Everolimus, Letrozole, and Metformin in Women with Advanced or Recurrent Endometrioid Endometrial Cancer: A Multi-Center, Single Arm, Phase II Study

Abstract

Purpose: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second-line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent EEC.Patients and Methods: A Simon two-stage design was employed. Women with 2 prior chemotherapy regimens for recurrence were eligible. Pretreatment biopsy was required, followed by everolimus 10 mg orally, letrozole 2.5 mg orally, and metformin 500 mg orally twice a day on a 4-week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity.Results: Sixty-two patients were enrolled. Median age was 62 years (40-77) with 401 cycles completed, median of 6 cycles (1-31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received >12 cycles. Median follow-up was 17.9 months (2-47). Median progression-free survival was 5.7 [95% confidence interval (CI), 3.0-8.1] and OS was 19.6 months (95% CI, 14.2-26.3). Positive progesterone receptor expression was associated with CB (89.5% vs. 27.3%, P ¼ 0.001).Conclusions: Everolimus, letrozole, and metformin resulted in 50% CB and 28% OR in women with recurrent EEC. Progesterone receptor-positive tumors may have better response; validation studies are needed.See related commentary by Madariaga et al., p. 523

Impact of hormonal biomarkers on response to hormonal therapy in advanced and recurrent endometrial cancer

“…Earlier studies have used cutoff values of 10% of positive tumor nuclei or cutoff values on combined staining intensity indices. 21,32,39 A cutoff of 1%, as is currently advised in breast cancer, was also inferior to the 50% cutoff value. 40 Another potential advantage of the 50% cutoff value is that it is in use for other predictive biomarkers and it is easy to apply when scoring IHC slides.…”

Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy

“… 69 Subsequently, the combination of everolimus, letrozole, and metformin was investigated, since prior research had demonstrated inhibition of proliferation and induction of apoptosis with metformin. 70 A clinical benefit in half of the 54 patients with metastatic endometrioid endometrial cancer was seen, with a partial response in 28% and stable disease in 22% after 16 weeks of therapy. However, the addition of metformin to the combination did not appear to improve the outcomes.…”

“…However, the addition of metformin to the combination did not appear to improve the outcomes. 70 The human epidermal growth factor receptor HER2 provides critical signaling for cancer cell growth, survival, and proliferation. 39 The majority of endometrial cancers, which over-express HER2 are mainly serous or TP53-mutated cancers, including carcinosarcomas.…”

Endometrial Cancer: When Upfront Surgery Is Not an Option

“…The development of a new generation of inhibitors with greater specificity and fewer side effects is strongly warranted for the management of EC [31]. The combination of aromatase inhibitors with mammalian target of rapamycin (m-TOR) inhibitors (such as everolimus), and of aromatase inhibitors with m-TOR inhibitors and metformin could offer promising perspectives of clinical research [32-34]. The employment of the cyclin-dependent kinase 4/6 inhibitor palbociclib in EC is still investigational [35].…”