Elsevier

Gynecologic Oncology

Volume 132, Issue 3, March 2014, Pages 585-592
Gynecologic Oncology

Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: A gynecologic oncology group study

https://doi.org/10.1016/j.ygyno.2014.01.015Get rights and content

Highlights

  • The combination of hormone therapy plus temsirolimus did not improve response rates compared to temsirolimus alone.

  • The combination of therapy with megestrol acetate/tamoxifen plus temsirolimus resulted in a 33% rate of venous thrombosis.

  • Two of four patients with clear cell carcinoma of the endometrium responded to temsirolimus.

Abstract

Objectives

To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.

Background

Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.

Methods

We performed a randomized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.

Results

There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.

Conclusions

Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.

Introduction

Advanced or recurrent endometrial carcinoma is an incurable disease with short overall survival. Standard initial therapy for many years consisted of treatment with medroxyprogesterone acetate or megestrol acetate, and response rates of 15%–27% to progestin-based regimens in chemotherapy-naïve patients have been published by a number of authors [1], [2]. However the median progression-free survival with such regimens is short, and although low-grade and estrogen or progesterone receptor-positive tumors have higher response rates to endocrine therapy, no reliable predictive factors for benefit have emerged [3]. Currently, most women with advanced disease are initially treated with platinum/taxane-based chemotherapy. Such regimens yield response rates in the range of 50%, but the median survival remains only about 12–15 months [4].

As targeted agents began to show promise in a number of different tumor types, interest was focused on the high frequency of aberrations in the PI3K/Akt/mTOR pathway in endometrial cancers [5]. A number of mTOR inhibitors have been tested in endometrial cancer and found to have only modest activity (Table 1). Phase II studies of temsirolimus conducted by the National Cancer Institute of Canada (NCIC) showed a 14% response rate in chemotherapy-naïve patients and a 4% response rate in patients with prior chemotherapy [6].

In endometrial cancer cell lines and mouse models, upregulation of PI3K/Akt/mTOR pathway activity is associated with resistance to progestin therapy, and inhibition of the pathway can reverse this resistance [7], [8]. Similar observations have been made regarding the association of resistance to tamoxifen and aromatase inhibitors with PI3K/Akt/mTOR pathway activity in breast cancer models. These led to a phase III trial in which breast cancer patients previously treated with a nonsteroidal aromatase inhibitor who were randomized to the combination of the mTOR inhibitor, everolimus, plus exemestane had significantly superior progression-free survival compared to those randomized to exemestane alone [9].

We therefore performed a randomized open-label two-stage phase II trial of temsirolimus alone versus the combination of temsirolimus plus a hormonal therapy regimen consisting of alternating megestrol acetate and tamoxifen. This hormonal therapy was chosen based on data published by the Gynecologic Oncology Group (GOG) showing a response rate of 27% and a median response duration of 28 months with the regimen [2]. While there are no data showing that such a regimen is superior to single agent progestin therapy, regimens including periodic tamoxifen have produced the highest response rates in the GOG experience. Archival tumor tissue was collected and stained for ER, PR, PTEN, and phospho-AKT.

Section snippets

Eligibility

Subjects were required to have measurable endometrial carcinoma (RECIST version 1.0) that was either stage III or IV, or persistent or recurrent after treatment for earlier stage disease. Prior endocrine therapy was prohibited; up to one prior chemotherapy regimen was allowed, but if that regimen was administered in the setting of stage IV disease it was required that the patient have been without evidence of disease at the completion of chemotherapy and have had at least six months of

Results

Seventy-three patients were registered to this trial between 9/29/08 and 11/22/10. Two were excluded from analysis; one did not meet eligibility requirements after central review and one never received any protocol therapy. Fig. 1(supplemental) shows the outcomes of all patients registered to the trial. Patient characteristics are shown in Table 2. At the time of writing two patients on the single agent temsirolimus arm were still receiving therapy at 30 and 45 months from enrollment.

Discussion

This trial confirms the activity level of single agent temsirolimus in women with endometrial cancer. The response rate in this group was 22%, which is very similar to that reported by Oza et al. (24% investigator-reported; 14% on independent radiology review) for chemotherapy naïve patients [17] and considerably better than Oza et al. observed in pretreated patients (4%). This suggests that patients who would have met eligibility for our trial, with prior adjuvant chemotherapy or at least

Conflict of interest statement

The authors wish to declare that there are no conflicts of interest.

Acknowledgments

The authors would like to acknowledge Dr. Meenakshi Singh from Stonybrook University Medical Center, as the GOG Core Laboratory Pathologist, as well as Dr. Yuping Zhang at the University of Iowa for assistance with these assays.

This study was supported by the National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), the GOG Statistical and Data Center (CA 37517).

The following Gynecologic Oncology Group member institutions

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