Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma Journal Article


Authors: Powles, T.; Lackner, M. R.; Oudard, S.; Escudier, B.; Ralph, C.; Brown, J. E.; Hawkins, R. E.; Castellano, D.; Rini, B. I.; Staehler, M. D.; Ravaud, A.; Lin, W.; O'Keeffe, B.; Wang, Y.; Lu, S.; Spoerke, J. M.; Huw, L. Y.; Byrtek, M.; Zhu, R.; Ware, J. A.; Motzer, R. J.
Article Title: Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma
Abstract: Purpose To the best of our knowledge, this study is the first to compare dual inhibition of PI3K/mammalian target of rapamycin (mTOR) by apitolisib (GDC-0980) against single inhibition of mTORC1 by everolimus in metastatic renal cell carcinoma (mRCC). Patients and Methods Patients with clear-cell mRCC who progressed on or after vascular endothelial growth factor- targeted therapy were randomly assigned to apitolisib 40 mg once per day or to everolimus 10 mg once per day. End points included progression-free survival, safety, overall survival, and objective response rate. Biomarker assessments were conducted. Results Eighty-five patients were randomly assigned. After 67 events, stratified analysis revealed that median progression-free survival was significantly shorter for apitolisib than for everolimus (3.7 v 6.1 months; hazard ratio, 2.12 [95% CI, 1.23 to 3.63; P , .01]); apitolisib was not favored in any stratification subgroup. Median overall survival was not significantly different but trended in favor of everolimus (16.5 v 22.8 months; hazard ratio, 1.77 [95% CI, 0.97 to 3.24; P = .06]). The objective response rate was 7.1% for apitolisib and 11.6% for everolimus. Patients administered apitolisib with a greater incidence of grade 3 to 4 adverse events were more likely to discontinue treatment (31% v 12% for everolimus). No drug-related deaths were observed. Apitolisib in comparison with everolimus was associated with substantially more high-grade hyperglycemia (40% v 9%) and rash (24% v 2%). Apitolisib pharmacokinetics suggested a relationship between exposure, and rash and hyperglycemia. Retrospective biomarker analyses revealed a relationship between VHL mutation status and outcome with everolimus but not with apitolisib. High hypoxia-inducible factor 1a protein expression was associated with better outcome in both arms. Conclusion This study demonstrated that dual PI3K/mTOR inhibition by apitolisib was less effective than was everolimus in mRCC, likely because full blockade of PI3K/mTOR signaling resulted in multiple ontarget adverse events. VHL mutation and hypoxia-inducible factor 1a expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required. ©2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 14
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-05-10
Start Page: 1660
End Page: 1668
Language: English
DOI: 10.1200/jco.2015.64.8808
PROVIDER: scopus
PUBMED: 26951309
PMCID: PMC5569691
DOI/URL:
Notes: Article -- Presented in part at the 50th Annual Meeting of the American Society of Clinical Oncology in Chicago, IL, May 30-June 3, 2014, and at the American Association for Cancer Research Special Conference: Targeting the PI3K-mTOR Network in Cancer in Philadelphia, PA, September 14-17, 2014. -- Export Date: 1 July 2016 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Robert Motzer
    1243 Motzer