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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.

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 1? 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 1? expression may be predictive of an mTOR inhibitor benefit, although prospective validation is required.

SUBMITTER: Powles T

PROVIDER: S-EPMC5569691 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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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.

Powles Thomas T Lackner Mark R MR Oudard Stéphane S Escudier Bernard B Ralph Christy C Brown Janet E JE Hawkins Robert E RE Castellano Daniel D Rini Brian I BI Staehler Michael D MD Ravaud Alain A Lin Wei W O'Keeffe Bridget B Wang Yulei Y Lu Shan S Spoerke Jill M JM Huw Ling-Yuh LY Byrtek Michelle M Zhu Rui R Ware Joseph A JA Motzer Robert J RJ

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20160307 14

<h4>Purpose</h4>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).<h4>Patients and methods</h4>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 ...[more]

PMID: 26951309

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Project description:BackgroundThe current single-arm, open-label trial was designed to evaluate the activity of apitolisib (GDC-0980), a dual phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC).MethodsPatients with recurrent or persistent EC who were treated with 1 to 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib at a dose of 40 mg daily during 28-day cycles until disease progression or intolerable toxicity occurred. Patients with type I/II diabetes who required insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate.ResultsA total of 56 women were enrolled, including 13 (23%) with well-controlled diabetes. Reasons for discontinuation were disease progression (24 patients; 43%), adverse events (13 patients; 23%), and withdrawal by subject (12 patients; 21%). Grade 3/4 apitolisib-related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The PFS rate at 6 months was 20% (Kaplan-Meier estimate; 95% confidence interval [95% CI], 7%-33%). The objective response rate was 6% (confirmed). The median PFS was 3.5 months (95% CI, 2.7-3.7 months) and the median overall survival was 15.7 months (95% CI, 9.2-17.0 months). Nineteen patients discontinued the study before the first tumor assessment. Dose reductions were required for 4 diabetic (31%) and 18 nondiabetic (42%) patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples demonstrated that 57% of patients had at least 1 alteration in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), or AKT1. All 3 patients with a confirmed response had at least 1 alteration in a PI3K pathway gene.ConclusionsThe antitumor activity noted with the use of a dose of 40 mg of apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutations may have derived enhanced benefit from apitolisib. Cancer 2016;122:3519-28. © 2016 American Cancer Society.

Project description:Renal dysfunction is associated with poor long-term outcomes after liver transplantation. We examined the renal sparing effect of everolimus (EVR) compared to standard calcineurin inhibitor (CNI) immunosuppression with direct measurements of renal function over 24 months.MethodsThis was a prospective, randomized, open-label trial comparing EVR and mycophenolic acid (MPA) with CNI and MPA immunosuppression. An Investigational New Drug Application (IND # 113882) was obtained with the Food and Drug Administration as EVR is only approved for use with low-dose tacrolimus. Serum creatinine, 24-hour urine creatinine clearance, iothalamate clearance, Cockcroft-Gault creatinine clearance (CrCl), and Modification of Diet in Renal Disease estimated glomerular filtration rate were prospectively measured at 4 study visits. Nonparametric statistical tests were used for analyses, including the Mann-Whitney U test for continuous outcomes and Pearson's chi-square test for binary outcomes. Effect size was measured using Cohen's d. Patients also completed quality of life surveys using the FACT-Hep instrument at each study visit. Comparison between the 2 groups was performed using the Student t test.ResultsEach arm had 12 subjects; 4 patients dropped out in the EVR arm and 1 in the CNI arm by 24 months. Serum creatinine (P = 0.015), Modification of Diet in Renal Disease estimated glomerular filtration rate (P = 0.013), and 24-hour urine CrCL (P = 0.032) were significantly better at 24 months with EVR. Iothalamate clearance showed significant improvement at 12 months (P = 0.049) and a trend toward better renal function (P = 0.099) at 24 months. There was no statistical significance with Cockcroft-Gault CrCl. Adverse events were not significantly different between the 2 arms. The EVR group also showed significantly better physical, functional, and overall self-reported quality of life (P = 0.01) at 24 months.ConclusionsEVR with MPA resulted in significant long-term improvement in renal function and quality of life at 24 months after liver transplantation compared with standard CNI with MPA immunosuppression.

Project description:BackgroundNon-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma.MethodsWe enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445.FindingsBetween Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none).InterpretationIn patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors.FundingNovartis and Pfizer.

Dataset Information

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.

Publications

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.

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