Everolimus/letrozole combo provides clinical benefit in recurrent endometrial cancer



A treatment regimen designed to combat endocrine resistance in patients with recurrent endometrial cancer resulted in high clinical benefit and objective response rates in a phase II trial.

The clinical benefit rate in 35 women who were treated with the mammalian target of rapamycin (mTOR) inhibitor everolimus along with the aromatase inhibitor letrozole was 40% after a median of 15 cycles, and the confirmed objective response rate was 32%, Dr. Brian M. Slomovitz of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported online Jan. 26 in the Journal of Clinical Oncology.

Most women with endometrial cancer (EC) are cured with surgery or with surgery and adjuvant therapy, but more than 8,000 die each year – largely as a result of resistance to conventional therapy, the investigators said.

Increased phosphoinositol-3 kinase (PI3K)/AKT/mTOR signaling has been linked with aggressive disease and poor prognosis, they noted.

Treatment with mTOR inhibitors such as everolimus has been shown in a number of studies to be of benefit for those with recurrent and/or metastatic endometrial cancer, and to have a favorable toxicity profile. Conversely, hormonal therapies in these patients have been associated with disappointing overall response rates.

However, given “the well-documented importance of estrogen receptor (ER) signaling as a driver of type I EC and cross-regulation between the ER and PI3K/AKT/mTOR pathways, synergistic antitumor effects might be achieved by combining PI3K/AKT/mTOR pathway inhibitors with agents that disrupt ER signaling,” the investigators wrote.

“We hypothesized that mTOR inhibition in combination with hormonal therapy may have an additive or synergistic effect and improve the overall response rates over either agent alone,” Dr. Slomovitz and his associates added, noting that success with everolimus and the aromatase inhibitor exemestane with respect to progression-free survival in patients with aromatase inhibitor­–refractory breast cancer served as proof of concept.

Patients included in the study had a median age of 62 years and measurable disease that was considered incurable. They were enrolled between May 2010 and September 2011, and all had been treated with up to two prior cytotoxic regimens.

For the current study, they were treated with 4-week cycles of 10 mg oral everolimus and 2.5 mg oral letrozole daily until progression, dose-limiting toxicity, or complete response, and they were followed for a median of 14 months, the investigators said.

The clinical benefit rate was defined as complete response, partial response, or stable disease by RECIST 1.0 criteria: nine women achieved complete response and seven were taken off therapy at the discretion of their clinician after a prolonged complete response (J. Clin. Oncol. 2014 Jan. 26 [doi:10.1200/JCO.2014.58.3401]).

None of the patients discontinued treatment because of toxicity. The most common adverse events considered possibly, probably, or definitely associated with treatment were fatigue, hypertriglyceridemia, hypercholesterolemia, mucositis, anemia, hyperglycemia, and nausea, each occurring in 53%-74% of patients. Most were easily managed grade-1 or -2 toxicities.

Correlative studies, including mutational analysis, showed that the best predictor of lack of response was serous histology; endometrioid histology and CTNNB1 mutations appeared to confer a good response.

“Because of the different pathogenesis of serous cancers and differing serous-like molecular profile defined by the Cancer Genome Atlas uterine analysis, a different treatment response may not be surprising. Further analysis of patients with endometrioid tumors suggests heterogeneity even within one subtype. A single group of responders is difficult to define in patients with endometrioid EC in this study, but there are hints at multiple molecular subgroups that may benefit from everolimus/letrozole treatment,” Dr. Slomovitz and his coworkers wrote, noting that additional studies are essential to clearly define these subgroups, and that more comprehensive molecular profiling will be necessary to identify important drivers behind response and nonresponse.

Given the encouraging clinical benefit rate and the fact that the majority of complete responders in the current trial also had extended response duration similar to that seen in a Gynecologic Oncology Group trial of alternating courses of megestrol acetate and tamoxifen, a randomized comparison of that regimen and the current study regimen is planned.

This study was supported by grants from the Uterine Specialized Programs of Research Excellence, University of Texas MD Anderson Cancer, Novartis, and the Ann Rife Cox Chair in Gynecology. Dr. Slomovitz reported having no disclosures. His coauthors reported research funding from Amgen, Merck, Novartis, MedImmune, BiPar/sanofi-aventis, Abbott Laboratories, Johnson & Johnson, and Array BioPharma; patents/royalties/other intellectual property from Elsevier, Informa UK, and UpToDate; and consulting or advisory roles with Esperance Pharmaceuticals, Genentech/Roche, AstraZeneca, MedImmune, Merck, Johnson & Johnson, Clovis Oncology, Endocyte, and Astellas Pharma.

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