Eric Jonasch

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (110)534.36 Total impact

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    ABSTRACT: Clear cell kidney cancer (CRCC) is initiated typically by loss of the tumor suppressor VHL, driving constitutive activation of HIF-1 and HIF-2. However, whereas HIF-1 has a tumor suppressor role, HIF-2 plays a distinct role in driving CRCC. In this study, we show that the HIF-1α E3 ligase HAF complexes with HIF-2α at DNA to promote HIF-2-dependent transcription through a mechanism relying upon HAF SUMOylation. HAF SUMOylation was induced by hypoxia, whereas HAF-mediated HIF-1α degradation was SUMOylation independent. HAF overexpression in mice increased CRCC growth and metastasis. Clinically, HAF overexpression was associated with poor prognosis. Taken together, our results show that HAF is a specific mediator of HIF-2 activation that is critical for CRCC development and morbidity. Copyright © 2014, American Association for Cancer Research.
    Cancer research. 11/2014;
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    ABSTRACT: Clinical trials have demonstrated that pazopanib prolongs progression-free survival (PFS), with an acceptable safety profile, in patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mTOR inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. This study evaluated outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting.Patients and Methods This was a retrospective analysis of eligible patients in US Oncology’s iKnowMed electronic health records database who were treated for aRCC between November 1, 2009, and August 31, 2012. Patients received first-line therapy with pazopanib (Cohort 1), followed by second-line therapy with either everolimus or temsirolimus (Cohort 2). Key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use.ResultsMedian OS in Cohort 1 (n=177) was 22 months; median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). Median persistence was 151 days with pazopanib. Median OS in Cohort 2 (n=35) was 16 months; median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). Median persistence was 93 days with everolimus and 49 days with temsirolimus.Conclusion Outcomes in patients treated with first-line pazopanib in this community setting were consistent with previous prospective and retrospective studies. Although the second-line cohort was small, results of mTOR inhibitors after pazopanib were also consistent with previous observations.
    Clinical Genitourinary Cancer 11/2014; · 1.43 Impact Factor
  • Thai H Ho, Eric Jonasch
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    ABSTRACT: Hereditary forms of renal cell carcinoma (RCC) have yielded clues regarding the molecular pathogenesis of sporadic RCC. The discovery of germline mutations in chromatin-modulating enzymes also defined a new hereditary RCC syndrome. Although histologically distinct RCC subtypes exist, emerging themes shared between hereditary and sporadic RCC include dysregulation of the von Hippel-Lindau tumor suppressor protein/hypoxia inducible factor axis, defective ciliogenesis, and aberrant tumor metabolism. This article describes the most common hereditary RCC syndromes and associated extrarenal manifestations. Recent evidence supports developing screening guidelines for early-onset RCC to identify persons with germline mutations in the absence of secondary clinical manifestations.
    Journal of the National Comprehensive Cancer Network: JNCCN 09/2014; 12(9):1347-1355. · 5.11 Impact Factor
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    ABSTRACT: Abstract Background: Second-line targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKIs). This study compares the effectiveness of these therapies in a multi-practice chart review and synthesizes the findings with those of a similarly-designed study. Methods: Medical oncologists/hematologists (N=36) were recruited to review charts for patients aged ≥ 18 years, received a 1st-line TKI and initiated 2nd-line targeted therapy in 2010 or later. The primary outcome was time from 2nd-line initiation to treatment failure (TTF; discontinuation, physician-assessed progression, or death, whichever occurred first). TTF was compared among patients receiving 2nd-line everolimus (EVE), temsirolimus (TEM), or TKI as a class, using a Cox proportional hazards model adjusting for type of initial TKI and response, histological subtype, performance status, and sites of metastasis. Hazard ratios (HRs) for TTF were pooled, in a meta-analysis, with previously-reported HRs for progression-free survival from a chart review with a similar design. Results: A total of 138, 64 and 79 patients received 2nd-line therapy with EVE, TEM or a TKI, respectively. Adjusting for baseline characteristics, EVE was associated with numerical, but not statistically significant, reductions of 28% (HR=0.72, 95% CI [0.45, 1.16]) and 26% (HR=0.74, 95% CI [0.48, 1.15]) in the hazard of TTF compared to TEM and TKI, respectively. After pooling the HRs from both studies, EVE was associated with significantly reduced hazards of TTF compared to TEM and TKI (HR=0.73, 95%CI [0.57, 0.93], and HR=0.75, 95%CI [0.57, 0.98], respectively). Limitations: Limitations include retrospective analyses with possible missing or erroneous chart data, confounding of unobserved factors due to non-randomization, and limited data for axitinib during the study period. Conclusions: In pooled results from two independent multi-practice chart reviews of 2nd-line mRCC treatment, EVE was associated with significantly reduced hazards of treatment failure compared to TEM and to TKIs as a class.
    Current Medical Research and Opinion 08/2014; · 2.37 Impact Factor
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    ABSTRACT: Abstract Background Vascular endothelial growth factor (VEGF) inhibitors, including targeted therapy with tyrosine kinase inhibitors (TKIs) and the angiogenesis inhibitor bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors are now the standard of care for metastatic renal cell carcinoma (mRCC). However, real-world treatment patterns are not well-characterized. Objective To describe treatment patterns during the 1(st), 2(nd), and 3(rd) lines of targeted therapies for mRCC among community oncologists in the US. Methods Participating physicians recruited from a nationwide panel each identified up to 15 adult mRCC patients who initiated a 2nd therapy after January, 2010. Information extracted from medical records included types of targeted therapies, reasons for treatment choices, patterns of treatment discontinuation, and dose adjustments. Results Thirty-six physicians contributed charts from 433 mRCC patients. Seventy-seven percent of patients received a VEGF inhibitor as 1(st) targeted therapy; 23% received an mTOR inhibitor. Among 1st-line VEGF users, 2(nd)-line treatments were 66% mTOR and 34% VEGF inhibitors. Among 1st-line mTOR users, 2(nd)-line treatments were 94% VEGF and 6% mTOR inhibitors. Sunitinib followed by everolimus was the most commonly used treatment sequence. Estimated median duration for 2(nd) targeted therapy was 8.6 months, and median overall survival (OS) and progression-free survival (PFS) were 27.4 and 10.8 months, respectively. Efficacy, treatment guidelines and mechanism of action were the most important considerations for treatment choice. Limitations Limitations include no adjustment for baseline characteristics, possible difference between physician-defined progression and central review in the clinical trial setting, and limited data availability for axitinib during the study period. Conclusion In this large retrospective chart review among community oncologists, VEGF-mTOR-VEGF was the most common treatment sequence for mRCC. The most common drugs were sunitinib in the 1(st)-line and everolimus in the 2(nd)-line.
    Current Medical Research and Opinion 07/2014; · 2.37 Impact Factor
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    ABSTRACT: This study sought to determine if there was an association between prognostic-based serum biomarkers, survival, and psychosocial factors in patients with metastatic renal cell carcinoma. Associations were found between psychosocial factors and biomarker levels (hemoglobin with depressive symptoms (r = -0.29), positive affect (r = 0.30), social support (r = 0.19), and perceived stress (r = -0.27); albumin with depressive symptoms (r = -0.19), positive affect (r = 0.22), and social support (r = 0.20); alkaline phosphatase with depressive symptoms (r = 0.21), all p values <0.05. After adjustment for disease-related risk factors, only the associations between positive affect and perceived stress with hemoglobin remained significant (p's < 0.05). Positive affect (HR = 0.90; 95 % CI = 0.83, 0.97; p = 0.009) and depressive symptom total scores (HR = 1.03; 95 % CI = 1.01, 1.06; p = 0.013), and alkaline phosphatase (HR 2.72; 95 % CI = 1.41, 5.24; p = 0.003) were associated with survival. This study suggests that measures of positive and negative psychological outlook may contribute differently to health, well-being, and survival.
    Journal of Behavioral Medicine 06/2014; · 3.10 Impact Factor
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    ABSTRACT: Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations.
    Cancer Research 04/2014; · 9.28 Impact Factor
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    ABSTRACT: BACKGROUND High-grade upper tract urothelial carcinoma (UTUC) is frequently upstaged after surgery and is associated with uniformly poor survival. Neoadjuvant chemotherapy may offer a way to improve clinical outcomes. The authors compared the survival rates of patients with UTUC who received neoadjuvant chemotherapy before surgery with the rates among patients who did not.METHODSA retrospective review was conducted of patients with high-risk UTUC who received neoadjuvant chemotherapy followed by surgery from 2004 to 2008 (study group) compared with a matched cohort who underwent initial surgery from 1993 to 2003 (control group). Fisher exact tests, Wilcoxon rank-sum tests, and Kaplan-Meier methods were used. The log-rank test and Cox proportional-hazards models were used to evaluate the association of the 2 outcomes with patient, treatment, and tumor characteristics in univariate and multivariate models.RESULTSOf 112 patients, there were 31 in the study group and 81 in the control group. Patients who received neoadjuvant chemotherapy had improved overall survival (OS) and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = .0204 and P = .0015, respectively). In multivariate analyses, the neoadjuvant group had a lower risk of mortality (OS: hazard ratio, 0.42 [P = .035]; DSS: hazard ratio, 0.19 [P = .006]).CONCLUSIONS Neoadjuvant chemotherapy improved the survival of patients with UTUC compared with a matched historic cohort of patients who underwent initial surgery. Patients with high-risk UTUC should be considered for neoadjuvant chemotherapy in view of the limited opportunity to administer effective cisplatin-based chemotherapy after nephroureterectomy. Cancer 2014. © 2014 American Cancer Society.
    Cancer 03/2014; · 5.20 Impact Factor
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    ABSTRACT: These NCCN Guidelines Insights highlight treatment recommendations and updates specific to the management of patients with advanced non-clear cell carcinoma included in the 2014 version of the NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer.
    Journal of the National Comprehensive Cancer Network: JNCCN 02/2014; 12(2):175-82. · 5.11 Impact Factor
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    ABSTRACT: This randomized controlled trial examined the quality-of-life benefits of an expressive writing (EW) intervention for patients with renal cell carcinoma (RCC) and identified a potential underlying mechanism of intervention efficacy. Patients (N = 277) with stage I to IV RCC were randomly assigned to write about their deepest thoughts and feelings regarding their cancer (EW) or about neutral topics (neutral writing [NW]) on four separate occasions. Patients completed the Center for Epidemiologic Studies Depression Scale (CES-D), MD Anderson Symptom Inventory (MDASI), Brief Fatigue Inventory (BFI), Pittsburgh Sleep Quality Index (PSQI), Medical Outcomes Study Short Form-36 (SF-36), and Impact of Event Scale (IES) at baseline and 1, 4, and 10 months after the intervention. The mean age of participants (28% stage IV; 41% female) was 58 years. Multilevel modeling analyses, using a Bonferroni-corrected α = .021 for six outcomes adjusted for the correlation among outcomes, revealed that, relative to the NW group, patients in the EW group reported significantly lower MDASI scores (P = .003) and higher physical component summary scores on the SF-36 (P = .019) at 10 months after the intervention. Mediation analyses revealed that significant group differences for MDASI scores at 10 months were mediated by lower IES scores at 1 month after the intervention in the EW group (P = .042). No significant group differences were observed in the BFI, CES-D, PSQI, and mental component summary of the SF-36. EW may reduce cancer-related symptoms and improve physical functioning in patients with RCC. Evidence suggests that this effect may occur through short-term improvements in cognitive processing.
    Journal of Clinical Oncology 01/2014; · 18.04 Impact Factor
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    ABSTRACT: Purpose: Cytoreductive nephrectomy (CN) remains the standard of care for appropriately selected patients with metastatic renal cell carcinoma (mRCC). Although the role of partial nephrectomy (PN) is well accepted in patients with localized disease, limited data are available regarding PN in the metastatic setting. We sought to identify the indications and outcomes for PN in the setting of mRCC with particular attention to different PN subgroups. Materials and Methods: We analyzed data from a consecutive cohort of 33 patients with mRCC who underwent PN at a single institution between 1996 and 2011. Non-parametric statistics were used to compare PN subgroups. Overall survival (OS) was estimated using Kaplan-Meier method, and survival functions were compared using the log-rank test. Results: Eight patients presented with bilateral synchronous renal masses; 20 with a metachronous contralateral renal mass; and 5 with a unilateral renal mass. Overall, 22 patients (67%) died of disease at a median of 27 months after PN. Patients who underwent PN for a metachronous contralateral renal mass and for a renal mass ≤4cm had the best OS (61 months and 42 months, respectively). Median OS for patients with and without metastatic disease at original diagnosis was 27 and 63 months, respectively (p=0.003). Conclusions: Our findings suggest that the presence of metastasis at original diagnosis and the timing of presentation of the PN index lesion play an important role in survival. These factors should be taken into consideration when determining which patients would benefit from partial nephrectomy in the setting of mRCC.
    The Journal of urology 01/2014; · 3.75 Impact Factor
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    ABSTRACT: Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.
    PLoS ONE 01/2014; 9(2):e89880. · 3.53 Impact Factor
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    ABSTRACT: Clear cell papillary renal cell carcinoma (CCPRCC) is a renal neoplasm that has recently received widespread recognition in the literature. There have been several reports of this tumor arising in a sporadic setting and in patients with end-stage renal disease; however, there is limited information available about the clinical, pathologic, and genetic characteristics of this tumor in the setting of Von Hippel-Lindau (VHL) disease. We herein report a series of three patients that developed CCPRCC in this unique clinical setting. The histology and immunohistochemical profile for all three cases was similar to that which has been previously reported for CCPRCC. All tumors were diffusely and strongly positive for Cytokeratin 7, negative for alpha methyl Co-A racemase and showed at least focal staining for CD10. Comparative genomic analysis was performed on tumors from all three patients. One tumor demonstrated monosomy 3 and the other two tumors showed normal chromosomal content. All three patients were alive without evidence of disease progression 5, 3 and 3 years after surgery. CCPRCC represents a distinct tumor type that may occur in the setting of VHL disease and should be considered in the differential diagnosis of extensively cystic renal tumors arising in this clinical setting. Molecular analysis in our series of cases suggests that CCPRCC does indeed represent a unique histologic subtype and must be distinguished from clear cell renal cell carcinoma (CCRCC) due to different biologic potentials. Ancillary studies for accurate classification are recommended due to significant morphologic overlap with CCRCC.
    Human pathology 01/2014; · 3.03 Impact Factor
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    ABSTRACT: The treatment of renal cell carcinoma (RCC) has changed greatly over the past 15 years. Progress in the surgical management of the primary tumor and increased understanding of the molecular biology and genomics of the disease have led to the development of new therapeutic agents. The management of the primary tumor has changed owing to the realization that clean margins around the primary lesion are sufficient to prevent local recurrence, as well as the development of more sophisticated tools and techniques that increase the safety of partial nephrectomy. The management of advanced disease has altered even more dramatically as a result of new agents that target the tumor vasculature or that attenuate the activation of intracellular oncogenic pathways. This review summarizes data from prospective randomized phase III studies on the surgical management and systemic treatment of RCC, and provides an up to date summary of the histology, genomics, staging, and prognosis of RCC. It describes the management of the primary tumor and offers an overview of systemic agents that form the mainstay of treatment for advanced disease. The review concludes with an introduction to the exciting new class of immunomodulatory agents that are currently in clinical trials and may form the basis of a new therapeutic approach for patients with advanced RCC.
    BMJ Clinical Research 01/2014; 349:g4797. · 14.09 Impact Factor
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    ABSTRACT: Introduction Limited data are available regarding patients with RCC and ESRD treated with targeted therapies (TTs). The objective of this study was to explore the tolerability and safety of TT in patients with metastatic renal cell carcinoma (mRCC) and end stage renal disease (ESRD). Methods We retrospectively indentified patients with mRCC and ESRD treated at the University of Texas MD Anderson Cancer Center from 2002-2012. Patients’ characteristics including demographics, histology, treatment, and adverse events (AEs) are reported. Time on treatment (TOT) was determined from date of drug initiation to discontinuation. Overall survival (OS) was determined from initiation of TT to death. Statistics are descriptive. Results Fourteen patients were identified. Ten patients had clear cell histology and 4 had papillary histology. The median number of TTs per patient was 3 (range 1-4) with median TOT of 28 months for all TT. Eighty-eight percent of all toxicities were grade 1-2; no grade 4 toxicities were noted. Treatment discontinuations included 3 patients treated with sorafenib due to hand-foot syndrome, intolerable fatigue, and squamous cell skin cancer development; 2 patients treated with pazopanib due to intolerable fatigue and increased transaminases; and 1 patient treated with everolimus due to pneumonitis . Eight patients died of progressive disease. Median OS from initiation of TT was 28.5 months and 35 months from time of diagnosis. Conclusions Toxicities were mild to moderate and consistent with those reported in previous studies. TTs appear to be safe, well tolerated and produce anti-tumor response in patients with mRCC and end-stage renal disease on dialysis.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Comprehensive sequencing of human cancers has identified recurrent mutations in genes encoding chromatin regulatory proteins. For clear cell renal cell carcinoma (ccRCC), three of the five commonly mutated genes encode the chromatin regulators PBRM1, SETD2, and BAP1. How these mutations alter the genomic landscape in ccRCC or other cancers is not understood. Here, we identified alterations in chromatin organization and transcription associated with mutations in chromatin regulators in a large cohort of primary human kidney tumors. By associating variation in chromatin organization with mutations in SETD2, which encodes the enzyme responsible for H3K36 trimethylation, we found that changes in chromatin accessibility occurred primarily within actively transcribed genes. This increase in chromatin accessibility was linked with widespread alterations in RNA processing, including intron retention and aberrant splicing, affecting approximately 25% of all expressed genes. Further, decreased nucleosome occupancy proximal to misspliced exons was observed in tumors lacking H3K36me3. These results directly link mutations in SETD2 to chromatin accessibility changes and RNA processing defects in cancer. Detecting the functional consequences of specific mutations in chromatin regulatory proteins in primary human samples could ultimately inform the therapeutic application of an emerging class of chromatin-targeted compounds.
    Genome Research 10/2013; · 14.40 Impact Factor
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    ABSTRACT: Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Pfizer Inc.
    The Lancet Oncology 10/2013; · 25.12 Impact Factor
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    ABSTRACT: To identify sunitinib alternative schedules (AS) that maintained dose intensity while decreasing adverse events (AEs) in patients with metastatic renal cell cancer (mRCC), and to determine impact of AS on clinical outcomes. A retrospective review of patients ≥ 18 yr of age with clear-cell mRCC who received first-line sunitinib between 1/26/06 and 3/1/11 at a major Comprehensive Cancer Center. Subset of patients switched at first intolerable AE from traditional schedule (28 d on, 14 d off; TS) to 14 d on/7 d off schedule or other AS. Control group underwent standard dose reduction. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of PFS and OS were analyzed using Cox regression. One hundred eighty five patients were included for analysis; 87% were on TS at baseline. During treatment, 53% of patients continued TS and 47% initiated or transitioned to AS. Baseline characteristics were similar. AEs prompting schedule modification included fatigue (64%), hand-foot syndrome (38%) and diarrhea (32%). Median time to AS was 5.6 mo. Median OS was 17.7 mo (95% confidence interval [CI], 10.8-22.2) on TS compared to 33.0 mo (95% CI, 29.3- not estimable) on AS (P < 0.0001). By multivariable analysis; poor ECOG PS, increased LDH, decreased albumin, unfavorable Heng criteria, and TS are associated with decreased OS (P < 0.05). Sunitinib administered on AS may mitigate AEs and has comparable outcomes as TS for mRCC patients. Prospective investigations of alternate dosing schemas are warranted.
    The Journal of urology 09/2013; · 3.75 Impact Factor
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    ABSTRACT: To characterize the incidence, onset, management, predictors, and clinical impact of mTOR inhibitor associated noninfectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma. Retrospective review of 310 patients with metastatic renal cell carcinoma who received temsirolimus and/or everolimus between 6/1/2007 and 10/1/2010. Clinical correlations were made with serial radiologic imaging. Fisher's exact, Wilcoxon rank sum, and logistic regression analysis were performed to evaluate the association of NIP with demographic or clinical factors. Log rank and Cox proportional hazards regression analysis were used for the time-to-event analysis. NIP occurred in 6% of temsirolimus and 23% of everolimus treated patients. Symptoms included cough, dyspnea, and fever (median of two and three symptoms per patient, respectively). Median NCI-CTCAE pneumonitis grade was 2 for both groups. Older age and everolimus treatment were predictive of NIP. Patients who developed NIP had significantly longer time on treatment (median 4.1 months vs 2 months) and overall survival (OS) (median 15.4 months vs 7.4 months). NIP was a predictor of improved OS by multivariate analysis. An increased incidence of NIP was observed in everolimus treated patients. Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy.
    BJU International 08/2013; · 3.05 Impact Factor
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    ABSTRACT: Currently approved treatments for metastatic renal cell carcinoma (RCC) include vascular endothelial growth factor (VEGF)-blocking agents, mammalian target of rapamycin (mTOR) inhibitors, and cytokine therapy. In the near future, we are likely to add immune checkpoint blocking agents to this list. As we develop treatment platforms around each therapeutic class, determining which drug is best for a particular patient becomes increasingly important. At this point, we do not have validated predictive biomarkers for patients with RCC. Here, we discuss the logistical challenges surrounding biomarker development, summarize the current crop of biomarker candidates, and explore potential avenues for the development of more effective predictive tools for patients with advanced RCC.
    Seminars in Oncology 08/2013; 40(4):444-58. · 4.33 Impact Factor

Publication Stats

1k Citations
534.36 Total Impact Points

Institutions

  • 2007–2014
    • University of Texas MD Anderson Cancer Center
      • • Genitourinary Medical Oncology
      • • Department of Systems Biology
      • • Department of Urology
      Houston, Texas, United States
    • McGill University
      • Division of Urology
      Montréal, Quebec, Canada
  • 2013
    • Centro Nacional de Investigaciones Oncológicas
      • Human Cancer Genetics Programme
      Madrid, Madrid, Spain
  • 2012
    • VU University Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Houston Methodist Hospital
      Houston, Texas, United States
  • 2010
    • University of Wisconsin, Madison
      • Department of Urology
      Madison, MS, United States
    • Netherlands Cancer Institute
      • Department of Urology
      Amsterdamo, North Holland, Netherlands
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2009
    • General University Hospital of Larissa
      Lárissa, Thessaly, Greece
    • Fox Chase Cancer Center
      • Department of Medical Oncology
      Philadelphia, PA, United States
    • University of Texas Health Science Center at Houston
      Houston, Texas, United States