Abstract and Introduction
Abstract
Introduction Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling.
Methods Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.
Results A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.
Conclusions Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation.
Trial registration ClinicalTrials.gov; identifier: NCT00963547.
Introduction
Approximately 20 to 25% of breast cancers[1,2] and 30% of gastric cancers[3] have overexpression and/or gene amplification of human epidermal growth factor receptor 2 (HER2), which serves as both a poor prognostic marker and a therapeutic target. HER2 amplification, detected by fluorescence in situ hybridization, or overexpression, determined by immunohistochemistry staining, predicts responsiveness to HER2-targeted agents, such as trastuzumab, lapatinib, and other newer agents. However, patients with metastatic HER2+ breast cancer or gastric cancer may have intrinsic resistance or develop partial or complete clinical resistance to HER2-targeted therapy during the course of treatment.[4–6] Understanding mechanisms of resistance could lead to the development of new strategies to overcome resistance in these patients. One mechanism of resistance to trastuzumab is mediated through activation of downstream signaling via the phosphatidylinositol-3 kinase (PI3K)/AKT pathway, which has been identified as a major determinant of trastuzumab resistance in breast cancer.[7,8] Several groups have shown that HER2+ breast cancer models that have been selected for trastuzumab resistance can be effectively targeted with PI3K or AKT inhibitors.[9,10] The potential to increase antitumor activity by blocking both AKT signaling and HER2 kinase has been further suggested by a study showing that combined inhibition of AKT and HER2 kinase activity is more effective than either one alone in HER2+ models.[11]
MK-2206 is an investigational allosteric inhibitor of AKT that requires the PH domain of AKT for activity, but does not interact with the ATP binding pocket. As a result, MK-2206 is highly selective for AKT inhibition, has higher potency against recombinant human AKT1 and AKT2 isoforms than AKT3, has little off-target kinase activities, and is less vulnerable to feedback activation of AKT compared with ATP-competitive inhibitors.[12] In prior phase 1 studies, MK-2206 was tested in over 100 patients with solid tumors using an every other day (QOD) or once weekly (QW) dosing schedule.[13] Overall, MK-2206 was well tolerated at biologically active doses, with the maximum tolerable dose (MTD) established at 60 mg QOD; the MTD for the QW dosing schedule (expected to be less than 250 mg) was not established due to early discontinuation of the trial. The most significant dose-limiting toxicity (DLT) was rash, which was maculopapular in nature with a truncal distribution, and was distinct from the acneiform rash seen with epidermal growth factor receptor inhibitors. Pharmacokinetic testing revealed that MK-2206 has a long half-life (60 to 90 hours) and no substantial departure from dose proportionality, and preliminary evidence of clinical activity was seen in various tumors. Based on the preclinical rationale for the combination of MK-2206 and trastuzumab, as well as promising preclinical results, we conducted a phase 1 trial to evaluate the QOD and QW dosing schedules from earlier trials and to determine the MTD and recommended phase 2 dose for MK-2206, administered in combination with standard doses of trastuzumab. We also assessed early clinical evidence of antitumor activity of this combination in patients with HER2+ solid tumors.
Breast Cancer Res. 2013;15(6) © 2013 BioMed Central, Ltd.
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