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author:("Kim, sindh T.")
1.  Circulating proteins as potential biomarkers of sunitinib and interferon-α efficacy in treatment-naïve patients with metastatic renal cell carcinoma 
Purpose
We investigated potential biomarkers of efficacy in a phase III trial of sunitinib versus interferon-alpha (IFN-α), first-line in metastatic renal cell carcinoma (mRCC), by analyzing plasma levels of vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGF receptor-3 (sVEGFR-3) and interleukin (IL)-8.
Methods
Seven hundred and fifty mRCC patients were randomized to oral sunitinib 50 mg/day in repeated cycles of a 4-week on/2-week off schedule or IFN-α 9 million units subcutaneously thrice weekly. Plasma samples collected from a subset of 63 patients on days 1 and 28 of cycles 1–4 and at end of treatment were analyzed by ELISA.
Results
Baseline characteristics of biomarker-evaluated patients in sunitinib (N = 33) and IFN-α (N = 30) arms were comparable to their respective intent-to-treat populations. By univariate Cox regression analysis, low baseline soluble protein levels were associated with lower risk of progression/death (all P < 0.05): in both treatment arms, baseline VEGF-A and IL-8 were associated with overall survival (OS) and baseline VEGF-C with progression-free survival (PFS); in the sunitinib arm, baseline VEGF-A was associated with PFS and baseline sVEGFR-3 with PFS and OS; in the IFN-α arm, baseline IL-8 was associated with PFS. In multivariate analysis, baseline sVEGFR-3 and IL-8 remained independent predictors of OS in the sunitinib arm, while no independent predictors of outcome remained in the IFN-α arm. Pharmacodynamic changes were not associated with PFS or OS for any plasma protein investigated.
Conclusions
Our findings suggest that, in mRCC, baseline VEGF-A and IL-8 may have prognostic value, while baseline sVEGFR-3 may predict sunitinib efficacy.
doi:10.1007/s00280-013-2333-4
PMCID: PMC3889677  PMID: 24220935
Metastatic renal cell carcinoma; Sunitinib; Biomarkers; Phase III clinical trial
2.  Analyzing the pivotal trial that compared sunitinib and interferon alfa in renal cell carcinoma, using a method that assesses tumor regression and growth 
Clinical Cancer Research  2012;18(8):2374-2381.
Purpose
We applied a method that analyzes tumor response, quantifying the rates of tumor growth (g) and regression (d), using tumor measurements obtained while patients receive therapy. We used data from the phase III trial comparing sunitinib and interferon-alfa (IFN-α) in metastatic renal cell carcinoma (mRCC) patients.
Methods
The analysis used an equation that extracts d and g.
Results
For sunitinib, overall survival (OS) was strongly correlated with log g (Rsq=0.44, p<0.0001); much less with log d (Rsq=0.04; p=0.0002). The median g of tumors in these patients (0.00082 per days; log g=−3.09) was about half that (p<0.001) of tumors in patients receiving IFN-α (0.0015 per day; log g=−2.81). With IFN-α, the OS/log g correlation (Rsq=0.14) was weaker. Values of g from measurements obtained by study investigators or central review were highly correlated (Rsq=0.80). No advantage resulted in including data from central review in regressions. Further, g can be estimated accurately four months before treatment discontinuation. Extrapolating g in a model that incorporates survival generates the hypothesis that g increased after discontinuation of sunitinib but did not accelerate.
Conclusions
In patients with mRCC, sunitinib reduced tumor growth rate, g, more than did IFN-α. Correlating g with OS confirms earlier analyses suggesting g may be an important clinical trial endpoint, to be explored prospectively and in individual patients.
doi:10.1158/1078-0432.CCR-11-2275
PMCID: PMC3328595  PMID: 22344231
Renal cell carcinoma; Tumor growth rates; Tumor regression rates; Sunitinib; Interferon
3.  Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results 
Purpose
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Methods
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175–200 mg/m2) plus carboplatin (AUC 6 mg•min/mL) on day 1 of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Results
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed (grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, grade 4 thrombocytopenia [n = 3]). The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Conclusions
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
doi:10.1007/s00280-010-1536-1
PMCID: PMC3400085  PMID: 21140147
Sunitinib; Phase I; Solid tumor; NSCLC; Antiangiogenesis; Chemotherapy
4.  Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma 
Journal of Clinical Oncology  2009;27(22):3584-3590.
Purpose
A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported.
Patients and Methods
Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up.
Results
Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor–signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).
Conclusion
Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.
doi:10.1200/JCO.2008.20.1293
PMCID: PMC3646307  PMID: 19487381
5.  Quality of Life Predicts Progression-Free Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib Versus Interferon Alfa 
Journal of Oncology Practice  2009;5(2):66-70.
In a randomized phase III trial, sunitinib was associated with significantly superior progression-free survival when compared with interferon alfa as first-line therapy in patients with metastatic renal cell carcinoma. This article investigates whether baseline quality of life and demographic and clinical variables were predictive for progression-free survival.
Purpose:
In a randomized phase III trial, sunitinib was associated with significantly superior progression-free survival (PFS) when compared with interferon alfa (IFN-α) as first-line therapy in patients with metastatic renal cell carcinoma. We investigated whether baseline quality-of-life (QOL) and demographic and clinical variables were predictive for PFS.
Methods:
Patients were randomly assigned to receive sunitinib or IFN-α at a ratio of one to one. QOL was measured using the Functional Assessment of Cancer Therapy–General scale (FACT-G), the FACT–Kidney Symptom Index–Disease-Related Symptoms subscale (FKSI-DRS), and the EuroQol (EQ) Group's visual analog scale (EQ-VAS; Rotterdam, the Netherlands). In all scales, higher scores indicate better QOL or fewer symptoms. Controlling for other baseline demographic and clinical variables, Cox proportional hazards models—one for each QOL variable—were used to test if difference in baseline QOL scores predicted PFS.
Results:
The superior treatment effect on PFS of sunitinib versus IFN-α remained robust (hazard ratio [HR], 0.34, 0.33, and 0.33 for each model, respectively; P < .0001 for each model). Higher baseline FACT-G, FKSI-DRS, and EQ-VAS scores were associated with longer PFS (HR, 0.93, 0.89, and 0.91, respectively; P ≤ .001, P ≤ .001, and P = .008, respectively). Presence of liver metastases (HR, 1.59 to 1.71; P = .0009 to .0044) and number of Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) risk factors (HR, 1.52 to 1.60; P < .0001 for each) were significant negative predictors of PFS, independent of other variables.
Conclusion:
Sunitinib conferred significantly superior PFS compared with IFN-α, irrespective of baseline QOL or clinical characteristics. Higher baseline QOL correlated with longer PFS, whereas the presence of liver metastases and more MSKCC risk factors at baseline correlated with shorter PFS. This remains an area for future study.
doi:10.1200/JOP.0922004
PMCID: PMC2790652  PMID: 20856722

Results 1-5 (5)