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Capivasertib may be helpful against tumors with rare AKT mutation

JAMA Oncology
Reuters Health - 08/01/2021 - The protein kinase B/AKT inhibitor capivasertib shows a clinically significant objective response rate in patients with an AKT1 E17K-mutated metastatic tumor, according to a study targeting genetic tumor abnormalities,

"As a field we are increasingly trying to move away from a one-size-fits-all approach when treating our patients with cancer," Dr. Kevin Kalinsky told Reuters Health by email. "In this National Cancer Institute-sponsored study, we identified that patients with previously treated metastatic cancer who have a rare mutation found in their tumor (AKT E17K mutation) can significantly respond when administering an oral drug that specifically targets that mutation."

Of the more than 5,500 patients in the NCI-MATCH trial who had central testing of their tumor, only 68 patients (1.2%) had an AKT1 E17-mutated tumor, Dr. Kalinsky of the Winship Cancer Institute at Emory University, in Atlanta, and colleagues note in JAMA Oncology.

All had progressed on standard treatment and 35 were ultimately enrolled and assigned to the subprotocol study. Most participants (30) were women, and breast and gynecologic cancers were the most common.

The patients were treated with oral capivasertib 480 mg twice daily for four days weekly in 28-day cycles until disease progression or unacceptable toxicity. Those who continued with hormone treatment for breast cancer received capivasertib at 400 mg per day. Median follow-up was for 28.4 months.

The overall response rate was 28.6% and one patient with endometrioid adenocarcinoma of the endometrium achieved a complete response and was still on therapy at 35.6 months. At six months, progression-free survival overall was 50%.

Fifteen patients (43%) had at least one adverse-event-related dose modification during treatment. Adverse events, including hyperglycemia and rash, led to discontinuation in 11 patients (31%).

The researchers stress that, "Interpretation of these results should be restricted to patients with an AKT1 E17K-mutated tumor. Patients with a tumor with concomitant KRAS, NRAS, HRAS, and BRAF sequence variations were excluded because of potential resistance concerns."

Dr. Kalinsky concluded, "This trial is another example of our goal of tailoring therapies based upon the biology of a patient's cancer."

Dr. Aditya Bardia, director of Precision Medicine in the Center for Breast Cancer at Massachusetts General Hospital Cancer Center, in Boston, told Reuters Health by email, "The results of the AKT arm of the NCI-MATCH trial demonstrated clinical activity with the pan-AKT inhibitor, capivasertib, in patients with AKT1 mutant solid tumors, and provides proof of principle for the precision medicine approach."

"As clinical trials further evaluate AKT inhibitors," said Dr. Bardia, who was not involved in the study, "consideration to both toxicity (31% of patients discontinued due to adverse effects) and genomic heterogeneity will need to be carefully considered to maximize the clinical efficacy for patients with solid tumors, including metastatic breast cancer."

SOURCE: https://bit.ly/3n8Zbn6 JAMA Oncology, online December 30, 2020.

By David Douglas

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