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|Ref Type||Journal Article|
|Authors||Powles T, Lackner MR, Oudard S, Escudier B, Ralph C, Brown JE, Hawkins RE, Castellano D, Rini BI, Staehler MD, Ravaud A, Lin W, O'Keeffe B, Wang Y, Lu S, Spoerke JM, Huw LY, Byrtek M, Zhu R, Ware JA, Motzer RJ|
|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.|
|Journal||Journal of clinical oncology : official journal of the American Society of Clinical Oncology|
|Date||2016 May 10|
|Abstract Text||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 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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||renal cell carcinoma||not applicable||Everolimus||Phase II||Actionable||In a Phase II clinical trial, Apitolisib (GDC-0980) was inferior to Afinitor (everolimus) by median PFS, 3.7 months (n=42) vs. 6.1 months (n=43), respectively and overall survival trended lower as well in patients with metastatic renal cell carcinoma (PMID: 26951309).||26951309|
|VHL inact mut||renal cell carcinoma||no benefit||GDC-0980||Phase II||Actionable||In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Apitolisib (GDC-0980) had no difference in progression free survival when stratified by the presence (n=5) or absence (n=17) of deleterious VHL mutations (PMID: 26951309).||26951309|
|VHL inact mut||renal cell carcinoma||predicted - sensitive||Everolimus||Phase II||Actionable||In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Afinitor (everolimus) had a trend towards improved in progression free survival when stratified by the presence (median PFS=8.6 months, n=15) or absence (median PFS=5.5 months, n=16) of deleterious VHL mutations (PMID: 26951309).||26951309|
|Unknown unknown||renal cell carcinoma||not applicable||GDC-0980||Phase II||Actionable||In a Phase II clinical trial, Apitolisib (GDC-0980) was inferior to Afinitor (everolimus) (median PFS, 3.7 months (n=42) vs. 6.1 months (n=43), respectively) and overall survival trended lower in the Apitolisib (GDC-0980) arm in patients with metastatic renal cell carcinoma (PMID: 26951309).||26951309|