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1.  Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer 
Journal of Clinical Oncology  2011;30(5):507-512.
Purpose
Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.
Patients and Methods
The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.
Results
In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.
Conclusion
In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.
doi:10.1200/JCO.2011.37.7002
PMCID: PMC4104290  PMID: 22184381
2.  Efficacy and Safety of Everolimus in Elderly Patients With Metastatic Renal Cell Carcinoma: An Exploratory Analysis of the Outcomes of Elderly Patients in the RECORD-1 Trial 
European urology  2012;61(4):826-833.
Background
Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy.
Objective
To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1.
Design, setting, and participants
The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n = 416).
Intervention
Everolimus 10 mg once daily (n = 277) or placebo (n = 139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity.
Measurements
Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety.
Results and limitations
In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation.
Conclusions
Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered.
doi:10.1016/j.eururo.2011.12.057
PMCID: PMC4142675  PMID: 22297244
Adverse events; Kidney cancer; mTOR inhibitor; Pneumonitis
3.  Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma 
Purpose
Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers.
Methods
Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1α) and carbonic anhydrase-IX or tumor Von Hippel–Lindau (VHL) gene inactivation status.
Results
Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1α percent of tumor expression groups 0–2 (HIF-1α low) versus 3–4 (HIF-1α high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86 % of VHL-inactive patients), methylation (14 %), and large deletion (7 %)] or mechanisms combined.
Conclusions
Serum Ang-2 and MMP-2 and tumor HIF-1α were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2539-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2539-0
PMCID: PMC4175044  PMID: 25100134
Sunitinib; Renal cell carcinoma; Serum marker; Germ line polymorphism marker; Tumor marker
4.  Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence 
The Oncologist  2011;16(Suppl 2):14-22.
This article reviews the clinical evidence supporting the benefits of targeted agents in the treatment of metastatic renal cell carcinoma, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
doi:10.1634/theoncologist.2011-S2-14
PMCID: PMC3868199  PMID: 21346036
Angiogenesis inhibitor; Combination drug therapy; Mammalian target of rapamycin; Renal cell carcinoma; Vascular endothelial growth factor
5.  Two Phase II Trials of the Novel Akt Inhibitor Perifosine in Patients with Advanced Renal Cell Carcinoma Following Progression on VEGF-Targeted Therapy 
Cancer  2012;118(24):6055-6062.
Background
The clinical activity of allosteric mTOR inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of PI3-Kinase/Akt resulting from mTORC1 inhibition. Based on this rationale, two independent Phase II trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed prior VEGF-targeted therapy.
Methods
In Perifosine 228, 24 patients with advanced RCC were treated with perifosine (100 mg PO daily). Perifosine 231 enrolled two groups treated with daily perifosine (100 mg PO daily): Group A: No prior mTOR inhibitor, 32 patients; Group B: one prior mTOR inhibitor, 18 patients.
Results
In Perifosine 228, one patient achieved a partial response (PR) (ORR 4%; 95% CI [0.7, 20]) and 11 patients experienced a best response of stable disease (SD) (46%). Median PFS was 14.2 weeks (95% CI [7.7, 21.6]). In Perifosine 231, five patients experienced a PR (ORR 10% 95% CI [4.5, 22.2]) and 16 patients experienced a best response of SD (32%). Median PFS was 14 weeks [95% CI (12.9, 20.7)]. Overall, perifosine was well tolerated with very few grade 3 and 4 events. Most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue.
Conclusion
Although perifosine shows activity in patients with advanced RCC following failure of VEGF-targeted therapy, this activity is not superior to currently available second-line agents. Nonethelesss, perifosine may be worthy of further study in RCC in combination with other currently available therapies.
doi:10.1002/cncr.27668
PMCID: PMC3934426  PMID: 22674198
Perifosine; Renal Cancer; RCC; Akt; Akt Inhibitor; mTOR
6.  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
7.  A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC) 
Purpose
Lenvatinib is an oral multi-targeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRβ, RET, and KIT. Everolimus is an oral mammalian target of rapamycin inhibitor approved for advanced renal cell carcinoma (RCC). This phase 1b study assessed safety, maximum tolerated dose (MTD), and preliminary antitumor activity of lenvatinib plus everolimus in metastatic RCC (mRCC) patients.
Methods
Patients with advanced unresectable or mRCC and Eastern Cooperative Oncology Group performance status 0–1 were eligible (number of prior treatments not restricted). Starting dose was lenvatinib 12 mg once daily with everolimus 5 mg once daily administered continuously in 28-day cycles using a conventional 3 + 3 dose-escalation design. At the MTD, additional patients were enrolled in an expansion cohort.
Results
Twenty patients (mean 58.4 years) received lenvatinib [12 mg (n = 7); 18 mg (n = 11); 24 mg (n = 2)] plus everolimus 5 mg. MTD was established as once daily lenvatinib 18 mg plus everolimus 5 mg. The most common treatment-related treatment-emergent adverse events (all dosing cohorts) were fatigue 60 % (Grade ≥3: 10 %), mucosal inflammation 50 %, proteinuria (Grade ≥3: 15 %), diarrhea (Grade ≥3: 10 %), vomiting (Grade ≥3: 5 %), hypertension, and nausea, each 40 %. In MTD and lowest-dose cohorts (n = 18), best responses of partial response and stable disease were achieved in 6 (33 %) and 9 (50 %) patients, respectively.
Conclusions
Lenvatinib 18 mg combined with everolimus 5 mg was associated with manageable toxicity consistent with individual agents and no new safety signals. Observed activity warrants further evaluation of the combination in advanced RCC patients.
doi:10.1007/s00280-013-2339-y
PMCID: PMC3889692  PMID: 24190702
Lenvatinib; Everolimus; Metastatic renal cell carcinoma; Antitumor; mTOR; VEGF
8.  Survival in BRAF V600–Mutant Advanced Melanoma Treated with Vemurafenib 
The New England journal of medicine  2012;366(8):707-714.
BACKGROUND
Approximately 50% of melanomas harbor activating (V600) mutations in the serine–threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600–mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial.
METHODS
We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vemurafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point.
RESULTS
A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients.
CONCLUSIONS
Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann–La Roche; ClinicalTrials.gov number, NCT00949702.)
doi:10.1056/NEJMoa1112302
PMCID: PMC3724515  PMID: 22356324
9.  RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors 
The New England journal of medicine  2012;366(3):207-215.
BACKGROUND
Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.
METHODS
We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.
RESULTS
Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.
CONCLUSIONS
Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann–La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.)
doi:10.1056/NEJMoa1105358
PMCID: PMC3724537  PMID: 22256804
10.  Targeted therapy for renal cell carcinoma: a new treatment paradigm 
Metastatic clear cell renal cell cancer has traditionally been treated with cytokines (interferon or interleukin-2). Improved understanding of biology has engendered novel targeted therapeutic agents that have altered the natural history of this disease. The vascular endothelial growth factor and its related receptor and the mTOR signal transduction pathway have particularly been exploited. Sunitinib malate, sorafenib tosylate, temsirolimus, and bevacizumab have improved clinical outcomes in randomized trials. Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib, pazopanib) and antiangiogenic agents (VEGF Trap, lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. The future of the therapy of renal cancer appears promising owing to the efficacy of these novel agents.
PMCID: PMC1906573  PMID: 17637878
11.  Abiraterone and Increased Survival in Metastatic Prostate Cancer 
The New England journal of medicine  2011;364(21):1995-2005.
BACKGROUND
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
METHODS
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
RESULTS
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.
CONCLUSIONS
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
doi:10.1056/NEJMoa1014618
PMCID: PMC3471149  PMID: 21612468
13.  New advancements and developments in treatment of renal cell carcinoma: focus on pazopanib 
OncoTargets and therapy  2010;3:147-155.
With the recent approval of pazopanib, an oral multitargeted tyrosine kinase inhibitor which potently targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor, and c-kit, six agents are now available for use in the management of metastatic renal cell carcinoma (RCC). Pazopanib has shown improved progression-free survival compared with placebo in treatment-naïve or cytokine-treated patients with metastatic RCC in large Phase II and Phase III clinical trials. Pazopanib has demonstrated a tolerable side effect profile and is currently being compared with sunitinib in a Phase III noninferiority trial. In this review, the outcomes of the clinical testing of pazopanib are discussed, as well as a perspective on the placement of pazopanib among other approved agents.
PMCID: PMC2962303  PMID: 21049083
renal cell carcinoma; targeted agents; vascular endothelial growth factor inhibitors; pazopanib
14.  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

Results 1-14 (14)