SORAFENIB IN ADVANCED RENAL CELL CARCINOMA (RCC): SURVIVAL AND BIOMARKER RESULTS FROM A PHASE III TRIAL

695 SORAFENIB IN ADVANCED RENAL CELL CARCINOMA (RCC): SURVIVAL AND BIOMARKER RESULTS FROM A PHASE III TRIAL Bukowski R.1, Heng D.2, Eisen T., Szczylik C.4, Stadler W.M.5, Porta C.6, Simantov R.7, Shan M.7, Elting J.7, Pena C.7, Escudier B.8, Sorafenib TARGET Clinical Trial Group 1

CCF Lerner College of Medicine of CWRU, CCF Taussig Cancer Centre, Cleveland, United States of America, 2Cleveland Clinic, Medical Oncology, Cleveland, United States of America, Royal Marsden Hospital, Dept. of Medicine, London, United Kingdom, 4Wojskowski Institute Medicine, Clinic Oncology, Warsaw, Poland, 5University of Chicago Hospitals, Dept. of Medicine, Chicago, United States of America, 6 IRCCS San Matteo University Hospital, Medical Oncology, Pavia, Italy, 7Bayer Healthcare, Oncology, West Haven, United States of America, 8,QVWLWXWH *XVWDYH 5RXVV\ 8QLW« ,PPXQRWKHUDS\ 9LOOHMXLI France Introduction & Objectives: $VLJQLᚏFDQWSURJUHVVLRQIUHHVXUYLYDO3)6 EHQHᚏWIRUVRUDIHQLE6RU YHUVXV SODFHER3 ZDVVHHQLQDODUJHPXOWLFHQWUH3KDVH,,,WULDO7$5*(7 LQSDWLHQWVSWV ZLWKDGYDQFHG5&& WKHUHIRUHLQ0D\3SWVZHUHDOORZHGWRFURVVRYHUWR6RU+HUHZHUHSRUWᚏQDO26DQGELRPDUNHU data. Material & Methods: )LQDO26DQDO\VLVZDVSODQQHGDWaHYHQWVD DIWHUDGMXVWLQJIRUSUHYLRXV DQDO\VHV 7RPLQLPL]HHᚎHFWRIFURVVRYHURQ26DVHFRQGDU\DQDO\VLVZDVSODQQHGFHQVRULQJ3GDWD RQ-XQHD  3ODVPD9(*)Q SWV DQGVROXEOH9(*)5V9(*)5 >Q @ZHUH PHDVXUHGE\(/,6$DWEDVHOLQH%/ F\FOHGD\&' DQGF\FOHGD\&' 3KRVSKR(5. was assessed by immunohistochemistry. Results: 3WV Q   ZHUH UDQGRPL]HG WR 6RU Q   RU 3 Q   7KH DQDO\VLV EHIRUH FURVVRYHU VKRZHGDQHVWLPDWHG26LPSURYHPHQWIRU6RUYV3+5 S  $Q,77DQDO\VLVPRQWKV DIWHU FURVVRYHU WKDW LQFOXGHG 3 SWV Q   ZKR KDG FURVVHG WR 6RU VKRZHG D  LPSURYHPHQW LQ 26 IRU 6RU YV 3 +5  S    3UHVSHFLᚏHG 2ಬ%ULHQದ)OHPLQJ VWDWLVWLFDO ERXQGDULHV ZHUH QRW UHDFKHGE\WKHVH26GLᚎHUHQFHV)LQDO26DWGHDWKVVKRZHGDQRQVLJQLᚏFDQWLPSURYHPHQWRI IRU 6RU YV 3 PHGLDQ  YV  PRQWKV +5  S  D   $ SUHSODQQHG VHFRQGDU\ DQDO\VLVFHQVRULQJ3GDWDVKRZHGWKHFRQIRXQGLQJHᚎHFWRIFURVVRYHUDVLJQLᚏFDQW26EHQHᚏWIRU6RU YV 3 ZDV VHHQ +5   &,   S  D   )ROORZLQJ 6RU WUHDWPHQW SODVPD 9(*) OHYHOV LQFUHDVHG E\  Q   DW &' DQG E\  Q   DW &' ,Q FRQWUDVW SODVPD V9(*)5 GHFUHDVHG E\  Q   DQG E\  Q   DW &' DQG &' UHVSHFWLYHO\ 8VLQJ a COX proportional hazards model examining VEGF and MSKCC score in P pts, BL VEGF was an independent prognostic factor for PFS (p=0.014). VEGF was also prognostic for OS in a model including ECOG PS, MSKCC, and treatment group as variables in P and Sor pts (p=0.001). High BL VEGF levels ZHUH VLJQLᚏFDQWO\ DVVRFLDWHG ZLWK KLJKHU (&2* 36 S  LQWHUPHGLDWH 06.&& FRPSDUHG ZLWK low, p<0.0001), BL Hb 10mg/dL (p=0.0004). Pts with high BL 9(*)!SJPO KDGDUHODWLYHO\SRRUSURJQRVLVLQWKH3DUPZKLOHDWUHQGWRZDUGDJUHDWHU3)6EHQHᚏW was observed in the Sor arm (Sor vs. P, HR=0.48 vs. 0.64 for high vs. low VEGF, p=0.096). Tumor DNA sequencing of the VHL exons from 68 pts showed that improved PFS in the Sor arm was independent of VHL mutational status (Sor vs. P, HR=0.52 vs. 0.49 for mutated VHL vs. wild-type VHL). Conclusions: $SUHSODQQHGVHFRQGDU\DQDO\VLVDGMXVWLQJIRUFURVVRYHUGHPRQVWUDWHGDVLJQLᚏFDQW26 EHQHᚏW RI 6RU 3ODVPD 9(*) OHYHO KDV SURJQRVWLF LPSRUWDQFH DQG 6RUDVVRFLDWHG FKDQJHV LQ 9(*) DQGV9(*)5DUHFRQVLVWHQWZLWK9(*)VLJQDOOLQJLQKLELWLRQ2EVHUYHG6RUEHQHᚏWZDVLQGHSHQGHQWRI sVEGFR2, VEGF, and pERK.

696 SORAFENIB PLUS INTERFERON-˞2A IN METASTATIC RENAL CELL CARCINOMA: RESULTS FROM RAPSODY (GOIRC STUDY 0681), A RANDOMISED PROSPECTIVE PHASE II TRIAL OF TWO DIFFERENT TREATMENT SCHEDULES Bracarda S.1, Porta C.2, Boni C., Santoro A.4, Artioli F.5, Contu A.6, Mentuccia L.7, Gasparro D.8, Caserta C.9, De Angelis V.10, GOIRC Study Group 1 Azienda Ospedaliera, Dept. of Medical Oncology, Perugia, Italy, 2IRCCS San Matteo University Hospital, Dept. of Medical Oncology, Pavia, Italy, Arcispedale Santa. Maria Nuova, Dept. of Medical Oncology, Reggio Emilia, Italy, 4Institute Clinic Humanitas, Dept. of Medical Oncology, Milan, Italy, 5 Hospital of Carpi, Dept. of Medical Oncology, Carpi, Italy, 6City Hospital of Sassari, Dept. of Medical Oncology, Sassari, Italy, 7University La Sapienza, Dept. of Medical Oncology, Rome, Italy, 8Azienda Ospedaliera University, Dept. of Medical Oncology, Parma, Italy, 9Ospedale Silvestrini, Dept. of Medical Oncology, Perugia, Italy, 10ASL 2, Dept. of Medical Oncology, Perugia, Italy

Introduction & Objectives: 6RUDIHQLELVDQRUDOPXOWLNLQDVHLQKLELWRUWKDWKDVGHPRQVWUDWHGHᚑFDF\ LQ PHWDVWDWLF UHQDO FHOO FDUFLQRPD 05&&  7KH SOHLRWURSLF PROHFXOH LQWHUIHURQ˞D ,)1  KDV antiangiogenic activity that is thought to be dependent on an appropriate administration schedule. The aim of this study was to evaluate the activity and safety of sorafenib combined with IFN in two GLᚎHUHQWVFKHGXOHV Material & Methods: In this single-stage study with a planned sample size of 100 patients to be HQUROOHGRYHUPRQWKVHOLJLEOHSDWLHQWVKDG05&&ZLWKDFOHDUFHOOFRPSRQHQWุSUHYLRXV nephrectomy, ECOG Performance Status 0–2, no cerebral metastases or previous treatment, and PHDVXUDEOHGLVHDVHDQ\0RW]HUVFRUHZDVDOORZHG3DWLHQWVUHFHLYHGRUDOVRUDIHQLEPJWZLFH GDLO\FRQWLQXRXVO\SOXVVF,)108WKUHHWLPHVDZHHNDUP$ RU08ᚏYHWLPHVDZHHNDUP B). In order to increase compliance, IFN was started 7 days after sorafenib. Primary endpoints were progression-free survival (PFS) and safety. Secondary endpoints were overall response (intention-totreat analysis) and overall survival. Results: 3DWLHQWV Q   ZHUH HQUROOHG IURP -DQXDU\  PHGLDQ DJH  \HDUV UDQJH ದ PDOHIHPDOH &RQᚏUPHGREMHFWLYHUHVSRQVHVZHUHDFKLHYHGLQSDWLHQWVRISDWLHQWVLQ DUP$DQGRISDWLHQWVLQDUP%>&,ದ@YV>&,ದ@S   while 24 and 22 patients (47.1% and 44.9%, respectively), achieved stable disease. The overall FOLQLFDOEHQHᚏWZDVWKHUHIRUHLQDUP$DQGLQDUP%S  $IWHUDPHGLDQIROORZ up of 8.5 months, the median PFS was 7.9+ months in arm A and 8.5+ months in arm B (p=0.21). 7KHPRVWFRPPRQJUDGHWR[LFLWLHVZHUHK\SRSKRVSKDWHPLDLQDUP$DQGLQDUP % KDQGIRRWVNLQUHDFWLRQRUVNLQUDVKದLQERWKDUPV IDWLJXHLQDUP$DQGLQ DUP%S  GLDUUKHDLQDUP$DQGLQDUP%S  OHXNRSHQLDYV DQG WKURPERF\WRSHQLDYV  Conclusions: Sorafenib plus low-dose IFN showed good tolerability, and was active, with an overall UHVSRQVH UDWH RI   SDUWLDO UHVSRQVH  FRPSOHWH UHVSRQVH  DQG D FOLQLFDO EHQHᚏW rate of approximately 80%. Our results show that this is a promising regimen, and support further investigation of the combination in the treatment of MRCC.

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698

SORAFENIB THERAPY IN THE MANAGEMENT OF ADVANCED RENAL CELL CARCINOMA WITH BRAIN METASTASES: RESULTS FROM THE ARCCS EXPANDED ACCESS PROGRAM

SUNITINIB AS FIRST-LINE TREATMENT FOR METASTATIC RENAL CELL CARCINOMA (MRCC): UPDATED RESULTS AND ANALYSIS OF PROGNOSTIC FACTORS FROM A PHASE III RANDOMISED TRIAL

Henderson C.A.1, Bukowski R.M.2, Stadler W.M., Dutcher J.P.4, Kindwall-Keller T.L.5, Hotte S.J.6, Logie K.W.7, Baltz B.P.8, Wilson K.9, Figlin R.A.10, Advanced Renal Cell Carcinoma Sorafenib (ARCCS)

Oudard S.1, Motzer R.J.2, Michaelson M.D., Hutson T.E.4, Tomczak P.5, Bukowski R.M.6, Rixie O.7, Negrier S.8, Kim S.T.9, Chen I.9, Figlin R.A.10

1

Peachtree Hematology Oncology Consultants, Dept. of Hematology/Oncology, Atlanta, United States of America, 2Taussig Cancer Centre, Dept. of Hematology-Oncology, Cleveland, United States of America, University of Chicago Medical Centre, Dept. of Medicine and Surgery, Chicago, United States of America, 4 Our Lady of Mercy Medical Centre, Dept. of Oncology, Bronx, United States of America, 5University Hospital of Cleveland, Dept. of Hematology/Oncology, Cleveland, United States of America, 6Juravinski Cancer Centre, Dept. of Oncology, Hamiton, Canada, 7Central Indiana Cancer Centres, Dept. of Oncology, Fischers, United States of America, 8Little Rock Hematology Oncology Associates, Dept. of Hematology/Oncology, Little Rock, United States of America, 9Bayer Pharmaceutical Corporation, Dept. of Oncology Medical Science, West Haven, United States of America, 10City of Hope Comprehensive Cancer Centre, Dept. of Medical Oncology & Therapeutics Research, Los Angeles, United States of America

+¶SLWDO(XURS«HQ*HRUJHV3RPSLGRX6HUYLFHGH&DQFHURORJLH0HGLFDOH3DULV)UDQFH 2Memorial Sloan-Kettering Cancer Centre, Oncology, New York, United States of America, Massachusetts General Hospital, Cancer Centre, Boston, United States of America, 4Baylor Sammons Cancer Centre, Texas Oncology, Dallas, United States of America, 5Klinika Onkologii Oddzial Chemioterapii, Oncology, Poznan, Poland, 6Cleveland Clinic, Taussig Cancer Centre, Cleveland, United States of America, 7+¶SLWDO3LWL«ದ6DOS¬WULªUH2QFRORJ\3DULV)UDQFH8&HQWUH/«RQ%«UDUG0HGLFDO2QFRORJ\ Lyon, France, 93ᚏ]HU *OREDO 5HVHDUFK DQG 'HYHORSPHQW 2QFRORJ\ /D -ROOD 8QLWHG 6WDWHV RI America, 10City of Hope Comprehensive Cancer Centre, Oncology, Los Angeles, United States of America

Introduction & Objectives: Renal cell carcinoma (RCC) represents the third leading cause of death among genitourinary malignancies with 5-year survival rates of 5-10% in patients (pts) with metastatic disease. Brain metastases (BM) occur in 5-10% of RCC pts and generally portend a poor prognosis. The Advanced 5HQDO&HOO&DUFLQRPD6RUDIHQLE$5&&6 H[SDQGHGDFFHVVSURJUDPDOORZHGHQUROOPHQWRISWVZLWK%0WKH FXUUHQWDQDO\VLVH[SORUHVWKHVDIHW\DQGHᚑFDF\RI6RUDIHQLELQWKLVVXEVHWRI$5&&6SWV

Introduction & Objectives: Sunitinib malate (SUTENT®) has demonstrated statistically superior SURJUHVVLRQIUHHVXUYLYDO3)6 DQGREMHFWLYHUHVSRQVHUDWH255 FRPSDUHGZLWK,)1DOID,)1˞ 3  LQ DQ LQWHUQDWLRQDO UDQGRPLVHG SKDVH ,,, WULDO RI ᚏUVWOLQH WKHUDS\ LQ SDWLHQWV SWV  ZLWK PHWDVWDWLF UHQDO FHOO FDUFLQRPD P5&&  >0RW]HU HW DO 1 (QJO - 0HG ದ@ 8SGDWHG HᚑFDF\ DQG VDIHW\ UHVXOWV IURP WKLV WULDO DQG DQDO\VLV RI SURJQRVWLF IDFWRUV IRU 3)6 DUH QRZ available.



Material & Methods: This was an open-label, nonrandomized, noncomparative treatment protocol for pts with advanced RCC who were not eligible for, or who did not have access to, other clinical trials with 6RUDIHQLELQWKH8QLWHG6WDWHVDQG&DQDGDSWVZHUH(DVWHUQ&RRSHUDWLYH2QFRORJ\*URXS(&2* VWDWXV ZLWKZDLYHUVJUDQWHGIRUSWVZLWKVWDWXVDJHุ\HDUV0DMRUH[FOXVLRQFULWHULDLQFOXGHGWUHDWPHQW <4 wks prior, life expectancy <2 months, uncontrolled hypertension and severe renal impairment requiring dialysis. Pts received Sorafenib 400 mg twice daily. Pts with BM were required to have prior local therapy for their brain lesions, whether or not successful. Pts who had surgery for BM also were eligible. The primary HQGSRLQWV ZHUH VDIHW\ DQG HᚑFDF\ SHU LQYHVWLJDWRU DVVHVVHG E\ 5HVSRQVH (YDOXDWLRQ &ULWHULD LQ 6ROLG Tumours (RECIST) guidelines every 4 weeks. BM were excluded as target lesions unless they were the only lesions being followed. Results: 2ISWVDVVHVVHGIRUVDIHW\LQWKH$5&&6VWXG\ KDGEHHQWUHDWHGSUHYLRXVO\IRU%0 SWV ZHUHPDOHZLWKDPHGLDQDJHRI\HDUV3ULRUDQWLFDQFHUWKHUDS\LQFOXGHGUDGLRWKHUDS\  QHSKUHFWRP\  LQWHUIHURQ˞   LQWHUOHXNLQ DQG  RWKHU 'UXJUHODWHG DGYHUVH HYHQWV $(V ZHUHUHSRUWHGLQDQGRISWVZLWKDQGZLWKRXW%0UHVSHFWLYHO\'UXJUHODWHG$(V*UDGH ุ RFFXUULQJLQ!RISWVZLWKDQGZLWKRXW%0ZHUHKDQGIRRWVNLQUHDFWLRQDQG IDWLJXH DQG   UDVK  DQG   GLDUUKRHD  DQG   DQG K\SHUWHQVLRQ  DQG   UHVSHFWLYHO\ 7KH seizure rates for pts with and without BM were 6% and 0%, respectively. Of note, there were no CNS-related bleeding events. Of the 50 pts with BM evaluable for response, partial response was reported in 2 (4%), VWDEOHGLVHDVHLQ DQGSURJUHVVLYHGLVHDVHLQ RISWV Conclusions: Treatment with Sorafenib was well tolerated in RCC pts with BM with no reports of cerebral KDHPRUUKDJH7R[LFLW\DQGHᚑFDF\RI6RUDIHQLELQWKHRYHUDOOSRSXODWLRQDQGLQWKH%0VXEVHWRISWVZHUH comparable with possible attenuated drug related AEs in certain subcategories such as hypertension. These results suggest that Sorafenib could serve as a standard treatment option for RCC with BM.

1

Material & Methods: Treatment-naive pts with mRCC received oral sunitinib 50 mg/day for 4 weeks, IROORZHGE\ZHHNVRᚎWUHDWPHQWVFKHGXOH RUVXEFXWDQHRXV,)1˞08WKUHHWLPHVSHUZHHN The primary endpoint was PFS. Results: SWVZHUHUDQGRPLVHGSWVWRVXQLWLQLEDQGWR,)1˞$WWKHWLPHRIDQDO\VLVWKH PHGLDQGXUDWLRQRIWUHDWPHQWIRUVXQLWLQLEDQG,)1˞ZDVPRUDQJHದ YVPRUDQJH ದ UHVSHFWLYHO\SWV RQVXQLWLQLEKDGGLVFRQWLQXHGGXHWR$(VYVSWV RQ ,)1˞255DVDVVHVVHGE\LQGHSHQGHQWFHQWUDOUHYLHZZDV&,෥ IRUVXQLWLQLEYV &,෥ IRU,)1˞3 0HGLDQ3)6ZDVPR&,෥ IRUVXQLWLQLE YVPR&,෥ IRU,)1˞6XQLWLQLEZDVIDYRXUHGDFURVVDOO06.&&ULVNIDFWRUJURXSV SWVZLWKULVNIDFWRUVKDGDPHGLDQ3)6RIPR&,෥ IRUVXQLWLQLEYVPR &,෥ IRU,)1˞SWVZLWKದULVNIDFWRUVKDGDPHGLDQ3)6RIPR&,෥  YVPR&,෥ UHVSHFWLYHO\DQGSWVZLWKุULVNIDFWRUVKDGDPHGLDQ3)6RIPR &,෥ YVPR&,෥ UHVSHFWLYHO\%DVHOLQHIHDWXUHVSUHGLFWLYHRIORQJHU LQYHVWLJDWRUDVVHVVHG3)6LQVXQLWLQLEWUHDWHGSWVZHUHWLPHLQWHUYDOIURPGLDJQRVLVWRWUHDWPHQWุ \HDUYV\HDU3 (&2*SHUIRUPDQFHVWDWXVYV3  DQGFRUUHFWHGFDOFLXPื PJG/YV!PJG/3  7KHPRVWFRPPRQWUHDWPHQWUHODWHG$(VIRUWKHVXQLWLQLEJURXS ZHUHGLDUUKRHDIDWLJXHDQGQDXVHDDQGIRU,)1˞IDWLJXHQDXVHDDQGS\UH[LD Conclusions: 6XQLWLQLELVVLJQLᚏFDQWO\VXSHULRUWR,)1˞LQWKHᚏUVWOLQHWUHDWPHQWRIP5&&DQGLVD QHZUHIHUHQFHVWDQGDUGLQWKLVVHWWLQJ7KHEHQHᚏWVRIVXQLWLQLEH[WHQGDFURVVDOOVXEJURXSVRIP5&& SWVDQGSUHYLRXVO\GHᚏQHG06.&&ULVNIDFWRUVSUHGLFWORQJHU3)6ZLWKVXQLWLQLE

Eur Urol Suppl 2008;7(3):245