Endometrial cancer (EC), particularly the endometrioid subtype, remains a leading gynecologic malignancy with limited options for advanced, ER-positive disease. Preclinical models demonstrate synergistic antitumor effects from concurrent inhibition of estrogen receptor (ER), cyclin-dependent kinase 4/6 (CDK4/6), and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways. Building on window-of-opportunity studies showing metformin’s suppression of PI3K/mTOR signaling in EC, we conducted a single-arm, non-randomized phase 2 trial (NCT03675893) to evaluate the combination of letrozole (an aromatase inhibitor), abemaciclib (a CDK4/6 inhibitor), and metformin (a PI3K/mTOR modulator) in patients with ER-positive endometrioid EC.
Eligible patients included those with treatment-naïve advanced or recurrent disease, stratified by molecular profiles (e.g., POLE, MSI-high, TP53-mutated, NSMP). The regimen consisted of letrozole 2.5 mg orally once daily, abemaciclib 150 mg orally twice daily, and metformin 500 mg orally once daily, administered continuously until progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR) per RECIST 1.1 criteria and progression-free survival at 6 months (PFS6). Secondary endpoints encompassed median PFS, overall survival, duration of response, and safety.
Twenty-five patients initiated therapy, with a median age of 65 years and predominantly stage IV disease (52%). The ORR was 32% (95% CI: 14.9%-53.5%), comprising 3 complete responses and 5 partial responses. Kaplan-Meier estimates revealed a PFS6 rate of 69.8% (95% CI: 46.9%-84.3%) and a median PFS of 19.4 months (95% CI: 5.7 months–not estimable). No patients discontinued due to adverse events; grade 3/4 toxicities were limited to neutropenia (12%) and diarrhea (8%), all manageable with dose adjustments.
Exploratory analyses identified no objective responses among TP53-mutated ECs (n=8) or no specific molecular profile (NSMP) tumors harboring RB1 or CCNE1 alterations (n=4), suggesting potential resistance mechanisms. Conversely, CTNNB1 mutations (n=9) strongly correlated with clinical benefit, with 56% response rate in this subgroup (p=0.02). Pharmacokinetic assessments confirmed a >3-fold increase in metformin area under the curve when co-administered with letrozole and abemaciclib, likely due to reduced renal clearance, without impacting other drug levels.
These results indicate promising efficacy and tolerability for this triplet in ER+ endometrioid EC, exceeding historical benchmarks for endocrine monotherapy (ORR ~10-20%). Molecular stratification, particularly CTNNB1 status, may refine patient selection. Future randomized trials are warranted to validate these findings and explore biomarkers for precision application in advanced EC management.
