Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma—Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study

AimTo assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC).Patients and methodsThis observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, ≥1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge.ResultsAnalyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90–100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported.ConclusionsSunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy.     

Phase II trial of continuous once-daily dosing of sunitinib as first-line treatment in patients with metastatic renal cell carcinoma

BACKGROUND:

Sunitinib at 50 mg/day on the 4‐weeks‐on‐2‐weeks‐off schedule is the current approved regimen for advanced/metastatic renal cell carcinoma (mRCC). Escudier et al reported that continuous, once‐daily dosing with sunitinib 37.5 mg had a manageable safety profile and significant antitumor activity as second‐line mRCC therapy. In this prospective, multicenter, phase II study, we evaluated the activity of continuous once‐daily dosing with sunitinib 37.5 mg as first‐line mRCC treatment.

METHODS:

One hundred nineteen treatment‐naive patients with measurable mRCC received sunitinib. The primary endpoint was objective response; secondary endpoints included progression‐free survival (PFS), safety, pharmacokinetic measurements, exploration of response biomarkers, and patient reported outcomes (PRO).

RESULTS:

Objective response rate (ORR) was 35.3%; median response duration was 10.4 months; 36% of patients had stable disease ≥12 weeks. Median PFS at 1 year was 9 months, and 1‐year survival probability was 67.8%. The most common any‐grade treatment‐related adverse events (AEs) were diarrhea (50%) and hand‐foot syndrome (43%); the most common grade 3‐4 treatment‐related AEs were hand‐foot syndrome (13%), neutropenia (11%), and diarrhea (9%). Steady‐state pharmacokinetics were reached within 3 weeks, with no disproportionate accumulation of sunitinib or its active metabolite throughout the study. No significant correlations between trough drug, active metabolite, or soluble protein levels and clinical response were observed. PRO was largely maintained, although fatigue appeared to worsen after treatment started, with improvement over time.

CONCLUSIONS:

Continuous once‐daily dosing with sunitinib 37.5 mg was active with a manageable safety profile as first‐line mRCC therapy, making this a feasible alternative dosing regimen. Cancer 2012. © 2011 American Cancer Society.     

Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab

BACKGROUND:

Bevacizumab and sunitinib are standard initial therapy in metastatic renal cell carcinoma (mRCC). Despite common use, the safety and activity of sorafenib in bevacizumab‐ or sunitinib‐refractory mRCC have not been prospectively investigated.

METHODS:

Metastatic RCC patients with Response Evaluation Criteria in Solid Tumors (RECIST)‐defined disease progression (PD) after treatment with either bevacizumab or sunitinib received twice daily 400 mg of sorafenib in a multicenter, prospective phase 2 study. Dose escalation was permitted in the absence of significant toxicity. The primary endpoint was tumor burden reduction rate, defined as the proportion of patients with ≥5% reduction in the sum of RECIST‐defined target lesions without other PD. Secondary endpoints included progression‐free survival (PFS), duration of response, overall survival, and safety. A 2‐stage accrual design was used to test the alternative hypothesis that the tumor burden reduction rate was >20% versus <5%.

RESULTS:

Forty‐eight patients were enrolled. The tumor burden reduction rate was 30% (95% confidence interval [CI], 17%‐45%). One unconfirmed objective partial response was observed. The median PFS was 4.4 months (95% CI, 3.6‐5.9). There was no association of PFS and tumor shrinkage with response to prior therapy. Most treatment‐related adverse events were of mild‐to‐moderate intensity, and included fatigue, hypertension, diarrhea, and palmoplantar erythrodysesthesia (PPE). Patients previously treated with bevacizumab tended to develop more PPE (P = .03) and mucositis (P = .06), whereas sunitinib‐treated patients tended to develop more skin rash (P = .06).

CONCLUSIONS:

Administration of sorafenib is safe and feasible in patients with mRCC refractory to either bevacizumab or sunitinib. Modest clinical activity was observed supporting current practice patterns of sequential vascular endothelial growth factor‐targeted therapy in mRCC. Cancer 2010. © 2010 American Cancer Society.     

Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome

BACKGROUND:

The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)‐targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long‐term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time.

METHODS:

A retrospective study of patients with mRCC who initiated VEGF‐targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave‐Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)‐defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression‐free survival (PFS), measured as the time from discontinuation of therapy to RECIST‐defined PD.

RESULTS:

Forty patients were identified. After a median follow‐up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4‐27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19‐5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04‐0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model.

CONCLUSIONS:

A select subset of mRCC patients achieving stable disease or better on VEGF‐targeted therapy can be observed off all therapy. Further prospective investigation is warranted. Cancer 2011. © 2011 American Cancer Society.     

Progression-free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary targeted therapy

BACKGROUND.

The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression‐free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown.

METHODS.

Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead‐time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS.

RESULTS.

In total, 1158 patients were included. The median follow‐up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log‐rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42‐3.84) and 2.96 (95% confidence interval, 2.39‐3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation.

CONCLUSIONS.

PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents. Cancer 2011;. © 2010 American Cancer Society.     

Hypothyroidism in patients with renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

METHODS:

Eighty‐seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid‐stimulating hormone (TSH), tri‐iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 μM/mL) with normal T3 and T4 levels.

RESULTS:

Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14‐0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014).

CONCLUSIONS:

The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered. Cancer 2011. © 2010 American Cancer Society.     

Third-line sunitinib following sequential use of cytokine therapy and sorafenib in Japanese patients with metastatic renal cell carcinoma

Background

The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC).

Methods

This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed.

Results

Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3–4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%).

Conclusion

Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.     

Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma

BACKGROUND.

In a randomized, phase 3 trial, sunitinib demonstrated superior efficacy over interferon‐alfa as first‐line therapy in patients with metastatic clear‐cell renal cell carcinoma (RCC). On the basis of outcome data from that trial, the authors developed a nomogram for predicting the probability of 12‐month progression‐free survival for patients who received sunitinib therapy.

METHODS.

Three‐hundred seventy‐five patients who received sunitinib in the phase 3 trial were the subject of the current analysis. Nomogram pretreatment predictor variables included corrected serum calcium levels, the number of metastatic sites, hemoglobin levels, prior nephrectomy, the presence of lung and liver metastases, thrombocytosis, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, and serum levels of alkaline phosphatase and lactate dehydrogenase. Investigator‐assessed progression‐free survival was the predicted outcome endpoint. Internal validation of the nomogram consisted of quantification of the discrimination with the concordance index and assessment of calibration.

RESULTS.

One‐hundred seventy‐four of 375 patients (46%) who received sunitinib achieved an objective response, and the median progression‐free survival was 10.8 months (95% confidence interval, 10.6‐12.6 months). A nomogram for predicting the probability of 12‐month progression‐free survival for patients who received sunitinib therapy was constructed on the basis of a Cox regression model from 11 parameters that were determined before treatment. The concordance index was 0.633.

CONCLUSIONS.

A nomogram was developed from pretreatment clinical features to predict the probability of achieving 12‐month progression‐free survival with sunitinib therapy for metastatic clear‐cell RCC. The authors concluded that independent validation of the nomogram and additional studies to identify tumor‐specific prognostic factors are warranted. Cancer 2008. © 2008 American Cancer Society.     

Sunitinib Rechallenge in Patients With Metastatic Renal Cell Carcinoma

BackgroundSunitinib has been the standard of care for patients with metastatic renal cell carcinoma (mRCC). However, nearly all patients will eventually develop resistance. Before the introduction of novel agents, few treatment options remained after sunitinib failure. Sunitinib rechallenge is a strategy based on the presumption that resistance might be only temporary. The aim of this analysis was to evaluate the efficacy and safety of sunitinib rechallenge in patients with mRCC.Patients and MethodsPatients who had undergone sunitinib rechallenge (SU2) at the Medical University of Vienna from 2010 to 2017 were identified for the present retrospective study. The primary endpoint was the treatment duration with rechallenge (TD^SU2). The secondary endpoints included the treatment duration with upfront sunitinib (TD^SU1), progression-free survival (PFS^SU1 and PFS^SU2), overall survival (OS^SU1 and OS^SU2), the objective response rate in both settings (ORR^SU1 and ORR^SU2), and toxicity.ResultsA total of 31 patients were eligible. The median TD^SU2 was 7.2 months, and the median TD^SU1 was 17.8 months. The median OS^SU1 and OS^SU2 was 57.9 months and 14.7 months, respectively. The median PFS^SU1 and PFS^SU2 was 14.2 months and 5.6 months, respectively. The ORR^SU1 and ORR^SU2 was 34% and 16%, and another 48% and 42% achieved stable disease (SD), respectively. Fatigue and hypertension were the most common adverse events.ConclusionsSunitinib rechallenge appears to benefit patients in later treatment lines. With the abundance of novel treatment options available, this approach might appear less relevant. However, novel agents are not yet available everywhere. Thus, sunitinib rechallenge could be an additional strategy to improve the outcomes of patients with mRCC.     

Prognostic and Predictive Value of Hematologic Parameters inPatients with Metastatic Renal Cell Carcinoma: Second LineSunitinib Treatment Following IFN-alpha

Background: Long-term survival is a problem with locally advanced and metastatic renal cell carcinomas.Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, but data on sunitinib use as a second linetreatment in metastatic renal cell carcinoma (mRCC) are limited. Prognostic and predictive value of peripheralblood markers has been shown for many cancers. Materials and Methods: Efficacy and safety profiles ofsunitinib after interferon alpha (IFN-α) were evaluated based on retrospective data for 23 patients with mRCC.Hematological parameters (neutrophils, lymphocytes, platelets, mean platelet volume, neutrophil/lymphocyteratio, platelet/lymphocyte ratio) were recorded at the time of metastasis. It was evaluated whether hematologicalparameters were prognostic and predictive factors. Results: Median progression-free survival (PFS) time was16.5 months (95%CI: 0-34.5). Median overall survival (OS) time was 25.7 months (95%CI: 10.8-40.0). Mostcommon side effects were neutropenia (52.2%), stomatitis (26.1%) and hand-food syndrome (26.1%). PFS wasfound 3.13 vs 17.1 months in patients with neutrophil / lymphocyte ratio (NLR)>3 vs NLR≤3 (p:0.012). MedianOS was 6.96 vs 27.1 months in patients with NLR>3 vs NLR≤3 (p:0.001).While 75% of patients who respondedto sunitinib had NLR≤3, in 72% of patients with no response to sunitinib NLR>3 was detected (p:0.036). Theassociation between the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria and NLR was statisticallysignificant (p:0.022). Conclusions: Data on second line sunitinib treatment following cytokine in mRCC arelimited. In our study, we observed second line sunitinib treatment following IFN-α to be effective and tolerable.NLRappeared to have prognostic and predictive value.     

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are small‐molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.

METHODS:

Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first‐line therapy with either sunitinib or sorafenib and subsequently receiving second‐line therapy with the other TKI agent.

RESULTS:

Twenty‐nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P = .016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P = .061).

CONCLUSIONS:

The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation. Cancer 2009. © 2008 American Cancer Society.     

The impact of tumor burden characteristics in patients with metastatic renal cell carcinoma treated with sunitinib

BACKGROUND:

An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor‐targeted therapy.

METHODS:

Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re‐reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST).

RESULTS:

A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1‐27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm‐42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression‐free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs >12; P < .001) were found to be significant predictors of survival after PD.

CONCLUSIONS:

The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib. Cancer 2011. © 2010 American Cancer Society.     

Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study

BackgroundA retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed.Patients and MethodsData on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand–foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash.ResultsThe cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort.ConclusionThe presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib.     

Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor

BACKGROUND.

Sunitinib malate is a novel multitargeted receptor tyrosine kinase inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib‐resistant gastrointestinal stromal tumor. This report describes the development of heart failure in cancer patients who received this novel agent.

METHODS.

A retrospective study was conducted at M. D. Anderson Cancer Center during a 1‐year period on patients who received sunitinib and developed heart failure.

RESULTS.

During 2006, 6 of 224 (2.7%) patients who received sunitinib developed heart failure (HF) that resulted in substantial morbidity and, in some cases, mortality. Symptomatic heart failure occurred soon after initiation of sunitinib (mean onset 22 days after initiation), was associated with decline in cardiac function and elevations in blood pressure, and was not completely reversible in most patients, even after termination of sunitinib therapy.

CONCLUSIONS.

These observations suggested that sunitinib‐associated heart failure may represent a potentially serious toxicity and underscore the need for careful monitoring of cardiac function and aggressive control of hypertension in these patients. Studies to elucidate potential mechanisms of heart failure and left ventricular dysfunction resulting from treatment with sunitinib are necessary to develop strategies for prevention and treatment of this complication. Cancer 2008. ©2008 American Cancer Society.     

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies

BACKGROUND:

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies.

METHODS:

Eligible patients had CNS malignancies that required a (minimum) 2‐week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3.

RESULTS:

Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8‐3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow‐up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6‐month progression‐free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT.

CONCLUSIONS:

Continuous 37.5‐mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Cancer 2011;. © 2011 American Cancer Society.     

Pretreatment assessment of tumor enhancement on contrast‐enhanced computed tomography as a potential predictor of treatment outcome in metastatic renal cell carcinoma patients receiving antiangiogenic therapy

BACKGROUND:

Tumor vascularity is a potential predictor of treatment outcomes in metastatic renal cell carcinoma (mRCC), and contrast enhancement of tumors in computed tomography (CT) is correlated significantly with microvessel density. In this study, the authors investigated whether tumor enhancement in contrast‐enhanced CT (CECT) is useful for predicting outcomes in patients with mRCC who are receiving antiangiogenic therapy.

METHODS:

Attenuation values were reviewed retrospectively on CECT images of all metastatic lesions in 66 patients from February 2007 to November 2008. All patients received a tyrosine kinase inhibitor (either sunitinib or sorafenib). Tumor response was evaluated on CECT studies every 12 weeks. The authors analyzed the association between contrast enhancement and treatment outcomes, including objective response, tumor size reduction rate, time to response, and time to progression.

RESULTS:

In 46 patients, 198 metastatic lesions were assessed. Tumor size was reduced in 140 lesions (70.7%) and was increased in 58 lesions (29.3%). The mean reduction in size was 23.8%. The overall mean time to response and the time to progression were 8.6 months and 16.4 months, respectively. In multivariate analyses, tumor enhancement and enhancement pattern were associated with objective responses (P = .003 and P = .028, respectively). In addition, tumor enhancement was associated with tumor size reduction (P = .004). In Cox proportional hazards models, only tumor enhancement was associated significantly with the time to size reduction and progression‐free survival (P = .03 and P = .015, respectively).

CONCLUSIONS:

Tumor enhancement on CECT images was associated with treatment outcomes and was identified as a potential predictor of treatment outcomes after antiangiogenic therapy in patients with mRCC. Cancer 2010. © 2010 American Cancer Society.     

Macrocytosis during sunitinib treatment predicts progression-free survival in patients with metastatic renal cell carcinoma

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, is a first-line treatment for metastatic renal cell carcinoma (mRCC) in patients in ‘low’ and ‘intermediate’ Memorial Sloan Kettering Cancer Center and Heng risk groups. Disruptions of hematopoiesis, such as anemia, neutropenia, and thrombocytopenia, are typically observed during sunitinib treatment. When it comes to RBC parameters, an increase in mean cell volume (MCV) tends to occur, meeting the criteria for macrocytosis in some patients (MCV > 100 fL). We examined changes in RBC parameters of 27 mRCC patients treated with sunitinib (initial dose of 50 mg/day, 6-week treatment: 4 weeks on, 2 weeks off) and correlated them with progression-free survival time (PFS). Patients who had macrocytosis after 3 treatment cycles had significantly longer PFS than those whose MCV stayed less than 100 fL (not reached vs. 11.2 months, p < 0.001). We also found a correlation between MCV values after the first and third treatment cycles and the risk of progression: HR of 0.9 (0.81–0.99) and 0.76 (0.65–0.90) per 1 fL increase in MCV, respectively. The mechanism of MCV elevation during sunitinib treatment has not yet been fully explained. One of the probable causes is sunitinib’s inhibitory influence on c-Kit kinase, as is the case with imatinib. For mRCC patients, this phenomenon could help predict PFS, but since our sample was small, further studies are essential.     

Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma

BACKGROUND:

On the basis of potential additive or synergistic immunostimulatory antitumor effects, in this phase 1 study, the authors evaluated the combination of sunitinib and tremelimumab (CP‐675206; an antibody against cytotoxic T‐lymphocyte–associated antigen 4 [CTLA4]) in patients with metastatic renal cell carcinoma (mRCC) was evaluated.

METHODS:

Adult patients with mRCC who had received ≤1 previous systemic treatment received tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg) intravenously once every 12 weeks and oral sunitinib (50 mg daily for 4 weeks then 2 weeks off or 37.5 mg daily as a continuous dose). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives were to assess antitumor activity, safety, and pharmacokinetics.

RESULTS:

Twenty‐eight patients were enrolled. Two of 5 patients who received 50 mg sunitinib plus tremelimumab 6 mg/kg experienced dose‐limiting toxicities (DLTs), and no further enrollment to the combination with sunitinib 50 mg dosing was pursued. Among patients who received continuous sunitinib 37.5 mg daily, 1 of 7 patients who received tremelimumab 10 mg/kg plus sunitinib suffered a sudden death, and 3 of 6 patients who received tremelimumab 15 mg/kg plus sunitinib experienced DLTs. An expansion cohort (n = 7) was enrolled at tremelimumab 10 mg/kg plus sunitinib 37.5 mg daily; 3 of those patients experienced DLTs. Overall, rapid‐onset renal failure was the most common DLT. Nine of 21 patients who were evaluable for response achieved partial responses (43%; 95% confidence interval, 22%‐66%), and 4 of those responses were ongoing at the time of the current report.

CONCLUSIONS:

In this study of tremelimumab plus sunitinib, rapid‐onset acute renal failure was observed unexpectedly, and further investigation of tremelimumab doses >6 mg/kg plus sunitinib 37.5 mg daily is not recommended. Preclinical investigation may be warranted to understand the mechanism of renal toxicity. Cancer 2011. © 2010 American Cancer Society.     

Phase 3 trial of everolimus for metastatic renal cell carcinoma

BACKGROUND:

A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor–tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.

METHODS:

Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression‐free survival (PFS) and safety were assessed to the end of double‐blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank‐preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus.

RESULTS:

The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank‐preserving structural failure time model, the survival corrected for crossover was 1.9‐fold longer (95% confidence interval, 0.5‐8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).

CONCLUSIONS:

These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib. Cancer 2010. © 2010 American Cancer Society.     

A population‐based study evaluating the impact of sunitinib on overall survival in the treatment of patients with metastatic renal cell cancer

BACKGROUND:

Sunitinib has replaced interferon (IFN) as a first‐line standard of care in the treatment of metastatic renal cell carcinoma (RCC). This study aimed to determine overall survival and to confirm effectiveness in a population that includes poor prognosis patients.

METHODS:

Data were collected on all patients identified by the BC Cancer Registry with metastatic RCC who were treated with IFN or sunitinib. The IFN group consisted of patients who received IFN between January 2000 and October 2005, and the sunitinib group included patients treated with first‐line sunitinib from October 2005 to September 2007.

RESULTS:

There were 131 and 69 patients in the IFN and sunitinib groups, respectively. The median follow‐up of those still alive was 12.6 months. The median age (62 vs 63 years; P = .41), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria (poor in 19% vs 30%; P = .41), and proportion with >1 metastasis (53% vs 62%; P = .21) were similar between the IFN and sunitinib groups, respectively. The median survival of the IFN and sunitinib groups was 8.7 and 17.3 months, respectively (log‐rank P = .004). The median survival of patients with favorable, intermediate, and poor MSKCC prognostic profiles in the IFN group was 22.9, 8.7, and 4.1 months, respectively (P < .001), whereas in the sunitinib group it was not reached, 16.8, and 10.7 months, respectively (P = .006). The hazard ratio of death after adjusting for MSKCC criteria was 0.49 (95% confidence interval, 0.31‐0.76; P = .001).

CONCLUSIONS:

The introduction of first‐line sunitinib was associated with a doubling of overall survival compared with patients treated with IFN alone. This benefit extended to patients with poor MSKCC prognostic profiles. Cancer 2009. © 2009 American Cancer Society.