NEW YORK – The US Food and Drug Administration on Monday approved AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) for previously treated patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low or HER2-ultralow breast cancer.
The approval expands use of the antibody-drug conjugate among patients with very low HER2 expression based on immunohistochemistry (IHC) testing. HER2-low is defined as an IHC result of 1+ or 2+ with a negative in situ hybridization (ISH) test, and HER2-ultralow is defined as IHC 0 with membrane staining.
In 2022 and 2023, Enhertu was approved in the US and Europe, respectively, for patients with unresectable or metastatic HER2-low breast cancer who had received prior chemotherapy based on results from the Phase III DESTINY-Breast04 trial. These approvals created a new category of HER2 expression and made previously ineligible patients eligible for HER2-targeted therapy.
Historically, a score of IHC 0 or 1+ or 2+ with negative ISH results has indicated a HER2-negative result. Before Enhertu, to be eligible for HER2-targeted treatment, patients had to have an IHC score of 3+ or 2+ with ISH positivity. These traditional scores still remain for determining patients' eligibility for other HER2-targeted drugs on the market.
The latest Enhertu approval was based on results from the Phase III DESTINY-Breast06 trial, which demonstrated similar outcomes among HER2-low patients and in the exploratory HER2-ultralow group, with a median progression-free survival of 13.2 months on Enhertu in both groups and response rates of 56.5 percent in HER2-low and 61.8 percent in HER2-ultralow patients. These results demonstrated improved outcomes on Enhertu for both groups compared to chemotherapy, which demonstrated a response rate of 32.3 percent and a progression-free survival of 8.1 months in the trial.
In the most recent publication of DESTINY-Breast06 data, researchers said that the overall survival analysis was not mature at data cutoff but noted that the 12-month survival rate was 87 percent on Enhertu versus 81.1 percent on chemo in the overall study. The 12-month survival rate between the HER2-low and -ultralow groups appeared similar, at 87.6 percent and 84 percent, respectively.
"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," Dave Fredrickson, executive VP in the oncology hematology business unit at AstraZeneca, said in a statement. "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."
Some pathologists have questioned how reliable IHC testing is in capturing lower levels of HER2 expression. Meanwhile, clinical guidelines bodies have not yet fully incorporated the HER2-low and -ultralow categories into their HER2 testing guidelines. The American Society of Clinical Oncology and the College of American Pathologists issued updated joint guidelines in 2023, acknowledging the new HER2-low indication for Enhertu, but they also concluded there was limited data in this setting and it was premature to change the traditional HER2 testing paradigm to add HER2 low.