Abstract CT163: Temsirolimus in combinaton with metformin in patients with advanced or refractory endometrial cancers
Authors: Naing Aung , Karp Daniel , Piha-Paul Sarina A. , Pant Shubham , Subbiah Vivek , Bodurka Diane C. , Fu Siqing , Jazaeri Amir A. , Kato Shumei , Schmeler Kathleen , Nick Alpa , Yang Yali , Akhmedzhanov Fechukwu O. , Fessahaye Senait , Gong Jing , Stephen Bettzy , Johnson Amber M. , Soliman Pamela T. , Sood Anil K. , Meric-Bernstam Funda , Lu Karen H. 
Published: September 2020

Abstract
Purpose: There is limited success with chemotherapeutic agents in women with advanced or recurrent endometrial cancer. Dysregulation of the PI3K/RAS signaling pathways in endometrial cancer have been well documented. However, responses with mTOR inhibitor such as temsirolimus have been modest. Previously we have shown that metformin prevents temsirolimus-induced AKT activation. Therefore, we enrolled patients with advanced endometrial carcinoma in the expansion cohort of a phase I study of temsirolimus in combination with metformin. Methods: Patients with advanced endometrial cancer refractory to or relapse after standard therapies, ECOG performance status 0 or 1, and with significant organ function reserve were enrolled. Patients were administered intravenous temsirolimus 25mg weekly and oral metformin 2000 mg daily in 28-day cycles. Response was assessed every 2 cycles by clinical evaluation, tumor markers, and imaging per RECIST 1.1. All toxicities were graded using NCI CTCAE, version 4.0. Results: Forty patients were treated. Median age is 67 years (range, 33-78). Drug-related adverse events of any grade were reported in 34 patients. The most common toxicities were mucositis (n=13), AST increase (n=13), anorexia (n=12), diarrhea (n=12) and anemia (n=10). Eleven grade 3 drug-related adverse events were reported. They were anemia (n=2), thrombocytopenia (n=2), mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, AST increase and ALT increase (n=1 each). Of the 33 patients evaluable for response, objective response was seen in 2 (6%) patients. Both had partial response (PR) and were on the study for 8.7 and 18.2 months respectively. In addition, 13 (39%) patients had stable disease (SD), including 11 with SD ≥4 months, representing a clinical benefit rate of 39%. Molecular characterization of tumor was available for 35 patients. Thirty of 35 patients had molecular alterations in the PI3K and/or RAS pathway. Of the 30 patients, 1 had benign PI3K mutation and 4 were not evaluable for response. Of the remaining 25 patients with PI3K and/or KRAS pathway, 11 (44%) had either objective response or SD ≥4 months. Eighteen of them had molecular alteration only in the PI3K pathway. Seven of 18 (39%) had objective response or SD ≥4 months. Importantly, all 3 patients who had molecular alterations in both the PI3K and RAS pathway achieved SD ≥4 months, while 3 of the 4 patients with exclusive resistant KRAS mutation had progressive disease. Collectively, of the 13 patients with either objective response or SD ≥4 months, 11 (85%) patients had molecular alteration in the PI3K and/or RAS pathway. Conclusion: Temsirolimus in combination with metformin was well tolerated. Anti-tumor activity was seen in patients with advanced/refractory endometrial cancer, particularly in patients with molecular alterations in the PI3K and/or RAS pathway that warrants further study.
Citation Format: Aung Naing, Daniel Karp, Sarina A. Piha-Paul, Shubham Pant, Vivek Subbiah, Diane C. Bodurka, Siqing Fu, Amir A. Jazaeri, Shumei Kato, Kathleen Schmeler, Alpa Nick, Yali Yang, Fechukwu O. Akhmedzhanov, Senait Fessahaye, Jing Gong, Bettzy Stephen, Amber M. Johnson, Pamela T. Soliman, Anil K. Sood, Funda Meric-Bernstam, Karen H. Lu. Temsirolimus in combinaton with metformin in patients with advanced or refractory endometrial cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT163.