Oct. 27, 2022

Trial led by Winship researcher shows that patients with rare mutation benefit from targeted therapy

Photo of Trial led by Winship researcher shows that patients with rare mutation benefit from targeted therapy

A national clinical trial led by a Winship Cancer Institute of Emory University researcher has found a promising signal for the AKT inhibitor ipatasertib. The single-arm phase 2 study of 32 patients with various cancer types harboring the rare AKT1 E17K mutation who received treatment with ipatasertib in the NCI-MATCH precision medicine cancer trial were presented at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics held in Barcelona, Spain, on October 26-28, 2022. Arm Z1K of NCI-MATCH met its primary endpoint, with ipatasertib demonstrating clinically significant activity in patients, warranting additional studies.

"The confirmed objective response rate for ipatasertib in tumors with AKT1 E17K mutations was 22% or 7 of 32 patients, and an additional 18 patients (56%) experienced stability of disease (tumors neither shrank nor grew)," said Carolyn McCourt, MD, a gynecologic oncologist at Washington University in St. Louis, Missouri, USA, who presented the findings at the conference.

The ECOG-ACRIN Cancer Research Group is leading the trial with the National Cancer Institute (NCI), part of the National Institutes of Health, and with the participation of the NCI National Clinical Trials Network (NCTN).

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 a given arm signals that the therapy warrants further study. 

"The 22% response rate is clinical validation that patients with AKT1 E17K mutations can respond to an AKT inhibitor, and the data warrants further evaluation," said McCourt. 

There are currently no approved AKT inhibitors for cancer treatment. "Several clinical trials have utilized AKT inhibitors either alone or in combination with other cancer-directed therapies with some success," she said. 

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% (10 of 35 patients) with AKT1 E17K-mutated metastatic tumors (Kalinsky KM. JAMA Oncol. December 30, 2020). Arm Z1K and Arm Y are among the few, if only, basket trials to study AKT inhibitors across multiple cancer types. 

"It is exciting to see another NCI-MATCH arm demonstrating anti-cancer activity and significant clinical benefit when targeting the AKT E17K mutation," said Kevin M. Kalinsky, MD, MS, the director of breast medical oncology and the Glenn Family Breast Center at Winship Cancer Institute of Emory University and associate professor at the Emory University School of Medicine, who led both Arm Z1K and Arm Y.

Although the PI3K-AKT pathway is one of the most commonly altered pathways in cancer, mutations in AKT genes rarely occur (only 2-3% of breast cancer cases, for example). 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 (Stempke-Hale K, Cancer Res, 2008).

"These positive results, especially in patients with women’s cancers harboring this genotype, open new avenues for treatment and should prompt trials directed to exploring the optimal way to incorporate ipatasertib into standard treatments for these diseases," said ECOG-ACRIN Group Co-Chair Peter J. O’Dwyer, MD, co-chair for NCI-MATCH trial and a medical oncologist at the Penn Medicine’s Abramson Cancer Center in Philadelphia, Pennsylvania, USA.

Trial Results

Among 32 evaluable patients, the histologies included breast (20), gynecologic (7), prostate (2) and other (squamous cell carcinoma of the anus, salivary gland and lung squamous cell carcinoma). 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.

Median overall survival was 18 months. The estimated 6-month progression-free survival (PFS) rate was 44%. Median PFS was 5.4 months. At the time of abstract submission, two patients remained on study treatment, at 19 and 26 months. There were no new safety signals.

"We have found a signal, but additional clinical trials will be needed to know why some patients did not have a response and why some had a prolonged time of therapy before the tumor grew," said McCourt. "In addition, we plan to further analyze tumor tissue to determine if there are additional molecular factors that help predict which patients will or won't respond to the drug."

This article was adapted from a press release issued by ECOG-ACRIN.



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