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Volume 1, Issue 23 Bi-weekly Oncology E-newsletter | November 12, 2008

BusinessNews

ResearchHighlights

ClinicalDevelopment

Biomarkers Regulatory

TREANDA® Approved for RelapsedIndolent NHL

Avastin® Use for AggressiveBrain Cancer

CHMP Positive Opinion for Erbitux®as 1st Line Use in SCCHN

Vidaza® Receives CHMP PositiveOpinion for MDS and AML

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Anti-Tumor Activity with Oral Hsp90 Inhibitor, IPI-493InfinityPharmaceuticals announcedpreclinical data thatdemonstratedanti-tumoractivitywith IPI-493, anoral heat shockprotein90 (Hsp90)inhibitor. Inpreclinical studies, IPI-493potently inhibitedHsp90andhas shownstrongpharmaceutical... Readmore...

EORTC Highlights:

20th EORTC–NCI–AACR Symposium on Molecular Targets and Cancer Therapeutics,21–24 October 2008, Geneva, Switzerland

Targeted Antibodies InduceAntitumor Immune Response

ALK Identified as Chief Offender inNeuroblastoma

Kinase Requirements in Human Cells

Molecular Pathways Associated withChemotherapy Resistance

Lung Cancer Susceptibility Locus at5p15.33

Tests Predict Benefit from CancerDrugs

Prognostic Significance of DTCs inProstate Cancer

PITX2Methylation to PredictOutcome in Breast Cancer

Merck Serono and Lpath formAlliance for ASONEP

Allergan and Spectrum Collaboratefor Apaziquone

Exelixis Retains Rights to Developand Commercialize XL184

Methylgene Reacquires Rights toMGCD0103

Interim Data from Phase IIIIMPACT Trial

Phase II Results from PROSTVAC™

VITAL-1 Phase III Trial Terminated

Phase III Trial of90Y–Ibritumomab Tiuxetan in NHL

Lenalidomide in Relapsed orRefractory NHL

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20th EORTC–NCI–AACR Symposium on MolecularTargets and CancerTherapeutics,21–24 October 2008, Geneva, Switzerland

Anti-Tumor Activity with Oral Hsp90 Inhibitor, IPI-493Infinity Pharmaceuticals announced preclinical data that demonstrated anti-tumor activity with IPI-493, an oral heat shockprotein 90 (Hsp90) inhibitor. In preclinical studies, IPI-493 potently inhibited Hsp90 and has shown strong pharmaceuticalproperties in vitro and in vivo, including selectivity for cancer cells over normal cells, as well as high oral bioavailability.Moreover, IPI-493 showed significant anti-tumor activity in multiple xenograft models. There was also evidence ofsignificant dose-dependent inhibition of tumor growth in a xenograft model of human-derived NSCLC, with tumorregression seen at higher doses. In another preclinical poster presented at EORTC, Infinity demonstrated the biochemical,cellular, and in vivo properties of its geldanamycin derived inhibitors IPI-504 and IPI-493 compared to a number of fullysynthetic Hsp90 inhibitors in clinical development. When tested against a broad panel of cancer cell lines, IPI-504 andIPI-493 demonstrated a competitive mix of pharmacological properties, including potent cell growth inhibition against abroad range of cancer cells, selectivity for cancer cells over normal cells, and pharmacodynamic activity in vivo.Source: Infinity

Tumor Growth Inhibition with IPI-926 in Human Pancreatic Cancer ModelInfinity Pharmaceuticals announced the results of the preclinical studies of IPI-926, an oral Hedgehog pathway inhibitor inhuman pancreatic cancer model. The findings showed that the compound significantly down-regulates Hedgehogsignaling in tumor stroma, thereby disrupting the communication process between tumor and stroma, ultimately leading totumor growth inhibition. A single administration of IPI-926 in a preclinical model of human pancreatic cancer resulted in rapidand sustained Hedgehog pathway inhibition in the stromal cells, as measured by Gli1 expression, a downstream mediator ofHedgehog signaling. Infinity has also recently announced that it has initiated a Phase I clinical trial evaluating IPI-926 inpatients with advanced solid tumors.The Phase I trial is designed to evaluate the safety, tolerability, and pharmacokinetics ofIPI-926 and to determine a recommended dose and schedule for subsequent studies. Additionally, Infinity will evaluatepotential anti-tumor activity of IPI-926 and examine pharmacodynamic markers of its biological activity.Source: Infinity

Interim Results from IL-21 Phase II Trial in RCCZymoGenetics announced interim results from a Phase II trial evaluating Interleukin 21 (IL-21) in combination withNexavar® (sorafenib) tablets in patients with metastatic renal cell cancer (RCC). Study endpoints were overall response rateand progression-free survival. Subjects had previously received one or two targeted therapies for RCC but had diseaseprogression. Outpatient therapy with IL-21 and Nexavar as a second or third-line therapy for metastatic RCC was associatedwith anti-tumor activity, with manageable side effects.

Of subjects treated and assessed by independent review, 3 of 18 patients had a confirmed partial response, for an overallresponse rate of 17%. Anti-tumor activity (including 3 confirmed partial responses) was observed in 16 of 18 patients (89%),with stable disease or partial or complete response at any time during the study as evaluated by an independent andinvestigator review board. Seven of the 13 patients (54%) who completed 3 treatment courses had stable disease. Interimresults suggest a potential additive effect of IL-21. Serious adverse events that were considered possibly related to IL-21occurred in 6 subjects and included acute renal failure; rash and dehydration; coagulopathy, metabolic acidosis, andneutropenia; dyspnea; and acute hemolytic anemia.Source: ZymoGenetics

EORTC Highlights

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24-Week Clinical Data of MDV3100 in Castration-Resistant Prostate CancerMedivation announced new data from an ongoing Phase I/II trial of MDV3100, a novel androgen receptor antagonist, incastration-resistant prostate cancer. The ongoing Phase I/II trial is an open-label US dose-escalation study in prostatecancer patients who have failed standard hormonal therapies. Till date, 120 patients have been enrolled in the trial withenrollment completed at doses up to 360 mg/day. A total of 73 patients in the three lowest expanded dose groups (60, 150,and 240 mg/day) have been followed for more than 24 weeks. Of the 73 patients, 31 have received MDV3100 over 24 weeks.At 12 weeks, the recommended time point for reporting PSA-based outcomes, 36 of 73 patients (49%) had a more than 50%decline in PSA compared to their baseline value. Patients also saw improvements as measured by radiographic changesand reductions in the number of circulating tumor cells (CTCs) to favorable counts, including 38% of patients with evaluablesoft tissue lesions in the 240 mg/day cohort showing a partial response at 24 weeks.The data suggests a dose-response trendwith a higher percentage of patients in the 240 mg/day dose cohort experiencing 90% reduction in PSA levels, radiographicpartial responses and conversions to favorable CTC counts of less than five post-treatment.Source:Medivation

Efficacy and Safety Data from Phase II Picoplatin Trial in Patients with Metastatic CRCPoniard Pharmaceuticals announced positive incremental data from its randomized, controlled Phase II trial of picoplatin inpatients with metastatic colorectal cancer (CRC). The expanded and updated results continue to indicate that picoplatin,given once every four weeks in combination with 5-fluorouracil and leucovorin (FOLPI), is associated with less frequent andsevere neurotoxicity than oxaliplatin given in combination with 5-fluorouracil and leucovorin in the modified FOLFOX-6regimen (FOLFOX).

The randomized, controlled, Phase II study enrolled 101 patients who had not received prior chemotherapy. Interim resultsshowed that 65% of 37 evaluable FOLFOX-treated patients showed evidence of neurotoxicity with 5% of these patientsexhibiting severe Grade 3 or 4 neurotoxicities. This is in contrast to 18% of 34 evaluable patients treated with FOLPI whoexhibited resolvable low-grade (Grade 2 or lower) neurotoxicities. In addition, the FOLPI-treated patients did not showany severe Grade 3 or 4 neurotoxicities. Nephrotoxicities and ototoxicities were rare and mild with the FOLPI regimen.Non-neurologic tolerability was similar between the two treatment groups. Anti-tumor activity was also found to besimilar in the FOLPI and FOLFOX groups. Of the 35 evaluable patients in the FOLPI arm, 20 achieved disease control (partialresponse combined with stable disease), including 6 with partial responses (or 17% of evaluable patients). Fifteen patientsin the FOLPI arm were not evaluable or too early to evaluate. Of the 51 patients in the FOLFOX arm, 23 achieved diseasecontrol, including 5 with partial responses (or 13% of evaluable patients). Nine patients in the FOLFOX arm were either notevaluable or too early to evaluate.Source: Poniard

SpotlightReport(cont’d)

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Merck Serono and Lpath form Alliance for ASONEPMerck Serono, a division of Merck KGaA, announced that it has entered a worldwide alliance with Lpath to develop andcommercialize ASONEP, a Phase I humanized monoclonal antibody currently being evaluated for the treatment of variouscancer types. Under the terms of the agreement, Merck Serono will provide Lpath upto $23 million of upfront payments andR&D funding to support Lpath’s completion of the Phase I clinical trial. If Merck Serono accepts the responsibility to developASONEP beyond Phase I, it will pay Lpath an additional $28 million and will fund all continuing development activities.Further payments will be made on achievement of development, regulatory, and sales milestones that could total up to $422million if ASONEP is approved in multiple indications. As part of the alliance, Merck Serono now has exclusive, worldwiderights to develop and commercialize ASONEP across all indications while Lpath will receive royalties on commercial sales ofthe product.Source:MerckSerono

Allergan and Spectrum Announce Collaboration Agreement for ApaziquoneAllergan and Spectrum Pharmaceuticals announced signing an exclusive collaboration for the development andcommercialization of apaziquone, an alkylating antineoplastic agent currently being investigated for the treatment ofnon-muscle invasive bladder cancer by intravesical instillation. Under the terms of the agreement, Allergan will paySpectrum $41.5 million at closing and will make additional payments of up to $304 million based on the achievement ofcertain development, regulatory and commercialization milestones. Spectrum retained exclusive rights to apaziquone inAsia, including Japan and China. Allergan received exclusive rights to apaziquone for the treatment of bladder cancer in therest of the world, including the US, Canada and Europe. In the US, Allergan and Spectrum will co-promote apaziquone andshare its profits and expenses. Allergan will also pay Spectrum royalties on all of its apaziquone sales outside of the US.Spectrum will continue to conduct the apaziquone clinical trials pursuant to a joint development plan, with Allerganbearing the majority of these expenses. Spectrum is currently conducting two Phase III clinical trials to explore apaziquone'ssafety and efficacy as a potential treatment for non-muscle invasive bladder cancer following surgery. Spectrum expects tocomplete enrollment by year-end 2009.Source:Allergan

Exelixis Retains Rights to Develop and Commercialize XL184Exelixis announced that GSK has decided not to exercise its option to license XL184. GSK also informed Exelixis that it haddecided not to license the earlier compounds in the collaboration, including XL281, XL228, XL820, and XL844. With GSK'sannouncement, the six-year collaboration between Exelixis and GSK to discover and develop oncology compounds,comes to an end. Exelixis retains the rights to develop, commercialize, and/or license all of the compounds, subject topayment to GSK of a 3% royalty on net sales of any product incorporating XL184. GSK will continue development andcommercialization of XL880, a compound developed under the collaboration and previously in-licensed by GSK, withpotential additional milestone payments of up to $90 million and double-digit royalty payments to Exelixis on XL880'ssuccessful development and commercialization.

XL184 inhibits vascular endothelial growth factor receptor-2, MET, and RET, which are key drivers of tumor formation, growth,and metastasis. A Phase Ib/II trial of XL184 with erlotinib in NSCLC patients who have progressed after prior benefit fromerlotinib and a Phase II trial in subjects with progressive or recurrent glioblastoma multiforme in first or second relapseare ongoing. A Phase III trial of XL184 as single-agent therapy in 315 patients with unresectable, locally advanced, ormetastatic medullary thyroid cancer was initiated in July 2008.Source: Exelixis

Business

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MethylGene Reacquires Rights to MGCD0103 from CelgeneMethylGene announced that Celgene has terminated their licensing agreement for oncology histone deacetylase (HDAC)inhibitors. As a result, MethylGene will reacquire the rights to MGCD0103 and other HDAC and sirtuin inhibitors interritories licensed to Celgene including North America and the European Union. As part of the termination provisions,Celgene will continue to support MGCD0103 for a period of 90-days to ensure a smooth transition.

Celgene acquired the rights to MGCD0103 through its March 2008 acquisition of Pharmion Corporation. MethylGene nowowns the worldwide rights to three compounds, MGCD0103 (with the exception of certain Asian territories), MGCD265 andMGCD290, all of which are at various stages of clinical development. MethylGene also announced that after a review of theCompany's current research, development and business activities, the Company will focus on advancing its clinical pipeline.These plans include the continuing development of MGCD265 into Phase II trials, MGCD290 through Phase I studies andpursuing the removal of the partial clinical hold on MGCD0103.The Company will also evaluate the status of MGCD0103 oncethe compound is released from partial clinical hold.Source:MethylGene

Business(cont’d)

Research HighlightsTRAIL-R2 and Erbb-2 Antibodies Induce Antitumor Immune ResponseHuman epidermal growth factor receptor-2 (ErbB-2/HER2) is overexpressed in 20–30% of breast cancer and is associated witha poor prognosis. Although the development of trastuzumab constitute a major advance in ErbB-2-overexpressing breastcancer, but unmet needs remain. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and monoclonalantibodies (mAbs), have now emerged as promising anticancer agents. In a study published in PNAS, John Stagg et al.investigated the therapeutic activity of anti-DR5 (TRAIL-R2) mAb against spontaneously arising mammary tumors inErbB-2/neuT transgenic mice and provided the evidence that administration of agonistic anti-DR5 mAb can synergize invivowith anti-ErbB2 mAb therapy for the treatment of spontaneous ErbB-2-driven breast cancer.

Invitro, anti-DR5 and anti-ErbB-2 mAbs significantly enhanced the antiproliferative effect induced by either mAb. Remarkably,treatment of established tumors with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in amajority of mice. Another important finding was that depletion of CD8+T cells provoked primary and secondary tumor relapse,revealing the induction of antitumor immunity by the combination treatment. Study demonstrated that combining ErbB2blockade and TRAIL receptor activation induces potent synergistic antitumor effect in vivo and could be an effective form oftherapy combining targeted tumor cell death and systemic antitumor immune response.Source: PNAS

ALK Identified as Chief Offender in NeuroblastomaNeuroblastoma, a tumor derived from the peripheral sympathetic nervoussystem, is the most common childhood cancer. Neuroblastoma can bean inherited or a sporadic tumor but, the genetics aetiology is largelyunknown. Four papers published in Nature have identified the geneanaplastic lymphoma kinase (ALK) as a chief offender in this disease.The protein product ofALK is a tyrosine kinase, an enzyme that regulatesthe activity of other proteins through phosphorylation. Abnormalactivity of the ALK protein has been implicated in the amplification andtranslocation of genomic sequences in non-Hodgkin’s lymphoma andvarious solid tumors, including non-small-cell lung cancers.

Analyses by John Maris et al. and Janoueix-Lerosey et al. showed thatALK is a major familial neuroblastoma predisposition gene. ALK iseither amplified or constitutively activated through mutations mainlywithin the kinase domain, phenylalanine 1174 and arginine 1275 beingtwo mutation hotspots. Most of the somatically acquired mutations fellinto either the catalytic loop or the C-helix kinase domains, bothfrequent sites for oncogenic activating mutations. The heritable mutations of ALK are the main cause of familialneuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for thislethal paediatric malignancy.

Mutation and amplification ofALK is associated with the more aggressive subtypes of neuroblastoma. Chen et al. identifiedALK as a frequent target of genetic alterations in advanced neuroblastoma. The down regulation of ALK throughRNA interference suppresses proliferation of neuroblastoma cells harboring mutated ALK. Since ALK is activated bychromosomal translocations in a number of other tumor types, small molecular targeted drugs are being developed totarget this kinase. George et al. showed that the use of small molecule inhibitor of ALK, TAE684, resulted in growthsuppression and cell death. These findings will encourage further work in the development of ALK targeted drugs, with aview to improving the outcome for children with more aggressive stages of neuroblastoma.Source:Nature 1,2, 3, 4

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ResearchHighlights(cont’d)

Homology Model of Wild - type ALK

Nature, 455, Oct 16, 2008

C helixP loop

Activation segment

Catalytic loop

Nature, 455,Oct 16, 2008

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Kinase Requirements in Human CellsshRNA loss of function screens have been used to study many biological processes.In a series of papers published in PNAS, Ed Harlow’s groupfrom Harvard MedicalSchool has studied protein kinases that were rate-limiting for cell proliferation andsurvival using shRNA screens. Initially, the group analyzed the 21 different cellpopulations from various sources and demonstrated that tumor cells from the sametissue withthe same histology differ significantly in the kinase requirements. Insubsequent studies the group studied the kinase requirements in a panel of tumorcell lines that differ by the expression of a chosen oncoprotein or tumor suppressorprotein. Specifically they chose the clear cell carcinoma cells with inactivation of thevon-Hippel-Lindau (VHL) tumor suppressor protein, cervical and renal human tumorcell lines and human papilloma-transformed colon cancer cells. Studies using renalcarcinoma cells showed that VHL inactivation leads to dependence on MET, CDK6and MEK1. Comparison of cervical and renal cancer cell lines identified 10 kinasesthat were required in HeLa but not renal and 5 kinases that were required in renal butnot HeLa cells. The identification of kinases whose loss leads to selective inhibitionof cell proliferation or viability of tumor cells provides a reasonable method toidentify interesting candidates for consideration in drug development.Source: PNAS 1,2, 3, 4

Molecular Pathways Associated with Chemotherapy ResistanceResistance to chemotherapy posesa significant problem to patientsand providers but the mechanismsunderlying the development ofresistance are partially understood.In a study published in MolecularCancer Therapeutics, Riedel et al.used integrated computationalapproaches to identify biologicalpathways implicated by differentialgene expression between sensitiveand resistant cell lines to identifyrational targets for combinationtherapy. Gene set enrichmentanalysis (GSEA) was used toassociate resistance pathways intwo data sets: the NCI-60 cancer celllines sensitive and resistant tospecific chemotherapeutic agents(Adriamycin, cyclophosphamide,docetaxel, etoposide, 5-fluorouracil,

paclitaxel, and topotecan) and a series of 40 lung cancer cell lines sensitive to cisplatin and docetaxel - two of the mostcommonly used agents, frequently in combination. To complement GSEA findings, the top genes up/down regulated fordocetaxel resistance, were analyzed using the Connectivity Map (cmap).

ResearchHighlights(cont’d)

Sensitivity Spectrum to Cisplatin in a Series of Lung Cancer Cell Lines

Cell Line

Range: 221-4662 nM

Mea

nEC

50nM

Cisplatin

Mean (SD): 1662 nM(398)

Resistant Cell Lines (n=7)

Sensitive Cell Lines (n=15)

MolCancer Ther, 7,October 2008

PNAS, 105, Oct 28, 2008

Differential Kinase Requirements Comparing Cell Lines Derived from Different

Tissue Origins and the Same Tissue

PNAS, 105,Oct 28, 2008

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Clinical DevelopmentInterim Data from Phase III IMPACT TrialDendreon announced the interim data from the Phase III, randomized, double-blind, placebo-controlled IMPACT(IMmunotherapy for Prostate AdenoCarcinoma Treatment) trial. This study was designed to assess the safety andefficacy of the investigational active cellular immunotherapy PROVENGE® (sipuleucel-T) in 512 men with metastaticandrogen-independent prostate cancer. While Dendreon remains blinded to the data, the Independent Data MonitoringCommittee (IDMC) reported to Dendreon a 20% reduction in the risk of death in the PROVENGE arm relative to placebo.TheIDMC observed no safety concerns and recommended that the study continue to its final analysis.

At the final analysis, which is anticipated in the middle of 2009, if the study demonstrates approximately a 22% reductionin the risk of death, based on 304 events, the Company would expect the study to meet its primary endpoint of overallsurvival.Source:Dendreon

Positive Phase II Results from Prostate Cancer Vaccine, PROSTVAC™Bavarian Nordic has evaluated the mature Phase II data from the therapeutic prostate cancer vaccine candidatePROSTVAC™ that had been obtained as part of the partnership with the NCI in the US. The results from the Phase IIprospective randomized placebo-controlled study of 125 patients with advanced prostate cancer after 4 years offollow-up show that patients receiving PROSTVAC had a statistically significantly longer median overall survival by 8.5months compared to the control group. Currently the only approved treatment for advanced prostate cancer extendsmedian overall survival by an average of approximately 2 months. In addition, PROSTVAC also had a favorable safety andtolerability profile.

Based on these promising results, Bavarian Nordic expects to initiate confirmatory Phase III studies for PROSTVAC togetherwith NCI in the first half of 2010 that will form the basis of approval for this therapy. Anders Hedegaard, President and CEO,Bavarian Nordic, said “Based on these data we believe that PROSTVAC offers a potential breakthrough and real hope forpatients suffering from advanced prostate cancer.”Source: BavarianNordic

Study analysis suggests that the biology associated with resistance is relatively specific to agents and significantly affectedby the context of the cell lines tested, as no single biological pathway was associated with all cytotoxic agents when theNCI-60 cell line data were analyzed and no pathway was found to be common to more than two agents. GSEA associatedfour pathways with resistance to more than one agent including Free Pathway (free radical-induced apoptosis), matrixmetalloproteinase, p53, and methionine metabolism in NCI-60 cell lines. Twenty pathways were associated with docetaxelresistance and 23 pathways with cisplatin resistance. Of these, the bcl-2 pathway was associated with cisplatin resistance.AKT and SA Programmed Cell Death pathways were associated with resistance to both agents. AKT gene sets along withPI3K specific gene sets were consistently associated with docetaxel resistance. This study shows that novel computationalmethods allow for the determination of appropriate biological relevance and identification of pathways that may serve astargets for novel therapeutics.Source:MolecularCancer Therapeutics

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Cell Genesys Announces Termination of VITAL-1 Phase III TrialCell Genesys announced its decision to terminate the VITAL-1 Phase III trial of GVAX immunotherapy in patients withasymptomatic metastatic hormone-refractory prostate cancer. The trial was fully enrolled in 2007 with 626 patients andcompared GVAX immunotherapy toTaxotere® (docetaxel) chemotherapy plus prednisone.The Company terminated the trialbased on the results of a previously unplanned futility analysis conducted by the study's Independent Data MonitoringCommittee (IDMC) which indicated that the trial had less than a 30% chance of meeting its predefined primary endpointof an improvement in survival.

On August 27, 2008, Cell Genesys announced that it had requested the IDMC to conduct a futility analysis of theVITAL-1 trialfollowing the termination of VITAL-2, the Company's other Phase III trial of GVAX immunotherapy for prostate cancer. TheVITAL-2 study was conducted in patients with symptomatic metastatic hormone-refractory prostate cancer and comparedthe combination of GVAX immunotherapy plusTaxotere toTaxotere plus prednisone as a control. In view of the terminationof both the VITAL-1 and VITAL-2 trials, the Company will place on hold further development of GVAX immunotherapy forprostate cancer pending a review of the program with its collaborator, Takeda Pharmaceutical.Source:CellGenesys

Phase IIITrial of ConsolidationTherapy with90Y–Ibritumomab Tiuxetan in NHLFollicular lymphoma is a radiosensitive malignancy,and earlier stages of the disease are treated withradiotherapy with curative intent. 90Y-ibritumomabtiuxetan (Zevalin®) was the first radioimmunotherapyagent to be approved by the FDA for the treatment ofpatients with relapsed, low-grade B-cell NHL .In a studypublished in JCO, Morschhauser et al. evaluated thesafety and efficacy of consolidation therapy with asingle dose of 90Y-ibritumomab tiuxetan (Zevalin®) inpatients who achieved a partial response (PR) or betterwith first-line induction treatment.

This international, randomized, open-label, controlled,Phase III First-Line Indolent Trial (FIT) enrolled 414patients with CD20+ stage III or IV follicular lymphoma, who were randomly assigned to receive 90Y-ibritumomab (twodoses of rituximab 250 mg/m2 followed by 90Y–ibritumomab tiuxetan) or no consolidation. 90Y-ibritumomab tiuxetanconsolidation significantly prolonged median PFS (after a median observation time of 3.5 years) in all patients (36.5 vs 13.3months in control arm). After 90Y-ibritumomab tiuxetan consolidation, 77% of patients in partial response after inductionconverted to complete response (CR)/unconfirmed CR, resulting in a final CR rate of 87%.The study results demonstrate thatconsolidation of first remission with 90Y-ibritumomab tiuxetan in advanced-stage follicular lymphoma is highly effectivewith no unexpected toxicities, prolonging PFS by 2 years and resulting in high PR-to-CR conversion rates regardless of typeof first-line induction treatment. Based on the FIT data, Cell Therapeutics has submitted a supplemental Biologics LicenseApplication to the FDA for use of Zevalin in first-line consolidation therapy.Source:Cell Therapeutics, JCO

ClinicalDevelopment(cont’d)

JCO, Oct 14, 2008 ( Advance Online Publication)

Kaplan-Meier Plots for PFS

0

Pro

gres

sion

-Fre

eS

urvi

val(

%)

Time After Random Assignment (months)

100

80

60

40

20

6 12 18 24 30 36 42 48 54 60 66

Control: Median13.3 months

90Y-ibritumomab tiuxetan: Median,38.5 months

JCO,Oct14, 2008 (AdvanceOnlinePublication)

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Lenalidomide Monotherapy in Relapsed or Refractory Aggressive NHLThe major cause of death in aggressive lymphoma is relapse ornon-response to initial therapy. Lenalidomide, an analog ofthalidomide, is a promising new therapeutic agent with activity in avariety of hematologic malignancies, including non-Hodgkin'slymphoma (NHL). In the present Phase II, single-arm, multicenter trialpublished in JCO, Wiernik et al evaluated the safety and efficacy oflenalidomide oral monotherapy in patients with relapsed or refractoryaggressive NHL. The study enrolled 49 patients with a median age of65 years who were treated with oral lenalidomide 25 mg once dailyon days 1 to 21, every 28 days, for 52 weeks, until disease progressionor intolerance. The primary end point was response; secondary endpoints included duration of response, progression-free survival (PFS),and safety.

An objective response rate of 35% was observed in 49 treated patients,including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressivehistologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patientswith stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated medianduration of response was 6.2 months, and median PFS was 4.0 months. The adverse events were predominantlyhematologic, manageable, and consistent with lenalidomide therapy in patients with other diseases. The study concludedthat oral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.Source: JCO

ClinicalDevelopment(cont’d)

JCO, 26, Oct 20, 2008

Kaplan-Meier Plot of PFS

Median PFS was 4.0 months

Pat

ient

s(%

)

Progression-Free Survival Time (months)

100

75

50

0

25

5.0 10.0 15.0

PatientsCensored

JCO, 26,Oct 20, 2008

Lung Cancer Susceptibility Locus at 5p15.33An international research team led by Paul Brennan has identified two genetic variations that appear to increase a person's riskof developing lung cancer by up to 60%.The study published in Nature Genetics, included researchers from 18 countries whocarried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by thegenome-wide data and replicated by the independent study series. The risk-associated allele was the more common allele ofrs402710 and the less common allele of rs2736100.The association with rs402710 was prominent in never-smokers, ex-smokersand current smokers, and there was no evidence of any heterogeneity by study, histology, age or sex. There was no apparentgeographical heterogeneity in the allele frequencies of rs402710. The effects observed with rs2736100 were similar, with theassociations for the less common (risk) allele being largely comparable to those for rs402710. The susceptibility region (5p15.33locus) contains two genes: the TERT (human telomerase reverse transcriptase) and the CLPTM1L (alias CRR9; cleft lip and palatetransmembrane 1 like), suggesting that one or both may have a role in lung cancer etiology. TERT is an essential component oftelomerase production and of carcinogenesis, and CLPTM1L, may induce apoptosis. However, there is no clear evidence tosuggest that rs402710 or rs2736100 are themselves causative alleles.Source:NatureGenetics

Biomarkers

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Tests Predict Benefit from Cancer DrugsTests based on genes, proteins or other molecular markers could predict benefit from cancer drugs for patients battling colon, lungand pancreatic tumors, scientists reported at the second annual meeting on Molecular Markers in Cancer co-sponsored by ASCO,the NCI and EORTC.

Freeman and colleagues analyzed the efficacy of panitumumab monotherapy in relation to KRAS mutational status for treatingmetastatic colorectal cancer (mCRC) from four clinical studies. Across all studies, 795 patients received panitumumab and hadtumor samples available for testing; of these patients, 715 had tumor samples analyzable for KRAS. In pateints with wild type(WT) KRAS, the response rate was 13.7%. PFS (3.3 months vs 1.7 months) and OS (8.3 months vs 5.7 months) were better inpatients with theWT KRAS compared to mutational type (MT) KRAS group. Consistently across all 4 clinical studies, responses withpanitumumab monotherapy were observed only in mCRC pts withWT KRAS. KRAS appears to be a valid predictive biomarker inselecting mCRC pts for panitumumab monotherapy.

R. Rosell et al evaluated EGFR mutations in tumor and matched serum at baseline and their role as a predictive marker in amulticenter trial of first- and second-line erlotinib in stage IV NSCLC patients. Investigators screened 2,281 NSCLC patients forEGFR mutations in tumors; 211 stage IV patients with mutations were treated with erlotinib. Progressive disease was observed in83.3% vs 17.6% with mutations in serum compared to patients with mutations in tumor. Overall time to progression (TTP) was13 months;TTP was 17 months for patients with EGFR mutations only in tumor and 12 months for patients with mutations in tumorand serum.These findings suggest that EGFR mutations in serum could be an ancillary non-invasive method for genotyping andcould help to identify the small subgroup of patients who will initially respond to erlotinib.

In another study, Biankin et al evaluated the utility of multiple biomarkers from distinct biological pathways as predictivemarkers of response to pancreatectomy in a cohort of 601 patients. Of the 17 candidate biomarkers examined, only elevatedexpression of calcium binding protein, S100A2 was an independent predictor of survival when assessed in a multivariate modelwith clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared tothose with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6. Patientswith S100A2 negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgicalmargins (median 15.7 months) or lymph node metastases (median 17.4 months). Prospective measurement of S100A2expression in diagnostic biopsies has potential clinical utility as a predictive marker of response to pancreatectomy and othertherapies that target loco-regional disease.Source: 2008MolecularMarkers 1 , 2 , 3

Prognostic Significance of DTCs in the Bone Marrow of Prostate Cancer PatientsIn patients with prostate cancer, current prognosticparameters incompletely reflect tumor biology.Additional diagnostic parameters are urgently neededto improve tumor characterization. The clinicalrelevance of the detection of disseminated tumor cells(DTCs) in bone marrow (BM) or in the peripheral bloodof solid tumor patients free of overt metastasis is stillunder investigation. In a study published in JCO,Köllermann et al investigated the prognostic relevanceof DTCs in BM of 193 patients with clinically localizedprostate cancer submitted to neoadjuvant hormonetherapy followed by radical prostatectomy. Patients’outcome was evaluated using prostate-specific antigen(PSA) blood serum measurements as surrogate markerfor recurrence. Median follow-up was 44 months.

Probability of PSA PFS according to Bone Marrow Status

JCO, 26, Oct 20, 2008

0

BM-negativeBM-positive

PSA

Prog

ress

ion-

Free

Surv

ival

(%)

Time (months)

100

80

60

40

20

50 100 150 200

P = .0035

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DTCs were detected in 44.6% of patients. Bone marrow status neither correlated with tumor grade and stage, nor with thepretreatment PSA risk category. However, a positive BM status was significantly associated with a shorter PSA recurrence-freesurvival. Univariate Kaplan-Meier analysis demonstrated that the presence of DTCs was a significant prognostic factor with respectto poor PSA progression-free survival. Using a multivariable piecewise Cox regression model, the presence of DTCs was anindependent predictor of PSA relapse. The study concluded that the detection of DTCs in the BM of patients with prostatecancer represents an independent prognostic parameter even in hormonally treated patients. DTCs appear to survive hormonetherapy and this might be an explanation for the well-known failure of neoadjuvant hormone therapy. However, improvedcharacterization of DTCs and larger multicenter studies are required to introduce BM examination for detection of DTCs into thefuture clinical management of patients with prostate cancer.Source: JCO

PITX2 Methylation to Predict Outcome in Tamoxifen-Treated, Breast Cancer PatientsAberrant DNA methylation has been well established as an early, frequent, and stable molecular event during tumor progression.Using fresh frozen tumor specimens, Harbeck et al previously reported DNA methylation of the paired-like homeodomaintranscription factor 2 (PITX2) gene to be a strong marker for outcome prediction in patients with steroid hormone receptor–positive,node-negative primary breast cancer treated with adjuvant tamoxifen monotherapy. In the present study published in JCO,investigators evaluated the clinical relevance of PITX2 as observed in fresh frozen breast cancer specimens for formalin-fixedparaffin-embedded (FFPE) tissue using real-time polymerase chain reaction (PCR) technology. The impact of PITX2 methylationon time to distant metastasis was then evaluated in FFPE specimens from hormone receptor–positive, node-negative breastcancer patients (n = 399, adjuvant tamoxifen monotherapy).

The study demonstrated reproducibility of the PCR assay in replicate measurements and concordant measurements between freshfrozen and FFPE tissues. Investigators analyzed the clinical impact ofPITX2DNAmethylation taking into account the establishedprognostic factors of tumor size, grade, and age. In the multivariate model, PITX2 DNA methylation contributed statisticallysignificant independent outcome information. However, univariate analysis showed that only tumor size was significantlyassociated with outcome, a result that is in line with previous observations. These findings suggest that PITX2 methylationanalysis holds promise as a practical assay for routine clinical use to predict outcome in node-negative, tamoxifen-treated breastcancer patients.Source: JCO

Biomarkers(cont’d)

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FDA Approval for TREANDA® to Treat Patients with Relapsed Indolent NHLCephalon announced that the FDA has approved TREANDA® (bendamustine hydrochloride) for Injection for the treatment ofpatients with indolent B-cell non-Hodgkin's lymphoma (NHL) that has progressed during or within six months oftreatment with rituximab or a rituximab-containing regimen. In March 2008, TREANDA received approval for the treatment ofpatients with chronic lymphocytic leukemia.

The FDA approval is supported by a pivotal trial of 100 patients with indolent B-cell NHL. The pivotal study demonstrated thatpatients had a high response rate to treatment with TREANDA, and these responses were durable. Treatment withTREANDA as a single agent resulted in an overall response rate of 74%. Additionally, patient response to treatment lasted amedian of 9.2 months and patients remained alive and their disease did not progress for a median of 9.3 months.Source:Cephalon

Regulatory

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Genentech Seeks Avastin® Use for Aggressive Brain CancerGenentech announced that the company submitted a supplemental Biologics License Application (sBLA) to the FDA for Avastin®(bevacizumab) as a therapy for people with previously treated glioblastoma. The Avastin application is based on a Phase IIclinical trial (BRAIN) in previously treated glioblastoma that evaluated Avastin as a single agent or in combination withirinotecan chemotherapy. The study enrolled 167 patients with glioblastoma whose cancer had relapsed after first- orsecond-line therapy. When Avastin was evaluated as a single agent, the study showed that at six months 43% patients livedwithout their disease advancing, as defined by progression-free survival (PFS), a primary endpoint in the study. Moreover, 28%patients responded to Avastin, meaning tumors decreased in size by at least 50%. Patients receiving Avastin had a medianoverall survival of 9.3 months, a secondary endpoint in the study.

Most adverse events related to Avastin in this trial appeared to be similar to those previously reported in other Avastinstudies. Genentech plans to initiate a global Phase III study in patients with newly diagnosed glioblastoma in the first half of 2009that will evaluate Avastin with standard of care chemotherapy and radiation. Avastin is already approved for thefirst- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapyand for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lungcancer (NSCLC) in combination with carboplatin and paclitaxel.Source:Genentech

Erbitux® Receives CHMP Positive Opinion for 1st Line Use in SCCHNMerck Serono announced that it has received a positiveopinion from the Committee for Medicinal Products for Human Use (CHMP),the scientific committee of the European Medicines Agency (EMEA), to extend the use of the targeted therapy Erbitux® (cetuximab)to include first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).

The submission to the EMEA was supported by the results of the EXTREME (ErbituX in first-line Treatment of REcurrent orMEtastatic head and neck cancer) study which investigated the efficacy of Erbitux in combination with platinum-basedchemotherapy in first-line treatment of recurrent and/or metastatic SCCHN. The study demonstrated that adding Erbitux toplatinum-based chemotherapy significantly prolongs patients’lives. Overall survival time increased from 7.4 to 10.1 months whenErbitux was added to standard platinum-based chemotherapy. Erbitux is already approved in combination with radiotherapy forlocally advanced SCCHN.Source:MerckSerono

Vidaza® Receives CHMP Positive Opinion for Treatment of MDS and AMLCelgene announced that its cancer drug, VIDAZA® (azacitidine), a pyrimidine nucleoside analog of cytidine, has received apositive opinion from the European Medicines Agency's CHMP for the treatment of adult patients who are not eligible forhaematopoietic stem cell transplantation with a) Intermediate-2 and high-risk myelodysplastic syndrome (MDS) b) Chronicmyelomonocytic leukaemia with 10-29% marrow blasts without myeloproliferative disorder and c) Acute Myeloid Leukemia with20-30% blasts and multi-lineage dysplasia.

The positive opinion from the CHMP was based upon safety and efficacy from clinical studies evaluating azacitidine in MDS, inparticular the AZA-001, the largest, international randomized Phase III controlled study ever conducted in higher-risk MDS. Themedian overall survival for patients treated with azacitidine was 24.5 months compared to 15 months for conventional careregimens (CCR), demonstrating a survival benefit of over 9 additional months. The extension of survival was seen across allpatient subgroups including those greater than 65 years, as well as poorer prognostic groups such as those with WHO classifiedacute AML, which formed over 30% of the enrolled patients, and patients with poor risk cytogenetics.The 2-year survival rate forpatients with higher-risk MDS treated with azacitidine was almost doubled with 50.8% compared vs. 26.2% for patients treatedwith CCR. VIDAZA is already indicated for treatment of patients with the French-American-British (FAB) MDS subtypes.Source:Celgene

Regulatory(cont’d)