More than three-quarters of heavily pre-treated patients given a drug that targets a mutated protein commonly linked to cancer formation and growth saw their tumors shrink or remain stable, according to a study presented at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Findings demonstrated that the drug, called ipatasertib, inhibits a mutated form of AKT1 E17K that's active in a variety of tumors, including resistant and rare cancers. About 22 percent of patients in the study saw their tumors shrink, while tumors in another 56 percent remained stable.
"Ipatasertib demonstrated significant activity in various histologies, including rare cancers, in patients with pre-treated AKT1 E17K mutant tumors," said Kevin Kalinsky, MD, MS, Director of Breast Medical Oncology and the Glenn Family Breast Center at Winship Cancer Institute of Emory University, who presented results during a conference press briefing.
The findings are part of a larger NCI-MATCH clinical trial whose goal is to find targeted cancer therapies based on genetic changes in patient tumors, rather than where in their body the tumor grows.
Study Details
For this study, a team of researchers focused on the protein kinase called AKT (also known as protein kinase B or PKB) which, when triggered by a signaling cascade called phosphoinositide 3-kinase (P13K), plays a pivotal role in cell growth, proliferation, survival, and metabolism.
One of the most common AKT mutations occurs at the 17th amino acid where the glutamate (E) is switched to a lysine (K). This E17K mutation causes AKT to be constantly turned on independently of P13K, the usual activator of AKT. This simple E17K mutation-or "hot spot"-caused by the substitution of a single amino acid, appears to cause cells to grow and divide uncontrollably, triggering a variety of tumor types of the breast, colon, lung, and ovaries.
What's more, many of these tumors are resistant to traditional chemotherapy. The mutation is estimated to be presented in 4 percent of breast tumors, around 2 percent of endometrial tumors, and a small proportion of other solid tumors.
Though researchers have been aware of AKT's role in cancer for decades, currently no AKT inhibitor has been approved for use by the FDA. For this reason, cancer researchers around the world have been trying to develop a drug that targets AKT with the hope and expectation that inhibiting this mutation would likely have a profound anti-cancer impact. One such drug is ipatasertib, a highly selective small molecule that binds to and blocks the activation of ATK, resulting in cell cycle arrest, inhibition of tumor cell proliferation, and initiation of tumor cell death.
From August 2019 to November 2020, some 35 patients with AKT1 E17K mutations were given 400 mg of ipatasertib once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response with a 16 percent response considered a promising result; secondary endpoints were progression-free survival (PFS), 6-month PFS, and toxicity.
Of the 35 patients, one never started the regimen while two others were ineligible resulting from prior recent therapy. Of the remaining 32 patients, 29 were female with nearly two-thirds having breast cancer (20/32). The majority of these women were HR+/HER2 negative where the prevalence of AKT1 E17K seems most common. Of the remaining patients, about 22 percent had gynecological tumors, with a small number of other cancers, including prostate (2/32), squamous cell carcinoma of the lung (1/32), squamous cell carcinoma, anus (1/32), and tumors of the salivary gland (1/32). Two-thirds of the patients had more than three lines of prior treatment.
Results showed that seven of the 32 patients (22%) saw their tumors shrink with a 9.9-month median duration of partial response. Tumors in another 18 patients or 56 percent of this cohort stopped growing or remained stable. Two patients remain on study, one with breast cancer and another with a gynecological cancer. Estimated PFS was 44 percent.
"I just wanted to highlight that this was a pre-treated population, where two-thirds of the patients had more than three prior lines of treatment," Kalinsky said. "So, this is a pre-treated population where we're seeing this sort of clinical activity."
Side effects among these patients were "something we see with this class of agents," he noted, including gastrointestinal issues, such as diarrhea and vomiting, high blood sugar, rash, and low-grade anorexia. Several patients required at least one dose modification with one patient discontinuing treatment due to progressive disease and adverse events.
"This is a relatively small patient population and we do not have a large number of individual tumor types," cautioned Carolyn McCourt, MD, Associate Professor of Obstetrics and Gynecology in the Division of Gynecologic Oncology at Washington University School of Medicine, and also co-author of the study.
"We need to do more research to understand why some patients' tumors did not respond to ipatasertib, while other patients experienced a prolonged time when their disease remained stable on this treatment," she added in a press release. "We need to investigate whether we can combine ipatasertib with other drugs to improve the outcome for more patients."
Kalinsky said other ongoing studies are trying to identify any other specific biomarkers that could predict which tumors might best respond to this drug. In addition, several other randomized clinical studies are testing a variety of AKT inhibitors, including ipatasertib by itself or in combination with other drugs.
"I think some of these have focused on specific histology," said James L. Gulley, MD, PhD, Co-Chair of the ENA Symposium who did not participate in this study. "I think from there we'll see whether there are specific populations that benefit, [and] if it's really limited to those who have alterations of the P13AKT pathway or not. I also think that will help inform if this drug is available based upon a specific histology."
Warren Froelich is a contributing writer.