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Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma
Brian M Slomovitz1, Yunyun Jiang1, Melinda S Yates1
1Brian M. Slomovitz, Yunyun Jiang, Melinda S. Yates, Pamela T. Soliman, Taren Johnston, Charles Levenback, Qian Zhang, Kari Ring, Mark F. Munsell, David M. Gershenson, Karen H. Lu, and Robert L. Coleman, The University of Texas MD Anderson Cancer Center, Houston, TX; Brian M. Slomovitz and Maureen Nowakowski, Morristown Medical Center, Morristown, NJ; and Brian M. Slomovitz, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL.
Purpose:
The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC.
Patients And Methods:
Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response.
Results:
Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole.
Conclusion:
Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way.
Insights
Everolimus and letrozole show promise for treating recurrent endometrial cancer (EC), offering a clinical benefit rate of 40% and an objective response rate of 32% in a phase II trial.
Area of Science:
- Oncology
- Pharmacology
Background:
- Endometrial cancer (EC) frequently exhibits dysregulation of the phosphoinositol-3 kinase (PI3K) pathway.
- While hormonal manipulation can be effective, resistance often emerges due to PI3K pathway activation.
- Targeting the mammalian target of rapamycin (mTOR) presents a potential strategy to overcome endocrine resistance in EC.
Purpose of the Study:
- To evaluate the efficacy of everolimus in combination with letrozole in women with recurrent endometrial cancer.
- To assess the clinical benefit rate (CBR) and objective response rate (RR) of this combination therapy.
Main Methods:
- A two-institution phase II trial was conducted involving patients with incurable, measurable recurrent EC who had received up to two prior cytotoxic regimens.
- Everolimus (10 mg daily) and letrozole (2.5 mg daily) were administered orally in 4-week cycles until disease progression, unacceptable toxicity, or complete response.
- The primary endpoint was the clinical benefit rate (CBR), defined as complete response (CR), partial response, or stable disease (≥ 16 weeks) per RECIST 1.0 criteria.
Main Results:
- The study enrolled 38 patients; 35 were evaluable for response. The overall CBR was 40% (14/35), with a median of 15 cycles among responders.
- The confirmed objective response rate (RR) was 32% (11/35), including nine CRs and two partial responses.
- Patients with endometrioid histology and CTNNB1 mutations showed a favorable response, while serous histology predicted a lack of response. No treatment-discontinuting toxicity was observed.
Conclusions:
- The combination of everolimus and letrozole demonstrates a high clinical benefit rate and objective response rate in patients with recurrent endometrial cancer.
- This combination therapy is a promising option for recurrent EC, particularly for those with endometrioid histology.
- Further investigation and development of this therapeutic strategy in recurrent endometrioid EC are warranted.
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