Highlights
- The triplet combination of letrozole, abemaciclib, and metformin achieved an objective response rate (ORR) of 32% and a clinical benefit rate (CBR) of 60% in patients with ER-positive endometrioid endometrial cancer.
- The median progression-free survival (PFS) was 19.4 months, with a 6-month PFS rate of 69.8%.
- Significant activity was observed in tumors with CTNNB1 mutations, while no responses were seen in TP53-mutated cases.
- A novel pharmacokinetic finding revealed a more than 3-fold increase in metformin exposure when co-administered with letrozole and abemaciclib.
Introduction: The Rationale for Vertical Pathway Inhibition in Endometrial Cancer
Endometrial cancer (EC) remains a significant challenge in gynecologic oncology, particularly for patients with advanced or recurrent disease. While the endometrioid subtype is frequently estrogen receptor (ER) positive and initially responsive to endocrine therapy, resistance often develops through the activation of compensatory signaling pathways. Preclinical evidence has long suggested that simultaneous inhibition of the estrogen receptor, the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway, and the phosphoinositide 3-kinase (PI3K)/AKT/mTOR axis could overcome this resistance.
The CDK4/6 pathway is frequently dysregulated in EC, and its inhibition has shown synergy with endocrine agents like letrozole in other hormone-driven cancers, most notably breast cancer. However, the PI3K pathway is the most frequently mutated pathway in endometrioid EC. Metformin, a biguanide commonly used for type 2 diabetes, has emerged as a potential modulator of this pathway. Window-of-opportunity studies have demonstrated that metformin can suppress PI3K/mTOR signaling in endometrial tissue. This clinical trial (NCT03675893) sought to evaluate whether the addition of metformin to a letrozole/abemaciclib backbone could provide a synergistic therapeutic effect in ER-positive endometrioid EC.
Study Design and Methodology
Patient Population
This non-randomized phase 2 trial enrolled 25 patients with ER-positive endometrioid endometrial cancer. The cohort included patients with various FIGO grades (13 with grade 1, 8 with grade 2, and 4 with grade 3). A significant portion of the participants had received prior systemic therapies, including hormonal agents (n=18) and chemotherapy (n=7).
Treatment Regimen and Endpoints
The protocol therapy consisted of a triplet regimen: letrozole 2.5 mg orally once daily, abemaciclib 150 mg orally twice daily, and metformin 500 mg orally once daily. The primary objectives were the objective response rate (ORR) and the rate of progression-free survival at 6 months (PFS6). Secondary objectives included median PFS, overall survival (OS), duration of response (DOR), and toxicity profiles.
Key Findings: Efficacy and Survival Outcomes
Objective Responses
Among the 25 evaluable patients, the ORR was 32% (95% CI, 14.9-53.5). This included three patients (12%) who achieved a complete response (CR) and five patients (20%) who achieved a partial response (PR). Notably, the duration of response was particularly encouraging; the median DOR could not be estimated at the time of data cut-off because only two of the eight responders had developed progressive disease.
The three patients who achieved a complete response provided significant insights into the regimen’s potential. The first patient, with grade 1 disease and multiple metastatic lung and lymph node nodules, carried PIK3CA, PTEN, and CTNNB1 mutations. The second patient had a grade 2, progesterone receptor (PgR)-negative tumor with extensive peritoneal and pleural involvement and a PIK3CA mutation. The third patient had a grade 1 tumor with AKT1 and CTNNB1 mutations and abdominal wall nodules. All three cases highlight the regimen’s activity in heavily pre-treated, multi-metastatic settings.
Clinical Benefit and Progression-Free Survival
The clinical benefit rate (CBR), defined as the sum of ORR and stable disease (SD) lasting at least 6 months, was 60% (95% CI, 38.7-78.9). Sixteen patients (64%) exhibited stable disease as their best response, with seven of these maintaining stability for over six months. The Kaplan-Meier estimate for PFS at 6 months was 69.8% (95% CI 46.9-84.3%), and the median PFS was 19.4 months (95% CI 5.7–not estimable).
When stratified by FIGO grade, the CBR was 69% for grade 1 and 75% for grade 2 tumors. However, none of the four patients with grade 3 tumors derived clinical benefit, suggesting that this endocrine-based triplet may be most effective in lower-grade, more hormone-dependent disease. Interestingly, the benefit was consistent regardless of prior hormonal therapy, with 61% of those previously treated with hormones deriving benefit compared to 57% of hormone-naïve patients.
Translational Insights: Genomic Correlates of Response
The study performed deep molecular profiling to identify biomarkers of response. A key finding was the correlation between CTNNB1 mutations and clinical benefit. Conversely, the researchers observed a lack of objective responses among patients with TP53 mutations. Additionally, tumors within the No Specific Molecular Profile (NSMP) category that also harbored RB1 or CCNE1 alterations did not respond to the therapy. These findings suggest that while the triplet is highly effective in certain molecular subsets, alternative strategies may be needed for TP53-mutant or high-grade serous-like endometrioid cancers.
Pharmacokinetics and Safety
One of the most surprising findings of the trial was the pharmacokinetic (PK) interaction between the agents. Pharmacokinetic analysis demonstrated that the administration of letrozole and abemaciclib alongside metformin resulted in a more than 3-fold increase in metformin exposure. Despite this increase, the regimen was remarkably well-tolerated. No patients discontinued therapy due to toxicity, a testament to the safety of the combination even with the altered PK profile.
Expert Commentary
The results of this phase 2 trial are highly significant for the management of ER-positive endometrioid endometrial cancer. The median PFS of 19.4 months is particularly striking when compared to historical benchmarks for endocrine therapy alone or even some chemotherapy regimens in the recurrent setting. The inclusion of metformin, while primarily intended to inhibit the PI3K/mTOR pathway, appears to have introduced a complex PK interaction that may have enhanced the overall therapeutic effect.
The high CBR in grade 1 and 2 tumors underscores the importance of patient selection based on both histology and molecular profile. The association of CTNNB1 mutations with clinical benefit is a crucial observation, as these mutations are common in the NSMP molecular subgroup of EC. This study provides a strong rationale for larger, randomized trials to confirm these findings and further investigate the mechanism behind the increased metformin exposure.
Conclusion
The combination of letrozole, abemaciclib, and metformin represents a promising, well-tolerated, and effective therapeutic strategy for patients with ER-positive, low-to-intermediate grade endometrioid endometrial cancer. With an ORR of 32% and a median PFS exceeding 19 months, this triplet regimen addresses a significant unmet need in the second-line setting and beyond. Future research should focus on validating the role of CTNNB1 as a predictive biomarker and exploring the therapeutic potential of this combination in earlier lines of treatment.
Funding and Trial Registration
This study was supported by institutional funds and pharmaceutical partnerships. ClinicalTrials.gov Identifier: NCT03675893.
References
Konstantinopoulos PA, Zhou N, Penson RT, et al. Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial. Nat Commun. 2025;17(1):395. doi:10.1038/s41467-025-67087-8.