Safety and efficacy of MK-8669 (ridaforolimus) + MK-2206 (AKT inhibitor) in patients with advanced breast cancer with PI3K pathway dependence
|Date||08 May 2014|
|Session||Welcome reception and Poster Walk|
|Topics|| Drug Development
Breast Cancer, Metastatic
|Citation||Annals of Oncology (2014) 25 (suppl_1): i25-i27. 10.1093/annonc/mdu071|
S. Gupta1, P. Munster2, A. Hollebecque3, G. Argiles4, T. Guren5, J. Cheng6, R. Wang6, A. Swift6, A. Tosolini6, S. Piha-Paul7
The PI3K/AKT/mTOR signaling pathway is aberrantly activated in various cancers, including breast cancer and ridaforolimus (mTOR inhibitor) and MK-2206 (AKT inhibitor) combination can lead to its complete blockade disrupting tumor cell proliferation, metabolism and survival signaling.
In a phase 1 study, ridaforolimus and MK-2206 were tested in advanced cancers and with dose expansion cohort of enriched breast cancer patients with low RAS gene signature (RNA transcription assay which derives a score from the expression of 147 transcripts) in archival or fresh tissue. In addition, ER positive breast cancer patients also had to demonstrate a high Ki67 index (a marker of high proliferation, ≥15%) in order to be eligible.
124 heavily pre-treated breast cancer patients were prescreened, 52% were biomarker-eligible and the total number of pateints with breast cancer was 17. Maximum-tolerated dose (MTD) was 10 mg qd ridaforolimus 5 days/week + 90 mg weekly MK-2206 with 1/17 patients experiencing a dose limiting toxicity (DLT) of grade 3 rash, median teratment durtion was 2 cycles. CR was defined as disappearance of non-nodal target lesions (TLs)/reduction of nodal lesions to <10 mm in short axis and PR was defined as at least 30% decrease (from baseline) in sum of diameters/volumes of TLs. Investigator-assessed objective responses using RECIST 1.1 were seen in 2/16 patients (2 partial response [PR] + 0 CR [complete response], 12.5%) (1 was non-evaluable), using volumetric 3-D tumor assessment, objective responses were seen in 4/14 patients (2 PR + 2 CR, 28.6%) (3 were non-evaluable). Stable disease (SD) ≥6 months was seen in 1 patient. The combination was well tolerated and main adverse events (AEs) were rash (44.4%), stomatitis (38.9 %), diarrhea (27.8%), anorexia (27.8%) and fatigue (22.2%).
Ridaforolimus and MK-2206 show activity in heavily pre-treated hormone positive and negative breast cancer patients exhibiting PI3K pathway dependence based on low RAS signature score and is well tolerated. This combination resulted in disease responses and was generally well tolerated with rash, asthenia, diarrhea and stomatitis being among the most common drug-related AEs, with less than 6% being grade 3 AEs. This offers a rationale for exploring this combination in further studies.
J. Cheng, R. Wang, A. Swift and A. Tosolini: Scientist for Merck Labs. All other authors have declared no conflicts of interest.