Trastuzumab Deruxtecan in DESTINY-Breast04 Meets Key End Points in HER2-Low Breast Cancer

Treatment with trastuzumab deruxtecan (Enhertu) achieved a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low unresectable and/or metastatic breast cancer regardless of hormone receptor (HR) status when compared with physician’s choice of chemotherapy, according to an announcement by AstraZeneca^.1

The primary end point and a key secondary end point of the phase 3 pivotal DESTINY-Breast04 clinical trial were met based on this result. Full results from the study will be presented during an upcoming medical meeting.

“Today’s historic news from DESTINY-Breast04 could reshape how breast cancer is classified and treated. A HER2-directed therapy has never, before, shown a benefit in patients with HER2-low metastatic breast cancer. These results for Enhertu are a huge step forward and could potentially expand our ability to target the full spectrum of HER2 expression, validating the need to change the way we categorize and treat breast cancer,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in a press release.

Destiny-Breast04 is a study of about 557 patients with HER2-low, unresectable and/or metastatic breast cancer who are treated with either trastuzumab deruxtecan or chemotherapy of physician’s choice. The study follows a multicenter, randomized, open-label, active controlled trial design with a goal of determining the safety and efficacy of trastuzumab deruxtecan in this patient population.²

In addition to PFS and OS, the study is assessing objective response rate (ORR) and duration of response (DOR) among the study subjects.

To be included in the study, patients are required to have reached the age of maturity in their country, have pathologically confirmed disease, documented radiographic progression, at least 1 protocol-defined measurable lesion, adequate archival tumor samples available or the ability to provide fresh tissue, and protocol-defined adequate cardiac, bone marrow, renal, hepatic and blood clotting functions.

The study excludes those who are ineligible for all options in the physician's choice arm, have breast cancer ever assessed with high-HER2 expression, were previously treated with any anti-HER2 therapy, including an antibody drug conjugate or who have uncontrolled or significant cardiovascular disease, spinal cord compression or clinically active central nervous system metastases, or history of certain lung diseases or condition that per protocol or in the opinion of the investigator is inappropriate for the study.

Trastuzumab deruxtecan 5.4mg/kg is already approved in the US as well as 39 other countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti-HER2-based regimens. These approvals were supported by data from the DESTINY-Breast01 trial.1 The agent demonstrated an ORR of 60.9% (95% CI, 53.4-68.0) with a 14.8-month median DOR (95% CI, 13.8-16.9) at a median follow-up of 1.1 months (range, 0.7-19.9).³

The median duration of PFS observed with trastuzumab deruxtecan in the study was 16.4 months (95% CI, 12.7 to not reached).

The most adverse events observed with the agent included grade 3 or higher decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%).

“Enhertu continues to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04 is the first ever Phase III trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer to show statistically significant and clinically meaningful benefit in progression-free and overall survival compared to standard treatment. We look forward to sharing the detailed findings of DESTINY-Breast04 with the medical community and initiating discussions with regulatory agencies globally with the goal of bringing Enhertu to patients with metastatic breast cancer previously considered to be HER2-negative,” said Ken Takeshita, global head, R&D, Daiichi Sankyo, in the press release.¹

_References:

_{1. Enhertu significantly improved both progression-free and overall survival in DESTINY-Breast04 trial in patients with HER2-low metastatic breast cancer. News release. February 21, 2022. Accessed February 22, 2022. https://bit.ly/3HdL365.}

_{2. Trastuzumab deruxtecan (DS-8201a) versus investigator's choice for HER2-low breast cancer that has spread or cannot be surgically removed [DESTINY-Breast04]. Clinicaltrials.gov. Accessed February 22, 2022. https://bit.ly/3IbGbQ1.}

_{3. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020; 382:610-62. doi: 10.1056/NEJMoa1914510.}