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1. Phase II Study of Everolimus and Letrozole in Patients With Recurrent Endometrial Carcinoma

Author

Charles F Levenback, Kari L. Ring, Brian M. Slomovitz, Robert E. Coleman, Qian Zhang, Melinda S. Yates, David M. Gershenson, Pamela T. Soliman, T. Johnston, Yunyun Jiang, Maureen Nowakowski, Mark F. Munsell, and Karen H. Lu

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Everolimus, business.industry, Endometrial cancer, Letrozole, Phases of clinical research, ORIGINAL REPORTS, Pharmacology, medicine.disease, Clinical trial, Internal medicine, Toxicity, medicine, Carcinoma, Clinical endpoint, business, medicine.drug
Abstract

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.

Published
2015

2. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma.

Author

Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, Levenback C, Zhang Q, Ring K, Munsell MF, Gershenson DM, Lu KH, and Coleman RL

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Bayes Theorem, Biomarkers, Tumor, Cohort Studies, DNA Mutational Analysis, Disease-Free Survival, Endometriosis complications, Everolimus, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Immunosuppressive Agents administration & dosage, Letrozole, Middle Aged, Neoplasm Recurrence, Local, Phosphoinositide-3 Kinase Inhibitors, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Sirolimus administration & dosage, TOR Serine-Threonine Kinases metabolism, Time Factors, Treatment Outcome, beta Catenin genetics, Endometrial Neoplasms drug therapy, Nitriles administration & dosage, Sirolimus analogs & derivatives, Triazoles administration & dosage
Abstract

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., (© 2015 by American Society of Clinical Oncology.)

Published
2015
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