A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors

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.

Figure 1

Patient flowchart. DLT, dose-limiting toxicity; QOD, every other day; QW, every week.

Figure 2

Activity of MK-2206 following treatment with the combination of MK-2206 and trastuzumab in patients with human epidermal growth factor receptor 2-positive breast cancer or gastric cancer. (A) Time to progression for all patients enrolled who progressed during the trial and (B) best change in the size of target lesions from baseline, following treatment with the combination of MK-2206 and trastuzumab in patients with human epidermal growth factor receptor 2-positive breast cancer or gastric cancer. One patient achieved complete response and one patient had partial response; both patients withdrew from the study due to adverse events and are not included in (A). In (B), Patient 01719 had a 41% decrease in tumor size while on trial and achieved an overall 68% decrease in the size of target lesions while continuing to receive treatment after discontinuation of the study. (C) One patient with breast cancer who achieved complete response had an area of erythematous skin lesion on the operative site at baseline (left panel) that completely resolved after receiving two cycles of treatment at the 60 mg every other day (QOD) MK-2206 dose level (right panel). QW, every week.

Figure 3

Mean MK-2206 plasma concentration profiles following administration of MK-2206 in combination with trastuzumab. Linear scale of plasma concentration following administration of MK-2206, in every other day (QOD) and every week (QW) schedules, in combination with trastuzumab.