Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 4, Pages 739-748Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-1901
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Funding
- Merck Co., Inc.
- AstraZeneca
- Cancer Research UK [C347/A18077]
- Experimental Cancer Medicine Centre grant
- National Institute for Health Research Biomedical Research Centre [A46/CCR-CCR4057, CCR4058]
- Academy of Medical Sciences (AMS) [AMS-SGCL10-Yap] Funding Source: researchfish
- Cancer Research UK [11566, 17782] Funding Source: researchfish
- National Institute for Health Research [CL-2012-22-001] Funding Source: researchfish
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Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies. (C) 2014 AACR.
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