ENHERTU® Gains U.S. Breakthrough Therapy Designation for Specific HER2 Low/Ultralow Metastatic Breast Cancer

ENHERTU® (fam-trastuzumab deruxtecan-nxki) has received the U.S. Breakthrough Therapy Designation (BTD) for treating patients with unresectable or metastatic hormone receptor positive HER2 low or HER2 ultralow breast cancer. This designation applies to patients who have undergone either two lines of endocrine therapy for metastatic disease or one line of endocrine therapy if they experienced disease progression within six months of starting first-line treatment with a CDK4/6 inhibitor or within 24 months of adjuvant endocrine therapy.

ENHERTU is a HER2 directed DXd antibody-drug conjugate (ADC) developed by Daiichi Sankyo and jointly commercialized with AstraZeneca. The U.S. Food and Drug Administration (FDA) grants BTD to expedite the review of drugs that treat serious conditions and fulfill unmet medical needs, demonstrating substantial improvement over existing therapies based on preliminary clinical evidence.

This BTD was issued based on results from the DESTINY-Breast06 phase 3 trial, an international study evaluating the efficacy and safety of ENHERTU against the investigator’s choice of chemotherapy in patients with HR positive, HER2 low, or HER2 ultralow advanced or metastatic breast cancer. Participants had either not received chemotherapy for advanced disease or had undergone prior endocrine therapy in the metastatic setting.

The primary endpoint of DESTINY-Breast06 is progression-free survival (PFS) in the HR positive, HER2 low patient population. Secondary endpoints include overall survival (OS), objective response rate, duration of response, and safety measures. The study involved 866 patients across various global sites.

Breast cancer remains the second most common cancer and a leading cause of cancer-related deaths worldwide, with over two million cases diagnosed in 2022 and significant mortality. Approximately 300,000 cases are diagnosed annually in the U.S. Despite high survival rates for early breast cancer, only about 30% of patients with metastatic breast cancer live beyond five years post-diagnosis.

HER2 is a protein promoting the growth of cancer cells, present in many tumor types, including breast cancer. Patients with high HER2 expression are classified as HER2 positive and treated with targeted therapies, comprising about 15-20% of all breast cancer cases. Historically, tumors not classified as HER2 positive were deemed HER2 negative, although many still show low levels of HER2 expression. Approximately 60-65% of HR positive, HER2 negative breast cancers are HER2 low, and 25% may be HER2 ultralow.

Standard treatments for HR positive metastatic breast cancer often involve endocrine therapies, but their efficacy diminishes after two lines of treatment, leading to chemotherapy, which typically yields poor response rates and outcomes. Before ENHERTU's approval for chemotherapy in HER2 low metastatic breast cancer, there were no targeted therapies for such low HER2 expression cases.

ENHERTU represents a significant advancement in breast cancer therapy. It is approved in over 65 countries for treating various HER2 positive or low cancers. This includes HER2 positive breast cancer (IHC 3+ or ISH+), HER2 low breast cancer (IHC 1+ or IHC 2+/ISH-), HER2 mutant non-small cell lung cancer (NSCLC), and HER2 positive gastric cancer. The development program for ENHERTU includes continued trials across multiple HER2 targetable cancers.

The collaboration between Daiichi Sankyo and AstraZeneca began in March 2019 for ENHERTU and expanded in July 2020 to include datopotamab deruxtecan. This partnership focuses on leveraging both companies' capabilities to develop and commercialize these innovative therapies worldwide.