CHICAGO (FRONTLINE MEDICAL NEWS) – The novel combination of everolimus, letrozole, and metformin was associated with improved clinical benefit and objective response rates, compared with everolimus and letrozole without metformin in patients with advanced or recurrent, previously treated endometrioid endometrial cancer (EEC) in an ongoing open-label, single-arm, prospective phase II study.

In 49 patients with an evaluable response to the combination therapy, 29 (60%) derived clinical benefit – defined as complete response, partial response, or stable disease confirmed at 8 weeks by RECIST 1.1, Dr. Pamela T. Soliman reported at the annual meeting of the American Society of Clinical Oncology.

The best overall response to date was 29% partial response and 31% stable disease (60% clinical benefit rate) with a median of six cycles, said Dr. Soliman of the University of Texas MD Anderson Cancer Center, Houston.

So far, 58 patients have been enrolled in the study, and 194 cycles have been completed. Eight patients have received more than 14 cycles, and of those, 6 have achieved a partial response and 2 have stable disease.

Eight remain on active treatment.

“Of note, at the time of first assessment at 8 weeks, the objective response rate was only 14%, so over half of the responses were seen after at least 4 cycles of therapy were administered,” she said.

Endometrial cancer is the most common gynecologic malignancy, with an estimated 52,000 cases to be diagnosed this year. Most cases are diagnosed early, and the overall prognosis is good; the 5-year survival rate is nearly 90%.

“Unfortunately, for those women who recur, treatment options are limited,” Dr. Soliman said, noting that the best response rate seen in studies of various single and combination chemotherapy agents has been about 25% – occurring with paclitaxel and with bevacizumab-temsirolimus.

The novel combination therapy used in the current study was developed based on prior studies, including one conducted by Dr. Soliman and her colleagues, showing promising results with combination everolimus and letrozole for recurrent EEC. The investigators found that in one study of 35 patients on the everolimus and letrozole regimen, the overall response rate was 23%, the clinical benefit rate was 38%, and progression-free survival was 1.9 months, but they noticed that in a subgroup of patients who had received metformin during the course of the study, the corresponding rates were 56%, 78%, and 14 months. Preclinical data suggested that the benefit of adding metformin to the combination was particularly pronounced in patients with KRAS mutation. The current study was designed to evaluate this approach.

Study subjects had advanced/recurrent EEC and up to two prior chemotherapy regimens for recurrence. Molecular testing was performed to determine KRAS mutation status.

A pretreatment biopsy was performed for histological confirmation and molecular analysis, followed by a 1 week metformin lead in and then treatment with 10 mg oral everolimus daily, 2.5 mg or oral letrozole daily, and 500 mg of oral metformin twice daily. A single dose reduction of everolimus was permitted, and patients were treated until their disease progressed or until they experienced toxicity. Response was evaluated by imaging at 8 weeks or after 2 cycles of therapy, and confirmation of response was performed at 16 weeks, or after 4 cycles of therapy.

In this preliminary evaluation, no significant difference was seen in the clinical benefit rate based on KRAS mutation status (67% in 15 patients with KRAS mutation, 77% in 26 patients without the mutation), but further correlation between molecular findings and response are currently being evaluated.

The most common side effects were diarrhea, anemia, fatigue, nausea, mucositis, hypertriglyceridemia, and elevated aspartate aminotransferase, Dr. Soliman said, noting that 43% of patients experienced a grade 3/4 toxicity, 4 required a dose reduction, and 2 withdrew from the study.

Additionally, one patient with a partial response after 1 cycle was removed from treatment due to increased liver enzymes.

A comparison with findings from the prior everolimus and letrozole study showed that metformin did not add significant toxicity to the regimen, she noted.

“The addition of metformin to the everolimus and letrozole backbone, increased the clinical benefit rate from 40% to 60%. Overall the toxicity of all three drugs was manageable and few patients came off study due to toxicity … Based on these findings and other studies, the use of targeted therapy in women with recurrent endometrial endometrioid cancer appears to benefit patients over standard cytotoxic chemotherapy,” Dr. Soliman concluded, adding that further development of this combination for use in patients with EEC is warranted.

She noted that an ongoing randomized clinical trial – GOG 3007 – is comparing everolimus and letrozole with tamoxifen alternating with megestrol acetate.

“This trial has recently completed accrual and results are pending. This will allow us to better identify how this treatment strategy compares to hormonal therapy alone in women with recurrent endometrial cancer. In addition, at our institution we are investigating other agents to be added to the everolimus and letrozole backbone to enhance response to patients with endometrioid endometrial cancer,” she said.

Dr. Soliman reported receiving research funding (to her institution) from Novartis.