scholarly journals Phase III trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: Exploratory pharmacogenomic analysis.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 576-576 ◽  
Author(s):  
Daniel J. George ◽  
Jean-Francois Martini ◽  
Michael D. Staehler ◽  
Yen-Hwa Chang ◽  
Jan Breza ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Statistical Tests ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Nucleotide Polymorphisms ◽  
Comparison Results

576 Background: In the phase III S-TRAC trial, adjuvant sunitinib (SU) prolonged disease-free survival (DFS) vs placebo (PBO) in patients with locoregional renal cell carcinoma at high risk of recurrence after nephrectomy (median 6.8 vs 5.6 y; hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59–0.98; P= 0.03). An exploratory analysis evaluated associations between single nucleotide polymorphisms (SNPs) in angiogenesis-related genes and clinical outcomes in S-TRAC. Methods: Prospectively collected blood samples were genotyped for 10 SNPs and 1 insertion/deletion mutation with TaqMan assays. DFS was compared with a log-rank test for each SNP genotype in SU vs PBO arms and between SNP genotypes within each arm. P-values are unadjusted for multiplicity comparison. Results: Of 615 patients, 286 (142 SU; 144 PBO) were analyzed. There were generally no genotype frequency deviations from the Hardy-Weinberg equilibrium, but linkage disequilibrium was seen between VEGFA rs699947 and rs833061 on chromosome 6 (D′ = 1.000, r2 = 0.979). Longer DFS was observed with SU vs PBO for VEGFR1 rs9554320 C/C (median: not reached [NR] vs 5.56 y; HR 0.44, 95% CI 0.21–0.91; P= 0.023), VEGFR2 rs2071559 T/T (median: NR vs 4.47 y; HR 0.46, 95% CI 0.23–0.90; P= 0.020), and eNOS rs2070744 T/T (median: 7.07 vs 3.44 y; HR 0.53, 95% CI 0.30–0.94; P= 0.028), with a trend for VEGFR1 rs9582036 A/A (median: NR in both arms; P= 0.054) and SH3GL2 rs10963287 C/T (median: NR vs 5.35 y; P= 0.088). Shorter DFS was observed for VEGFR1 rs9582036 C/A vs C/C in the SU, PBO, and combined arms ( P< 0.05); for A/A vs common, the association was only seen in the SU arm ( P= 0.022). VEGFR1 rs9554320 A/C was associated with shorter DFS vs A/A in the PBO ( P= 0.038) and combined arm ( P= 0.006), with a trend in the SU arm ( P= 0.051). VEGFR2 rs1870377 T/T was associated with longer DFS vs A/A in the combined arms, but not in the PBO arm (n = 7 with A/A genotype in the SU arm precluded statistical tests). Conclusions: Correlations between common VEGFR1 and VEGFR2 SNPs and longer DFS with SU suggest germline SNPs are predictive of improved outcomes with adjuvant SU. Due to the exploratory nature of this analysis, prospective validation studies are needed to confirm these findings. Clinical trial information: NCT00375674.

scholarly journals Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial

2020 ◽  
Vol 38 (34) ◽  
pp. 4064-4075
Author(s):  
Tim Eisen ◽  
Eleni Frangou ◽  
Bhavna Oza ◽  
Alastair W.S. Ritchie ◽  
Benjamin Smith ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Outcome Analysis ◽  
Double Blind ◽  
Risk Of Recurrence

PURPOSE SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. PATIENTS AND METHODS We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. RESULTS Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. CONCLUSION Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART.

scholarly journals Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study

2018 ◽  
Vol 24 (7) ◽  
pp. 1554-1561 ◽  
Author(s):  
Daniel J. George ◽  
Jean-François Martini ◽  
Michael Staehler ◽  
Robert J. Motzer ◽  
Ahmed Magheli ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Immune Biomarkers ◽  
Disease Free

Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial

2003 ◽  
Vol 21 (16) ◽  
pp. 3133-3140 ◽  
Author(s):  
Joseph I. Clark ◽  
Michael B. Atkins ◽  
Walter J. Urba ◽  
Steven Creech ◽  
Robert A. Figlin ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Locally Advanced ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Group Randomized Trial

Purpose: This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC). Patients and Methods: Eligibility requirements were resected locally advanced (LA; T3b-4 or N1–3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history. Results: Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P = .73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P = .38). Analysis including metastasectomy patients made no difference in DFS or overall survival. Conclusion: One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.

scholarly journals Predictive Ability for Disease-Free Survival of the GRade, Age, Nodes, and Tumor (GRANT) Score in Patients with Resected Renal Cell Carcinoma

2020 ◽  
Vol 14 (2) ◽  
pp. 98-104
Author(s):  
Alessio Cortellini ◽  
Sebastiano Buti ◽  
Melissa Bersanelli ◽  
Katia Cannita ◽  
Giada Pinterpe ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Multivariate Analysis ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Free Survival ◽  
Risk Of Recurrence ◽  
Significant Difference ◽  
Disease Free

Background: Recently, the GRANT (GRade, Age, Nodes, and Tumor) score was validated through an adjuvant trial population. Methods: This retrospective study evaluated the performance of the GRANT score as a prognostic model for disease-free survival (DFS), compared to the University of California Los Angeles Integrated Staging System (UISS) score, in a “real-life” population of early renal cell carcinoma patients. A uni-/multivariate analysis of DFS was also performed, to weigh the roles of baseline clinical factors. Results: From February 1998 to January 2018, 134 consecutive patients were enrolled, of which 85 patients (63.4%) had a favorable GRANT score, 49 (36.6%) an unfavorable GRANT score, and 21 (15.7%), 84 (62.6%), and 29 (21.6%) patients had a low, intermediate, or high risk of recurrence according to the UISS score, respectively. The median follow-up was 96 months. The median DFS of the overall study population was 53.7 months (95% CI: 38.4-87.8). Only bilateral renal cell carcinoma (p = 0.0041), Fuhrman grade 3/4 (p = 0.0008), pT3b- 4 (p = 0.0324), and pN1-2 (p = 0.0303) pathological status were confirmed as independent predictors of a shorter DFS by the multivariate analysis. The median DFS of patients with favorable and unfavorable GRANT scores were 84.9 (95% CI: 49.8-129) and 38.4 months (95% CI: 24.4-87.8), respectively, with a statistically significant difference (p = 0.0147). The median DFS of patients with low, intermediate, and high risk of recurrence according to the UISS score were 92.3 (95% CI: 18.1-153.9), 51.7 (95% CI: 36.2-87.8), and 49.8 months (95% CI: 31.3-129), respectively, without statistically significant differences (p = 0.4728). DFS c-statistic values were 0.59 (95% CI: 0.51-0.67) and 0.51 (95% CI: 0.42-0.60) for the GRANT and the UISS scores, respectively. Conclusion: The GRANT score might be a useful tool that is user-friendly and easy to perform in clinical practice.

TARIBO trial: Cytoreductive nephrectomy in metastatic renal cell carcinoma patients treated with targeted agents.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4601-TPS4601
Author(s):  
Paolo Grassi ◽  
Elena Verzoni ◽  
Alessandra Bearz ◽  
Sergio Bracarda ◽  
Marco Bregni ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Clinical Benefit ◽  
Renal Cell ◽  
Primary Objective ◽  
Phase Iii ◽  
Rank Test ◽  
Cytoreductive Nephrectomy ◽  
To Receive

TPS4601 Background: In the cytokine era cytoreductive nephrectomy (CN) has been shown to increase survival in patients (pts) with metastatic renal cell carcinoma (mRCC). Efficacy of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib has been demonstrated. It is unclear if similar survival benefit could be achieved without CN with TKIs since most of pts enrolled into phase III trials had undergone CN. Methods: A total of 270 mRCC pts will be randomized to receiveCN followed by TKIs vs upfront TKIs without CN. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: to compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: i) to compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs; ii) Safety; iii) Exploratory analyses: evaluation of the predictive role of circulating tumor cells count and circulating tumor DNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression. Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; histological diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary tumor in place; up to three different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( > or = 4 metastatic organ sites); disease suitable of metastasectomy ( < 3 lesions confined at one organ site). Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. To date 10/270 pts have been enrolled. Clinical trial information: NCT02535351.

scholarly journals Conditional disease-free survival in high-risk renal cell carcinoma treated with sunitinib

Aging ◽  
2019 ◽  
Vol 11 (23) ◽  
pp. 11490-11503
Author(s):  
Ning Shao ◽  
Hengchuan Su ◽  
Dingwei Ye
Keyword(s):  
Renal Cell Carcinoma ◽  
High Risk ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free

Overall survival results from a phase III study of tivozanib hydrochloride versus sorafenib in patients with renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 350-350 ◽  
Author(s):  
Robert John Motzer ◽  
Timothy Eisen ◽  
Thomas E. Hutson ◽  
Cezary Szczylik ◽  
Mizue Krygowski ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Phase Iii ◽  
Extension Study ◽  
Standards Of Care ◽  
Rank Test ◽  
Significant Difference

350 Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor targeting all three vascular endothelial growth factor receptors, with a long half-life. Tivozanib has shown tolerability and superior progression-free survival and overall response rate versus sorafenib in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma. Final overall survival (OS) data (August 27, 2012) from TIVO-1 and its open-label, multicenter extension study are reported. Methods: A total of 517 patients were randomized 1:1 to tivozanib 1.5 mg/d (3 weeks on, 1 week off) or sorafenib 400 mg/d (twice a day, continuously) (J Clin Oncol2012;30[suppl]:Abstract 4501). In the extension study, patients who progressed (PD) on sorafenib based on investigator assessment were eligible to receive tivozanib, and patients with PD on tivozanib received subsequent treatment according to regional standards of care. Final OS analysis was planned to be conducted after all patients had died or were lost to follow-up, or when all patients in follow-up had been on study for at least 2 years, whichever occurred first. OS was compared using the stratified log-rank test. OS distribution was estimated using the Kaplan-Meier method. Hazard ratio (HR) was estimated using the Cox proportional hazard regression model. Results: At the time of final OS analysis (2 years after last patient was enrolled), 219 deaths had occurred (tivozanib, n=118 [45.4%]; sorafenib, n=101 [39.3%]) (stratified HR=1.245; 95% confidence interval [CI] 0.954–1.624; p=0.105), trending in favor of the sorafenib arm. Median OS (95% CI) was 28.8 months (22.5–NA) for tivozanib and 29.3 months (29.3–NA) for sorafenib. Of the 257 patients on sorafenib, 155 (60.3%) had started next-line tivozanib at the time of the analysis. Conclusions: There was no significant difference in OS between the two treatment arms. The high rate of utilization of second-line tivozanib in patients following PD on sorafenib may have affected the OS outcome. Clinical trial information: NCT01030783.

Sign in / Sign up

Export Citation Format

Share Document