AKT Inhibitor MK-2206 In Patients Research Articles

Abstract B24: Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

Abstract Background: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT Inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. Methods: The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6m PFS), predictive and pharmacodynamic markers, safety and tolerability. Patients had pretreatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry and reverse phase protein arrays (RPPA) were performed. Results: Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations and one had a PIK3CA mutation as well as PTEN loss. ORR and 6m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pretreatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pretreatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. Conclusions: MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pretreated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. Citation Format: Yan Xing, Nancy U. Lin, Mathew Mauer, Huiqin Chen, Armeen Mahvash, Aysegul Sahin, Argun Akcakanat, Yisheng Li, Vandana Abraham, Jennifer Litton, Mariana Chavez-McGregor, Vicente Valero, Sarina A. Piha-Paul, David Hong, Kim-Anh Do, Emily Tarco, Dianna Riall, Karina Agda Eterovic, Lewis Cantley, Gordon B. Mills, L. Austin Doyle, Eric Winer, Gabriel Hortobagyi, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam. Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B24.

Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation

BackgroundThe PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation.MethodsThe primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed.ResultsTwenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders.ConclusionsMK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection.Trial registrationClinicalTrials.gov, NCT01277757. Registered 13 January 2011.

Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers

Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60-80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic-pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488).

Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.

Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.

OT3-01-03: Pre-Surgical Evaluation of the AKT Inhibitor MK-2206 in Patients with Operable Invasive Breast Cancer: New York Cancer Consortium Trial P8740.

Abstract Background: To serve as a bridge between pre-clinical and early clinical testing, pre-surgical studies are being designed to expose patients to a limited duration of an anti-cancer agent before launching a lengthy clinical trial program. In this model, modulation of predictive tissue and serum biomarkers are assessed. At Columbia University, we have completed 3 pre-surgical studies. The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). The first allosteric Akt inhibitor to enter clinical development, MK-2206 is well-tolerated and has demonstrated anti-cancer properties in pre-clinical and early-phase clinical studies. The purpose of this study (NCI P8740) is to determine the effects of MK-2206 on women with newly diagnosed BC between breast biopsy and surgery. Trial Design: Patients (n=30) will receive 2 doses of weekly MK-2206 (200 mg): first dose at day −9 and second at day −2 from surgery. This drug administration consistency will decrease the potential for noise in detecting true biomarker response. This time period was selected based upon the pharmacokinetic profile of weekly MK-2206. The main eligibility criteria for this open-label pre-surgical trial include operable, clinical stage I (at least T1c) to IIIC invasive BC. Patients not considered for neoadjuvant chemotherapy are eligible. Specific Aims: Our hypothesis is that MK-2206 will decrease phospho-AktSer473 in tumor tissue after 2 weekly doses. To maintain sample quality and ensure that phospho-Akt evaluated on formalin-fixed paraffin-embedded (FFPE) tissue is comparable across samples (given the 20 minute half life of AKT), all samples will be processed rapidly by a standardized protocol. Secondary objectives include the following in FFPE: modulation of downstream PI3K/Akt pathway signaling [immunohistochemistry and reverse phase-protein microarray analysis (RPPA)]; change in tumor proliferation (Ki-67 staining); and exploration of whether PI3K/Akt signaling change depends upon tumor genetics (PIK3CA mutation or PTEN loss) or expression (Hormone Receptor/HER2 status). Pre- and post-MK-2206 blood will be collected for phospho-expression analysis in peripheral blood mononuclear cells (RPPA and western blotting). Statistical Methods: With the expectation that 20% of the matched pre- and post-treatment tissue samples will not be analyzable, we will enroll 30 patients to ensure that matched tumor samples from 24 patients are available for our primary analysis. A sample size of 24 patients will yield greater than 90% power to detect a difference in the mean score between pre-and-post treatment samples of 60 units, paired t-test (2-sided, 0.05 significance level). This trial was recently activated by the NCI and currently ready to accrue patients. Patients will be enrolled and treated at affiliated institutions in the New York Cancer Consortium. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-03.

Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.

2613 Background: The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). MK-2206 is the first allosteric Akt inhibitor in clinical development. The purpose of this p...