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Powles, Thomas; Lackner, Mark R.; Oudard, Stéphane; Escudier, Bernard; Ralph, Christy; Brown, Janet E.; Hawkins, Robert E.; Castellano, Daniel; Rini, Brian I.; Staehler, Michael D.; Ravaud, Alain; Lin, Wei; O'Keeffe, Bridget; Wang, Yulei; Lu, Shan; Spoerke, Jill M.; Huw, Ling-Yuh; Byrtek, Michelle; Zhu, Rui; Ware, Joseph A. and Motzer, Robert J. (2016): 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. In: Journal of Clinical Oncology, Vol. 34, No. 14: 1660-U204

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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 1 alpha 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 1 alpha expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required. (C) 2016 by American Society of Clinical Oncology

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