AstraZeneca's Capivasertib: A First-in-Class AKT Inhibitor Nears Approval for HR+/HER2- Advanced Breast Cancer

AKT, also known as phosphokinase B (PKB), plays a key role in various cascade signaling mechanisms involving cell growth and division, inhibition of apoptosis, and angiogenesis.

For AKT, which is at the central node of the key PI3K/AKT/mTOR signaling pathway, events such as PTEN loss, AKT/PIK3CA mutations, or amplifications can lead to the overactivation of the AKT signaling pathway, triggering the occurrence and development of tumors. Relevant studies have also indicated that AKT activation is associated with drug resistance in cancer treatment. Consequently, AKT has become a popular target in cancer therapy.

Reviewing the Development History of AKT Drugs: The earliest companies to engage in the exploration and clinical development of AKT inhibitors were giants such as GlaxoSmithKline, Merck, Eli Lilly, Bayer, AstraZeneca, and Roche (Genentech). However, despite their prestigious origins, the AKT inhibitors developed by these companies were either sold off or had their development terminated. Examples include Eli Lilly's LY2780301 and Bayer's BAY1125976, which, to a certain extent, highlight the uncertainty of new drug development as well as the immense complexity and challenges associated with the AKT signaling pathway. Merck's MK-2206 also ultimately failed after more than 40 early trials.

On June 12, AstraZeneca announced that the FDA had accepted the company's new drug application (NDA) for its first-in-class AKT inhibitor capivasertib in combination with Faslodex (fulvestrant) and granted it priority review status., 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 receiving endocrine-based therapy. The FDA is expected to make a regulatory decision in the fourth quarter of 2023.This also meansAfter more than 40 years of arduous exploration, the AKT target has finally seen a glimmer of hope.

This NDA is also under review by the Orbis Project, an FDA initiative that provides a framework for the simultaneous submission and review of oncology drugs among participating international partners to accelerate drug approvals worldwide.

Capivasertib is a highly efficient and selective inhibitor of three AKT subtypes (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 NDA is based on data from a Phase III trial, code-named CAPItello-291, the results of which were recently published online in The New England Journal of Medicine.

CAPItello-291 Study is a global, multicenter, double-blind, randomized Phase III clinical trial that enrolled 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 who experienced disease recurrence or progression during or after AI treatment. The study allowed patients to have previously received CDK4/6 inhibitor therapy (at least 51%) but not prior treatment with SERD, mTOR inhibitors, PI3K inhibitors, or AKT inhibitors.

For the primary endpoint, in the overall population, the median PFS for the capivasertib + fulvestrant group and the placebo + fulvestrant group were 7.2 months and 3.6 months, respectively. Capivasertib + fulvestrant reduced the risk of disease progression or death by 40% (HR=0.60 (0.51-0.71, two-sided P＜0.001)).

In the population with AKT pathway alterations, the median PFS for the capivasertib + fulvestrant group and the placebo + fulvestrant group were 7.3 months and 3.1 months, respectively, HR=0.50 (0.38-0.65, two-sided P＜0.001).

Exploratory analysis showed that in the population with unaltered AKT pathway (including unknown status), the median PFS for the two groups were 7.2 months and 3.7 months, respectively, HR=0.70 (0.56-0.88).

Regardless of the presence of liver metastases or prior treatment with CDK4/6 inhibitors, the HR of the capivasertib + fulvestrant group showed superiority.

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 any adverse events leading to treatment discontinuation were 13.0% and 2.3%, respectively. Common adverse reactions included diarrhea, nausea, rash, fatigue, vomiting, headache, etc.

Breast cancer is the most common cancer globally, with an estimated 2.3 million patients diagnosed annually. It is projected that in 2023, over 290,000 patients will be diagnosed and more than 43,000 people will die from the disease in the United States. More than 65% of breast cancer tumors are considered HR-positive and HER2-low or negative. Endocrine therapy is widely used to treat HR-positive breast cancer; however, many patients with advanced disease develop resistance to first-line CDK4/6 inhibitors and endocrine therapies, necessitating alternative treatment options.

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