Abstract A121: Temsirolimus in combination with metformin in patients with advanced or recurrent endometrial cancer
Authors: Ahmed Jibran , Stephen Bettzy , Beyaz Samir , Chung Charlie , Kilic Ece , Khawaja Muhammad R , Yang Yali , Nick Alpa M , Raso Maria G , Toro Elizve B , Karp Daniel D , Piha-Paul Sarina A , Sood Anil , Ng Chaan , Johnson Amber M , Soliman Pamela T , Meric-Bernstam Funda , Lu Karen H , Naing Aung 
Published: December 2023

Abstract
Background: Molecular alterations in the PI3K/AKT and Ras/Raf/MAPK are frequently seen in endometrial cancers and mTOR is a downstream target activated by both pathways. Blocking mTOR with temsirolimus produced modest response. Studies have shown that metformin, in addition to producing metabolic changes, also causes activation of AMPK, which in turn inhibits the mTOR pathway. Therefore, we enrolled patients with advanced or recurrent endometrial cancer in the expansion cohort of a phase I study of temsirolimus in combination with metformin.
Methods: Patients received intravenous (IV) temsirolimus 25 mg weekly and oral metformin 2000 mg daily in 28-day cycles. The objective of this study was to evaluate the efficacy of this combination and assessment of correlatives of target inhibition in tumor biopsies from patients with known mutations. 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. TIL (tumor infiltrating lymphocyte) percentage was assessed in tumor tissue samples collected at baseline and on treatment.
Results: A total of 40 patients were included in this study. Among the 33 patients evaluable for response, 2 patients had partial response (PR) and 13 had stable disease (SD), including 11 with SD ≥4 months. The objective response rate was 6% and clinical benefit rate 39%. Molecular alteration in the PI3K and/or RAS pathway was seen in 25 of 33 patients. Eleven of the 25 patients (44%) had either PR or SD ≥4 months. Interestingly, all 3 patients with molecular alteration in both the pathways had SD ≥4 months. The most common treatment-related adverse events included hypertriglyceridemia (n=14), diarrhea (n=13), mucositis (n=13), anorexia (n=12) and anemia (n=10). The grade 3 AEs were anemia and thrombocytopenia (n=2 each) and mucositis, fatigue, weight loss, hypokalemia, hypophosphatemia, and increase in aspartate aminotransferase and alanine transaminase (n=1 each). Although baseline TIL scores did not distinguish responder from non-responder (p=0.25), on-treatment increase in TIL score was significantly higher among responders compared to non-responders (p-value 0.034). Metabolomics portion of the study is ongoing.
Conclusions: In conclusion, the combination of temsirolimus with metformin had modest anti-tumor activity in patients with advanced or recurrent endometrial cancer without added safety concerns. Correlative studies may provide further insight about this combination.
Citation Format: Jibran Ahmed, Bettzy Stephen, Samir Beyaz, Charlie Chung, Ece Kilic, Muhammad R Khawaja, Yali Yang, Alpa M Nick, Maria G Raso, Elizve B Toro, Daniel D Karp, Sarina A Piha-Paul, Anil Sood, Chaan Ng, Amber M Johnson, Pamela T Soliman, Funda Meric-Bernstam, Karen H Lu, Aung Naing. Temsirolimus in combination with metformin in patients with advanced or recurrent endometrial cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A121.