AstraZeneca, Daiichi tout Enhertu trial win in earlier, broader HER2-low breast cancer

AstraZeneca and Daiichi Sankyo’s trailblazing Enhertu appears to have outdone itself.

After spearheading the new HER2-low category in breast cancer treatment, Enhertu has shown it could be useful against HR-positive metastatic breast cancer with even lower expression of the HER2 protein.

Enhertu significantly outperformed standard chemotherapy at extending the time before tumor progression or death among patients with HR-positive, HER2-low metastatic breast cancer who had tried at least one prior line of endocrine therapy, AZ and Daiichi said Monday. The phase 3 DESTINY-Breast06 trial has therefore met its primary endpoint.

The trial was designed to move the HER2-targeted antibody-drug conjugate one line earlier in the HER2-low breast cancer treatment sequence than its existing FDA approval designating it for use after chemotherapy. That 2022 nod marked the first for a HER2-low indication.

Besides its earlier-line setting, the new phase 3 trial also boasted a positive readout that could potentially help Enhertu reach patients whose tumors have even lower HER2 expression than the current HER2-low definition.

Researchers observed a “statistically significant and clinically meaningful” improvement in progression-free survival for Enhertu in a broader trial population that also included patients with HER2-ultralow cancer, AZ and Daiichi said. A subgroup analysis showed that the improvement was consistent between the HER2-low and HER2-ultralow populations, the companies added.

“Plans for global regulatory submissions are underway,” Daiichi said.

The HER2-low category allows HER2 expression as low as a IHC 1+ reading. For HER2-ultralow, a tumor’s HER2 expression is deemed below IHC 1+, or IHC 0 but with membrane staining. The broader IHC 0 category currently includes no or incomplete staining that’s barely perceptible in less than 10% of tumor cells.

As AZ’s oncology R&D head, Susan Galbraith, Ph.D., noted during the company’s first-quarter earnings call last week, HER2-ultralow patients still have a higher-than-normal number of HER2 receptors on the cell surface.

“That’s one of the reasons why we think there’s a potential to go beyond the 1+ group into that ultralow group,” Galbraith said on the call.

By AZ and Daiichi’s estimate, about 60% to 65% of HR-positive, HER2-negative breast cancers are actually HER2-low, and another 25% may be HER2-ultralow, leaving just about 10% true HER2-negative cases.

Data on whether Enhertu could prolong patients’ lives remained immature in DESTINY-Breast06, but the trial showed an “early trend” toward an overall survival improvement for Enhertu in both the primary HER2-low group and in the overall trial population, AZ and Daiichi said.

The data “reinforce the potential for use of Enhertu earlier in the treatment landscape and in an even broader patient population,” Daiichi Sankyo’s global head of R&D, Ken Takeshita, said in a statement Monday.

“DESTINY-Breast06 shows that Enhertu could become a new standard of care for patients with HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy,” Galbraith said in her Monday statement.

Pioneering new treatment paradigms won’t be easy. Back on AZ’s full-year 2023 earnings call in February, the company’s oncology business chief, Dave Fredrickson, acknowledged that while Enhertu was still expanding market share in the traditional HER2-positive field, it had reached a bottleneck in HER2-low market penetration. At that time, Fredrickson pointed to the need for a “more complicated discussion” with doctors about multiple treatment options within the traditional HR-positive, HER2-negative category.  

Between AZ and Daiichi, Enhertu brought in $879 million in sales in the first quarter. For Daiichi, the Japanese pharma projects its Enhertu sales—including profit share in AZ’s territory—could jump 28% to reach 508.4 billion Japanese yen ($3.2 billion) for its fiscal year 2024, which ends in March 2025.

Earlier this month, the HER2 ADC snagged a tumor-agnostic approval from the FDA for previously treated HER2-positive solid tumors regardless of their location.