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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. | LitMetric
Thomas Powles, Queen Mary University of London, London; Christy Ralph, University of Leeds, Leeds; Janet E. Brown, University of Sheffield, Sheffield; Robert E. Hawkins, University of Manchester, Manchester, United Kingdom; Mark R. Lackner, Wei Lin, Bridget O'Keeffe, Yulei Wang, Shan Lu, Jill M. Spoerke, Ling Yuh Huw, Michelle Byrtek, Rui Zhu, and Joseph A. Ware, Genentech, South San Francisco, CA; Robert J. Motzer, Memorial Sloan Kettering Cancer Center, New York, NY; Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Bernard Escudier, Institut Gustave Roussy, Villejuif; Alain Ravaud, Hospital Saint Andre, Bordeaux; Stéphane Oudard, University Paris Descartes, Paris, France; Daniel Castellano, University Hospital 12 de Octubre, Madrid, Spain; and Michael D. Staehler, University Hospital Munich-Grosshadern, Marchioninistrasse, Germany.
Published: May 2016
AI Article Synopsis
Article 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 1α 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 on-target adverse events. VHL mutation and hypoxia-inducible factor 1α expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required.
