PMID- 27036973 OWN - NLM STAT- MEDLINE DCOM- 20171016 LR - 20220316 IS - 1938-0682 (Electronic) IS - 1558-7673 (Linking) VI - 14 IP - 4 DP - 2016 Aug TI - Phase 2 Study of Bevacizumab and Temsirolimus After VEGFR TKI in Metastatic Renal Cell Carcinoma. PG - 304-313.e6 LID - S1558-7673(16)30035-0 [pii] LID - 10.1016/j.clgc.2016.02.007 [doi] AB - BACKGROUND: Inhibiting VEGF and mammalian target of rapamycin (mTOR) pathways are standard treatment approaches for patients with metastatic renal cell carcinoma (mRCC). Here we report the activity and safety of the VEGF ligand inhibitor bevacizumab and the mTOR inhibitor temsirolimus combination in patients with clear cell (CC) and non-clear cell (NCC) mRCC whose disease had failed to respond to prior VEGF blockade. PATIENTS AND METHODS: In this phase 2 investigator-initiated multicenter study, patients received bevacizumab and temsirolimus. The primary end point was 4-month progression-free survival (PFS) rate. Secondary end points included overall response rate, median overall survival (OS), toxicity, and correlative studies of biomarkers downstream of mTOR. RESULTS: Forty patients received at least 1 dose of therapy. Thirty-three (82.5%) had favorable/intermediate risk disease according to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 13 (32.5%) with nccRCC histology. Nineteen (48.7%) had primary vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-refractory disease. The 4-month PFS rate was 65%. Overall median PFS and OS were 5.6 and 12.2 months. Median PFS and OS were 6.5 and 9.6 months in patients with primary VEGFR TKI-refractory disease, and 5.6 months and 13.1 months in patients with nccRCC. Dose reductions were needed in 80% of patients. Most frequent toxicities included fatigue, hypertension, dyslipidemia, and proteinuria. Dose discontinuation due to adverse events occurred in 27.5% of patients. Baseline tumor immunohistochemistry for phospho-S6 protein was not associated with clinical benefit. CONCLUSION: Combining bevacizumab and temsirolimus in patients previously treated with VEGFR TKI was possible but with dose reductions and treatment discontinuations. This combination resulted in modest activity, including in patients with primary VEGF-refractory disease and NCC histology. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Mahoney, Kathleen M AU - Mahoney KM AD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. FAU - Jacobus, Susanna AU - Jacobus S AD - Department of Statistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. FAU - Bhatt, Rupal S AU - Bhatt RS AD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. FAU - Song, Jiaxi AU - Song J AD - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. FAU - Carvo, Ingrid AU - Carvo I AD - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. FAU - Cheng, Su-Chun AU - Cheng SC AD - Department of Statistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. FAU - Simpson, Mekailah AU - Simpson M AD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. FAU - Fay, Andre P AU - Fay AP AD - PUCRS School of Medicine, Porto Alegre, Brazil. FAU - Puzanov, Igor AU - Puzanov I AD - Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN. FAU - Michaelson, M Dror AU - Michaelson MD AD - Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA. FAU - Atkins, Michael B AU - Atkins MB AD - Department of Medical Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC. FAU - McDermott, David F AU - McDermott DF AD - Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. FAU - Signoretti, Sabina AU - Signoretti S AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. FAU - Choueiri, Toni K AU - Choueiri TK AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address: toni_choueiri@dfci.harvard.edu. LA - eng GR - P50 CA101942/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160223 PL - United States TA - Clin Genitourin Cancer JT - Clinical genitourinary cancer JID - 101260955 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 624KN6GM2T (temsirolimus) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Angiogenesis Inhibitors/*administration & dosage/therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/therapeutic use MH - Bevacizumab/*administration & dosage/therapeutic use MH - Carcinoma, Renal Cell/*drug therapy MH - Disease-Free Survival MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Kidney Neoplasms/*drug therapy MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Protein Kinase Inhibitors/*administration & dosage/therapeutic use MH - Sirolimus/administration & dosage/*analogs & derivatives/therapeutic use MH - Treatment Outcome OTO - NOTNLM OT - Bevacizumab OT - Renal cell carcinoma OT - TKI-refractory disease OT - Temsirolimus EDAT- 2016/04/03 06:00 MHDA- 2017/10/17 06:00 CRDT- 2016/04/03 06:00 PHST- 2015/12/03 00:00 [received] PHST- 2016/02/08 00:00 [revised] PHST- 2016/02/14 00:00 [accepted] PHST- 2016/04/03 06:00 [entrez] PHST- 2016/04/03 06:00 [pubmed] PHST- 2017/10/17 06:00 [medline] AID - S1558-7673(16)30035-0 [pii] AID - 10.1016/j.clgc.2016.02.007 [doi] PST - ppublish SO - Clin Genitourin Cancer. 2016 Aug;14(4):304-313.e6. doi: 10.1016/j.clgc.2016.02.007. Epub 2016 Feb 23.