Phase 3 Trial to Compare Enhertu to Kadcyla in HER2-Positive, High Risk Patients

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oncolytic virus combo, IRENE trial

Daiichi Sankyo and AstraZeneca are initiating a global Phase 3 trial to compare Enhertu (fam-trastuzumab deruxtecan-nxki) to Kadcyla (ado-trastuzumab emtansine, also called T-DM1) as adjuvant therapy in patients with HER2-positive early breast cancer, who remain at high risk of recurrence after neo-adjuvant therapy.

These two types of therapy— adjuvant and neo-adjuvant — address different aspects of cancer treatment.

Neo-adjuvant therapy aims to make tumors easier to remove by shrinking them before surgery. Adjuvant treatment aims to eradicate cancer cells that remain after surgery,  helping to lower the chance that the cancer returns.

“Despite recent improvements and approvals of new medicines, there remain significant clinical needs for patients with HER2 positive early breast cancer with residual invasive disease after completing neo-adjuvant treatment. We recognize the important opportunity that exists post-surgery to slow disease progression with further adjuvant treatment,” Antoine Yver, MD, MSc, executive vice president of Daiichi Sankyo said in a press release.

The open-label and randomized trial, named DESTINY-Breast05, will recruit patients with invasive cancer that remains in the breast or lymph nodes following neo-adjuvant treatment.

These patients tend to have a higher risk of disease recurrence or death than those with no detectable cancer after surgery, or what is known as a pathological complete response.

Patients will be defined as high-risk based on the operability of their tumors, and randomized 1:1 to receive either Enhertu or Kadcyla.

The study’s primary endpoint, or goal, is invasive disease-free survival. Secondary goals include overall survival and disease-free survival. Patients will be monitored throughout for adverse side effects, and investigators will measure each medication’s pharmacokinetics (how the medication moves through the body) and disease-related biomarkers.

DESTINY-Breast05 aims to enroll up to 1,600 patients across about 400 sites in North America, Europe, and Asia, the press release stated.

Enhertu is an antibody-drug conjugate, made by combining a HER2-specific antibody and the cancer-killing agent deruxtecan, a derivative of exatecan. The antibody latches onto the HER2 protein on the surface of cancer cells, whereupon exatecan can kill the cell. This mechanism makes it a potential treatment for all types of HER2-positive cancers. (HER2 stands for human epidermal growth factor receptor 2.)

In the earlier Phase 2 DESTINY-Breast01 trial (NCT03248492), 56% of participants taking Enhertu saw their tumors shrink significantly. Tumors disappeared completely in 4.3% of patients.

The U.S. Food and Drug Administration granted Enhertu accelerated approval for the treatment of inoperable or metastatic HER2-positive breast cancer this year. It carries boxed warnings for interstitial lung disease and embryo-fetal toxicity.

The medication is also approved in Japan to treat adults with HER2-positive inoperable or metastatic breast cancer that is resistant to chemotherapy, or those who cannot tolerate it, and is under scientific review by the European Medicines Agency.

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