Enhertu Approved for HER2-Low Cancer

This approval, which is based on results from the DESTINY-Breast06 phase III trial presented at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and published in The New England Journal of Medicine, follows Priority Review and Breakthrough Therapy Designation by the FDA for Enhertu in this indication. In the DESTINY-Breast06 trial,  Enhertu  demonstrated a 36% reduction in the risk of disease progression or death versus chemotherapy in the overall trial population of patients with chemotherapy-naïve HR positive, HER2 low or HER2 ultralow metastatic breast cancer (n=866) (hazard ratio [HR] 0.64; 95% confidence interval [CI]: 0.54-0.76; p<0.0001). A median progression-free survival (PFS) of 13.2 months (95% CI: 12.0-15.2) was seen in patients treated with  Enhertu  compared to 8.1 months (95% CI: 7.0-9.0) in patients treated with chemotherapy. 

The confirmed objective response rate (ORR) in the overall trial population was 62.6% (95% CI: 57.6-67.4) in the  Enhertu  arm versus 34.4% (95% CI: 29.7-39.4) in the chemotherapy arm as assessed by blinded independent central review (BICR). There were 10 (2.5%) complete responses (CRs) and 236 (60.1%) partial responses (PRs) seen in the Enhertu  arm compared to zero (0%) CRs and 134 (34.4%) PRs in the chemotherapy arm. The median duration of response (DOR) was 14.3 months in the  Enhertu  arm (95% CI: 12.5-15.9) versus 8.6 months in the chemotherapy arm (95% CI: 6.9-11.5) as assessed by BICR. In the HER2 low population (n=713) (HR 0.62; 95% CI: 0.52-0.75; p<0.0001), median PFS was 13.2 months (95% CI: 11.4-15.2) in the  Enhertu arm compared to 8.1 months (95% CI: 7.0-9.0) in the chemotherapy arm. Confirmed ORR was 62.0% (95% CI: 56.5-67.3) versus 35.2% (95% CI: 30.0-40.7) in the chemotherapy arm. There were 9 (2.8%) CRs and 193 (59.2%) PRs seen in the Enhertu  arm compared to zero (0%) CRs and 114 (35.2%) PRs in the chemotherapy arm. Median DOR was 14.1 months (95% CI: 11.9-15.9) versus 8.6 months (95% CI: 6.7-11.3) in the chemotherapy arm.

An exploratory analysis of the HER2 ultralow population (n=153) (HR 0.76; 95% CI: 0.49-1.17) showed the clinically meaningful improvement in PFS was consistent between patients with HER2 low and HER2 ultralow expression, with 15.1 months (95% CI: 10.0-17.3) reported in the Enhertu arm and 8.3 months (95% CI: 5.8-15.2) in the chemotherapy arm. Confirmed ORR was 65.7% (95% CI: 53.1-76.8) in the Enhertu arm and 30.8% (95% CI: 19.9-43.4) in the chemotherapy arm. Median DOR was 14.3 months (95% CI: 11.8-not estimable [NE]) versus 14.1 months (95% CI: 5.9-NE) in the chemotherapy arm.

DESTINY-Breast06 is a global, randomized, open-label, phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab paclitaxel) in patients with HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (defined as IHC 0 with membrane staining) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients also were eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting first-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

"Enhertu continues to redefine the classification and treatment of HR positive metastatic breast cancer with important new data across the spectrum of HER2 expression,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. “Approval underscores our ongoing commitment to realizing the full potential of this innovative antibody drug conjugate and represents another paradigm shift in how certain breast cancers can be treated.”

“Building on the practice-changing previous approvals for Enhertu this new approval brings this important medicine to an earlier treatment setting and a broader patient population with HER2 expressing metastatic breast cancer,” said Dave Fredrickson, Executive Vice President, Oncology Hematology Business Unit, AstraZeneca. “The approval also highlights the importance of testing metastatic breast cancer tumors for detectable staining with a standard IHC test to identify those who may be eligible for treatment with Enhertu following endocrine therapy.

" Endocrine therapy is typically used in the initial treatment of HR positive metastatic breast cancer and following progression, subsequent chemotherapy is associated with poor outcomes,” said Dr. Aditya Bardia,  Program Director of Breast Oncology and Director of Translational Research Integration, UCLA Health Jonsson Comprehensive Cancer Center and Investigator in the DESTINY-Breast06 trial. “With a median progression-free survival exceeding one year and a response rate of more than 60 percent, trastuzumab deruxtecan offers a potential new standard of care for patients with hormone receptor positive, HER2 low or HER2 ultralow metastatic breast cancer following endocrine therapy.”

 Krissa Smith, Vice President, Education, Susan G. Komen said “It is critical for patients to understand the HER2 status of their metastatic breast cancer to help them make informed treatment decisions. Patients with tumors that are HER2 low or HER2 ultralow now have more options to consider with their healthcare team.”

See citation- Bardia A, Hu X, Dent R, Yonemori K, et al. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med 2024;391:2110 DOI: 10.1056/NEJMoa24070