Thomas Powles1, Matthew Wheater2, Omar Din3, Thomas Geldart4, Ekaterini Boleti5, Andrew Stockdale6, Santhanam Sundar7, Angus Robinson8, Imtiaz Ahmed9, Akhila Wimalasingham10, Wendy Burke11, Shah-Jalal Sarker10, Syed Hussain12, Christy Ralph13. 1. 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. 2. Southampton NHS Foundation Trust, Southampton, UK. 3. Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. 4. Royal Bournemouth Hospital, Bournemouth, UK. 5. The Royal Free NHS Foundation Trust, London, UK. 6. Arden Cancer Centre, University Hospital, Coventry, UK. 7. Nottingham University Hospitals NHS trust, Nottingham, UK. 8. Sussex Cancer Centre, Brighton, UK. 9. Southend NHS Trust, Southend, UK. 10. Barts Cancer Institute, Experimental Cancer Medicine Centre, Barts Health, Queen Mary University of London, London, UK. 11. AstraZeneca UK Limited, Quantitative Clinical Pharmacology, Macclesfield, UK. 12. University of Liverpool, Clatterbridge Cancer Centre, Liverpool, UK. 13. St. James's University Hospital, University of Leeds, Leeds, UK.
Abstract
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.
RCT Entities:
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 everolimuspatients (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.
Authors: Helong Dai; Alicia R Watson; Daniel Fantus; Longkai Peng; Angus W Thomson; Natasha M Rogers Journal: Kidney Int Date: 2018-09-04 Impact factor: 10.612
Authors: Jessica L F Teh; Phil F Cheng; Timothy J Purwin; Neda Nikbakht; Prem Patel; Inna Chervoneva; Adam Ertel; Paolo M Fortina; Ines Kleiber; Kim HooKim; Michael A Davies; Lawrence N Kwong; Mitch P Levesque; Reinhard Dummer; Andrew E Aplin Journal: Cancer Discov Date: 2018-03-01 Impact factor: 39.397
Authors: I Duran; J Lambea; P Maroto; J L González-Larriba; Luis Flores; S Granados-Principal; M Graupera; B Sáez; A Vivancos; O Casanovas Journal: Target Oncol Date: 2017-02 Impact factor: 4.493
Authors: Daniel Fantus; Helong Dai; Yoshihiro Ono; Alicia Watson; Shinichiro Yokota; Kanishka Mohib; Osamu Yoshida; Mark A Ross; Simon C Watkins; Bala Ramaswami; Anna Valusjkikh; David M Rothstein; Angus W Thomson Journal: Transplantation Date: 2017-12 Impact factor: 4.939