An Italian multicenter retrospective real-life analysis of patients with brain metastases from renal cell carcinoma: the BMRCC study.

BACKGROUND: The treatment of patients with brain-spread renal cell carcinoma (RCC) is an unmet clinical need, although more recent therapeutic strategies have significantly improved RCC patients' life expectancy. Our multicenter, retrospective, observational study investigated a real-world cohort of patients with brain metastases (BM) from RCC (BMRCC). PATIENTS AND METHODS: A total of 226 patients with histological diagnosis of RCC and radiological evidence of BM from 22 Italian institutions were enrolled. Univariate and multivariate models were performed to investigate the impact of clinicopathological features and multimodal treatments on both overall survival (OS) from the BM diagnosis and intracranial progression-free survival (iPFS). RESULTS: The median OS from the BM diagnosis was 18.8 months (interquartile range: 6.2-43 months). Multivariate analysis confirmed the following as positive independent prognostic factors: a Karnofsky Performance Status >70% [hazard ratio (HR) = 0.49, 95% confidence interval (CI) 0.26-0.92, P = 0.0026] and a single BM (HR = 0.51, 95% CI 0.31-0.86, P = 0. 0310); in contrast, the following were confirmed as worse prognosis factors: progressive extracranial disease (HR = 1.66, 95% CI 1.003-2.74, P = 0.00181) and only one line of systemic therapy after the BM occurrence (HR = 2.98, 95% CI 1.62-5.49, P = 0.029). Subgroup analyses showed no difference in iPFS according to the type of the first systemic treatment [immunotherapy (IT) or targeted therapy (TT)] carried out after the BM diagnosis (HR = 1.033, 95% CI 0.565-1.889, P = 0.16), and revealed that external radiation therapy (eRT) significantly prolonged iPFS when combined with IT (10.7 months, 95% CI 4.9-48 months, P = 0.0321) and not when combined with TT (9.01 months, 95% CI 2.7-21.2 months, P = 0.59). CONCLUSIONS: Our results suggest a potential additive effect in terms of iPFS for eRT combined with IT and encourage a more intensive multimodal therapeutic strategy in a multidisciplinary context to improve the survival of BMRCC patients.

Validation of the Meet-URO score in patients with metastatic renal cell carcinoma receiving first-line nivolumab and ipilimumab in the Italian Expanded Access Program.

BACKGROUND: The Meet-URO score allowed a more accurate prognostication than the International Metastatic RCC Database Consortium (IMDC) for patients with pre-treated metastatic renal cell carcinoma (mRCC) by adding the pre-treatment neutrophil-to-lymphocyte ratio and presence of bone metastases. MATERIALS AND METHODS: A post hoc analysis was carried out to validate the Meet-URO score on the overall survival (OS) of patients with IMDC intermediate-poor-risk mRCC treated with first-line nivolumab plus ipilimumab within the prospective Italian Expanded Access Programme (EAP). We additionally considered progression-free survival (PFS) and disease response rates. Harrell's c-index was calculated to compare the accuracy of survival prediction. RESULTS: Overall the EAP included 306 patients, with a median follow-up of 12.2 months, median OS was not reached, 1-year OS was 66.8% and median PFS was 7.9 months. By univariable analysis, both the IMDC score and the two additional variables of the Meet-URO score were associated with either OS or PFS (P < 0.001 for all comparisons). The four Meet-URO risk groups (G) had 1-year OS of 92%, 72%, 50% and 21% for G2 (29.1% of patients), G3 (28.8%), G4 (33.0%) and G5 (9.1%), respectively. OS was significantly shorter in each consecutive G (P = 0.001 for G3, P < 0.001 for both G4 and G5 compared to G2). Similarly, Meet-URO Gs 2-5 showed decreasing median PFS and response rates. The Meet-URO score showed the highest c-index for both OS (0.73) and PFS (0.67). Limitations include the post hoc nature of this analysis and the lack of a comparative arm to assess predictive value. CONCLUSION: The Meet-URO score appeared to show better prognostic classification than the IMDC alone in patients with mRCC at IMDC intermediate-poor risk treated with first-line nivolumab and ipilimumab.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.

BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

BACKGROUND: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. METHODS: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. RESULTS: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). CONCLUSION: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Comparing comparators: a look at control arms in kidney cancer studies over the years.

In the past decade, an increasing number of frequently positive randomised clinical trials have been completed, allowing new consideration of the present therapeutic armamentarium for advanced renal cell carcinoma. These studies were predominantly designed to compare the experimental drugs with 1 of 2 active control arms: interferon alpha-2a or sorafenib. Different from expectations, the final results of some of these studies were not in line with the predictions, and the reasons have not been fully investigated. Consequently, there is a great need for careful analysis of the studies carried out so far, chiefly the role and validity of the control arms. In this regard, the examination of patient baseline characteristics and other factors of potential interest seems fundamental for a correct analysis of the results of these trials and consequent optimal use of the available targeted agents.

Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial.

BACKGROUND: The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. PATIENTS AND METHODS: In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan-Meier method and compared with the two-sided log-rank test. RESULTS: After a median follow-up of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in arms A and B, respectively (P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9-43.5) and 23.1% (95% CI 13.2-40.5) for the combination- and single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. CONCLUSIONS: This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. CLINICALTRIALSGOV IDENTIFIER: NCT00609401.

Are post-docetaxel treatments effective in patients with castration-resistant prostate cancer and performance of 2? A meta-analysis of published trials.

BACKGROUND: About 20% of patients with prostate cancer have an ECOG performance status (PS) 2 at diagnosis. We investigate if current treatment options for castration-resistant prostate cancer (CRPC) may decrease the risk of death even in patients with ECOG PS of 2. METHODS: PubMed was reviewed for phase III randomized trials in patients with CRPC progressed after docetaxel chemotherapy. Characteristics of each study and the relative hazard ratio (HR) for overall survival and 95% confidence interval (CI) were collected. Summary HR was calculated using random- or fixed-effects models depending on the heterogeneity of included studies. RESULTS: A total of 3,149 patients was available for meta-analysis. In the overall population, the experimental treatments decrease the risk of death by 31% (HR=0.69; 95% CI: 0.63-0.76; P<0.001). The activity of experimental treatments was similar in 2,859 patients with ECOG-PS=0 or 1 with a reduced risk of death of 31% (HR=0.69; 95% CI: 0.62-0.76). A total of 290 patients (9.2%) had ECOG-PS=2 and experimental treatments decreased the risk of death by 26% (HR=0.74; 95% CI: 0.56-0.98; P=0.035) compared with the controls even in this sub-group. When patients were stratified by type of treatment, the reduction of the risk of death was confirmed for hormonal therapies: abiraterone and enzalutamide (HR=0.72; 95% CI: 0.52-0.99; P=0.046), but not for chemotherapy (HR=0.81; 95% CI: 0.48-1.37; P=0.43). CONCLUSIONS: We believe this is the first study reporting a benefit in second-line setting for CRPC patients previously treated with docetaxel and poor PS.

A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN.

BACKGROUND: Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-α2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with low-dose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity. METHODS: BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatment-naive, clear cell mRCC and favourable/intermediate Memorial Sloan-Kettering Cancer Center scores received bevacizumab (10 mg/kg every 2 weeks) and IFN (3 MIU thrice weekly) until disease progression. Descriptive comparisons with AVOREN patients having favourable/intermediate MSKCC scores treated with bevacizumab plus IFN (9 MIU) were made. Primary end points were grade ≥3 IFN-associated adverse events (AEs) and progression-free survival (PFS). All grade ≥3 AEs and bevacizumab/IFN-related grade 1-2 AEs occurring from first administration until 28 days after last treatment were reported. RESULTS: A total of 146 patients were treated; the median follow-up was 29.4 months. Any-grade and grade ≥3 IFN-associated AEs occurred in 53.4% and 10.3% of patients, respectively. The median PFS and overall survival were 15.3 [95% confidence interval (CI): 11.7-18.0] and 30.7 months (95% CI: 25.7-not reached), respectively. The ORR was 28.8%. CONCLUSIONS: Compared with a historical control AVOREN subgroup, low-dose IFN with bevacizumab resulted in a reduction in incidence rates of IFN-related AEs, without compromising efficacy [NCT00796757].

FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO).

BACKGROUND: The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. PATIENTS AND METHODS: We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², and folinate 200 mg/m² on day 1, followed by fluorouracil 3000 mg/m² as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m² after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab ± fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). RESULTS: Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow-up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7-12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. CONCLUSIONS: Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising.

Sorafenib tolerability in elderly patients with advanced renal cell carcinoma: results from a large pooled analysis.

BACKGROUND: Elderly patients tend to be underrepresented in renal cell carcinoma (RCC) clinical trials. The Sorafenib RCC Integrated Database includes data from six clinical trials and two expanded-access studies evaluating sorafenib monotherapy in >4600 patients with RCC. Using this database, sorafenib tolerability and treatment patterns were analysed according to age group (<55, 55-<65, 65-<75, or ≥ 75 years). METHODS: Dosing patterns, and incidence, prevalence and cumulative incidence of drug-related adverse events (DRAEs) and fatal DRAEs were assessed. RESULTS: Overall, 4684 patients were evaluable (<55 years, n=1126; 55-<65, n=1579; 65-<75, n=1382; ≥ 75, n=559). Treatment patterns were generally similar across subgroups, although sorafenib treatment duration was ∼30% shorter in the ≥ 75-years subgroup. There were no substantial differences in any-grade DRAEs with sorafenib between subgroups. Drug-related adverse events and dose modifications due to DRAEs tended to occur in months 0-3 and declined thereafter; there was no evidence of cumulative toxicity. Fatal DRAEs were rare (0.7% overall; 95% confidence interval, 0.5-1.0%). CONCLUSION: Sorafenib was well tolerated regardless of age in a heterogeneous population of RCC patients.

Metronomic chemotherapy may be active in heavily pre-treated patients with metastatic adreno-cortical carcinoma.

OBJECTIVE: The potential benefit of further chemotherapy approaches in patients with adrenocortical carcinoma (ACC) showing progressive disease after 2 chemotherapy lines is actually unknown. This study provides explorative information on the activity of metronomic chemotherapy in heavily pre-treated ACC patients. DESIGN AND METHODS: We tested the activity of cytotoxic treatments administered on a metronomic schedule in metastatic ACC patients showing disease progression after treatment with gemcitabine and capecitabine scheme. RESULTS: Eight patients out of 28 consecutively enrolled in that trial were treated with several metronomic cytotoxic regimens. Six of them showed disease progression, but 2 patients obtained a clear benefit. The first patient was treated with oral etoposide (50 mg daily) as the 6th-line therapy and obtained a partial response lasting 24 months, while the second patient obtained a partial response lasting 10 months with metronomic oral cyclophosphamide (50 mg daily) as the 5th chemotherapy line. Both patients had sex hormone secreting tumors and were bearing a rather indolent ACC. CONCLUSIONS: The administration of several chemotherapy lines in advanced ACC patients cannot be routinely recommended outside prospective clinical trials. Few patients with indolent tumors, however, may benefit from this approach. According to our experience, oral cyclophosphamide and oral etoposide may be used in this setting.

Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis.

BACKGROUND: A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity. METHODS: Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan-Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model. RESULTS: In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations. CONCLUSION: Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.

Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study.

INTRODUCTION: In the phase III RECORD-1 trial (ClinicalTrials.gov: NCT00410124), patients with metastatic renal cell carcinoma (mRCC) who progressed on previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy were randomised 2:1 to everolimus 10mg once daily (n=277) or placebo (n=139). Median progression-free survival (PFS) was 4.9months with everolimus and 1.9months with placebo (hazard ratio [HR], 0.33; P<.001). This preplanned, prospective sub-analysis evaluated PFS benefit of everolimus versus placebo in patients who had previously received 1 or 2 VEGFr-TKIs. PATIENTS AND METHODS: Median PFS was estimated using the Kaplan-Meier method, and Cox proportional hazards model was used to analyse differences in PFS. RESULTS: All patients (100%) received ⩾1 previous VEGFr-TKI; 26% of patients received 2 previous VEGFr-TKIs. Among patients who received 1 previous VEGFr-TKI, median PFS was 5.4months with everolimus and 1.9months with placebo (HR, 0.32; 95%confidence interval [CI], 0.24-0.43; P<.001). Among patients who received 2 previous VEGFr-TKIs, median PFS was 4.0months with everolimus and 1.8months with placebo (HR, 0.32; 95%CI, 0.19-0.54; P<.001). The everolimus safety profile was similar for both groups. CONCLUSIONS: Everolimus was associated with prolonged PFS relative to placebo in patients who received 1 or 2 previous VEGFr-TKIs. Patients who received only 1 previous VEGFr-TKI had apparently longer PFS with everolimus in reference to those who received 2 previous VEGFr-TKIs. These results support the use of everolimus as the standard of care in patients who fail initial VEGFr-TKI therapy.

Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial.

BACKGROUND: Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC). METHODS: In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability. RESULTS: After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone (P=0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand-foot syndrome, hypertension, and diarrhoea. Grade 3-4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively. CONCLUSION: The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.

Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings.

BACKGROUND: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study provided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed. The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe. PATIENTS AND METHODS: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. End points included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, and number and sites of metastases. RESULTS: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverse events (AEs) of any grade, with the most common grade ≥3 AEs including hand-foot skin reaction (13%), diarrhea (7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups was similar to that in the overall population. Median PFS was 6.6 months; DCR at ≥8 and ≥12 weeks was 85% and 78%, respectively. CONCLUSIONS: The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients.

First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with untreated metastatic renal cell carcinoma (mRCC), progression-free survival (PFS) was longer with bevacizumab + interferon (IFN)-alpha than IFN + placebo (AVOREN trial). In this hypothesis-generating study, subgroup analysis was carried out to determine the effect of IFN dose reduction. PATIENTS AND METHODS: A total of 649 patients received IFN 9 MIU s.c. three times weekly plus bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity. Differences between treatment arms in PFS, response rate and tolerability were analysed in the reduced-dose group. RESULTS: IFN dose was reduced in 131 patients in the bevacizumab + IFN arm and 97 patients in the IFN + placebo arm during the trial. PFS rates in the bevacizumab + reduced-dose IFN group were comparable with the total population (Kaplan-Meier estimates of event-free rate at 1 year: 0.524 versus 0.427). Bevacizumab + reduced-dose IFN was well tolerated, with substantial decreases in the rate of adverse events following dose reduction. CONCLUSION: This retrospective subgroup analysis suggests that the dose of IFN can be reduced to manage side-effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.