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Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.

ABSTRACT: BACKGROUND:The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). PATIENTS AND METHODS:Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases. RESULTS:A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8-14.0) versus 5.3 months (95% CI 3.0-8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31-0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0-30.8) versus 9% (95% CI 3.7-17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6-not estimable) with cabozantinib and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR 0.80 [95% CI 0.53-1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib. CONCLUSIONS:In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk. TRIAL REGISTRATION NUMBER:NCT01835158.

SUBMITTER: Choueiri TK

PROVIDER: S-EPMC6057479 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Project description:BackgroundCabozantinib Versus Sunitinib as Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial (CABOSUN) was a randomized, open-label, phase 2 trial evaluating first-line cabozantinib versus sunitinib in patients with advanced renal cell carcinoma (aRCC). This post hoc analysis evaluated quality-adjusted survival using Quality-adjusted Time Without Symptoms of disease or Toxicity of treatment (Q-TWiST).MethodsSurvival plots for cabozantinib and sunitinib (650-day follow-up) were partitioned into 3 health states: time spent before disease progression without toxicity (TWiST; toxicity based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] grade 3/4 adverse events), time spent before disease progression with toxicity (TOX; durations of adverse events based on published literature), and time after disease recurrence (relapse) or progression to death (REL). Q-TWiST was the sum of the mean time spent in each state, with each state weighted to reflect patient preferences (from 0 [worst] to 1 [best]) using utility scores. TWiST was always weighted as 1. Overall survival and time to disease progression were based on all randomized patients (157 patients); TOX was based on all randomized and treated patients (150 patients).ResultsAcross all utility combinations tested, Q-TWiST was found to be longer with cabozantinib versus sunitinib (range of differences, +24 days to +137 days). Q-TWiST differences that were found to be statistically significant (+92 days [95% confidence interval, 5-178 days] to +137 days [95% confidence interval, 60-214 days]) were of a clinically meaningful effect size (?80 days), and were based on utility values that included those considered relevant for patients with aRCC (REL utility weight of 0.355, TOX utility weight of 0-1, and TWiST utility weight of 1).ConclusionsIn patients with aRCC, first-line cabozantinib was found to provide longer quality-adjusted survival compared with sunitinib. These findings may help to inform clinical decision making.Lay summaryCabozantinib and sunitinib are drugs that are used to treat patients with advanced kidney cancer. Clinical trials have shown that cabozantinib offers benefits over sunitinib, giving patients more time before their cancer progresses. It is important that this additional time before disease progression does not come at the expense of patients' quality of life, which can be affected by treatment side effects and/or ongoing cancer symptoms. Both quantity and quality of life are central to optimal treatment. In the current analysis of patients with advanced kidney cancer who were initiating treatment for the first time, cabozantinib provided more quality time before cancer progression compared with sunitinib.

Project description:Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS) data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR) to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]). However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months). The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real-world observational data, is needed to compare effectiveness between cabozantinib and nivolumab.

Project description:BackgroundThe efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.MethodsIn this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.ResultsOverall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.ConclusionsNivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Project description:Background: Nucleolar and spindle-associated protein 1 (NUSAP1) was previously reported to be associated with poor prognosis in multiple cancers. In the present study, we comprehensively investigated the clinicopathological features and potential prognostic value of NUSAP1 in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Methods: The expression profiles of the genes were extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), Cancer Cell Line Encyclopedia (CCLE), Gene Expression Profiling Interactive Analysis (GEPIA), and The Human Protein Atlas databases. The association between clinicopathological characteristics and NUSAP1 was analyzed using logistic regression in TCGA patients and receiver operating characteristic (ROC) curve analysis for GSE7803, GSE9750, and GSE63514 datasets. The prognostic value of NUSAP1 in TCGA patients was evaluated using the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was conducted using TCGA dataset. Results: A total of 68 differentially expressed genes (DEGs) were identified in CESC. ROC analysis of NUSAP1 suggested that the area under the ROC curve was 0.968. Kaplan-Meier survival analysis indicated that CESC with low expression of NUSAP1 has a worse prognosis than CESC with high NUSAP1 expression (P = 0.005). The logistic regression revealed that low NUSAP1 expression in CESC was related to advanced tumor stage in TCGA database. Moreover, Cox regression analysis showed that NUSAP1 expression correlated significantly with prognosis in the case of patients in TCGA database. GSEA demonstrated that CESC patients with high expression of NUSAP1 were enriched in the G2M checkpoint, MYC targets, and breast cancer ZNF217. Conclusion: The results suggest that identification of DEGs might enhance our understanding of the causes and molecular mechanisms underlying the development of CESC. Moreover, NUSAP1 may play an important role in CESC progression and prognosis and may serve as a valuable indicator of poor survival in CESC.

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Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.

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