Daiichi Sankyo and AstraZeneca’s Enhertu Receives Third FDA Breakthrough Therapy Designation in Breast Cancer for HER2-Low Metastatic Disease

On April 27, AstraZeneca and Daiichi Sankyo jointly announced that the HER2 ADC drug Enhertu has received FDA Breakthrough Therapy Designation (BTD) for patients with unresectable or metastatic breast cancer who are HER2-low (IHC 1+ or IHC 2+/ISH-negative) and have relapsed or progressed within six months of adjuvant therapy after receiving at least one prior systemic treatment.

This is Enhertu's third BTD in breast cancer. Enhertu previously received Breakthrough Therapy Designations for second-line HER2-positive metastatic breast cancer in 2021 and for later-line HER2-positive metastatic breast cancer in 2017.

DESTINY-Breast04 is a randomized, open-label, global multicenter registrational Phase III clinical trial evaluating Enhertu (5.4mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel) in patients with HR-positive (n=480) or HR-negative (n=60) HER2-low unresectable and/or metastatic breast cancer who had previously received one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either Enhertu or chemotherapy. The primary endpoint was PFS assessed by BICR in HR-positive patients, and key secondary endpoints included PFS assessed by BICR in all patients, OS in HR-positive patients, and OS in all patients.

The results showed that DESTINY-Breast04 met its primary endpoint, with Enhertu demonstrating superior PFS compared to SOC in HR-positive, HER2-low metastatic breast cancer patients previously treated. Additionally, the trial achieved all key secondary endpoints, significantly improving both PFS and OS regardless of HR expression status. The safety profile was consistent with previous clinical trials, with no new safety signals identified.

The breakthrough in the DESTINY-Breast04 study is expected to help AstraZeneca and Daiichi Sankyo cover the entire field of breast cancer treatment with their leading ADC drugs, including exploration in different HER2 expression states and different HR expression states. Meanwhile, beyond broad coverage, Daiichi Sankyo and AstraZeneca are also advancing the development of these therapies to earlier lines of treatment (see figure below). Following breast cancer, the efficacy of Enhertu will also be explored in gastric cancer (GC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC).

Enhertu (HER2) Breast Cancer Development Program