Sunitinib re-challenge in advanced renal-cell carcinoma.
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ABSTRACT:
SUBMITTER: Porta C
PROVIDER: S-EPMC4453836 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
Sunitinib re-challenge in advanced renal-cell carcinoma.
Porta C C Paglino C C Grünwald V V
British journal of cancer 20140506 6
Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal sequences of therapy is therefore the focus of much current research. There is also evidence that treatment 're-challenge' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior t ...[more]
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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.).
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Project description: Not available
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Project description:Of the many targeted therapies introduced since 2006, sunitinib has carved its way to become the most commonly used first-line therapy for the treatment of metastatic renal cell carcinoma (RCC). Despite significant improvements in progression-free survival, 30% of the patients are intrinsically resistant to sunitinib and the remaining 70% who respond initially will eventually become resistant in 6-15 months. While the molecular mechanisms of acquired resistance to sunitinib have been unravelling at a rapid rate, the mechanisms of intrinsic resistance remain elusive. Combination therapy, sunitinib rechallenge and sequential therapy have been investigated as means to overcome resistance to sunitinib. Of these, sequential therapy appears to be the most promising strategy. This mini review summarises our emerging understanding of the molecular mechanisms, and the strategies employed to overcome sunitinib resistance.
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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.
| S-EPMC3882163 | biostudies-literature
Project description:BackgroundRenal cell carcinoma (RCC) contributed to 403,262 new cases worldwide in 2018, which constitutes 2.2% of global cancer, nevertheless, sunitinib, one of the major targeted therapeutic agent for RCC, often developed invalid due to resistance. Emerging evidences suggested sunitinib can impact tumor environment which has been proven to be a vital factor for tumor progression.MethodsIn the present study, we used ssGSEA to extract the immune infiltrating abundance of clear cell RCC (ccRCC) and normal control samples from GSE65615, TCGA, and GTEx; key immune cells were determined by Student's t-test and univariable Cox analysis. Co-expression network combined with differentially expressed analysis was then applied to derive key immune-related genes for ccRCC, followed by the identification of hub genes using differential expression analysis. Subsequently, explorations and validations of the biological function and the immune-related and sunitinib-related characteristics were conducted in KEGG, TISIDB, Oncomine, ICGC, and GEO databases.ResultsWe refined immature dendritic cells and central memory CD4 T cells which showed associations with sunitinib and ccRCC. Following, five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) were identified for their strong relationships with sunitinib and immune infiltration in ccRCC. Further validations in external data refined CRYBB1, CEACAM4, and HAMP which play a vital role in sunitinib resistance, immune infiltrations in ccRCC, and the development and progression of ccRCC. In conclusion, our findings could shed light on the resistance of sunitinib in ccRCC and provide novel biomarkers or drug targets for ccRCC.
| S-EPMC8495283 | biostudies-literature
Project description:Background:Compared with the standard of care with sunitinib, avelumab plus axitinib can increase progression-free survival in the first-line of advanced renal cell carcinoma (RCC), but the economic effect of the treatment is unknown. The purpose of the research was to evaluate the cost-effectiveness of the avelumab plus axitinib versus sunitinib in first-line treatment for advanced RCC from the US payer perspective. Methods:A Markov model was developed to evaluate the economic and health outcomes of avelumab plus axitinib vs sunitinib in the first-line setting for advanced RCC. The clinical data were obtained from the JAVELIN Renal 101 Clinical Trials. Deterministic and probabilistic sensitivity analyses were performed to assess uncertainty in the model. Health outcomes were measured in quality-adjusted life-years (QALYs). Results:The incremental cost-effectiveness ratio (ICER) of avelumab plus axitinib compared with sunitinib was $565,232 per QALY, the costs were $884,626 and $669,838, QALYs were 3.67 and 3.29, respectively. Sensitivity analysis demonstrated that differences in utilities in PFS and after progression were the most influential factors within the model. When avelumab was at 30% of the full price or axitinib was at 40% of the full price, avelumab and axitinib were approved to be cost-effective if the WTP threshold was $150,000 per QALY. The subgroup analysis showed the ICER of avelumab plus axitinib compared with sunitinib for the patients with PD-L1-positive tumors was $588,105. Conclusion:Avelumab plus axitinib in the first-line treatment was not cost-effective in comparison with sunitinib when the threshold of willingness to pay (WTP) was $150,000 per QALY.
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