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Description : This medical presentation on cancer titled "Nexavar in Patients with Renal Cell Carcinoma" talks about use of nexavar in patients with renal cell carcinoma. Nexavar is a prescription medicine used to treat hepatocellular carcinoma (HCC) that cannot be removed by surgery. Hepatocellular carcinoma (HCC)a type of liver cancer.

Tags : Cancer, Nexavar, Patient, Renal Cell Carcinoma, prescription medicine, treatment, hepatocellular carcinoma, HCC, liver cancer

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Nexavar in Patients with Renal Cell Carcinoma Naomi B. Haas
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Nephrectomy Metastectomy Solitary lesions Cytokine combination Combined modalities Adjunctive nephrectomy prior to cytokine therapy Cytokine therapy followed by nephrectomy Clinical trials Historical Management of Advanced-Stage RCC National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006. Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.
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BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau. Modified from Linehan WM et al. J Urol. 2003;170:2163-2172. RCC is not one disease *2004 WHO lists over 50 different types of kidney cancer (Sarcomatoid variant can occur with any subtype) Undifferentiated type and Collecting duct carcinoma constitute the other 2 types listed in AJCC classification
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Treatment of Advanced Disease Based in part on risk factors
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Motzer RJ et al. J Clin Oncol. 2002;20:289-296. MSKCC Risk Factor Model in mRCC 0 risk factors (n=80 patients) 1 or 2 risk factors (n=269 patients) 3, 4, or 5 risk factors (n=88 patients) Risk factors associated with worse prognosis KPS <80 Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) High corrected calcium (10 mg/dL) High LDH (300 U/L) Time from Dx to IFN- <1 yr Time From Start of IFN- (years) Proportion Surviving 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 16 14 13 11 9 5 4 3 6 15 12 10 8 7 6
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ADVERSE PROGNOSTIC FACTORS FOR RENAL CELL CARCINOMA Motzer et al, JCO 17:2530-2540, 1999 Risk # Risk Factors Median Survival Favorable 0 29 mo. Intermediate 1-2 14 mo. Poor 3 and + 4 mo.
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Do patients with advanced disease do better with nephrectomy? Performance status matters This issue has not been addressed in the era of targeted therapy
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Advanced Disease Therapy in 2007 Multitargeted tyrosine kinase inhibitors Mammalian target of rapamycin (mTor) inhibitors Anti VEGF antibodies VEGF Trap Other angiogenesis inhibitors-thrombospondin inhibitors, pure PDGFR and VEGFR inhibitors
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The molecular profiles associated with the various histologic RCC subtypes have identified logical targets Pathways associated with EGFR, AKT/mTOR, MAPK/MEK, and VEGF are important in RCC Drugs available in 2007 Multitargeted TK inhibitors: sunitinib, sorafenib, (FDA approved) GW786034, AG013736,ABT869 Antibodies: Bevacizumab Imids: CC-5013 mTor inhibitors: temsirilimus, RAD001, rapamycin
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Common Treatment related side effects
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Bevacizumab for mRCC: Phase II Study Design High dose = 10 mg/kg (n=39) Low dose = 3 mg/kg (n=37) Placebo (n=40) Second randomization of placebo group at TTP to low-dose bevacizumab +/- thalidomide. Yang JC et al. N Engl J Med. 2003;349:427-434. 1° end points: TTP and ORR 2° end point: OS Study arms were balanced for demographics mRCC patients (N=116) ECOG PS <2 All patients have prior therapy (mostly IL-2)
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Bevacizumab for mRCC: Summary No significant difference in OS between treatment groups High dose (10 mg/kg) PR = 10% (95 CI, 2.9%–24.2%) Significantly prolonged PFS (median 4.8 months, P<.001) Moderate toxicity profile No Grade 4 AE or deaths related to therapy Proteinuria 64% (any grade) Hypertension 36% (any grade) Low dose (3 mg/kg) Not significant
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Phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon- α2a as first-line therapy in metastatic RCC Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3 641 patients + nephrectomy + clear cell RCC IFN (9 MIU 3x weekly) + bevacizumab(10mg/kg) IVq2w (320) IFN (9 MIU 3x weekly) + placebo (321) The addition of BEV to IFN-a2a significantly increased PFS (10.2 vs. 5.4 mo) (HR=0.63; p<0.0001) and objective tumor response rate (30.6% vs. 12.4%; p<0.0001). A trend toward improved OS was observed with the addition of BEV to IFN-a2a (p=0.0670).
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Sorafenib (Nexavar®) Small-molecule receptor TKI1 Inhibits VEGFR-2, VEGFR-3, FLT-3, PDGFR, c-KIT, Raf kinases1 Formulation: 200 mg tablets2 Dosing: 2 tablets bid continuous (1 hr ac or 2 hrs pc)2 FDA approved December 20, 2005 for advanced RCC3 Wilhelm SM et al. Cancer Res. 2004;10:7099-7109. Nexavar [package insert]. West Haven, CT: Bayer Pharmaceutical Corporation and Emeryville, CA: Onyx Pharmaceuticals, Inc.; 2005. Food and Drug Administration. FDA approves new treatment for advanced kidney cancer. Available at: www.fda.gov/bbs/topics/NEWS/2005/NEW01282.html. Accessed January 24, 2006.
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Median PFS from randomization Sorafenib=24 weeks Placebo=6 weeks P=.0087 Sorafenib for mRCC: Phase II (RDT) Progression-Free Survival Time From Randomization (days) Proportion of Patients Progression-Free 1.00 0.75 0.50 0.25 0 12-week period 84 0 100 200 300 400 500 Ratain MJ et al. Presented at: ASCO; May 13-17, 2005; Orlando FL.
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Sorafenib for mRCC: Tumor Reduction* (TARGET) * Investigator assessment. Patients randomized at least 6 weeks before data cut-off of May 31, 2005. Escudier B et al. Presented at: ECCO; October 30-November 3, 2005; Paris, France. Sorafenib (n=451) Placebo (n=452) Tumor Reduction Tumor Reduction PR (30% or reduction, RECIST). Change From Baseline (%)* 25% 76% Change From Baseline (%)* 0 50 100 150 -50 -100 0 50 100 150 -50 -100 PD (20% increase, RECIST);
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Conclusions Statistically significant improvement in progression free survival compared to placebo in patients with prior cytokine therapy Improvement in OS may have been affected by crossover and was not achieved in final analysis
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Randomized Phase II Trial of First-line Treatment With Nexavar vs Interferon in Patients With Advanced Renal Cell Carcinoma: Final Results Adapted from Szczylik C et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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First-line Nexavar vs IFN in Advanced RCC—Study Design Period 1 Period 2 Period 1 Period 2 Eligibility Criteria Clear-cell histology No prior systemic therapy ECOG Performance Status 0 or 1 All MSKCC risk groups Open-label randomization 1:1 Stratification MSKCC N=189 PROGRESSION PROGRESSION IFN=interferon. Adapted from Szczylik C et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. 1º endpoints: Period 1: PFS (Nexavar vs IFN); database cutoff: 29 Sep 06: 121 PFS events Period 2: PFS and clinical benefit; database cutoff: 31 Dec 06: 52 PFS events 2º endpoints: Quality of life Nexavar 400 mg bid N=97 IFN 9 MIU tiw N=92 Nexavar 400 mg bid N=50 Nexavar 600 mg bid N=44
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Period 1: Nexavar vs IFN Median PFS comparable between IFN (5.6 mo) and Nexavar (5.7 mo)* Clinical benefit and tumor shrinkage greater with Nexavar than IFN Quality of life was markedly better with Nexavar vs IFN Adverse events as expected with Nexavar and IFN Period 2: crossover, dose escalation IFN to Nexavar crossover mirrored results of TARGET study Nexavar 400 → 600 mg bid Well tolerated Additional benefit following dose escalation Delay of progression for 4.1 months Improvement of clinical outcome for 46% of patients Quality of life benefit was maintained First-line Nexavar vs IFN in Advanced RCC—Results *Hazard ratio (IFN/NEX)=0.883 (95% CI: 0.613-1.272.) TARGET=Treatment Approaches in Renal Cancer Global Evaluation Trial. Adapted from Szczylik C et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Sunitinib (Sutent®) Small-molecule receptor TKI1 Inhibits all VEGFRs, PDGFR-a, PDGFR-b, c-KIT, and FLT-31 Formulation: 12.5 mg, 25 mg, 50 mg capsules2 Dosing: 50 mg qd ± food (4 wks on, 2 wks off)2 FDA approved January 26, 2006 for advanced RCC Pietras K, Hanahan D. J Clin Oncol. 2005;23:939-952. Sutent [package insert]. New York, NY: Pfizer Inc.; 2006.
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Results Median PFS 11 months for sunitinib vs. 5 months for IFN-α (p<0.000001)]. The objective response rate by third-party independent review was 31% for sunitinib vs. 6% for IFN-α (p<0.000001). 8% withdrew from the study due to adverse event on sunitinib arm vs. 13% on IFN-α arm.
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Conclusion Statistically significant improvement in PFS and objective response rate for sunitinib over IFN-α in first-line treatment of patients with metastatic RCC
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Targeted Therapy: More Questions Than Answers First Line:Should we combine these agents? Sequentially or concurrently? Vertical inhibition or horizontal inhibition? Which Type of Agent should be used first? mTKI or mTor inhibitor? At Progression Dose escalation of mTKI vs other mechanism?
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Treatment duration-are these agents purely angiostatic? Assessment of Response- Which is more important: RECIST or PFS? Predictors of Response Blood flow/ vascularity histology Imaging- PET/CT, DCE/MRI, CT Role of agents-Adjuvant?, First-line? Before or after cytokines? Exposure to agent- drug levels of sunitinib correlated with response Dose escalation of agent –some patients can tolerate dose escalation at the time of progression How to treat non clear cell and other variants
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Sequential Use of Nexavar and Sunitinib: Retrospective Analysis in 90 Patients
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MKI Sequencing: Study Design N=90 4 sites in France RCC patients in expanded access programs Reviewed Patient demographics MSKCC No. of metastatic sites Efficacy OS PFS Best response Safety Retrospective review of sequential therapy with MKIs in RCC Nexavar → Sunitinib n=68 Sunitinib → Nexavar n=22 MKI=multikinase inhibitor. Adapted from Sablin MP et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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MKI Sequencing: Results 68 patients received Nexavar first, while 22 received sunitinib first The 2 groups are comparable in terms of ECOG PS and MSKCC groups 38% of the patients in the Nexavar→sunitinib group are still on treatment vs 19% in the sunitinib→Nexavar group 50% of the patients have died in the sunitinib→Nexavar group compared to 32% in the Nexavar→sunitinib Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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MKI Sequencing: Efficacy of Treatment NR=not reached. Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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MKI Sequencing: Efficacy of Nexavar→Sunitinib Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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MKI Sequencing: Efficacy of Sunitinib→Nexavar Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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MKI Sequencing: Conclusions This study supports the sequential administration of Nexavar and sunitinib even though these 2 drugs share the same targets In our study, using Nexavar first appears to be superior with A better PFS for each arm The achievement of PR after PD with sunitinib after Nexavar (20%) A longer duration on therapy (61 vs 49 weeks) A trend toward better survival (to be confirmed) These data will have to be confirmed in prospective studies Adapted from Sablin MP et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Phase II Trial of Intrapatient Dose-Escalated-Nexavar in Patients With Metastatic Renal Cell Cancer
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Dose-Escalated Nexavar for RCC: Study Design 1º endpoints: Safety and toxicity 2º endpoints: RR, PFS, and OS Treatment continues until PD or intolerance Target accrual: 44 patients. Response assessed by RECIST every 8 weeks. DLT=dose-limiting toxicities; Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. Eligibility Metastatic RCC, component of clear-cell ≤1 prior cytokine therapy Adequate PS Adequate pancreatic and cardiac function After 4 weeks, patients with no DLT (grade 3/4) increase dose After 4 weeks, patients with no DLT (grade 3/4) increase dose Nexavar 800 mg po bid Days 57+ Nexavar 400 mg po bid Days 1-28 Nexavar 600 mg po bid Days 29-56
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Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Dose-Escalated Nexavar for RCC: Baseline Patient Characteristics (cont’d) CR=complete response; IL-2=interleukin 2; PR=partial response. Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Dose-Escalated Nexavar for RCC: Intensity of Therapy At 800-mg dose level: 5 patients had dose held between Weeks 2 through 4 3 patients were dose reduced Doses were escalated to 1200 mg in 41 of 44 patients Doses were escalated to 1600 mg in 32 of 41 patients 25 patients maintained dose 7 patients were dose reduced Summary 41 patients were able to receive 1200 or 1600 mg per day of Nexavar 3 patients were unable to be dose escalated Those with early toxicity have difficulty with dose escalation Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Dose-Escalated Nexavar for RCC: Best Response by RECIST Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Dose-Escalated Nexavar for RCC: Incidence of Treatment-Related AEs AEs=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase. Adapted from Amato RJ et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Dose-Escalated Nexavar for RCC: Conclusions Dose-escalated Nexavar was well tolerated when given twice daily by oral administration 93% of patients were able to be dose escalated to either 1200 or 1600 mg per day A high level of antitumor activity was demonstrated by a 55% complete and partial response rate in patients with metastatic RCC Follow-up trials are in progress to verify these data Adapted from Amato R et al. Presented at: ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
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Sorafenib for mRCC: Tumor Response (TARGET) Pre-Therapy 8 Weeks Post-Therapy Image courtesy of Laura Wood, RN, MSN, OCN.
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Management of Early-Stage RCC Surgery Partial or radical nephrectomy Open surgery Laparoscopic Cryoablation or radiofrequency ablation Adjuvant Tx No benefit from adjuvant interleukin2 or interferon No benefit from radiation therapy Benefit from adjuvant targeted therapy is unknown Neoadjuvant- investigational National Comprehensive Care Network. Clinical Practice Guidelines in Oncology: Kidney Cancer: Version 2. 2006. Jenkintown, PA: National Comprehensive Cancer Network; 2006. Figure adapted from Urban BA, Fishman EK. Radiographics. 2000;20:197-212.
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Predictors of Relapse Prognostic models based on postoperative score: UCLA Integrated Staging System (UISS) Leibovich Model Frank Model (SSIGN) Kattan Model Prognostic Models based on preoperative score: Yaycioglu Cindolo
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Contributors to Prognosis Pathologic stage Histology Fuhrman Grade Nuclear grade Performance status Necrosis Size Clinical Presentation
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The UCLA Integrated staging system (UISS)
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Stratify Risk by TNM Stage/Grade Intermediate Risk High Risk Histologic Subtype Clear cell Non-clear cell Performance status Surgery Open vs laparoscopic Arm B Sorafenib 800mg daily for 1 year Arm C Placebo Daily for 1 year RANDOMIZE Non-Metastatic Kidney Cancer That meets radiologic criteria to be clinically  T1bNany (resectable) M0 disease S U R G E R Y Arm A Sunitinib 50 mg daily for 1 year REGISTRATION1 REGISTRATION2 A.S.S.U.R.E. (ECOG 2805)
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Objectives Primary Question: Can adjuvant therapy with an oral raf kinase inhibitor/ receptor tyrosine kinase inhibitor (Sorafenib) or pure receptor tyrosine kinase inhibitor (Sunitinib) improve disease-free survival in locally advanced RCC over placebo after surgical resection? Primary endpoint is DFS
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Secondary Objectives Overall survival Toxicity in the adjuvant setting Prospective collection of tumor and biologic specimens /Correlatives: Measures of angiogenesis Mutational analyses (oncogenes/TSG) Hypermethylation Polymorphisms
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Nexavar for 1 year, then placebo for 2 years (n=621) Nexavar in Adjuvant RCC: MRC SORCE Phase III Trial 1º endpoint: Metastasis-free survival 2º endpoints: RCC-specific survival time, toxicity, QoL, and biomarkers (1.5:1.5:1) Randomization (N=1656) High and intermediate risk, resected RCC Nephrectomy Placebo for 3 years (n=414) Nexavar for 3 years (n=621) MRC=Medical Research Council; QoL=quality of life; SORCE=SOrafenib versus placebo in patients with Resected primary renal CEll carcinoma.
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Developments ECOG BEST Trial (4 arm) of Doublet Targeted therapy (tem/bev vs bev vs sorafenib/bev vs sorafenib/tem Temsirolimus versus sunitinib trial for non clear cell RCC mTKI to mTOR vs mTor to mTKI trial Adjuvant trials SORCE and ASSURE are ongoing
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Conclusions Surgery remains the most effective therapy for early RCC and plays a role in advanced RCC New molecular targets have been identified which are critical to the pathogenesis of different types of RCC and new targeted therapies are replacing traditional biologic therapies The ultimate role that these agents will play in RCC has yet to be decided
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Common Treatment related side effects
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Targeted Therapy: More Questions Than Answers First Line:Should we combine these agents? Sequentially or concurrently? Vertical inhibition or horizontal inhibition? Which Type of Agent should be used first? mTKI or mTor inhibitor? At Progression Dose escalation of mTKI vs other mechanism?
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Treatment duration-are these agents purely angiostatic? Assessment of Response- Which is more important: RECIST or PFS? Predictors of Response Blood flow/ vascularity histology Imaging- PET/CT, DCE/MRI, CT Role of agents-Adjuvant?, First-line? Before or after cytokines? Exposure to agent- drug levels of sunitinib correlated with response Dose escalation of agent –some patients can tolerate dose escalation at the time of progression How to treat non clear cell and other variants
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Stratify Risk by TNM Stage/Grade Intermediate Risk High Risk Histologic Subtype Clear cell Non-clear cell Performance status Surgery Open vs laparoscopic Arm B Sorafenib 800mg daily for 1 year Arm C Placebo Daily for 1 year RANDOMIZE Non-Metastatic Kidney Cancer That meets radiologic criteria to be clinically  T1bNany (resectable) M0 disease S U R G E R Y Arm A Sunitinib 50 mg daily for 1 year REGISTRATION1 REGISTRATION2 A.S.S.U.R.E. (ECOG 2805)