A combination of mTOR inhibitor, ridaforolimus and novel AKT inhibitor, MK-2206 showed activity in heavily pretreated hormone positive and negative breast cancer patients who exhibit PI3K pathway dependence based on low RAS signature score. The combination was well tolerated in a phase I study. The results provide a rationale for exploring this combination in further studies, according to Dr Shilpa Gupta of the Lee Moffitt Cancer Center, University of South Florida, Tampa, USA who presented the study in a poster session on 'New drug development' at the IMPAKT 2014 Breast Cancer Conference (8-10 May 2014, in Brussels, Belgium).
A combination of mTOR inhibitor and AKT inhibitor
The PI3K/AKT/mTOR signaling pathway is aberrantly activated in various cancers, including breast cancer. The study rationale was that a combination of mTOR inhibitor and AKT inhibitor can lead to complete blockade of this pathway and disrupt tumour cell proliferation, metabolism and survival signalling.
In a phase I study, ridaforolimus and MK-2206 were tested in advanced cancers. The study included a dose expansion cohort of enriched breast cancer patients with low RAS gene signature in archival or fresh tissue. RAS signature was a RNA transcription assay that derived a score from the expression of 147 transcripts. In order to be eligible for the study, patients with ER positive breast cancer had also to demonstrate a high Ki67 index.
In total, 124 heavily pretreated breast cancer patients were prescreened for the study with 52% being biomarker-eligible. The total number of patients with breast cancer was 17.
Maximum-tolerated dose for ridaforolimus was 10 mg per day during 5 days in a week plus 90 mg of MK-2206 as a weekly dose. One of 17 patients experienced a dose limiting toxicity of grade 3 rash.
Median teratment durtion was 2 cycles. Complete response (CR) was defined as disappearance of non-nodal target lesions or reduction of nodal lesions to less than 10 mm in short axis. Partial response (PR) was defined as at least 30% decrease from baseline in sum of diameters/volumes of target lesions. Objective responses (12,5%) as assessed by investigators by RECIST 1.1 criteria were seen in 2 out of 16 patients, basically there were 2 patients with PR and none with CR. By volumetric 3-D tumour assessment, objective responses were seen in 4 out of 14 patients (28,6%), with 2 PR and 2 CR. Stable disease of at least 6 months was seen in one patient.
The combination was well tolerated and main adverse events were rash (44.4%), stomatitis (38.9 %), diarrhoea (27.8%), anorexia (27.8%) and fatigue (22.2%).
The authors concluded that the combination treatment resulted in disease responses in some of heavily pretreated patients. The treatment was generally well tolerated with rash, asthenia, diarrhoea and stomatitis as most common drug-related adverse events and with less than 6% being grade 3.
Abstract 69P: S. Gupta, P. Munster, A. Hollebecque, et al. Safety and efficacy of MK-8669 (ridaforolimus) + MK-2206 (AKT inhibitor) in patients with advanced breast cancer with PI3K pathway dependence. Annals of Oncology (2014) 25 (suppl_1): i25-i27. 10.1093/annonc/mdu071.
Among study authors J. Cheng, R. Wang, A. Swift and A. Tosolini are scientists in Merck Labs.
All other authors have declared no conflicts of interest.
IMPAKT is an annual conference that was launched in 2009 by the Breast International Group (BIG) and the European Society for Medical Oncology (ESMO), in collaboration with a multidisciplinary alliance of European breast cancer organisations and patient groups - referred to as partners. Partners include the Foundation St. Gallen Oncology Conferences and the EBC Council. It is designed for breast cancer researchers and clinicians who have a specific interest in translational research, new agents, molecular and functional diagnostics, biomarkers and cutting-edge research applications in the clinical setting. The theme of IMPAKT 2014 was 'Anticipating the future of personalised medicine in breast cancer'.