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Interim phase 2 data show nab-sirolimus plus letrozole produced an ORR of 41% and 13.6-month PFS with manageable safety in endometrioid endometrial cancer.
The combination of nab-sirolimus (Fyarro) and letrozole elicited responses with acceptable safety in patients with advanced or recurrent endometrioid endometrial cancer, according to findings from an interim analysis of the phase 2 ECC-201 study (NCT05997017).1
The findings, which were reported at the 2025 ESMO Congress, showed that the regimen elicited a confirmed objective response rate (ORR) of 40.9% (95% CI, 20.7%-63.6%) in evaluable patients (n = 22), which comprised a complete response (CR) rate of 4.5% (95% CI, 0.1%-22.8%) and a partial response (PR) rate of 40.9% (95% CI, 20.7%-63.6%); the stable disease rate was 45.5% (95% CI, 24.4%-67.8%) and 9.1% (95% CI, 1.1%-29.2%) experienced disease progression. The disease control rate (DCR) with the combination was 68.2% (95% CI, 45.1%-86.1%).
Moreover, the median time to response (TTR) was 2.8 months (95% CI, 1.2-5.5) and the median duration of response (DOR) was not estimable (NE; 95% CI, 1.3-15.5). The median progression-free survival (PFS) with the combination was 13.6 months (95% CI, 5.4-NE).
Responses were observed irrespective of prior exposure to chemotherapy, with an ORR of 33.3% observed in chemotherapy-naive patients, and an ORR of 50% in those who previously received chemotherapy.
“Dual inhibition of mTOR and estrogen pathways with nab-sirolimus plus letrozole showed encouraging activity in patients with advanced or recurrent [endometrioid endometrial cancer],” Lauren E. Dockery, MD, MS, a gynecologic oncologist at Stephenson Cancer Center of Oklahoma University Health, in Oklahoma City, and colleagues, wrote in the poster. “While the sample size is limited, further exploration of this non-chemotherapy approach is warranted given the observed efficacy and safety in this population with limited treatment options.”
Patients with advanced or recurrent endometrial cancer have 5-year survival rates below 50% and limited therapeutic options. It is known that approximately 80% to 95% of patients with endometrioid endometrial cancer have dysregulation in the PI3K/AKT/mTOR signaling pathway; those with this subtype also have an environment that is enriched for estrogen receptor (ER) expression, according to the study authors. Because the crosstalk between mTOR/ER pathway has been linked with resistance to endocrine therapy, investigators have hypothesized that pairing mTOR inhibitors with hormonal therapies could be effective in this population.
Preclinical data with nab-sirolimus has indicated that the drug has higher intratumoral drug concentration, enhanced inhibition of key mTOR targets, and greater antitumor activity vs other mTOR inhibitors.2 In vitro studies have also revealed that when nab-sirolimus has been paired with the ER antagonist fulvestrant (Faslodex), it doubled the tumor cell death rate vs single-agent fulvestrant. For the current study, investigators set out to evaluate the safety and efficacy of nab-sirolimus when paired with letrozole in endometrioid endometrial cancer.3
The open-label, single-arm, multicenter, phase 2 EEC-201 study enrolled patients with advanced, metastatic, or recurrent endometrioid endometrial cancer who were not candidates for surgical resection.1 Patients were required to have at least 1 measurable target lesion by RECIST 1.1 criteria and an ECOG performance status no higher than 1. They could not have prior exposure to mTOR inhibition.
However, patients were able to receive prior adjuvant chemotherapy, hormonal therapy, immune checkpoint inhibition, or other options; and up to 1 prior chemotherapy or non–chemotherapy-based treatment in the advanced, metastatic, or recurrent setting.
Patients must have experienced a CR or PR with at least 1 prior therapy. Study participants were administered 100 mg/m2 of intravenous nab-sirolimus on days 1 and 8 plus 2.5 mg of letrozole on days 1 through 21.
The primary end point of the study was ORR by investigator assessment and RECIST 1.1 criteria. Key secondary end points included DOR, DCR, TTR, PFS, overall survival, and safety. Key exploratory end points included evaluation of baseline biomarkers linked with clinical outcomes.
The study utilized a Simon 2-stage design wherein 10 patients received 6 months of therapy in stage 1, and 19 additional patients would be enrolled in stage 2 unless no responses were achieved in the first stage of the research.
The data cutoff date for the analysis was July 28, 2025. Of the 24 patients enrolled, 8 were still receiving treatment. The median patient age was 66.5 years (range, 38-80), with 41.7% of patients younger than 65 years and 58.3% aged 65 years or older. Most patients were White (91.7%) and not Hispanic or Latino (83.3%), and half had Federation of Gynecology and Obstetrics grade 1 disease.
All patients had positive ER status per immunohistochemistry (IHC) and 83.3% had progesterone receptor positivity. Moreover, 66.7% of patients had mismatch repair–proficient/microsatellite stable (66.7%) and TP53 wild-type (79.2%) disease. Additionally, 58.3% of patients received prior systemic anticancer therapy, which included chemotherapy (50.0%), hormonal therapy (20.1%), and other targeted therapy (20.1%). Approximately 29% (29.2%) of patients had prior immune checkpoint inhibition.
The most common treatment-related adverse effects experienced by at least 20% of patients included dysgeusia (any grade, 54.2%; grade 3/4, 0%), fatigue (37.5%; 8.3%), stomatitis (37.5%; 4.2%), diarrhea (29.2%; 8.3%), hypokalemia (33.3%; 4.2%), decreased appetite (33.3%), peripheral edema (33.3%), anemia (16.7%; 12.5%), nausea (25.0%; 4.2%), cough (29.2%), maculopapular rash (29.2%), vomiting (29.2%), pruritus (25.0%), hypertriglyceridemia (8.3%; 12.5%), increased alanine aminotransferase level (20.8%; 0%), hot flush (20.8%; 0%), insomnia (20.8%; 0%), nail disorder (20.8%; 0%), decreased platelet count (20.8%; 0%), and decreased white blood cell count (20.8%; 0%).
“Two patients had pneumonitis, one grade 1 and one grade 3, a known adverse [effect] associated with the mTOR inhibitor drug class,” the study authors noted.
TRAEs led to dose interruption or reduction for 50% and 42% of patients, respectively. Only 2 patients experienced TRAEs that ultimately led to study discontinuation. No treatment-related deaths occurred.
Safety proved to generally align with the known safety profiles of the agents examined, the study authors concluded, adding that there was minimal overlap with the toxicity profile of letrozole.
