CHICAGO, IL—Combination ridaforolimus + MK-2206 AKT inhibitor therapy yielded modest early clinical efficacy results for patients with low-RAS advanced breast cancer and PTEN-deficient prostate cancer, according to a phase 1 maximum-tolerated dose (MTD) and preliminary efficacy study presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.
“Combination of ridaforolimus and MK-2206 shows promising activity in breast cancer patients with low RAS, including heavily pretreated patients; this combination was overall well tolerated with rash, stomatitis, diarrhea, and asthenia being the most common drug-related AEs [adverse events],” reported lead author Shilpa Gupta, MD, of the H. Lee Moffitt Cancer Center & Research Institute in Tampa, FL, and coauthors. “In the prostate cancer patients there were no responses seen, but one patient did demonstrate a stable disease for nine months,” Dr. Gupta noted.
Ridaforolimus is an investigational targeted inhibitor of the mTOR protein, which regulates cell proliferation. MK-2206 is an oral allosteric inhibitor of the serine/threonine protein kinase AKT (protein kinase B).
“The PI3K/AKT/mTOR signaling pathway is aberrantly activated in a variety of cancers,” explained Dr. Gupta. “The combination of ridaforolimus mTOR inhibitor and MK-2206 may lead to a more complete blockade of the PI3K pathway. AKT and mTOR are integrated, but with unique inputs and outputs.”
After an initial dose escalation study, a dose confirmation and initial efficacy assessment was undertaken with 19 biomarker-eligible patients with estrogen receptor–positive (ER-positive) breast cancer with low RAS gene signatures and high Ki67 index, and 8 patients with prostate cancer and evidence of PTEN deficiency, Dr. Gupta reported.
Low RAS correlates with high PI3K pathway dependency and better responsiveness to PI3K pathway inhibition, Dr. Gupta noted in describing the study’s rationale.
“Low RAS is associated with approximately 50% of ER-positive breast cancers and less than 30% of ER-negative breast cancer subtypes,” she said.
The MTD was determined to be 10 mg ridaforolimus once daily, 5 days a week plus 90 mg MK-2206 once weekly, the coauthors reported.
Clinical efficacy was modest.
That might because of the lower-than-anticipated MTD, suggested commenter Timothy Yap, PhD, MRCP, of the Institute of Cancer Research and Royal Marsden Hospital in London, England.
“During this study, multiple dose-limiting toxicities were observed at the first dose level, necessitating de-escalation down to a dose where the MTD was established,” he explained. “This did mean that both drug doses were much lower than the established monotherapy doses and likely represented subtherapeutic drug doses. Overlapping drug toxicities were also still observed despite intermittent dosing of both drugs.”
However, hyperglycemia was reported for only one patient at MTD, Dr. Yap noted. “This suggests that this combination was not hitting the pathway hard enough or long enough at these low drug doses,” he said. “There were only two durable (partial) responses observed out of 17 low-risk [patients with] breast cancer, although one of these patients was treated at a toxic dose level” higher than the MTD, Dr. Yap noted. These two cases were “fascinating and probably worth exploring” further, he said.
MTD study drug-related AEs (any grade) included rash (44.4%), stomatitis (38.9%), diarrhea and decreased appetite (27.8%), asthenia, and nausea and fatigue (22.2%), the coauthors reported. Grade 3/4 treatment-related adverse events included stomatitis, rash, diarrhea and fatigue (5.6% each).
Clinical trial information: NCT01295632.
- Gupta S, Munster PN, Hollebecque A et al. Abstract 2509. Presented at: 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2014; Chicago, IL.