First Quarter 2008 - Issues in Hematology - ION Solutions

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drug updatehad been met. Median OS was 10.7 months and 7.9months for the Nexavar and placebo groups, respectively,representing a significant 44% improvement in OS inthe Nexavar-treated patients (hazard ratio [HR], 0.69;95% confidence interval [CI]: 0.55 - 0.88; P=.0006)(See Figure 1). Furthermore, subgroup analysis showedthat Nexavar’s survival benefit was maintained in patientswith HCC representing a range of potential clinicalpresentations, i.e., those with ECOG performancestatus of 0, ECOG performance status of 1 and 2, andin patients both with and without macroscopic vascularinvasion and/or extrahepatic spread of disease.Therapy with Nexavar also resulted in a 73%improvement in time to cancer progression relative toplacebo treatment (median time to progression, 5.5months versus 2.8; HR, 0.58; 95% CI: 0.44, 0.74;P=.000007), and an improved disease control rate(43% versus 32%). Side effects in the Nexavar andplacebo groups (52% and 54%) were predictable, withsimilar adverse event rates. The most common grade 3/4effects were diarrhea (11% versus 2%), hand-foot skinreaction (8% versus 1%), fatigue (10% versus 15%), andbleeding (6% versus 9%), respectively.Revised National ComprehensiveCancer Network (NCCN) GuidelinesInclude Nexavar as Treatment Optionfor Child-Pugh A and B Patients with HCCBased on recent findings with Nexavar in patientswith HCC, the NCCN has updated the clinical practiceguideline for hepatobiliary cancers to include Nexavaras a treatment option for selected patients with bothChild-Pugh A and B liver function status. 4 This includespatients with unresectable tumors, those with localdisease who are deemed inoperable based on poorperformance status or comorbidities, and those withmetastatic disease. The guidelines caution that there islimited safety data available for Child-Pugh B patients. 4Figure 1oncologistics volume 7, issue 1 - spring 2008 3Survival Probability1.000.750.50NEXAVARMedian: 46.3 wk (10.7 mo)(95% CI: 40.9, 57.9)PlaceboMedian: 34.4 wk (7.9 mo)(95% CI: 29.4, 39.4)0.25 Hazard ratio(NEXAVAR/placebo): 0.69(95% CI: 0.55, 0.87)P=.00058*00 8 16 24 32 40 48 56 64 72 80Time (Weeks)Patients at riskNEXAVAR: 299 274 241 205 161 108 67 38 12 0 0placebo: 303 276 224 179 126 78 47 25 7 2 0Overall survival curve from the international Phase III SHARP trial of sorafenib vs. placebo in patients with inoperable HCC (N=602).Results show a statistically significant benefit of sorafenib (n=299) vs. placebo (n=303) (intention-to-treat population). *O’Brien-Flemingthreshold for statistical significance was P=.0077. 3
oncologistics drug updateIn the placebo-controlled Phase III SHARP trial,therapy with Nexavar resulted in a significant 44%survival improvement in HCC patients, and is thus theonly agent that has demonstrated a survival benefitin this malignancy.Nexavar Inhibits Both Tumor CellProliferation and AngiogenesisTwo processes that are important for HCC tumor growthare angiogenesis and signaling through the Raf/mitogenactivatedprotein (MAP)/extracellular signal-regulatedkinase (ERK) kinase (MEK)/ERK (Raf/MEK/ERK) cascade.Nexavar exerts its antitumor effects by targeting multiplekinases involved in both of these processes (SeeFigure 2). 5,6 The Raf/MEK/ERK pathway, which relayssignals from cell surface receptors to the nucleus, playskey roles in governing cell proliferation, differentiation, andsurvival, and has been shown to be activated in HCC and5, 7-10other solid tumors.Nexavar targets the Raf/MEK/ERK pathway at thelevel of the serine-threonine kinase Raf, resulting inreduced tumor cell proliferation. 5,6 Furthermore, HCCtumors are highly angiogenic, 11 and in-vitro modelsshow that Nexavar reduces HCC tumor angiogenesisby targeting multiple receptor tyrosine kinases, includingvascular endothelial growth factor receptor (VEGFR)-2,VEGFR-3, platelet-derived growth factor-betaFigure 2Tumor CellEndothelial Cell or PericyteEGF/HGFAutocrine LoopParacrineStimulationPDGF-ßVEGFPDGFR-ßRAFMEKERKRASNexavarHIF-2NucleusApoptosisMitochondriaEGF/HGFPDGFVEGF }ProliferationSurvivalMitochondriaApoptosisRAFMEKERKNucleusRASNexavarVEGFR-2Angiogenesis:DifferentationProliferationMigrationTubule FormationMechanism of action of Nexavar in preventing tumor growth. Nexavar targets multiple tyrosine kinases in tumor cells,endothelial cells, and pericytes, resulting in reduced tumor cell proliferation and angiogenesis. 5oncologistics 4
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First Quarter 2008 - Issues in Hematology - ION Solutions

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