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 (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 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. Electronic supplementary material The online version of this article (10.1186/s13058-019-1154-8) contains supplementary material, which is available to authorized users.

Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics

“…These results suggest that detailed molecular and functional analyses should be performed for rapamycin before considering its use in clinical trials. The AKT1 inhibitor MK-2206 (1 µM), which is currently being tested in a clinical phase 2 study against breast cancer ( 29 ), reduced SARS-CoV-2 propagation up to 50% ( Figure 4a, lower right, Figure S3d , e ). AKT1 blocks mTORC1 inhibitor TSC2 ( 30 ) and further supports the suggestion that up-regulation of mTORC1 components has antiviral effects.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…In a large panel of cancer cell lines, T-cell acute lymphoblastic leukemia (T-ALL) with Notch mutation were highly sensitive to Akt inhibitor (AZD5363) and the mTORC1/2 inhibitor (AZD2014) but only partially sensitive to PI3K inhibitors [325]. While combining mTOR with Akt inhibition showed promise with less toxicity, it seems that Akt inhibitor monotherapy had low clinical activity partly due to poor tolerability [322][323][324]. Pre-clinical studies on inhibition of SGK, another target of mTORC2, for the treatment of a variety of cancers are also showing promise [327,328,331].…”

The Clinical Kinase Index: Prioritizing Understudied Kinases as Targets for the Treatment of Cancer

“…42 kinases in total were found to have significant hotspot mutations, with kinases from the TK family being mutated most frequently. The most commonly mutated kinases were PIK3CA (12 cancers), BRAF (5 cancers) and AKT1 (4 cancers), all of which have mutant-targeted inhibitors in clinic or in trial (Figure 3D, Supplemental Table 2) [36, 39, 40]. 8 understudied kinases were found to have hotspot mutations in at-least 1 cancer ( CDC42BPA, DYRK1B, DYRK4, LMTK3, MAPK15, NEK7, TSSK1B and TTBK1 ), with DYRK4, LMTK3, MAPK15, NEK7 all having significant hotspot mutations in stomach adenocarcinoma (STAD).…”