Everolimus, letrozole, metformin: Triple threat against recurrent endometrial cancer

The combination of metformin, everolimus and letrozole has demonstrated clinical activity in patients with recurrent endometrioid endometrial cancer (EEC), inducing better response in those with progesterone receptor (PgR)-positive tumours, according to the results of a phase II study.

The trial included 62 women (median age, 62 years; median body mass index, 33.3 kg/m²) with ≤2 prior chemotherapy regimens for recurrence. Majority of them (93 percent) had pure endometrioid histology; 85 percent had received at least one prior chemotherapy agent for recurrence, while 65 percent had received prior radiotherapy.

All patients underwent pretreatment biopsy, followed by everolimus 10 mg, letrozole 2.5 mg and metformin 500 mg, all of which were administered orally twice a day on a 4-week cycle. Treatment was given until progression or toxicity. Only 54 patients were evaluable for response, with 401 cycles completed (median, 6 cycles). Thirteen patients received >12 cycles.

Twenty-seven patients achieved the primary endpoint of clinical benefit (defined as complete response, partial response [PR] or stable disease [SD]) at week 16, yielding a rate of 50 percent. Best overall response was PR, which was observed in 15 patients (28 percent); twelve patients (22 percent) had SD. The median follow-up was 17.9 months.

Median progression-free survival was 5.7 months, while median overall survival was 19.6 months. Response was notably more favourable in the subgroup of patients with PgR-positive disease (clinical benefit rate, 89.5 percent vs 27.3 percent; p=0.001).

The present data indicate that “the backbone of everolimus and letrozole are effective in treating women with recurrent EEC and may be a reasonable choice in second-line therapy,” researchers said. Also, the study provides evidence that the addition of metformin to the said combination is beneficial, without increasing toxicity for patients.