A randomized phase II trial of everolimus and letrozole or hormonal therapy in women with advanced, persistent or recurrent endometrial carcinoma: A GOG Foundation study

Gynecol Oncol. 2022 Mar;164(3):481-491. doi: 10.1016/j.ygyno.2021.12.031. Epub 2022 Jan 19.


Background: Blocking the PI3K/AKT/mTOR pathway decreases resistance to hormonal therapy in endometrial carcinoma (EC).

Objective: In this study, the aim was to assess the efficacy and tolerability of everolimus(E)/letrozole (L) or medroxyprogesterone acetate(M)/tamoxifen(T) in the treatment of metastatic EC.

Study design: This single stage, open-label two arm randomized phase II trial accrued women with advanced/persistent/recurrent EC. Treatment with E (10 mg daily) and L (2.5 mg daily) or T (20 mg twice daily) and M (200 mg daily alternating weeks) was randomly assigned, and stratified by prior adjuvant therapy. Treatments were administered orally. Primary endpoint was response rate.

Results: Between February 2015 and April 2016, everolimus/letrozole (n = 37) or MT (n = 37) was assigned to 74 patients. Median follow-up was 37 months. Eight (22%; 95% CI 11% to 37%) patients responded on EL (one CR) and nine (25%; 95% CI 14% to 41%) patients responded on MT (three CRs). Median PFS for EL and MT arms was 6 months and 4 months, respectively. On EL, chemo-nave patients demonstrated a 28 month median PFS; prior chemotherapy patients had a 4-month median PFS. On MT, patients without prior therapy had a 5-month median PFS; those with prior chemotherapy demonstrated a 3-month PFS. Common grade 3 adverse events were anemia (9 [24%] patients EL vs 2 [6%] MT) and mucositis (2 [5%] vs 0 [0%]). Grade 3/4 thromboembolic events were observed with MT but not with EL (0 [0%] vs 4 [11%]).

Conclusions: EL and MT demonstrated clinically meaningful efficacy in recurrent EC patients. The higher PFS observed in chemo-naïve patients is worthy of confirmation in future studies.

Keywords: Aromatase inhibitor; Clinical trial; Endometrial carcinoma; Endometrioid; Megace; mTOR inhibtion.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Drug Combinations
  • Endometrial Neoplasms* / drug therapy
  • Endometrial Neoplasms* / pathology
  • Estradiol
  • Estriol
  • Estrone
  • Everolimus / therapeutic use
  • Female
  • Humans
  • Letrozole / therapeutic use
  • Neoplasm Recurrence, Local* / drug therapy
  • Neoplasm Recurrence, Local* / pathology
  • Phosphatidylinositol 3-Kinases


  • Drug Combinations
  • Estrone
  • Estradiol
  • hormonin
  • Letrozole
  • Everolimus
  • Estriol