Experimental Antibody Therapy Leads to Significant Responses in HER2-positive Breast Cancer, Phase 2 Trial Shows

Trastuzumab deruxtecan (DS-8201), an investigational antibody-drug conjugate developed by AstraZeneca with Daiicho Sankyo, led to clinically meaningful responses in patients with advanced HER2-positive breast cancer, a Phase 2 clinical trial shows.

Trastuzumab deruxtecan is a combination of the anti-cancer HER2-targeting antibody trastuzumab (marketed under the brand name Herceptin), and an investigational cancer-killing agent called deruxtecan (a derivative of exatecan).

According to findings from a previous pivotal Phase 1 trial (NCT02564900), treatment with trastuzumab deruxtecan led to unprecedented clinical activity, without significant side effects, in a group of 115 women who had been diagnosed with HER2-positive breast cancer.

In this Phase 1 trial, patients had received a median of seven prior treatments, including several HER2-targeted therapies, but 60% still responded to trastuzumab deruxtecan, and 94% had their disease stabilized for a considerable period of time.

Responses lasted for a median of 20.7 months, and patients remained alive and without signs of disease worsening for 22.1 months.

According to the companies, these results have now been confirmed by the top-line findings from the ongoing, multicenter, randomized, open-label Phase 2 DESTINY-Breast01 trial (NCT03248492).

The study was designed to assess the safety and efficacy of trastuzumab deruxtecan at a dose of 5.4 mg/kg in 253 patients with inoperable and/or metastatic HER2-positive tumors who had been previously treated with the HER2 therapy Kadcycla (ado-trastuzumab emtansine).

The first phase of the trial included a pharmacokinetic stage, to assess drug absorption and excretion properties, and a dose-finding stage, in which the optimal dose of trastuzumab deruxtecan was determined.

The second phase of the study focused on assessing the safety and efficacy of trastuzumab deruxtecan in two groups of patients: those who had either failed trastuzumab emtansine and those who discontinued treatment with that agent.

The trial’s primary outcome was to determine the percentage of patients achieving an objective response rate (in which the cancer disappeared, or shrank considerably). Secondary outcomes included:

• duration of response (the time patients kept responding to treatment)
• progression free-survival (the time patients lived without their disease worsening)
• overall survival (the time patients remained alive)
• disease control rate (the percentage of patients whose disease was kept under control)
• clinical benefit rate

“We are encouraged to see positive data from trastuzumab deruxtecan, with the DESTINY-Breast01 trial now reinforcing what earlier data have shown. We believe this antibody drug conjugate has the potential to redefine the treatment of patients with HER2-expressing cancers, and we are eager to bring it as quickly as possible to patients with refractory HER2-positive breast cancer who continue to have high unmet medical need,” José Baselga, executive vice president of oncology research and development at AstraZeneca, said in a press release.

In 2016, trastuzumab deruxtecan was granted fast track status by the U.S. Food and Drug Administration (FDA). Then, in 2017, it received breakthrough therapy designation from the FDA. Now, both companies are hopeful the new findings will support the submission of a biologics license application they are planning to file with the FDA later this year.

“These results confirm our commitment to pursue accelerated regulatory pathways in HER2-positive metastatic breast cancer with trastuzumab deruxtecan. We are more dedicated than ever to our comprehensive and ambitious development strategy evaluating the potential across a spectrum of HER2–expressing cancers including breast, gastric, lung and colorectal,” said Antoine Yver, MD, executive vice president and global head of oncology research and development at Daiichi Sankyo.

AstraZeneca and Daiichi Sankyo are planning to present data from the DESTINY-Breast01 trial at an upcoming medical meeting.