A phase II clinical and translational study of MK-2206 in patients with metastatic neuroendocrine tumors (NETs).

Abstract

e15133 Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poor prognosis in NET cell lines. In patients treated with mTOR inhibitors, up-regulation of AKT may be a key driver in development of resistance. We hypothesized that blockade of AKT in patients with refractory NETs would result in eliminating one of the key drivers of tumor growth and prolong PFS. We evaluated the safety and efficacy of MK-2206, an orally active, allosteric Akt inhibitor of human Akt1, Akt2, and Akt3 as monotherapy in metastatic well differentiated progressive neuroendocrine patients. Methods: A phase II study was performed in which patients received MK-2206 at a dose of 200 mg PO once weekly. Archived pretreatment tumor tissue was obtained for putative biomarkers. Results: The study terminated early on the basis of a business decision by the sponsor. Eight patients were treated (6 carcinoid, 2 pNET); female, 25%; median age, 58.5 years, range 66-25). There were no complete or partial responses. 1 patient (atypical thymic carcinoid with brain metastases refractory to all standard therapies including mTOR and VEGF inhibitors) experienced a 17% decrease in tumor size (SD) for over 10 months and an additional 3 patients had SD for 12 weeks or longer by RECIST 1.0 (4/8, 50%; range 4.2-10.2 months). The most common grade 3 adverse events potentially related to MK-2206 were hyperglycemia (3 pts, 37.5%), elevated liver function tests (3 pts, 37.5%), and rash (3 pts, 37.5%). There were no serious adverse events (SAEs) related to MK-2206. Tumor from the patient with greatest radiographic response was evaluated by next generation sequencing, which failed to identify mutations in the AKT pathway (i.e., PTEN, AKT, and PI3KCA). Conclusions: MK-2206 alone was well tolerated, except for hyperglycemia, transaminitis, and rash, all of which were manageable. Although the study was incomplete, evidence of antitumor response in a refractory carcinoid tumor is of interest. Further evaluation of agents targeting AKT and/or PI3K are warranted in NETS. Preclinical studies are ongoing to better define a potential targeted population. Clinical trial information: NCT01169649.