MSKCC Poor Risk Research Articles

Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.

600 Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.

Meta-analysis of upfront VEGF targeted therapy prior to nephrectomy in metastatic clear cell renal cancer.

514 Background: The safety and efficacy of upfront VEGF targeted, before nephrectomy in metastatic clear cell renal cancer (mCCRC) has not been robustly evaluated. Methods: In this study we performed a meta-analysis of 3 studies (NCT) with an almost identical design and included a single institution experience (which adopted this approach as a standard). Patients with newly diagnosed mCCRC had 12-18 weeks of sunitinib or pazopanib therapy prior to planned cytoreductive nephrectomy (CN). Results: 224 patients were included in this analysis (54% had sunitinib and 46% pazopanib). Overall, 73% had MSKCC intermediate risk and 23% poor risk disease. 20% of patients had an ECOG performance status of 0.84% of patients obtained stable disease or a response to therapy (by RECIST) before surgery. The median reduction of size of the primary tumour was 14%. 60% of patients had CN. The commonest reason for not performing CN was progression of disease. Progression free survival (PFS) and overall survival (OS) was 6.2 (95% CI 5.7-6.7) and 13 (95% CI: 10.2-15.7) respectively. Patients with MSKCC poor risk disease had a poor outcome irrespective of CN (OS = 7.5 months 95% CI 5.8-9.2). A comparison of sunitinib and pazopanib showed no significant difference in median PFS 7.1 (95% CI, 6.0-9.2) and 6.0 (95% CI: 5.1-6.8) or surgical complications (p<0.05). Conclusions: Outcomes with this approach are in line with expected survival for this population. Results with sunitinib and pazopanib were similar. This approach is attractive for patients with MSKCC intermediate risk disease.

PD04-10 IDENTIFYING MRCC PATIENTS WITH VENOUS THROMBUS WHO ARE LIKELY TO BENEFIT FROM CYTOREDUCTIVE SURGERY

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2016PD04-10 IDENTIFYING MRCC PATIENTS WITH VENOUS THROMBUS WHO ARE LIKELY TO BENEFIT FROM CYTOREDUCTIVE SURGERY E. Jason Abel, Kamran Zargar, Vitaly Margulis, Michael A. Mann, Philippe E. Spiess, Kenan Ashouri, Leonardo Borregales, Ahmed Haddad, Charles Rew, Gong Chen, Fangfang Shi, Surena Matin, Christopher G. Wood, and Jose A. Karam E. Jason AbelE. Jason Abel More articles by this author , Kamran ZargarKamran Zargar More articles by this author , Vitaly MargulisVitaly Margulis More articles by this author , Michael A. MannMichael A. Mann More articles by this author , Philippe E. SpiessPhilippe E. Spiess More articles by this author , Kenan AshouriKenan Ashouri More articles by this author , Leonardo BorregalesLeonardo Borregales More articles by this author , Ahmed HaddadAhmed Haddad More articles by this author , Charles RewCharles Rew More articles by this author , Gong ChenGong Chen More articles by this author , Fangfang ShiFangfang Shi More articles by this author , Surena MatinSurena Matin More articles by this author , Christopher G. WoodChristopher G. Wood More articles by this author , and Jose A. KaramJose A. Karam More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2415AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nephrectomy with tumor thrombectomy is associated with increased risk for morbidity especially when IVC thrombus extends above the hepatic veins. Some patients with metastatic RCC are less likely to benefit from cytoreductive surgery if their expected survival is short. The purpose of this study was to identify risk factors for poor overall survival in metastatic RCC patients with tumor thrombus. METHODS Data was collected from 4 centers for patients with mRCC and venous thrombus at presentation treated surgically from 2000-2014. MSKCC, IMDC, or MDACC (Cancer 2010) prognostic systems were used to classify patients and Kaplan Meier analysis was used to estimate OS. Univariate and multivariate Cox proportional hazard models were used to evaluate the association of individual variables with OS. RESULTS A total of 293 patients were evaluated and median OS (IQR) was 17.2 (6.4-41.0) months for the entire cohort. Venous thrombus level (Neves system) was 0,1,2,3, and 4 for 77, 38, 104, 45, and 29 patients. Median OS was worse (p=0.03) for patients with IVC thrombus above the diaphragm 6.8 (IQR 2.2-19.1) months compared to renal vein only thrombus 18.8(IQR 8.1-37.8) months or IVC thrombus below the diaphragm 18.9 (IQR 6.7-44.5) months (figure). Risk groups stratification was used to compare the ability of systems to predict short OS. MSKCC poor risk patients had median OS 13.4 (IQR 4.4-28.2) months, IMDC risk poor risk patients had median OS 12.5 (IQR 5.0-35) months and MDACC unfavorable risk patients had median OS 6 (IQR 4.4-28.2) months. Preoperative variables that were independent predictors of OS included: IVC thrombus above diaphragm HR 5.2 (95%CI 2.4-11.3); p<0.001, serum lactate dehydrogenase> ULN HR 1.7 (95%CI 1.1-2.6); p=0.01, and systemic symptoms (fatigue, weight loss, etc.) HR 2.2 (95%CI 1.4-3.3); p=0.0002. CONCLUSIONS Metastatic RCC patients with IVC thrombus above the diaphragm or patients classified as unfavorable using MDACC criteria have poor OS and may not benefit from cytoreductive nephrectomy with thrombectomy. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e123-e124 Advertisement Copyright & Permissions© 2016MetricsAuthor Information E. Jason Abel More articles by this author Kamran Zargar More articles by this author Vitaly Margulis More articles by this author Michael A. Mann More articles by this author Philippe E. Spiess More articles by this author Kenan Ashouri More articles by this author Leonardo Borregales More articles by this author Ahmed Haddad More articles by this author Charles Rew More articles by this author Gong Chen More articles by this author Fangfang Shi More articles by this author Surena Matin More articles by this author Christopher G. Wood More articles by this author Jose A. Karam More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effect of glandular metastases on overall survival of patients with metastatic clear cell renal cell carcinoma in the antiangiogenic therapy era

BackgroundGlandular metastases (GMs) (pancreas, breast, parotid, thyroid, or contralateral adrenal) are rare in metastatic clear cell renal cell carcinoma (mccRCC).In a multicenter study we have assessed outcome from mccRCC with or without GMs. Patients and methodsPatients with mccRCC and GM or non-GM (NGM) at first presentation of mccRCC, treated at 9 European centers (5 French, 3 UK, and 1 Belgian centers) between January 2004 and October 2013, were retrospectively analyzed. Association between overall survival (OS) and site of metastases was assessed using the log-rank test for univariate analysis and the chi-square test for multivariable Cox regression. ResultsIn all, 138 patients with GM mccRCC and 420 with NGM mccRCC were included; 37.2% patients with GM had Memorial Sloan-Kettering Cancer Center (MSKCC)-favorable risk vs. 18% NGM patients; 10.7% patients with GM had MSKCC-poor risk vs. 27% NGM patients (P<0.0001). Median interval from metastases to treatment was 4.2 months (range: 0–221.3mo). Median OS was 61.5 months (51.4–81.6mo) for GM and 37.4 months (31.3–42mo) for NGM (hazard ratio [HR] = 1.7; 95% CI = 1.3–2.2, P<0.001). In univariate OS analysis, age, delay between initial diagnosis and metastases, MSKCC, bone/lung metastases, and GM or NGM group were significant parameters (P<0.001). In multivariate analysis, adjusted according to MSKCC risk group, NGM vs. GM was a strong prognostic factor (HR = 1.4; 95% CI = 1.0–1.8, P=0.026); bone or liver metastases were also significant (HR = 1.3; 95% CI = 1.1–1.7, P<0.02; HR = 1.4; 95% CI = 1.1–1.7, P<0.02, respectively). Even in patients without bone or liver metastases, GM status was significant (HR = 1.8; 95% CI = 1.2–2.7, P<0.004). ConclusionsThis large retrospective study shows that the presence of at least 1 GM site in development of mccRCC was associated with a significantly longer OS. The presence of GMs vs. NGM disease was an independent prognostic factor for survival irrespective of the presence or absence of bone or liver metastases. This finding could affect daily practice in which patients with mccRCC and GMs should receive more aggressive treatment with a potential for long-term survival.The causal mechanisms for this improved prognosis in GM mccRCC would be evaluated in translational studies.

810O - Randomized, Dose-Ranging Phase Ii Trial of Nivolumab for Metastatic Renal Cell Carcinoma (Mrcc)

ABSTRACT Aim: Nivolumab, a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, has shown encouraging survival and manageable safety in pretreated mRCC patients (pts). This phase II trial (NCT01354431) assesses 3 nivolumab doses in mRCC pts pretreated with targeted VEGF pathway agents. We previously reported no dose response relationship with 3 doses of nivolumab (primary objective). Here we present updated overall survival (OS) and duration of response (DOR) data. Methods: Pts with clear-cell mRCC (≥1 agent targeting VEGF pathway; ≤3 prior systemic therapies) were randomized (blinded 1:1:1) to IV nivolumab 0.3, 2, or 10 mg/kg every 3 weeks until progression or toxicity. The primary objective was to evaluate the dose response relationship measured by progression-free survival (PFS). Secondary objectives included OS, objective response rate (ORR), and safety. Results: All pts (N = 168) received prior systemic therapy (70% received ≥2) including VEGF receptor TKIs (98%), mTOR inhibitors (38%), and immunotherapy (24%). 25% were MSKCC poor risk. PFS and ORR were similar across doses (Table). The median DOR was not reached for 0.3 and 2 mg/kg, and was 22.3 months for 10 mg/kg (Table). Median OS was 18.2 months for 0.3 mg/kg and approximately 25 months for 2 and 10 mg/kg (Table). Across doses, 19/35 responders (54%) had objective responses lasting >12-20+ months. Rates of grade 3-4–related adverse events (AEs) were ≤17% for all doses (Table). There was no grade 3-4 pneumonitis. For 0.3, 2, and 10 mg/kg, 1 (2%), 6 (11%), and 4 (7%) pts, respectively, had treatment-related AEs that led to discontinuation. Conclusions: In this phase II trial nivolumab was associated with encouraging efficacy, with no dose response relationship observed for PFS or ORR. Median OS range was 18.2-25.5 months; longer median OS was reported at 2 and 10 mg/kg. The safety profile of nivolumab was acceptable for all doses with no grade 3-4 pneumonitis observed. Nivolumab 0.3 mg/kg n = 60a 2 mg/kg n = 54 10 mg/kg n = 54 Median PFS, months (80% CI) 2.7 (1.9-3.0) 4.0 (2.8-4.2) 4.2 (2.8-5.5) ORR, n (%) 12 (20) 12 (22) 11 (20) Median DOR, months NR NR (4.2-NR) 22.3 (4.8-NR) Median OS, months (80% CI) 18.2 (16.2-24.0) 25.5 (19.8-28.8) 24.7 (15.3-26.0) Treatment-related AEs, n(%) 44 (75) 36 (67) 42 (78) Grade 3-4 AEs, n (%) 3 (5) 9 (17) 7 (13) aSafety analysis included 59 treated pts. CI, confidence interval; NR, not reached. Disclosure: R.J. Motzer: I have: consulted for the following companies: Pfizer, Merck, Genentech received funding for research from the following companies: Bristol Myers Squibb, Pfizer, GSK, Novartis provided expert testimony for the following companies: Pfizer; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; T. Kuzel: I have received funding for research from Bristol Myers Squibb; M.R. Harrison: I have: • consulted/worked in advisory role to: Novartis, AVEO, Exelixis, Bayer • received honoraria from: Novartis, Prometheus • received funding for research from: BMS, Argos, Exelixis, Pfizer, Exelixis; S. George: I have consulted/worked in advisory role to: Bayer/ Algeta, Novartis, Sanofi and Astellas (Aveo/ Medivation). Received research funding from: GSK; T. Logan: consulted to and received research funding from: Argos,Aveo, BMS, Celgene, GSK, Novartis, Pfizer, Prometheus, Schering Plough, Wyeth research funding from: Entremed, Exelixis, Genetech, GSK, Inmatics, Lilly, MedImmune, Roche, Synta, Threshold; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; I. Waxman: I am an employee of Bristol Myers Squibb; A. Lambert: I am an employee of and have stock or other ownership interest in BMS; H. Hammers: Has received Honoraria from Ono Pharma USA. All other authors have declared no conflicts of interest.

MSKCC and Heng prognostic risk assessment for synchronous metastatic renal cell carcinoma (syncmRCC) and the tumor in place treated in the targeted therapy era.

e15525 Background: SyncmRCC is heterogenous and selection for cytoreductive nephrectomy (CN) and targeted therapy is required. MSKCC and Heng models for overall survival (OS) are validated for targeted therapy. However, they were developed from predominantly metachronous mRCC patients. It is unknown how they perform in syncmRCC and if they can be used to decide about CN. Methods: Retrospective study of pretherapeutic MSKCC and Heng scores and outcome from 146 patients with syncmRCC and the primary tumor in place treated at a single institute with targeted therapy since 2006. CN was performed in patients WHO 0-1 and low metastatic burden. Results: Table: distribution of risk and OS compared to Heng et al., JCO 27:5794, 2009 . Only n=2 were favorable risk. Overall, n=117 were treated by sunitinib, others by temsirolimus or sorafenib. CN was performed in n=94 (64.3%). Among Heng poor risk 46% (n=29) were intermediate risk by MSKCC. Of Heng poor risk n=37 (58.7%) had CN with a median OS of 8.5 months; 2y OS was 18.9% and higher than for MSKCC poor risk. Of Heng intermediate risk n=57 (69.5%) underwent CN (median OS 15.5 months (1-68); 2y OS 36.8%). Conclusions: In syncmRCC MSKCC and Heng intermediate risk patients have shorter OS than previously reported for each model in the targeted therapy era. However, 25-30 % of intermediate risk patients live &gt;2 y and a potential benefit of CN may be apparent in this group. A discrepancy exists between Heng and MSKCC poor risk percentage. We speculate that the primary tumor in place may influence thrombocyte and neutrophile counts resulting in significantly more Heng poor risk among patients with MSKCC intermediate risk. Especially MSKCC poor risk carries a dismal median and 2y OS in syncmRCC. MSKCC risk assessment performs well in identifying poor risk patients unlikely to benefit from CN. [Table: see text]

747 MODIFIED CISPLATIN, ETOPOSIDE AND IFOSFAMIDE (PEI) SALVAGE THERAPY FOR MALE GERM-CELL TUMORS (GCT). LONG-TERM EFFICACY AND SAFETY OUTCOMES

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease (II)1 Apr 2013747 MODIFIED CISPLATIN, ETOPOSIDE AND IFOSFAMIDE (PEI) SALVAGE THERAPY FOR MALE GERM-CELL TUMORS (GCT). LONG-TERM EFFICACY AND SAFETY OUTCOMES Andrea Necchi, Luigi Mariani, Patrizia Giannatempo, Nicola Nicolai, Daniele Raggi, Elena Fare', Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Giorgio Pizzocaro, Alessandro Gianni, and Roberto Salvioni Andrea NecchiAndrea Necchi Milan, Italy More articles by this author , Luigi MarianiLuigi Mariani Milan, Italy More articles by this author , Patrizia GiannatempoPatrizia Giannatempo Milan, Italy More articles by this author , Nicola NicolaiNicola Nicolai Milan, Italy More articles by this author , Daniele RaggiDaniele Raggi Milan, Italy More articles by this author , Elena Fare'Elena Fare' Milan, Italy More articles by this author , Luigi PivaLuigi Piva Milan, Italy More articles by this author , Davide BiasoniDavide Biasoni Milan, Italy More articles by this author , Mario CatanzaroMario Catanzaro Milan, Italy More articles by this author , Tullio TorelliTullio Torelli Milan, Italy More articles by this author , Silvia StagniSilvia Stagni Milan, Italy More articles by this author , Giorgio PizzocaroGiorgio Pizzocaro Milan, Italy More articles by this author , Alessandro GianniAlessandro Gianni Milan, Italy More articles by this author , and Roberto SalvioniRoberto Salvioni Milan, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.310AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Second-line chemotherapy (CT) of advanced GCT is vividly debated and no standard of care has been established. Since 1985 we introduced the modified PEI combination with the aim to reduce toxicity while maintaining efficacy over the original regimen. METHODS We retrieved data of pts who received ifosfamide at 2.5 gr/m2 (with mesna) on days 1-2, etoposide, and cisplatin at 100 mg/m2 and 33 mg/m2, respectively, on days 3-5 every 21 days for a maximum of 4 cycles, followed by surgery of residuals. Multivariable analysis (MVA) was undertaken for pre-specified variables and IGCCCG-2 score was analysed as a continuous covariate. ITT analysis was applied. RESULTS From 02/85 to 01/12, 189 pts failing cisplatin, bleomycin, and vinblastine (PVB, N=25) or etoposide (PEB, N=164) were treated. 87% had a gonadal primary, 50.3% were MSKCC poor risk, 74.7% were IGCCCG-2 intermediate-to-very high risk, 21.8% had liver, bone or brain (LBB) mets, 16.7% were late relapses. 35 pts (18.5%) had a complete response (CR), 68 (35.9%) a marker normalization (PRm-) (major response-rate: 54.4%). 41/68 PRm-were rendered disease-free (total NED-rate: 40.2%). After a median follow-up of 122.1 mos (IQR 71.4-232), median (95%CI) PFS was 7.2 mos (6.2-9.5) and median OS was 21.7 mos (16.7-69.5). 2yr PFS was 34.3% (28.1-41.9) and 5yr OS was 42.1% (35.3-50.2). Mediastinal primary (HR 3.06, 95%CI, 1.68-5.58), LBB mets (HR 2.02, 95%CI, 1.30-3.16), and AFP>1000 ng/mL (HR 2.78, 95%CI, 1.51-5.14) were negative prognostic factors for OS at MVA while no effect was seen according to IGCCCG-2 category. 70.3% of grade 3-4 neutropenia (25% febrile neutropenia), 48.1% thrombocytopenia, 21.1% anemia, 3% neurotoxicity, and no severe renal toxicity were recored. 81 pts (78% before 2000) had a dose reduction of ≥1 drug for ≥1 cycle. No discontinuations for toxicity occurred. CONCLUSIONS Dose-modified Italian PEI showed activity comparable with the best one achievable by conventional-dose CT (CDCT) in an unselected patient population, and a favorable toxicity profile. Results are among the most robust available for a CDCT, and should be considered as an appropriate benchmark to be compared with high-dose CT. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e307-e308 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrea Necchi Milan, Italy More articles by this author Luigi Mariani Milan, Italy More articles by this author Patrizia Giannatempo Milan, Italy More articles by this author Nicola Nicolai Milan, Italy More articles by this author Daniele Raggi Milan, Italy More articles by this author Elena Fare' Milan, Italy More articles by this author Luigi Piva Milan, Italy More articles by this author Davide Biasoni Milan, Italy More articles by this author Mario Catanzaro Milan, Italy More articles by this author Tullio Torelli Milan, Italy More articles by this author Silvia Stagni Milan, Italy More articles by this author Giorgio Pizzocaro Milan, Italy More articles by this author Alessandro Gianni Milan, Italy More articles by this author Roberto Salvioni Milan, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ-cell tumors (GCT): Long-term efficacy and safety outcomes.

328 Background: Second-line chemotherapy (CT) of advanced GCT is vividly debated and no standard of care has been established. Since 1985 we introduced the modified PEI combination with the aim to reduce toxicity while maintaining efficacy over the original regimen. Methods: We retrieved data of pts who received ifosfamide at 2.5 gr/m2 (with mesna) on days 1-2, etoposide and cisplatin at 100 mg/m2 and 33 mg/m2, respectively, on days 3-5 every 21 days for a maximum of 4 cycles, followed by surgery of residuals. Multivariable analysis (MVA) was undertaken for pre-specified variables and IGCCCG-2 score was analysed as a continuous covariate. ITT analysis was applied. Results: From 02/85 to 01/12, 189 pts failing cisplatin, bleomycin, and vinblastine (PVB, N=25) or etoposide (PEB, N=164) were treated. 87% had a gonadal primary, 50.3% were MSKCC poor risk, 74.7% were IGCCCG-2 intermediate-to-very high risk, 21.8% had liver, bone or brain (LBB) mets, 16.7% were late relapses. 35 pts (18.5%) had a complete response (CR), 68 (35.9%) a marker normalization (PRm-) (major response-rate: 54.4%). 41/68 PRm- were rendered disease-free (total NED-rate: 40.2%). After a median follow-up of 122.1 mos (IQR 71.4-232), median (95%CI) PFS was 7.2 mos (6.2-9.5) and median OS was 21.7 mos (16.7-69.5). 2yr PFS was 34.3% (28.1-41.9) and 5yr OS was 42.1% (35.3-50.2). Mediastinal primary (HR 3.06, 95%CI, 1.68-5.58), LBB mets (HR 2.02, 95%CI, 1.30-3.16), and AFP&gt;1000 ng/mL (HR 2.78, 95%CI, 1.51-5.14) were negative prognostic factors for OS at MVA while no effect was seen according to IGCCCG-2 category. 70.3% of grade 3-4 neutropenia (25% febrile neutropenia), 48.1% thrombocytopenia, 21.1% anemia, 3% neurotoxicity, and no severe renal toxicity were recored. 81 pts (78% before 2000) had a dose reduction of ≥1 drug for ≥1 cycle. No discontinuations for toxicity occurred. Conclusions: Dose-modified Italian PEI showed activity comparable with the best ones achievable by conventional-dose CT (CDCT) in an unselected patient population, and a favorable toxicity profile. Results are among the most robust available for a CDCT, and should be considered as an appropriate benchmark to be compared with high-dose CT.

1768 PROGRESSION-FREE AND OVERALL SURVIVAL OF PATIENTS TREATED WITH PRESURGICAL SUNITINIB PRIOR TO CYTOREDUCTIVE NEPHRECTOMY (CN) IN CLEAR CELL SYNCHRONOUS METASTATIC RENAL CELL CARCINOMA (MRCC)

You have accessJournal of UrologyKidney Cancer: Advanced1 Apr 20111768 PROGRESSION-FREE AND OVERALL SURVIVAL OF PATIENTS TREATED WITH PRESURGICAL SUNITINIB PRIOR TO CYTOREDUCTIVE NEPHRECTOMY (CN) IN CLEAR CELL SYNCHRONOUS METASTATIC RENAL CELL CARCINOMA (MRCC) Axel Bex, Christian Blank, Simon Chowdhury, David Nichol, John Peters, Simon Horenblas, Tim O'Brien, Naveed Sarwar, John Haanen, and Thomas Powles Axel BexAxel Bex Amsterdam, Netherlands More articles by this author , Christian BlankChristian Blank Amsterdam, Netherlands More articles by this author , Simon ChowdhurySimon Chowdhury London, United Kingdom More articles by this author , David NicholDavid Nichol London, United Kingdom More articles by this author , John PetersJohn Peters London, United Kingdom More articles by this author , Simon HorenblasSimon Horenblas Amsterdam, Netherlands More articles by this author , Tim O'BrienTim O'Brien London, United Kingdom More articles by this author , Naveed SarwarNaveed Sarwar London, United Kingdom More articles by this author , John HaanenJohn Haanen Amsterdam, Netherlands More articles by this author , and Thomas PowlesThomas Powles London, United Kingdom More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2096AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Presurgical sunitinib can be safely administered in clear cell mRCC. This upfront approach may have advantages over initial CN followed by sunitinib. Here we describe progression free survival (PFS) and overall survival (OS) results for this upfront approach. METHODS The study combined the data from 2 prospective phase II studies which assessed upfront sunitinib (12–16 weeks) prior to CN in previously untreated patients with clear cell mRCC. Patients had MSKCC intermediate and poor risk disease. The Kaplan Meier method was used to assess outcome. Radiological PFS was evaluated using RECIST v1.1. The amount of necrosis at the time of surgery was assessed pathologically. RESULTS Sixty five patients with clear cell mRCC were entered into these 2 studies between 2007 and 2010. The median age of the cohort was 61 (range: 44–78) year and 53 (81%) were male. Twenty patients (31%) had MSKCC poor risk disease; the remainder had intermediate risk disease. CN was performed in 46 (71%) patients. The commonest reason for not performing surgery was disease progression 13 (20%). The median PFS and OS for the cohort was 7 months (95% CI 6–11 months) and 15 months (95%CI: 10-NA). Fourteen (30%) patients had progression of disease during the treatment break for surgery, 9 of whom achieved further clincal benifit with further sunitinib. The OS for patients with intermediate and poor risk disease was 26 months (11-not reached(NR) months) and 8 months (4-NR months) respectively. The MSKCC poor risk patients fell into 2 groups, those with progressive metastasis who did not undergo surgery (55%) as opposed to a subgroup who obtained clinical benefit with therapy and went on to have CN (45%). These patients had an improved outcome compared to those with primary refractory disease (median OS 6 vs 12 months). Neither a reduction in the size of the primary tumour (above median: 14%) or increased necrosis at surgery (>50%) correlated with outcome (HR 1.8 [0.89–4.06] and HR 1.68 HR 0.64–4.39] respectively). CONCLUSIONS The outcome of patients with MSKCC intermediate risk treated with sunitinib prior to CN is encouraging and consistent with results seen in the phase III trial sunitinib versus interferon in which most patients had initial nephrectomy, most of them with metachronous mRCC. The role of surgery in the poor risk population remains unclear. It may be useful in those who have clinical benefit with upfront sunitinib. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e709-e710 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Axel Bex Amsterdam, Netherlands More articles by this author Christian Blank Amsterdam, Netherlands More articles by this author Simon Chowdhury London, United Kingdom More articles by this author David Nichol London, United Kingdom More articles by this author John Peters London, United Kingdom More articles by this author Simon Horenblas Amsterdam, Netherlands More articles by this author Tim O'Brien London, United Kingdom More articles by this author Naveed Sarwar London, United Kingdom More articles by this author John Haanen Amsterdam, Netherlands More articles by this author Thomas Powles London, United Kingdom More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1769 A PHASE I TRIAL OF VEGFR1 PEPTIDE VACCINES FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

The commonest reason for not performing surgery was disease progression 13 (20%). The median PFS and OS for the cohort was 7 months (95% CI 6–11 months) and 15 months (95%CI: 10-NA). Fourteen (30%) patients had progression of disease during the treatment break for surgery, 9 of whom achieved further clincal benifit with further sunitinib. The OS for patients with intermediate and poor risk disease was 26 months (11-not reached(NR) months) and 8 months (4-NR months) respectively. The MSKCC poor risk patients fell into 2 groups, those with progressive metastasis who did not undergo surgery (55%) as opposed to a subgroup who obtained clinical benefit with therapy and went on to have CN (45%). These patients had an improved outcome compared to those with primary refractory disease (median OS 6 vs 12 months). Neither a reduction in the size of the primary tumour (above median: 14%) or increased necrosis at surgery ( 50%) correlated with outcome (HR 1.8 [0.89–4.06] and HR 1.68 HR 0.64– 4.39] respectively). CONCLUSIONS: The outcome of patients with MSKCC intermediate risk treated with sunitinib prior to CN is encouraging and consistent with results seen in the phase III trial sunitinib versus interferon in which most patients had initial nephrectomy, most of them with metachronous mRCC. The role of surgery in the poor risk population remains unclear. It may be useful in those who have clinical benefit with upfront sunitinib.

A meta-analysis of bevacizumab plus interferon alfa for previously untreated patients with metastatic clear-cell renal carcinoma (mRCC).

366 Background: mRCC was highly resistant to conventional chemotherapy. Both CALGB study and AVOREN study failed to detect statistic differences in overall survival (OS). To evaluate the effectiveness and adverse-effect of bevacizumab plus IFN-α for untreated mRCC, we performed a meta-analysis. Methods: We searched RCTs that compared bevacizumab plus IFN- alpha with other treatments. For trials without heterogeneity, meta-analysis was carried out by using review manager (Revman 4.2) with fixed or random-effects models. Hazard ratio (HR), relative risk (RR), and 95 percent confidence intervals (CI) were calculated. The primary outcome was overall survival. The secondary outcomes were PFS and the adverse effects. Subgroup analyses were performed by MSKCC risk factors. Results: Two RCTs (CALGB study and AVOREN study) were identified as eligible for inclusion in our meta-analysis. Overall survival: Meta- analysis including 1,381 patients showed a trend in favor of bevacizumab plus IFN-alpha with an HR of 0.89 (95% CI, 0.80-1.00, p=0.05). Meta-analysis of OS which adjusted on stratification factors showed extent improvement in favor of bevacizumab plus IFN-alpha (HR=0.86, 95% CI, 0.76-0.97, p=0.02). Progress-free survival: Meta-analyses showed statistic differences in favor of bevacizumab plus IFN-alpha in both unstratified PFS (HR=0.68, 95% CI, 0.61-0.77, p&lt;0.00001) and stratified PFS (HR=0.67, 95% CI, 0.59-0.75, p&lt;0.00001). Subgroup analysis: There were no statistic differences between bevacizumab plus IFN-alpha and IFN-alpha in MSKCC favorable risk group (HR=0.91, 95% CI, 0.70-1.17, p=0.45) and MSKCC poor risk group (HR=0.79, 95% CI, 0.55-1.14, p=0.21). For MSKCC intermediate risk group, there was statistic difference in favor of bevacizumab plus IFN-alpha (HR=0.85, 95% CI, 0.73-0.99, p=0.04). Adverse effects: There were statistic differences in favor ofIFN-alpha in anorexia, fatigue proteinuria, and bleeding, while no statistic difference in gastrointestinal perforation. Conclusions: Bevacizumab plus IFN-alpha prolonged both OS and PFS as first line therapy for mRCC, especially for MSKCC intermediate risk group. The toxicity was acceptable and well tolerated. No significant financial relationships to disclose.

Bevacizumab (B) plus low-doses immunotherapy (IT) plus chemotherapy (CT) (BIC) in metastatic renal cell cancer (mRCC): Antitumor effects and variations of T-regulatory cells (Treg) and other T lymphocytes subsets. A study of the Italian Oncology Group for Clinical Research (GOIRC)

5121 Background: B is effective in mRCC and has a synergistic effect with CT in many tumors. The activity of B plus interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Aim of this study is to explore the efficacy of B+IT+CT and to correlate its efficacy with the variations in circulating T lymphocytes and Treg. Methods: Pts with histological diagnosis of mRCC, previous nephrectomy, PS 0–1, adequate organ function, no CNS metastases and 0–2 previous systemic regimens were treated with B (10 mg/kg d 1 and 15) plus CT (gemcitabine: 1,000 mg/m2 i.v. in 1 hour followed by 5-fluorouracil 600 mg/m2 iv bolus d 1 and 8 every 28 d) plus IT (IL-2: 1 MUI/m2 bid sc d 8, 9, 15, 16 and 1 MUI/m2/die sc from d 10 to 12 and from 17 to 19; and IFN-α: 3 MUI sc on d 10, 12, 17, 19). This phase II study was conducted according to two stages Minimax Simon design. CT was repeated for a maximum of 6 cycles followed by maintenance with B and IT until progressive disease (PD). In 30 pts, blood samples for Treg and other T lymphocytes subsets were evaluated on days: 1, 8, 15, 22, 29 and at the disease progression. Recist criteria and ITT analysis were applied. Results: 45 pts were included: male 66%; median age 58 years; 49% pre-treated; 41 pts were evaluable for response (4 too early) and we observed 33% PR, 35% SD and 32% PD for an overall disease control rate (DCR) of 68%. Median TTP was 8.2 mos (95% CI: 6.9–9.4). In 21 not pre-treated pts DCR was 78%. In MSKCC poor risk group we observed 20% PR and a DCR of 80% with a TTP of 8.7 mos. Treatment was well tolerated, gr. 3–4 toxicity included neutropenia non-febrile 57%, febrile 2%, thrombocytopenia 27%, flu-like syndrome 19%, hypertension 12%. Preliminary data show increased percentage of Treg, identified by FACS analysis as CD4+/CD25high/FoxP3+ in PBMCs, after the first week of IT (d 15) and a decrease after the treatment with B (d 22). Variation in Treg seems to be correlated with the response to treatment. Conclusions: BIC combination is effective in all subgroups of mRCC and is well tolerated. The final analysis of its activity and Treg variations and correlations with clinical outcome will be presented at the meeting. No significant financial relationships to disclose.