Abstract | 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 (Trial NCT number NCT01021748).
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Authors | Anthony W Tolcher, Khurum Khan, Michael Ong, Udai Banerji, Vassiliki Papadimitrakopoulou, David R Gandara, Amita Patnaik, Richard D Baird, David Olmos, Christopher R Garrett, Jeffrey M Skolnik, Eric H Rubin, Paul D Smith, Pearl Huang, Maria Learoyd, Keith A Shannon, Anne Morosky, Ernestina Tetteh, Ying-Ming Jou, Kyriakos P Papadopoulos, Victor Moreno, Brianne Kaiser, Timothy A Yap, Li Yan, Johann S de Bono |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 21
Issue 4
Pg. 739-48
(Feb 15 2015)
ISSN: 1557-3265 [Electronic] United States |
PMID | 25516890
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- AZD 6244
- Benzimidazoles
- Heterocyclic Compounds, 3-Ring
- KRAS protein, human
- MK 2206
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-akt
- MAP Kinase Kinase Kinases
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Animals
- Antineoplastic Combined Chemotherapy Protocols
(administration & dosage, adverse effects)
- Benzimidazoles
(administration & dosage, adverse effects)
- Cell Line, Tumor
- Female
- Heterocyclic Compounds, 3-Ring
(administration & dosage, adverse effects)
- Humans
- MAP Kinase Kinase Kinases
(antagonists & inhibitors)
- Male
- Mice
- Middle Aged
- Neoplasms
(drug therapy, enzymology, genetics)
- Proto-Oncogene Proteins
(genetics)
- Proto-Oncogene Proteins c-akt
(antagonists & inhibitors)
- Proto-Oncogene Proteins p21(ras)
- Xenograft Model Antitumor Assays
- ras Proteins
(genetics)
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