PMID- 26364551 OWN - NLM STAT- MEDLINE DCOM- 20161114 LR - 20211203 IS - 1873-7560 (Electronic) IS - 0302-2838 (Linking) VI - 69 IP - 3 DP - 2016 Mar TI - A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer. PG - 450-6 LID - S0302-2838(15)00780-0 [pii] LID - 10.1016/j.eururo.2015.08.035 [doi] AB - BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. DESIGN, SETTING, AND PARTICIPANTS: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. INTERVENTION: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. RESULTS AND LIMITATIONS: Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02). CONCLUSIONS: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. PATIENT SUMMARY: There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile. CI - Copyright (c) 2015. Published by Elsevier B.V. FAU - Powles, Thomas AU - Powles T AD - Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK; The Royal Free NHS Foundation Trust, London, UK. Electronic address: thomas.powles@bartshealth.nhs.uk. FAU - Wheater, Matthew AU - Wheater M AD - Southampton NHS Foundation Trust, Southampton, UK. FAU - Din, Omar AU - Din O AD - Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. FAU - Geldart, Thomas AU - Geldart T AD - Royal Bournemouth Hospital, Bournemouth, UK. FAU - Boleti, Ekaterini AU - Boleti E AD - The Royal Free NHS Foundation Trust, London, UK. FAU - Stockdale, Andrew AU - Stockdale A AD - Arden Cancer Centre, University Hospital, Coventry, UK. FAU - Sundar, Santhanam AU - Sundar S AD - Nottingham University Hospitals NHS trust, Nottingham, UK. FAU - Robinson, Angus AU - Robinson A AD - Sussex Cancer Centre, Brighton, UK. FAU - Ahmed, Imtiaz AU - Ahmed I AD - Southend NHS Trust, Southend, UK. FAU - Wimalasingham, Akhila AU - Wimalasingham A AD - Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK. FAU - Burke, Wendy AU - Burke W AD - AstraZeneca UK Limited, Quantitative Clinical Pharmacology, Macclesfield, UK. FAU - Sarker, Shah-Jalal AU - Sarker SJ AD - Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK. FAU - Hussain, Syed AU - Hussain S AD - University of Liverpool, Clatterbridge Cancer Centre, Liverpool, UK. FAU - Ralph, Christy AU - Ralph C AD - St. James's University Hospital, University of Leeds, Leeds, UK. LA - eng PT - Clinical Trial, Phase II PT - Comparative Study PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20150911 PL - Switzerland TA - Eur Urol JT - European urology JID - 7512719 RN - 0 (Antineoplastic Agents) RN - 0 (Benzamides) RN - 0 (Morpholines) RN - 0 (Multiprotein Complexes) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0BSC3P4H5X (vistusertib) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM CIN - Eur Urol. 2016 Mar;69(3):457-9. PMID: 26463319 MH - Aged MH - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use MH - Benzamides MH - Carcinoma, Renal Cell/*drug therapy/metabolism/mortality/secondary MH - Disease Progression MH - Disease-Free Survival MH - Early Termination of Clinical Trials MH - Everolimus/adverse effects/*therapeutic use MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Kidney Neoplasms/*drug therapy/metabolism/mortality/pathology MH - Male MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Middle Aged MH - Molecular Targeted Therapy MH - Morpholines/adverse effects/pharmacokinetics/*therapeutic use MH - Multiprotein Complexes/antagonists & inhibitors/metabolism MH - Protein Kinase Inhibitors/adverse effects/pharmacokinetics/*therapeutic use MH - Pyrimidines MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Time Factors MH - Treatment Outcome MH - United Kingdom MH - Vascular Endothelial Growth Factor A/*metabolism OTO - NOTNLM OT - Renal cancer OT - Survival OT - TORC2 OT - mTOR EDAT- 2015/09/15 06:00 MHDA- 2016/11/15 06:00 CRDT- 2015/09/15 06:00 PHST- 2015/06/21 00:00 [received] PHST- 2015/08/24 00:00 [accepted] PHST- 2015/09/15 06:00 [entrez] PHST- 2015/09/15 06:00 [pubmed] PHST- 2016/11/15 06:00 [medline] AID - S0302-2838(15)00780-0 [pii] AID - 10.1016/j.eururo.2015.08.035 [doi] PST - ppublish SO - Eur Urol. 2016 Mar;69(3):450-6. doi: 10.1016/j.eururo.2015.08.035. Epub 2015 Sep 11.