Phase 3 Study Initiated to Explore Adjuvant Trastuzumab Deruxtecan in HER2+ Breast Cancer

On the heels of practice-changing data with trastuzumab deruxtecan in the DESTINY-Breast01 trial, a phase 3 study was initiated for a head-to-head comparison of fam-trastuzumab deruxtecan-nxki (Enhertu) versus ado-trastuzumab emtansine (T-DM1) as adjuvant treatment of patients with HER2-positive early breast cancer who have a high risk of disease recurrence and residual invasive disease in the breast or axillary lymph nodes following neoadjuvant treatment, Daiichi Sankyo Company and AstraZeneca announced in a press release.¹

DESTINY-Breast05 will explore the use of adjuvant therapy following surgical resection in an attempt to eradicate remaining cancer cells in the breast or other parts of the body to reduce the risk of recurrence. Neoadjuvant therapy, on the other hand, is given prior to surgery to shrink the tumor so that it is easier to remove, but patients with residual invasive disease in the breast or lymph nodes at surgery with this approach are suspected to be at a greater risk for disease recurrence or death compared with those who achieve a pathological complete response.

“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 neoadjuvant treatment. We recognize the important opportunity that exists post-surgery to slow disease progression with further adjuvant treatment,” said Antoine Yver, MD, MSc, executive vice president and global head, Oncology Research and Development, Daiichi Sankyo, in a statement.

The global trial will be conducted in collaboration with the National Surgical Adjuvant Breast and Bowel Project Foundation (NSABP), German Breast Group (GBG), and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO-B), as well as the SOLTI Breast Cancer Research Group.

“NSABP and our academic collaborators are committed to designing and conducting trials that have potential for further improving the way breast cancer is treated by evaluating promising new therapies that may provide patients and physicians with additional treatment options,” stated Charles E. Geyer, Jr, MD, chair of the NSABP Foundation Breast Cancer Committee and Deputy Director of the Houston Methodist Cancer Center. “We are excited to collaborate with Daiichi Sankyo and AstraZeneca on this important study, with the goal of comparing the safety and clinical benefit of the two currently available HER2-directed antibody-drug conjugates in early stage breast cancer.”

Trastuzumab deruxtecan is currently available for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer following at least 2 prior lines of anti-HER2-based therapy in the metastatic setting, which was granted accelerated approval in 2019 based on findings from the phase 2 DESTINY-Breast01 clinical trial. The study demonstrated that the therapy induced an encouraging confirmed objective response rate of 60.3% per independent central review.²

“This research builds on the data from DESTINY-Breast01 which showed durability of response in previously treated HER2-positive metastatic breast cancer,” Yver continued in a statement.¹ “DESTINY-Breast05 will evaluate ENHERTU in patients with early HER2-positive breast cancer, versus T-DM1, the current standard of care, which marks the first time we will evaluate the clinical benefit of ENHERTU in early breast cancer, reflecting our commitment to transforming treatment for even more patients with HER- targetable disease.”

DESTINY-Breast05 is a multicenter, randomized, open-label, active-controlled study in patients with high-risk HER2-positive primary breast cancer who have residual invasive disease in breast and axillary nodes after neoadjuvant therapy. These patients are defined as high risk based on the inoperable cancer at presentation of the disease, including clinical stages T-4, N0-3, M0, or T1-3, N2-3, M0; or operable at presentation, such as clinical stages T1-3, N0-1, or M0, with positive pathological node status (ypN1-3) after neoadjuvant treatment.

Patients will be randomized 1:1 to receive either trastuzumab deruxtecan or T-DM1. The primary end point of the study is invasive disease-free survival per investigator assessment, and secondary end points include overall survival and disease-free survival. Safety end points in DESTINY-Breast05 also include serious adverse events (AEs), treatment-emergent AEs, and AEs of special interest.

_References

_{1. DESTINY-Breast05 head-to-head phase 3 trial of Enhertu versus t-dm1 initiated in patients with her2-postive early breast cancer at high risk after neo-adjuvant therapy. November 2, 2020. Accessed November 10, 2020. https://bwnews.pr/3klM6W2}

_{2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. FDA. December 20, 2019. Accessed November 10, 2020. https://bit.ly/2tzcabv}​