LAUSR

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.