The results of a phase I basket trial suggest that the AKT1 E17K mutation is a valid therapeutic target. AZD5363, an investigational pan-AKT inhibitor, may benefit patients with a range of solid tumors bearing this genetic alteration.
According to data from a phase I basket study, the investigational pan-AKT inhibitor AZD5363 (AstraZeneca) shows promising activity against a variety of solid tumors bearing the AKT1 E17K mutation. The results were presented by David Hyman, MD, acting director of developmental therapeutics at Memorial Sloan Kettering Cancer Center in New York, NY, during the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held in Boston, MA, November 5–9.
The E17K mutation is the most common in AKT1, and “behaves as a classic driver oncogene,” Hyman said. However, the frequency of this mutation “is seldom higher than 2% to 3% across multiple tumor types,” he added. As such, until the recent emergence of basket trials, which enroll patients with different cancers but the same genetic alteration, determining the viability of AKT1 E17K as a therapeutic target hasn't been possible.
Hyman shared data on 45 patients—20 with estrogen receptor (ER)–positive breast cancer, 13 with gynecologic tumors, and 12 with a range of other solid tumors. Thirty-seven patients experienced tumor shrinkage; among these, there were seven confirmed and four unconfirmed partial responses to AZD5363. At the data cut-off point (October 5), one patient in the gynecologic tumor cohort was still on therapy after 39 weeks. Hyman called this “a striking duration,” given that the study participants were all heavily pretreated, having had nearly six prior regimens on average. He also observed that the tumor histology in this group was mainly endometrial—“an association with the AKT1 E17K mutation not previously reported, which could provide a strategy to screen more effectively for such patients,” he said.
The researchers also analyzed circulating tumor DNA from 21 of the 45 study participants and noted that AKT1 E17K mutation levels declined in 20 patients after treatment with AZD5363. This decrease was largely transient; however, persistent declines beyond 21 days—in 7 patients, the mutation became entirely undetectable—were associated with durable responses to therapy.
“We think AZD5363 has an early antitumor effect, but the cells then adapt and develop resistance,” Hyman explained, “which happens more quickly in some cases than others.”
Jean-Charles Soria, MD, PhD, chair of drug development at the Institut Gustave Roussy in Villejuif, France, described AZD5363 as “a drug with legs.” However, he noted that “the true duration of response remains an open question.”
“Our general feeling is that as a single agent, AZD5363's activity is real but modest,” Hyman said, “and we need to explore combinations with other drugs.”
Based on preclinical data suggesting a close interplay between AKT and ER signaling, the researchers decided to test AZD5363 alongside the ER-degrader fulvestrant (Faslodex; AstraZeneca) in two patients from the study's ER+ breast cancer cohort. One derived no further benefit, but the other is still receiving treatment and has shown radiographic improvement in her primary breast tumor and liver metastases. Her case is “anecdotal, but convincing evidence of synergy between the two compounds,” Hyman said.
With broad-based genomic sequencing becoming more common in oncology, “information on mutant AKT will come along for the ride as we test for other biomarkers,” he added, “making it easier to identify this rare patient population.”
- ©2015 American Association for Cancer Research.