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

J Clin Oncol. 2016 May 10;34(14):1660-8. doi: 10.1200/JCO.2015.64.8808. Epub 2016 Mar 7.


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.

Trial registration: ClinicalTrials.gov NCT01442090.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Carcinoma, Renal Cell / blood supply
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / enzymology
  • Carcinoma, Renal Cell / metabolism
  • Disease-Free Survival
  • Everolimus / therapeutic use*
  • Female
  • Humans
  • Kidney Neoplasms / blood supply
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / enzymology
  • Kidney Neoplasms / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Middle Aged
  • Multiprotein Complexes / antagonists & inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / therapeutic use*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors


  • 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Bridged Bicyclo Compounds, Heterocyclic
  • Multiprotein Complexes
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Everolimus
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases

Associated data

  • ClinicalTrials.gov/NCT01442090