Metformin With IUD Boosts Responses in EIN and Endometrial Cancer

Treatment of metformin plus standard-of-care levonorgestrel-releasing (LR) intrauterine devices (IUD) was well tolerated and demonstrated potential activity in patients with endometrial intraepithelial neoplasia (EIN) and endometrial cancer (EC), according to data from a real-world study presented at the 2025 SGO Annual Meeting on Women’s Cancer.

Efficacy data revealed an overall complete response (CR) rate of 80% (95% CI, 52%-96%) at 6 months among all efficacy-evaluable patients treated on trial; including CR rates of 100% (95% CI, 66%-100%) and 40% (95% CI, 5%-85%) in the EIN and EC groups, respectively. Additionally, the CR rate at 12 months among all comers was 87.5% (95% CI, 62.0%-98.0%).

“The addition of metformin to standard LR-IUD therapy is a well-tolerated combination with potential activity in EIN and EC,” Jennifer Haag, MD, fellow of Gynecologic Oncology of the Department of Obstetrics and Gynecology at UNC Health, said during the presentation. “Our study demonstrated [a] slightly higher CR rate [with] metformin plus LR-IUD compared with prior studies of LR-IUD alone. This combination is worthy of continued exploration in patients desiring fertility preservation or those with comorbidities prohibitive to surgery, as few other options currently exist.”

Patients with biopsy-proven EIN or grade 1 EC desiring fertility preservation or those with unacceptable surgery risk were enrolled on trial. Initially, those with EC underwent MRI. Then, those in both groups underwent dilation and curettage (D&C) with LR-IUD placement and began metformin dosing.

Patients underwent concurrent Eosin-Methylene Blue (EMB) agar testing, as well as concurrent adverse effect (AE) and adherence evaluations. Those whose biopsy showed disease progression or a qualifying AE were removed from protocol treatment; and those who experienced a CR, regression, or stable disease continued treatment with metformin plus LR-IUD for a maximum of 12 months.

The primary end point of the study was 6-month CR in the overall population. Secondary end points included 6-month CR rate in the EIN and EC groups separately, 12-month CR rate in the overall population, adherence rates, and AE incidence. The study sought to evaluate the response and safety of metformin with standard LR-IUD in EIN and EC to assess its impact on CR rates through its reversal of progestin resistance.

Among 15 evaluable patients at 6 months, the median age was 41.4 years (SD, 16.8), the median body mass index (BMI) was 55.2 kg/m2 (range, 30.4-80.9), and 75% were White. Responders to treatment (n = 12) had a median age of 31.0 years, 83% were White, and had a median BMI of 55.2 kg/m2 at baseline. Among non-responders (n = 3), the median age was 35.0 years, all patients were White, and the median BMI was 55.6 kg/m2

A total of 8.3% and 33.3% of responders and non-responders, respectively, had diabetes at diagnosis; adherence of 80% of greater was observed in 83% and 100%; and the reason for no surgery was for fertility preservation in 66.7% and 66.7% of respective groups and was due to unacceptable surgical risk in 25.0% and 33.3%. The most common pathology was EIN (66.7%) among responders and EC among non-responders (100%).

The most common any-grade AEs observed on trial included diarrhea (55%), nausea (55%), transaminitis (15%), anorexia (15%), and headache (15%). There were singular instances of grade 3 diarrhea, vomiting, and renal calculus.

According to investigators, future considerations for further research would entail evaluating metabolic markers that predict clinical response to treatment, as well as LR-IUD in combination with weight loss strategies, including GLP-1 agonists, to optimize weight loss.

Reference

Haag J, Moore D, Schuler K, Doll K, Bae-Jump V. Metformin with the levonorgestrel-releasing intrauterine device for the treatment of endometrial intraepithelial neoplasia and endometrial cancer in non-surgical patients. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO); Seattle, WA, March 14-17, 2025.