A phase I study of the AKT inhibitor (MK-2206) with concurrent trastuzumab and lapatinib in patients with HER2-positive solid tumors.

Abstract

3028 Background: Trastuzumab (T) is effective in HER2 overexpressing breast and gastric cancer, but patients eventually develop clinical resistance. Lapatinib (L) with chemotherapy is active after progression on T. Preclinical data suggest that signaling downstream of HER2 via PI3K-AKT pathway may be one mechanism of resistance. MK-2206, an investigational allosteric AKT inhibitor, should inhibit this compensatory signaling. As a single agent, DLTs of MK-2206 are rash and diarrhea. Combined with either T or T/L, MK-2206 could provide more effective HER-family signaling blockade in HER2 positive disease. Methods: Patients with HER2+ treatment-refractory breast and gastroesophageal cancer with adequate organ function were enrolled. In part 1, patients were treated with standard doses of IV T (8 mg/kg load, followed by 6 mg/kg Q3W), and escalating dose levels of PO MK-2206 using either a QOD or QW schedule. In part 2, patients are treated with MK-2206 at the MTD dose derived from part 1 with standard T and escalating doses of L. Results: Between Sept. 2009 and Jan. 2011, a total of 40 HER2+ patients were screened and 32 were enrolled. The MTD for MK-2206 in combination with q3W T (part 1) is 60 mg for QOD schedule and 135 mg QW schedule. The major toxicity is consistent with prior experience and no grade 4 or 5 toxicity. The DLT is skin rash in the 200 mg QW cohort occurring in 2/4 patients. There were one complete remission (CR) after 12 weeks of therapy for a breast cancer patient who had skin only metastasis during enrollment, and another unconfirmed partial remission (PR) lasting less than 4 weeks but 4/24 patients have had prolonged stable disease (SD) for at least 4 months despite progression on multiple prior T and L-based therapies. Part 2 (T/L/MK-2206) is anticipated to start in Feb. 2011 and updated information will be available for the ASCO meeting. Conclusions: The AKT inhibitor MK-2206 can be safely combined with T and is associated with clinical activity in phase I. The addition of L is predicted to further increase efficacy and is now being tested. Updated results will be provided.