A phase II evaluation of selumetinib (AZD6244, ARRY-142886), a selective MEK-1/2 inhibitor in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study

Abstract

Background: Activation of the mitogen activated protein kinase pathway plays a pivotal role in cell proliferation and is frequently activated in endometrial cancer. We sought to evaluate the efficacy/safety of selumetinib, a selective MEK-1/2 inhibitor in women with recurrent endometrial cancer.

Methods: This was a phase II, single-arm, open-label study evaluating response and 6-month event-free survival (EFS) as primary endpoints. Eligible patients had measurable disease, 1-2 prior cytotoxic regimens, and performance status 0-2. Selumetinib 75mg PO BID was administered daily until progression or intolerance. One cycle was 28days.

Results: Fifty-four patients were enrolled; 2 were excluded due to improper pre-study treatment (1) and never treated (1), leaving 52 evaluable for efficacy/safety. Median age was 62; histology included endometrioid (58%), serous (17%) and mixed (23%). Seventeen patients (33%) had 2 prior cytotoxic regimens. The median number of cycles administered was 2 (1-34). Three (6%) patients had objective response (1 CR, 2 PR); 13 had SD as best response. The proportion of patients with 6-month EFS was 12%. Median EFS, progression-free and overall survival was 2.1, 2.3, and 8.5months, respectively. Drug-attributed grade 3/4 adverse events were observed (≥5%) were fatigue (15%), anemia (10%), pain (10%), extremity edema (8%), and dyspnea (6%). There was 1 grade 4 infection (renal), 1 grade 4 anemia, and 1 death due to hemorrhage (rectum).

Conclusions: Selumetinib was tolerable in this population but did not meet pre-trial specifications for clinical efficacy.

Trial registration: ClinicalTrials.gov NCT01011933.

Keywords: MEK inhibitor; Phase II trial; Selumetinib; endometrial cancer; toxicity.

Conflict of interest statement

CONFLICTS OF INTEREST

All other co-authors have no conflicts of interest to declare.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

A comparison of the Kaplan-Meier (KM) estimates of the survival function for event-free survival (EFS), progression-free survival (PFS) and overall survival (OS) for patients on this study (N=52). Median PFS is 2.3 months (interquartile range: 1.7 to 5.6 months); EFS is 2.1 months (interquartile range: 1.7 to 3.9 months); and Median OS is 8.5 months (interquartile range 3.5 to 15.5 months). Almost twice as many patients were progression-free at 6 months (21.2%) as were event-free at 6 months (11.5%). Five of the eleven patients who experienced progression more than 6 months after starting study treatment began another therapy within 6 months of study entry and were censored for the KM estimates. Most of these therapies involved a taxane and/or carboplatin. The reasons for discontinuing the study therapy were toxicities (3 with rash, itching, fatigue, SOB, and abdominal pain), patient refusal (1), and interactions with other drugs (1).

Figure 2

Efficacy assessment in the Gynecologic Oncology Group’s 229 queue. The shaded region in the lower left corner represents uninteresting effectiveness by response and EFS at 6 months. The white area encompasses a region of uncertain effectiveness between the null and alternative hypothesis. The shaded areas in the upper and right regions of the plot contain proportions of response and EFS at 6 months that are clearly interesting. Selumetinib at this dose and schedule was associated with a rate of non-progression in line with target parameters, but with limited objective response. Other agents evaluated in this queue are provided for reference as they were assessed under the same eligibility criteria and similar statistical plans. Gefitinib, lapatinib, and thalidomide had EFS at 6 months estimated with PFS at 6 months. Abbreviations: PFS: progression-free survival; RR: response rate; bev/tem: bevacizumab and temsirolimus combination