enrolled into the DESTINY-Breast03 trial at multiple centers across North American, South America, Europe, Asia, and Oceania. Trastuzumab deruxtecan was administered to patients at 5.4mg/kg intravenously. Patients in the T-DM1 arm received the FDA-approved dose. In addition to the key survival end points, patients were also assessed for the secondary end points of objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and PFS per investigator assessment and safety.

Trastuzumab deruxtecan is already an FDA-approved agent for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. It was granted accelerate approval in 2020 based on results from the DESTINY-Breast01 trial, in which trastuzumab deruxtecan clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic breast cancer.^2,3

The confirmed ORR was 60.3% with single-agent trastuzumab deruxtecan in DESTINY-Breast01 per independent central review (ICR; 95% CI, 52.9-67.4), which included a 4.3% complete response (CR) rate, and a 56% partial response (PR) rate. Stable disease (SD) was observed in 36.4% of patients and progressive disease developed in 1.6%. The median DOR observed was 14.8 months (95% CI, 13.8-16.9), and the control rate (DCR) of 97.3% (95% CI, 93.8-99.1). Results also showed a 6-month CBR of 76.1% (95% CI, 69.3%-82.1%).

In terms of survival, treatment with single-agent trastuzumab deruxtecan achieved a median (PFS) of 16.4 months (95% CI, 12.7-NE). Among the 24 patients with brain metastases, the median PFS was 18.1 months (95% CI, 6.7-18.1 months). The median overall survival was not reached (95% CI, NE-NE).

Safety observed in the DESTINY-Breast01 population showed that 99% of patients experienced treatment-emergent adverse events (TEAE), and these TEAEs were grade 3 or higher for 51% of patients. The most common any-grade TEAEs were nausea (77%), alopecia (48%), fatigue (48%), vomiting (45%), constipation (34%), decreased neutrophil count (31%), decreased appetite (29%), diarrhea (27%), and anemia (26%). The most common grade ≥ 3 AEs were decreased neutrophil count (in 31% of the patients), nausea (7.6%), and anemia (in 26%).

Analyses in the head-to-head DESTINY-Breast03 study are ongoing and full results will be preened at an upcoming medical meeting and shared with health authorities. Outside of breast cancer, trastuzumab deruxtecan is being tested in other HER2-driven cancers like gastric, lung, and colorectal cancers.¹

“There is a continued need for new options and better outcomes for patients with HER2-positive metastatic breast cancer who often experience disease progression after initial treatment with available standards of care. These transformative progression-free survival results demonstrate the superiority of Enhertu compared to T-DM1, and the encouraging safety data may open future opportunities to bring this benefit to patients in earlier treatment settings, said Susan Galbraith, executive vice president, Oncology Research & Development at AstraZeneca, in a press release.”

_References:

_{1. Enhertu significantly improved progression-free survival in DESTINY-Breast03 head-to-head trial vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. News release. AstraZeneca and Daiichi Sankyo Company, Limited. August 9, 2021. Accessed August 9, 2021. https://bit.ly/3ixqQyS}

_{2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. News release. FDA. December 20, 2019. Accessed August 9, 2021. https://bit.ly/2VvjGCV}

_{3. Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01). Presented at: the San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Texas. Abstract GS1-03.}