Results from a single-arm
phase 2 study of 32 patients with various cancer types harboring the rare AKT1
E17K mutation who received treatment with the oral AKT inhibitor ipatasertib in
the NCI-MATCH precision medicine cancer trial are part of the 34th EORTC-NCI-AACR
Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. Arm Z1K of NCI-MATCH met its primary
endpoint, with ipatasertib demonstrating clinically significant activity in
patients, warranting additional studies.

The primary objective of each of the 39 arms
in NCI-MATCH is to determine the proportion of patients who experience an
objective response, including partial or complete. Under predefined criteria,
an overall response rate greater than 16% in given arm signals that the therapy
warrants further study.

Arm Z1K is the second NCI-MATCH arm to explore
the clinical activity of an AKT inhibitor in patients with AKT1 E17K mutations. The final results of Arm Y show
that capivasertib, another orally administered AKT inhibitor, had a clinically
significant objective response rate of
28.6% with AKT1 E17K-mutated metastatic tumors.

Although the PI3K-AKT pathway is one of the
most commonly altered pathways in cancer, mutations in AKT genes rarely occur. Of those that are reported, the majority are an AKT1 point
mutation in the pleckstrin homology domain that replaces a glutamic acid with
lysine at residue 17 (E17K). Studies of both tumors and cancer cell
lines confirm a quantitative increase in activated AKT due to the E17K point
mutation, and overall levels of pan-AKT antibodies appear to correlate with
sensitivity to AKT inhibition

Among 32 evaluable patients,
the histologies included breast (20), gynecologic (7), prostate (2), and other. It was a heavily pretreated population, with 27/32 patients having
received three or more prior lines of treatment.

Patients received ipatasertib 400 mg orally once daily in 28-day cycles
until progression or unacceptable toxicity. Tumor assessments were repeated
every two cycles. The histologies among patients with a partial response are as
follows: four cases of breast cancer (three HR+/HER2- and one HR+/HER2+), one
endometrioid adenocarcinoma, one squamous cell of the anus, and one salivary
gland cancer. The median duration of response was 8.5 months. There were no complete responses.

overall survival was 18 months. The estimated 6-month progression-free survival
(PFS) rate was 44%.


NCI-MATCH cancer trial finds a promising signal for the AKT inhibitor ipatasertib, (2022, October 27), MEETING 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, ECOG-ACRIN Cancer Research Group,

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