Notch Up Another Win for Enhertu, This One in Metastatic Breast Cancer

Photo courtesy of Daiichi Sankyo

Photo courtesy of Daiichi Sankyo

The clinical study compared Enhertu to Kadcyla in HER2+ metastatic breast cancer patients who previously received trastuzumab.

Photo courtesy of Daiichi Sankyo.

On Monday, Daiichi Sankyo and AstraZeneca reported positive topline data from their head-to-head DESTINY-Breast-03 Phase III trial.

The clinical study compared Enhertu (trastuzumab deruxtecan) to Genentech, Inc.(Roche)’s Kadcycla (trastuzumab emtansine) in HER2+ unresectable and/or metastatic breast cancer patients who previously received trastuzumab and a taxane chemotherapy agent. Enhertu was found to be superior to the Kadcyla combination.

Enhertu is a HER2-directed antibody drug conjugate (ADC). It is approved in Canada, Europe, Israel, Japan, UK and the U.S. for adults with unresectable or metastatic HER2+ breast cancer patients who had two or more previous anti-HER2-based therapies in the metastatic setting. It has also been approved in Israel, Japan and the U.S. for adults with locally advanced or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma who received a prior trastuzumab-based regimen.

The drug is a monoclonal antibody targeting HER2 linked to a topoisomerase I inhibitor through a cleavable linker molecule.

An Independent Data Monitoring Committee (IDMC) conducted a planned interim analysis and concluded that the trial hit the primary endpoint of progression-free survival (PFS), demonstrating a highly statistically significant and clinically meaningful improvement in PFS in this patient group. Enhertu also showed a strong trend toward improved overall survival (OS) compared to Kadcyla, a secondary endpoint, although this data was not yet mature.

“DESTINY-Breast03 is the first global Phase III 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 treatment with trastuzumab and a taxane,” said Ken Takeshita, Global Head, Research and Development for Daiichi Sankyo.

“We believe this specifically engineered ADC, with a highly sophisticated delivery system, 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, as well as many other HER2-expressing tumor types across our broad clinical trial program.”

Kadcyla was approved for adjuvant treatment of HER2+ early breast cancer in patients with residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment in May 2019. Patients are chosen based on an FDA-approved companion diagnostic.

Enhertu won accelerated approval in December 2019, only nine months after the two companies entered into their collaboration deal. Under the terms of that agreement, AstraZeneca paid Daiichi Sankyo $1.35 billion upfront, half at execution, the rest 12 months later. Contingent payments of up to $5.55 billion include $3.5 billion for various regulatory milestones and another $1.75 billion in sales-related milestones.

At the time, Pascal Soriot, chief executive officer of AstraZeneca, noted, “We believe that trastuzumab deruxtecan could become a transformative new medicine for the treatment of HER2-positive breast and gastric cancers. In addition, it has the potential to redefine breast cancer treatment as the first therapy for HER2-low expressing tumors. It also has the potential to treat other HER2-mutated or HER2-overexpressing cancers, including lung and colorectal cancers.”

The companies plan to present the data at an upcoming medical conference and submit the data to regulators.

DESTINY-Breast03 enrolled approximately 500 patients in Asia, Europe, North America, Oceania, and South America. The IDMC recommended unbinding the data.

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