• Joyce F Liu, Kathryn P Gray, Alexi A Wright, Susana Campos, Panagiotis A Konstantinopoulos, Ariana Peralta, Kimberley MacNeill, Stephanie Morrissey, Christin Whalen, Deborah Dillon, and Ursula A Matulonis.
• Division of Gynecologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America. Electronic address: joyce_liu@dfci.harvard.edu.
• Gynecol. Oncol. 2019 Jul 1; 154 (1): 95-101.

BackgroundImproved treatment for advanced cervical cancer is needed; currently, treatment options include combined chemotherapy and bevacizumab or pembrolizumab monotherapy for PD-L1 positive disease. PIK3CA and KRAS mutations have been reported in cervical cancers; this study therefore tested dual inhibition of PI3K and RAS signaling by combining the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 in recurrent cervical cancer.MethodsThis was an investigator-initiated phase II study combining trametinib and GSK2141795 in patients with recurrent cervical cancer. Primary endpoint was best tumor response; secondary endpoints included progression free survival, overall survival, and safety assessment. Translational objectives included characterization of molecular alterations in PI3K and RAS signaling pathway genes.ResultsPlanned accrual was 35 patients; 14 patients were enrolled and received at least one dose of study drug before the study was terminated due to discontinuation of GSK2141795 development. There were no confirmed responses; 1 patient had an unconfirmed PR, 8 had stable disease, 3 had progression as best response, and 2 were unevaluable. Toxicities were mostly grade 1 and 2, although 57% of patients experienced grade 3/4 adverse events and 50% patients required a dose reduction.ConclusionsThe combination of trametinib and GSK2141795 was feasible but required dose holds and modifications for adverse events; however, anti-cancer activity was minimal, even in patients with PI3K or RAS pathway alterations. Although the study was terminated early after GSK2141795 development was halted, the findings in these 14 patients do not support further development of this combination in cervical cancer.Copyright © 2019 Elsevier Inc. All rights reserved.

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