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Plasma cytokine and angiogenic factors associated with prognosis and therapeutic response to sunitinib vs everolimus in advanced non-clear cell renal cell carcinoma.

ABSTRACT: No biomarkers are available to predict relative clinical benefit from targeted therapies in patients with non-clear cell renal cell carcinoma (nccRCC). To identify candidate predictive markers, we investigated a set of cytokines and angiogenic factors (CAFs) in previously untreated patients with nccRCC participating in the phase II ESPN trial comparing first-line sunitinib to everolimus. Pre-treatment concentrations of 30 CAFs were measured in plasma from 37 patients treated with everolimus (n=16) or sunitinib (n=21), and associated with progression-free (PFS) and overall survival (OS) after adjusting for potential confounders. High (>median) concentrations of soluble glycoprotein 130 (sgp130) were predictive of a longer PFS with sunitinib compared with everolimus (HR = 0.30; 95% CI: 0.11-0.85; P = 0.024). Significantly shorter PFS was noted, independently of treatment arm, in patients with high (>median) levels of IL-8 (HR = 3.13; 95% CI: 1.41-6.92), IL-13 (HR = 3.36; 95% CI: 1.49-7.58), and soluble tumor necrosis factor receptor II (HR = 2.21; 95% CI: 1.04-4.72). High IL-8 levels were also associated with significantly shorter OS (HR = 3.55; 95% CI: 1.55-8.14). Thus, using CAF profiling we identified candidate prognostic and predictive circulating biomarkers that can be used to inform therapeutic decisions in nccRCC.

SUBMITTER: Msaouel P

PROVIDER: S-EPMC5522056 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Plasma cytokine and angiogenic factors associated with prognosis and therapeutic response to sunitinib vs everolimus in advanced non-clear cell renal cell carcinoma.

Msaouel Pavlos P Zurita Amado J AJ Huang Shixia S Jonasch Eric E Tannir Nizar M NM

Oncotarget 20170601 26

No biomarkers are available to predict relative clinical benefit from targeted therapies in patients with non-clear cell renal cell carcinoma (nccRCC). To identify candidate predictive markers, we investigated a set of cytokines and angiogenic factors (CAFs) in previously untreated patients with nccRCC participating in the phase II ESPN trial comparing first-line sunitinib to everolimus. Pre-treatment concentrations of 30 CAFs were measured in plasma from 37 patients treated with everolimus (n=1 ...[more]

PMID: 28178674

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Project description:Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC).To conduct a randomized phase 2 trial comparing sunitinib and everolimus in non-clear cell RCC (non-ccRCC).Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive sunitinib or everolimus with crossover at disease progression.Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with sunitinib to 20 wk with everolimus.Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with sunitinib and 4.1 mo with everolimus (p=0.6); median overall survival (mOS) was not reached with sunitinib and was 10.5 mo with everolimus, respectively (p=0.014). At final analysis, mOS was 16.2 and 14.9 mo with sunitinib and everolimus, respectively (p=0.18). There were four partial responses (PRs) in first-line therapy (sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors (n=49), mOS was 31.6 mo with sunitinib and 10.5 mo with everolimus (p=0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation.In this trial, everolimus was not superior to sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC.This randomized phase 2 trial provides the first head-to-head comparison of everolimus and sunitinib in patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC.

Project description:Sunitinib is a standard-of-care treatment in advanced clear cell renal cell carcinoma (ccRCC). Retrospective and expanded access data suggest sunitinib has activity in advanced non-clear cell renal cell carcinoma (nccRCC).To prospectively determine the clinical efficacy and safety of sunitinib in patients with advanced nccRCC.This is a single-arm phase 2 trial with a two-stage design. Eligibility criteria included pathologically confirmed nccRCC or ccRCC with ? 20% sarcomatoid histology, performance status 0-2, measurable disease, a maximum of two prior systemic therapies, and no prior treatment with tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptors.Patients received sunitinib 50mg daily on a 4-wk on, 2-wk off schedule.Primary end points were objective response rate (ORR) and progression-free survival (PFS). Secondary end points were safety and overall survival (OS).Fifty-seven patients were eligible (nccRCC histology: papillary, 27; chromophobe, 5; unclassified, 8; collecting duct or medullary carcinoma, 6; sarcomatoid, 7; and others, 4). Median PFS for 55 evaluable patients was 2.7 mo (95% confidence interval [CI], 1.4-5.4). Two patients with chromophobe and one patient with unclassified histology had a confirmed partial response (5% ORR). Median PFS for patients with papillary histology was 1.6 mo (95% CI, 1.4-5.4). Median PFS for patients with chromophobe histology was 12.7 mo (95% CI, 8.5-NA). Median OS for all patients was 16.8 mo (95% CI, 10.7-26.3). Treatment-emergent adverse events were consistent with sunitinib's mechanism of action. The nonrandomized design and small number of patients are limitations of this study.The differential response of chromophobe histology to sunitinib suggests a therapeutically relevant biological heterogeneity exists within nccRCC. The low ORR and short PFS with sunitinib in the other nccRCC subtypes underscore the need to enroll patients with these diverse tumors in clinical trials.

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.

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Plasma cytokine and angiogenic factors associated with prognosis and therapeutic response to sunitinib vs everolimus in advanced non-clear cell renal cell carcinoma.

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Plasma cytokine and angiogenic factors associated with prognosis and therapeutic response to sunitinib vs everolimus in advanced non-clear cell renal cell carcinoma.

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