BOSTON – A novel pan-AKT inhibitor was associated in a phase 1 trial with tumor shrinkage in a large proportion of patients with solid tumors bearing a mutation in AKT1.
The investigational compound, labeled AZD5363, targets the AKT1 E17K mutation, which occurs in approximately 0.5% to 4% of many different types of solid tumors. In a phase I trial, 33 of 41 assessable patients with tumors bearing the mutation had regression of tumors, reported Dr. David M. Hyman, acting director of experimental therapeutics at Memorial Sloan Kettering Cancer Center in New York.
Dr. David M. Hyman
“We believe this is the first clinical data suggesting that the AKT1 E17K mutations are targetable driver mutations in solid tumors,” he said at a briefing at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Mutations in the PI3K/AKT/mTOR pathway are frequently found in human cancers, and dysregulation of the pathway has been shown to drive tumor growth and survival of malignant cells.
“Although this pathway is among the most commonly activated in all human cancer, it is rarely activated by somatic mutation of AKT itself,” Dr. Hyman said. “When you see AKT mutations, they are almost always of a single allele at the 17 amino acid position, which is the E17K mutation. This is a mutation that has been extensively functionally classified, and behaves as a classic driver oncogene.”
The E17K mutation occurs in approximately 4% of breast cancers, 2% of bladder cancers, 1.5% of colorectal tumors, 1% each of cervical, ovarian, and prostate cancers, and 0.5% of lung adenocarcinomas.
AZD5363 is a catalytic inhibitor of all AKT isoforms 1, 2, and 3. In preclinical studies, it has been shown to inhibit tumor cell proliferation in vitro, and tumor growth in vivo in tumor xenograft models.
Dr. Hyman and colleagues reported on early results from one part of a four-part, phase I study of AZD5363 in adults with advanced solid tumors. Part D of the ongoing study focuses on patients with tumors bearing AKT1 mutations.
At present, 45 patients with E17K mutations have been treated with the agent, including 21 with estrogen receptor (ER)-positive breast cancer, four with triple-negative breast cancer, 14 with gynecological cancers, and eight with other tumor types.
As noted, of 41 patients with sufficient data for assessment, 33 had some degree of tumor regression, and of this group 12 met RECIST (Response Evaluation Criteria in Solid Tumors) parameters for partial responses. Among patients assessable for response, 14 of 18 with ER-positive breast cancer had lesion shrinkage, and five of these patients had partial responses (3 confirmed and 2 unconfirmed).
Among patients with gynecological tumors, 9 of 11 had shrinkage of their target lesion, including 3 with confirmed partial responses. Two of these patients are still on study, with the longest follow-up at the time of data cutoff of 39.2 months
Among patients with 12 other tumor types (apocrine anal, triple-negative breast cancer, colon, lung, prostate, squamous anal, thyroid) 10 patients had demonstrated target lesion shrinkage, one had a confirmed partial response that is ongoing, and two had unconfirmed partial response, one of which is ongoing.
The investigators also used cell-free DNA (cfDNA) analysis to evaluate efficacy of AZD5363 during treatment, and found that declines in AKT1 cfDNA allele fractions were transient among non-responders, whereas declines persisting for 21 days or more correlated with both durable tumor regression and RECIST response (P = .0049).
Dr. Hyman noted that there were also preclinical signs that AZD5363 could lead to reactivation of ER signaling.
“It became a natural question to ask whether patients did better with a combination of ER-directed therapy and AKT-directed therapy,” he said.
To answer this question, the investigators offered sequential therapy to patients with ER-positive breast cancer who had previously had resistance to the ER degrader fulvestrant and who had progressed on AZD5363 monotherapy. Two patients were offered crossover to AZD5363 with fulvestrant, regardless of prior hormonal therapy.
One of the patients had disease progression while on the combination. The second patient, who had received 10 prior lines of therapy and had disease progression before starting on the combination at 120 days on treatment, had significant shrinkage of her breast lesion 6 weeks after starting on the combination, and liver lesions that had previously enhanced on imaging are no longer enhancing, and her cfDNA allele fractions have declined. She remains on the combination after more than 160 days.
“This was very convincing evidence to us of synergy between these two compounds,” he said.
Dr. Jean-Charles Soria, from the Institut Gustave Roussy, Villejuif, France, who moderated the briefing, commented that “although this [mutation] is a rare situation, in the range of 2% to 3%, it’s certainly important, because 2% to 3% of breast cancer patients is a significant number, so this drug has legs,” he said.