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

Thomas Powles, Mark R Lackner, Stéphane Oudard, Bernard Escudier, Christy Ralph, Janet E Brown, Robert E Hawkins, Daniel Castellano, Brian I Rini, Michael D Staehler, Alain Ravaud, Wei Lin, Bridget O'Keeffe, Yulei Wang, Shan Lu, Jill M Spoerke, Ling-Yuh Huw, Michelle Byrtek, Rui Zhu, Joseph A WareRobert J Motzer

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1660-8
Number of pages9
JournalJournal of Clinical Oncology
Issue number14
Early online date7 Mar 2016
Publication statusPublished - 10 May 2016


  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Bridged Bicyclo Compounds, Heterocyclic
  • Carcinoma, Renal Cell
  • Disease-Free Survival
  • Everolimus
  • Female
  • Humans
  • Kidney Neoplasms
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Multiprotein Complexes
  • Phosphatidylinositol 3-Kinases
  • Pyrimidines
  • TOR Serine-Threonine Kinases
  • Clinical Trial, Phase II
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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