CHICAGO—Adding metformin to a combination everolimus plus letrozole regimen for women with advanced or recurrent endometrioid endometrial cancer (EEC) might offer clinical benefits, according to findings from an open-label phase II trial presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 5506).
“Everolimus, letrozole, and metformin resulted in a confirmed CBR [clinical benefit rate] of 60%,” reported lead study author Pamela T. Soliman, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Twenty-nine percent of patients had an objective response. The combination was well tolerated, with manageable toxicity.”
There are limited treatment options for women with advanced or recurrent endometrial cancer. Everolimus plus letrozole have shown “promising results” for the treatment of recurrent EEC, Soliman noted. Preclinical observations and clues from a previous phase II clinical trial have suggested that metformin may enhance that combination treatment’s effectiveness, “particularly in the presence of a KRAS mutation,” she said. A post-hoc analysis from a previous phase II study of everolimus plus letrozole in 35 women with endometrial cancer showed that overall response rates and CBR had been better among women who were taking metformin, and that progression-free survival (PFS) was longer among these patients.
In order to estimate the CBR associated with adding metformin to everolimus plus letrozole for women with advanced or recurrent endometrial cancer, the researchers conducted a single-arm phase II study of women with endometrial cancer of mixed or endometrioid histology, who had undergone two or fewer prior chemotherapy regimens. Women underwent pretreatment biopsy followed by lead-in metformin treatment, then everolimus (10 mg) and letrozole (2.5 mg) therapy with metformin (1,000 mg). Responses were evaluated at week 8, and confirmed at week 16.
They enrolled 49 evaluable patients, 45 of whom (92%) had EEC and 4 of whom (8%) had mixed endometrioid cancer. Sixty-three percent of participants had previous radiation and 67% had undergone chemotherapy for recurrence.
After a median of 6 cycles (range, 2–18), the CBR was 60% (29 of 49 women), with no complete responses, 14 (29%) partial responses, and 15 (31%) women with stable disease. Disease progressed in 20 (40%) women. Eight patients had completed more than 14 cycles at the time of analysis (6 partial responses, 2 with stable disease).
Eleven patients (22%) experienced anemia and 8 (14%) experienced hypertriglyceridemia. Four patients required dose reductions (three for everolimus and one for metformin), and two patients discontinued the study because of toxicities.
The CBR was not related to the presence or absence of KRAS mutations (P = .49).