AstraZeneca Submits NDA for Capivasertib, a First-in-Class AKT Inhibitor, in China for HR+/HER2- Advanced Breast Cancer

On October 10, the CDE website showed that AstraZeneca's AKT inhibitor Capivasertib marketing application was accepted. Based on clinical trial progress, the indications are speculated to be for use in combination with Faslodex (fulvestrant) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer, whose disease has recurred or progressed during or after receiving endocrine-based therapy.

Capivasertib is a potential first-in-class highly selective inhibitor of AKT1/2/3. Activation of the AKT signaling pathway, including alterations in PIK3CA, AKT1, and PTEN, can be observed in many patients with HR+/HER2- advanced breast cancer, but may also occur in patients without these genetic alterations. The AKT signaling pathway is associated with the development of resistance to endocrine therapy.

This marketing application is based on positive data from a Phase III study codenamed CAPItello-291. This study is a global, multicenter, double-blind, randomized Phase III clinical trial that enrolled a total of 708 patients. It aims to evaluate the efficacy and safety of capivasertib plus fulvestrant versus placebo plus fulvestrant in patients with HR+/HER2- advanced breast cancer whose disease has recurred or progressed during or after treatment with aromatase inhibitors (AI). The study allowed patients who had previously received CDK4/6 inhibitor therapy (at least 51%), but had not been previously treated with SERD, mTOR inhibitors, PI3K inhibitors, or AKT inhibitors.

The results showed that, for the primary endpoint, the median PFS was 7.2 months in the capivasertib plus fulvestrant group and 3.6 months in the placebo plus fulvestrant group in the overall population; capivasertib plus fulvestrant reduced the risk of disease progression or death by 40% (HR=0.60 (0.51-0.71, two-sided P＜0.001)).

In terms of ORR, the ORR in the overall population was 22.9% for the capivasertib + fulvestrant group and 12.2% for the placebo + fulvestrant group; in the AKT pathway-altered population, the ORR was 28.8% and 9.7% for the two groups, respectively. OS data are not yet mature (28% overall maturity).

In terms of safety, in the overall population, the proportions of any adverse events in the capivasertib + fulvestrant group and the placebo + fulvestrant group were 96.6% and 82.3%, respectively; the proportions of any serious adverse events were 16.1% and 8.0%, respectively; the proportions of discontinuation due to any adverse event were 13.0% and 2.3%, respectively. Common adverse reactions included diarrhea, nausea, rash, fatigue, vomiting, headache, etc.

In June 2023, AstraZeneca announced that the FDA had accepted the New Drug Application (NDA) for capivasertib in combination with Faslodex (fulvestrant) and granted it Priority Review for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer whose disease has recurred or progressed during or after treatment with an endocrine-based regimen. The PDUFA date for this application is in the fourth quarter of 2023. If approved, capivasertib will become the first AKT inhibitor to be marketed.

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