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Enhertu Data in Ultra-Low HER2-Expressing Breast Cancer Offers Opportunities for Label Expansion

NEW YORK – AstraZeneca and Daiichi Sankyo on Monday said they will discuss with regulators new data from the Phase III DESTINY-Breast06 trial, which tested Enhertu (trastuzumab deruxtecan) as a treatment for hormone receptor (HR)-positive metastatic breast cancer patients after they've gotten endocrine therapy and who have low and very low HER2-expressing tumors.

Results from the DESTINY-Breast06 trial showed an improvement in median progression-free survival over chemotherapy in patients with both low HER2-expressing and ultralow HER2-expressing breast cancer. HER2-low tumors are those with an immunohistochemistry (IHC) expression score of 1+ or an IHC 2+ score with a negative result for HER2 gene amplification by in situ hybridization (ISH) testing. HER2-ultralow tumors are those with an IHC 0 result with faint membrane staining or an IHC result of greater than 0 and less than 1.

Enhertu is already approved in the US and Europe for HR-positive or triple-negative breast cancer patients with HER2-low unresectable or metastatic disease after getting chemotherapy in the metastatic setting or developing disease recurrence within six months of completing adjuvant chemotherapy. For this approval, HER2-low expression was defined as an IHC 1+ score or an IHC2+ and ISH negative score. The US Food and Drug Administration has also approved Roche's Pathway Anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody test as a companion diagnostic for Enhertu to identify HER2-low patients.

Historically, tumors were only considered HER2-positive if they had an IHC result of 3+. However, in clinical trials, Enhertu has been effective for patients with lower HER2 expression scores. 

At the time of the earlier approval in the HER2-low setting, experts noted that since the pivotal study included triple-negative breast cancer patients who can have zero or very faint HER2 expression based on traditional testing classifications, there needed to be more clarity on the HER2-low cutoff at which patients would still respond to Enhertu. If AstraZeneca and Daiichi Sankyo achieve regulatory approval for Enhertu based on the DESTINY-Breast06 data, it could provide this needed specificity on the HER2-low cutoff associated with treatment benefit. It will also make the antibody-drug conjugate available to certain HR-positive breast cancer patients earlier in their treatment trajectory and to more patients with even lower HER2 expression in their tumors. 

"The top-line results from DESTINY-Breast06 highlight the importance of continuing to challenge current treatment paradigms and established breast cancer classifications to evolve how we treat patients with HR-positive, HER2-expressing metastatic breast cancer," Ken Takeshita, global head of R&D at Daiichi Sankyo, said in a statement. "Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of Enhertu earlier in the treatment landscape and in an even broader patient population."

AstraZeneca and Daiichi Sankyo said overall survival data from DESTINY-Breast06 are not yet mature, but Enhertu showed an early trend toward overall survival improvement compared to standard-of-care chemotherapy in the trial. Researchers will present the full results at an upcoming medical meeting.