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

Breast Cancer Research

卷:21

Yisheng Li¹  Huiqin Chen¹  Kim-Anh Do¹  Ana Maria Gonzalez-Angulo²  Vicente Valero²  Mariana Chavez-MacGregor²  Jennifer Litton²  Gabriel N. Hortobagyi²  Matthew A. Maurer³  Lewis C. Cantley⁴  Nancy U. Lin⁵  Eric Winer⁵  Gerburg M. Wulf⁶  Dianna Riall⁷  Armeen Mahvash⁸  Argun Akcakanat⁹  Funda Meric-Bernstam⁹  Yan Xing⁹  Emily Tarco⁹  Sarina A. Piha-Paul⁹  David Hong⁹  L. Austin Doyle¹⁰  Aysegul Sahin¹¹  Agda Karina Eterovic¹²  Gordon B. Mills¹²  Vandana Abramson¹³ 

[1] Biostatistics, The University of Texas MD Anderson Cancer Center;

[2] Breast Medical Oncology, The University of Texas MD Anderson Cancer Center;

[3] Columbia University;

[4] Cornell University;

[5] Department of Medical Oncology, Dana Farber Cancer Institute;

[6] Department of Medicine, Beth Israel Deaconess Medical Center and Dana Farber Harvard Cancer Center;

[7] IND Office, The University of Texas MD Anderson Cancer Center;

[8] Interventional Radiology, The University of Texas MD Anderson Cancer Center;

[9] Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center;

[10] National Cancer Institute;

[11] Pathology, The University of Texas MD Anderson Cancer Center;

[12] Systems Biology, The University of Texas MD Anderson Cancer Center;

[13] Vanderbilt University;

关键词: AKT signaling;    PTEN loss;    Genomics;    PIK3CA mutation;    Biomarkers;   

DOI  :  10.1186/s13058-019-1154-8

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown