AstraZeneca and Daiichi Sankyo’s Enhertu could unlock another blockbuster market thanks to a new trial win in breast cancer with low HER2 expression, which affects a much larger population than the drug’s existing HER2-positive indication.
In previously treated HER2-low unresectable or metastatic breast cancer, Enhertu topped chemotherapy at prolonging patients’ lives, the companies said. Further, the HER2-targeted antibody-drug conjugate (ADC) was better at staving off tumor progression or death in the pivotal DESTINY-Breast04 trial. The improvements covered patients regardless of their HR status and were “statistically significant and clinically meaningful,” AZ and Daiichi said.
Enhertu is currently approved to treat HER2-positive breast cancer after two or more prior anti-HER2-based regimens in the metastatic setting. The DESTINY-Breast04 trial enrolled HER2-low patients who had progressed on endocrine therapy and who had previously received one to two lines of chemotherapy in the metastatic setting.
While HER2-positive disease represents 15% to 20% of breast cancer cases, about 55% of primary breast cancers are considered HER2-low.
Based on the large patient population, Jefferies analyst Naoya Miura has pegged Enhertu’s risk-adjusted peak sales in the DESTINY-Breast04 third-line patient group at 151 billion Japanese yen ($1.31 billion). Across all indications, Enhertu could reach $5.8 billion global sales at peak, Jefferies’ Peter Welford said in a Monday note.
Enhertu is now the first HER2-directed therapy to show a survival benefit in HER2-low metastatic breast cancer, AZ and Daiichi noted. Low HER2 expression is currently grouped into HER2-negative disease, and the patients are therefore not eligible for HER2-targeted therapies. HER2-low is defined as HER2 protein expression on an immunohistochemistry assay at 1+ or 2+, together with a lack of HER2 gene amplification measured by in situ hybridization.
Beyond efficacy, Enhertu’s rates of a side effect called interstitial lung disease were similar between the current HER2-low breast cancer trial and in late-line HER2-positive disease trials. The potentially life-threatening lung scarring problem is considered a major hurdle to Enhertu achieving more success.
AZ and Daiichi will present detailed data from DESTINY-Breast04 at an upcoming medical meeting and will share the results with regulatory authorities.
Enhertu’s HER2-low success followed another head-to-head win against Roche’s rival ADC Kadcyla in second-line HER2-positive breast cancer. The FDA has put that application under priority review, with a decision expected in the second quarter of this year.
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Meanwhile, hoping to move Enhertu earlier in the treatment order, AZ and Daiichi are also running DESTINY-Breast06 for chemo-naïve, HER2-low, HR-positive patients whose disease progressed on endocrine therapy.
As AZ’s oncology R&D head Susan Galbraith, Ph.D., noted in a statement, the DESTINY-Breast04 results mark a big step forward to potentially expand AZ’s ability to target the full spectrum of HER2 expression. AZ is also collaborating with Daiichi on datopotamab deruxtecan, an ADC targeting TROP-2, which is overexpressed in several cancers including up to 80% of triple-negative breast cancers.