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

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

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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 WHOLE BEAN COFFEE 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 (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.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 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 2 Layered Wooden Car Visor Clip 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 pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection.

Trial registration ClinicalTrials.gov, NCT01277757.Registered 13 January 2011.