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Volume 1, Issue 22 Bi-weekly Oncology E-newsletter | October 22, 2008

BusinessNews

ResearchHighlights

ClinicalDevelopment

Biomarkers Regulatory

Roche Lowers Price of Tarceva toGet UK Approval

EpiCept Receives Ceplene®Marketing Approval in Europe

NICE Rejects GSK's Tyverb

FDA Grants Full Approval toONTAK® in CTCL

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Smart Combinations for Cancer TreatmentsCancer therapies are characterized by combination regimens consisting of cytotoxic,targeted, anti-angiogenic and hormonal agents since many of these agents haveminimal efficacy as monotherapies. These agents are often confounded by themultitude of abnormalities and compensatory mechanisms in tumor cells that actto resist treatment efficacy. Read more...

In the Spotlight:

Targeting of the Innate AntiviralResponse by HDIs

Tumor Regression byT Cell–Engaging Antibody

Inhibition of Hsp90 ActivatesOsteoclast c-Src Signaling

Interplay among BRCA1, SIRT1and Survivin

Genetic Variability in VEGF andVEGFR-2 as a Biomarker

OPN Plasma Levels as a Biomarker inUnresectable NSCLC

TP53 Gene Mutations in LymphomaPredict Clinical Outcome

Lilly Announces Collaboration andMerger Agreements

Genentech, Glycart and Roche todevelop GA101

Affymetrix Collaborates forMicroarray Technology

Antisoma Collaborates onPPM1D Inhibitors

Primary Endpoint Not Met inAvastin-Tarceva Study

Efficacy of Pegylated IFN-α-2a in PV

Phase III results of Rituximab inCLL and FL

BiovaxID® Prolongs Cancer-FreeSurvival

Efficacy of Axitinib and Sorafenibin Thyroid Cancer

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Smart Combinations for Cancer Treatments

Cancer therapies are characterized by combination regimens consisting of cytotoxic, targeted, anti-angiogenic andhormonal agents since many of these agents have minimal efficacy as monotherapies. These agents are often confoundedby the multitude of abnormalities and compensatory mechanisms in tumor cells that act to resist treatment efficacy. A majorchallenge is to identify the appropriate combinations that will synergize to significantly improve treatment outcomes. Tworecent reports highlight this theme by showing how combining two novel agents with other approved drugs can result insynergistic effect on tumor-cell apoptosis.

In the first study Kung and colleagues investigated the resistance of glioblastoma multiforme (GBM) cells to PDFR kinaseinhibitor imatinib. Despite promising laboratory results in GBMs receptor tyrosine kinase inhibitors (RTKs) have thus far nottranslated into clinical success. The authors hypothesized that antiapoptosis pathways may confer resistance to RTKs andobserved that inhibition of PDGFR in GBM cells initiated the apoptotic pathway but downstream caspase activation wasblocked by inhibitor of apoptosis proteins (IAPs). Consistent with this observation although small molecule IAP inhibitor,LBW242 had no activity on its own, combination with imatinib increased sensitization to its apoptotic effects. In a mousexenograft model of GBM, animals treated with both imatinib and LBW242 had complete inhibition of tumor growth, whereaseither agent alone had little effect.

In the second study Johnstone and colleagues have shown that combining histone deacetylase inhibitor vorinostat withMD5-1 an antibody that is an activator of TRAIL (tumor necrosis related apoptosis-inducing ligand) resulted in synergisticeffect on tumor-cell apoptosis. Importantly, in a mouse breast cancer model, combination of vorinostat and MD5-1was shown to induce regression of established tumors, whereas single agent treatment had little or no effect. Functionalanalyses showed that vorinostat sensitized tumor cells to death receptor-5 mediated apoptosis by decreasing the levels ofc-FLIP- a negative regulator of caspase 8 and thereby relieving negative regulation of the death receptor pathway.

These two studies demonstrate that understanding molecular mechanisms by which these anti-cancer agents act on tumorcells and the basis for resistance is valuable in developing appropriate combinations for maximizing efficacy.Source: JCI, PNAS

Spotlight ReportSchematic of the apoptotic pathway with structure and site of action of of IAP inhibitor

JCI, 118, Sept, 2008

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Lilly Announces Collaboration and Merger AgreementsEli Lilly and Company and Deciphera Pharmaceuticals announced that the two companies have entered into acollaboration and worldwide licensing agreement related to Deciphera’s preclinical B-Raf kinase inhibitor program forthe study of potential oncology therapeutics. BRAF kinase is one of the most frequently mutated members of the kinasefamily across all cancers, and is particularly common in malignant melanomas, colon, and thyroid cancers. Thiscollaboration will apply Deciphera’s phylomechanics discovery platform, a unique approach to kinase inhibitor design,together with Lilly’s expertise in discovery and development to pursue first-in-class candidates for a variety of cancers.Under the terms of the agreement, Lilly will obtain exclusive worldwide rights to any products developed as part of thiscollaboration. In return, Deciphera will receive an upfront payment and research funding over the next two years from Lilly,and may also receive up to $130 million in potential development, regulatory and sales milestones. If a product issuccessfully commercialized from this collaboration, Deciphera will be entitled to royalties on sales.

Lilly has also entered into merger agreement with ImClone Systems under which Lilly will acquire ImClone through anall cash tender offer of $70 per share, or approximately $6.5 billion.This strategic combination will create one of the leadingoncology franchises in the biopharmaceutical industry, offering both targeted therapies and oncolytic agents along with apipeline spanning all phases of clinical development. The transaction will immediately enable Lilly to offer physicians andtheir patients a complementary portfolio of leading oncolytic agents and targeted therapies including Gemzar®, Alimta® andErbitux®.Source: Deciphera, Lilly

Genentech, Glycart and Roche Enter into Collaboration for Potential Cancer TherapyGenentech, GlycArt, a company wholly-owned by Roche, and Roche have entered into a collaboration agreement,including a licence from GlycArt to Genentech, for the joint development and commercialization of GlycArt’s GA101molecule.The companies will be developing GA101, a humanized anti-CD20 monoclonal antibody engineered to increaseboth direct- and immune-mediated target cell death, for the potential treatment of hematological malignancies and otheroncology-related B-cell disorders such as non-Hodgkin’s lymphoma (NHL).

Under this agreement, Genentech will receive commercialization rights in the US. GA101 is currently in Phase I/II clinicaltrials for CD20-positive B-cell malignancies, such as NHL and chronic lymphocytic leukemia (CLL). GlycArt and Roche planto provide an update on Phase I data for GA101 at the American Society of Hematology meeting in December 2008.Source: Roche

Business

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Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Affymetrix and MPI Collaborate to Develop Cancer Treatment ProductsAffymetrix and Medical Prognosis Institute A/S (MPI), a leading cancer diagnostic development company, announced thatthey have signed a Powered by Affymetrix™ (PbA) agreement. With this agreement, MPI gains non-exclusive access toAffymetrix microarray technology to develop and commercialize drug sensitivity prediction and prognostic products forpatients with cancer. Based on Affymetrix microarray technology, MPI aims to market its own proprietary products targetedat individual cancer prognosis and prediction of anti-cancer treatment response.The Affymetrix GeneChip® System 3000Dxis the only microarray instrumentation platform to receive regulatory clearance by the FDA and is CE marked in the EU forin vitro diagnostic use.

Our partnership with Affymetrix enables us to translate our discoveries into robust tools with broad clinical utility to greatlyimprove the prognosis and treatment of millions of people living with cancer. It also boosts the probability of successfulanti-cancer drug development in partnership with drug companies," said Jesper Drejet, president and CEO of MPI.Source: Affymetrix

Antisoma and the Institute of Cancer Research to Collaborate on PPM1D InhibitorsAntisoma, The Institute of Cancer Research (The Institute) and Cancer Research Technology (CRT) announced acollaboration and licensing agreement under which Antisoma has acquired rights to develop and commercialize novelanti-cancer compounds called PPM1D (protein phosphatase magnesium-dependent 1 δ) inhibitors. These compoundsinhibit PPM1D and selectively kill cells that over-express this phosphatase. Over-expression of PPM1D occurs in many casesof cancer, and can be readily detected. PPM1D inhibitors could therefore have potential as highly targeted treatments forpatients whose cancers are known to express the phosphatase.

Antisoma plans to continue the preclinical development of PPM1D inhibitors fromThe Institute's pipeline. Antisoma andTheInstitute have also formed a collaboration to explore further the potential of PPM1D-based approaches to cancer treatment.This work will continue to take place at the Breakthrough Breast Cancer Research Centre and the Cancer Research UKCentre for Cancer Therapeutics. Antisoma will make an immediate upfront payment and fund certain research at TheInstitute. Further payments will be made on achievement of development and regulatory milestones, and royalties will bepaid on any sales of compounds resulting from the collaboration.Source: Antisoma

Business(cont’d)

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Research HighlightsTargeting of the Innate Antiviral Response by HDIsOncolytic virotherapy (OV) is an innovative alternative to conventional cancer therapies based on the concept that virusescould be engineered to preferentially replicate in and kill tumor cells. Intratumoral innate immunity can play a significant rolein blocking the effective therapeutic spread of a number of OVs. Histone deacetylase inhibitors (HDIs) are known to havepotent anti-tumor activity and also known to prevent the transcriptional activation of antiviral genes after interferon (IFN)stimulation or virus infection. HDIs markedly blunt the cellular IFN response in tumor cells. Based on this, researchers of thestudy published in PNAS, hypothesized that HDIs could complement OVs and facilitate the infection and killing of tumorsthat had an impaired antiviral response. Vesicular stomatitis virus (VSV) is a prototypical rhabdovirus that grows poorly innormal tissues but replicates efficiently in cells lacking an intact IFN response. Researchers examined that pretreatment ofPC3 prostate tumor cells with the HDIs would sensitize them to VSV infection and subsequent virus-induced apoptosis.Importantly, the combination of VSV and HDIs enhances tumor killing but does not significantly increase VSV infection ofnormal human or mouse tissues. These results illustrate the general utility of HDIs as chemical switches to regulate cellularinnate antiviral responses and to provide controlled growth of therapeutic viruses within malignancies.Source: PNAS

Tumor Regression in Cancer Patients by T Cell–Engaging AntibodySubstantial evidence suggests that cytotoxicT lymphocytes participate in controllingtumor growth and that they can beharnessed in immunotherapeutic settings.However, therapies aimed at inducingspecific T cell responses against cancer cells,including vaccination have been limited byrelatively low response rates and relapses,presumably because of immune escapemechanisms of cancer cells. In a studypublished in Science, Bargou and colleaguesinvestigated the clinical activity and safety ofincreasing doses of bispecific T-cell engager

(BiTE) antibody blinatumomab with dual specificity for CD19 (B cells) and CD3, the T-cell receptor complex.

In a Phase I clinical trial, blinatumomab was tested in 38 patients with relapsed B-cell non-Hodgkin’s lymphoma.The majorityof the patients had already undergone multiple rounds of chemotherapy and treatment with rituximab.The study showedthat doses of blinatumomab as low as 0.005 mg per m2 lead to an elimination of target cells in the blood. All 4 complete and7 partial tumor regressions occurred at doses of 0.015 mg/m2 per day. All 7 patients treated at a dose level of 0.06 mg/m2

experienced a tumor regression. Importantly, the first confirmed responses to blinatumomab occurred at serumlevels that were five-orders of magnitude lower than the serum levels required for rituximab to elicit a response. Thisenormous potency difference was attributed to the high lytic potential of the T cells and their proliferation at the site ofactivation. The authors argued that the BiTE approach is particularly attractive as its independence from tumor-antigenpresentation and T-cell specificity might allow it to overcome the immune-escape mechanisms that limit otherimmunotherapeutic strategies.Source: Science

Science 321 Aug 15 2008

Micrographs of marrow biopsies of patient. Blue indicates tumor cells(hematoxylin staining); brown,T cells (CD3 staining)

Antitumor Activities of T Cell–Engaging Antibody BlinatumomabBaseline Treatment

Science, 321, Aug 15, 2008

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Inhibition of Hsp90 Activates Osteoclast c-Src SignalingHeat shock protein (Hsp) 90,a molecular chaperone, isrequired for the stability andfunction of multiple mutatedand overexpressed signalingproteins that promote thegrowth and/or survival ofcancer cells. Hsp90 inhibitorscause the destabilization andeventual degradation ofHsp90 client proteins. Recentstudies have shown that

Hsp90 interaction maintains c-Src in a metastable state. Disruption of Hsp90-c-Src association by 17-AAG, an Hsp90 inhibitor,resulted in transient Src kinase activation before Src destabilization and degradation.

Breast and prostate tumors have shown favorable responses to Hsp90 inhibitors. Because these cancers have a propensity tometastasize to bone, it is important to determine the impact of Hsp90 inhibitors on tumor cells growing in this setting. SinceSrc kinase is essential for osteoclast maturation, Yano et al. in a study published in PNAS, examined the role of 17-AAG-inducedSrc activation in osteoclastogenesis. This study showed that Hsp90 inhibition promoted osteoclast maturation through Srckinase activation and strongly synergized with the cytokines macrophage colony stimulating factor (M-CSF) and receptoractivator of nuclear factor kappa B ligand (RANKL), two crucial drivers of this process. As a result 17-AAG indirectly stimulatedthe intraosseous growth of PC-3M prostate cancer cells. However, this can be counteracted by three mechanistically distinctinhibitors of osteoclastogenesis, a Src kinase inhibitor dasatinib, a bisphosphonate alendronate, and the osteoclast-specificapoptosis inducer reveromycin A.This study emphasizes the importance of obtaining a more complete understanding of thecomplex role played by Hsp90 in regulating normal tissue homeostasis, and how these events impact tumor growth andresponse to targeted therapy.Source: PNAS

Interplay among BRCA1, SIRT1, and SurvivinBRCA1 is the most frequently mutated tumor suppressor genefound in familial breast cancers. It is estimated that BRCA1 mutationcarriers have a 50%–80% risk of developing breast cancer by age70. Resveratrol, a phytoalexin found in grapes, fruits, and rootextracts has demonstrated chemopreventive activity againstvarious cancers. Studies have shown that resveratrol has the abilityto activate SIRT1 deacetylase activity and to inhibit intracellularSurvivin level. Survivin is one of the apoptosis inhibitors thathas been implicated in controlling cell division and inhibitingapoptosis. In this study published in PNAS, Deng et al. investigatedthe relationship among BRCA1, SIRT1, Survivin, and resveratrol.

Investigators found that SIRT1 and Survivin serve as downstream mediators of BRCA1 function in tumor suppression.The absenceof BRCA1 resulted in low levels of SIRT1 and high levels of Survivin, allowing BRCA1-deficient cells to overcome growth defects andapoptosis and finally undergo malignant transformation. This study demonstrated that Sirt1 negatively regulates Survivinexpression through its deacetylase activity, which epigenetically modifies the Survivin promoter into a transcription-silentconfiguration. Also, the activation of Sirt1 and inhibition of Survivin expression by resveratrol demonstrated a more profoundinhibitoryeffectonBRCA1 mutantcancercellsthanonBRCA1-wild-typecancercellsboth invitroand invivo.Thesefindingsprovidea basis for the use of resveratrol on chemoprevention and therapeutic treatment of BRCA1-associated cancer patients.Source: Molecular Cell

ResearchHighlights(cont’d)

Control 17-AAG Dasatinib 17-AAG Alendronate 17-AAG Reveromycin A 17-AAG+ + +

Dasatinib Alendronate Reveromycin A

17-AAG Accelerates in vivo Tumor Growth Of Prostate Cancer Cells In Bone andthis is Abrogated by Distinct Inhibitors of Osteoclastogenesis

PNAS, 105, Oct 7, 2008

A Model Showing a BRCA1-SIRT1-Survivin Axis Signaling Pathway

Molecular Cell, 32, Oct 10, 2008

BRCA1 BRCA1

SIRT1 SIRT1

Survivin/others (?) Survivin/others (?)

Tumor Cell SurvivalProliferation

Apoptosis

Resveratrol

Molecular Cell, 32, Oct 10, 2008

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Clinical DevelopmentPrimary Endpoint Not Met in Avastin-Tarceva Study in Advanced NSCLCRoche, Genentech, and OSI Pharmaceuticals announced top line results from a randomized Phase III study (BeTa Lung)evaluating Avastin® (bevacizumab) in combination with Tarceva® (erlotinib) in patients with advanced non-small celllung cancer (NSCLC) whose disease had progressed following platinum-based chemotherapy. BeTa Lung is a global,multicenter, placebo-controlled, randomized, double-blinded Phase III study that enrolled 636 patients with advancedNSCLC. This study did not meet its primary endpoint of improving overall survival (OS) with the Avastin-Tarcevacombination compared to Tarceva alone. However, there was clear evidence of clinical activity with improvements in thesecondary endpoints of progression-free survival (PFS) and response rate when Avastin was added toTarceva compared toTarceva alone in this study. Median survival was similar in both arms of BeTa Lung. No new or unexpected safety signals foreither Avastin or Tarceva were observed in this study. The companies are further analyzing the study results and willpresent the data at the 2008 Chicago Multidisciplinary Symposium in Thoracic Oncology in Chicago in November.

We are disappointed this study did not show an improvement in survival for patients with advanced lung cancer who havea poor prognosis and a disease that is extremely difficult to treat. We are, however, encouraged to see the combination ofAvastin andTarceva had clear evidence of biological activity, and will fully analyze the data so that we can apply the insightsto our ongoing lung cancer research," said Hal Barron, M.D., Genentech's senior vice president, Development and chiefmedical officer.Source: Genentech

Pegylated IFN-α-2a Induces Complete Hematologic and Molecular Responses in PVPolycythemia vera (PV) is a myeloproliferative disorder marked by a long-term risk of evolution to myelofibrosis,myelodysplastic syndrome, and acute leukemia. Interferon-α (IFN-α), a nonleukemogenic drug for the treatment of PV caninduce cytogenetic remissions. However, its use is limited by toxicity, leading to treatment discontinuation in approximately20% of patients. In the recent issue of Blood, Kiladjian et al. reported a Phase II multicenter study of pegylated IFN-α-2a in 40PV patients to evaluate the efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F).Median follow-up was 31.4 months. All patients had hematologic response within the first year of treatment, includingcomplete hematologic response in 94.6% cases. 92% of patients could receive peg-IFN-α-2a for at least 12 months,resulting from moderate short-term toxicity. Molecular response (JAK2V617F undetectable) was achieved in 24% ofpatients at time of last analysis. No vascular event was recorded.These findings demonstrated that pegylated IFN-α-2a yieldshigh rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutatedclone in selected cases.Source: Blood

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Positive Phase III results of Rituximab in Relapsed CLL and Advanced FLRituxan® (Rituximab), discovered by Biogen Idec, is a genetically engineered chimeric murine/human monoclonal antibodydirected against the CD20 antigen found on the surface of normal and malignant B lymphocytes. REACH, a multi-center,randomized, open-label, international Phase III study of rituximab in combination with fludarabine and cyclophosphamidechemotherapy met its primary endpoint of PFS, as assessed by investigators, in 552 patients with previously treated CD20-positive chronic lymphocytic leukemia (CLL) compared to chemotherapy alone.There were no new or unexpected safetysignals reported in the study.The REACH results are promising, and we look forward to submitting an application to the FDAfor Rituxan's potential approval in this indication”, said Cecil Pickett, Biogen Idec's president of Research and Development.

In another study published in JCO, Marcus et al. compared the long-term outcome of patients with previously untreatedfollicular lymphoma (FL), after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plusrituximab (R-CVP). Patients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cyclesof R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months. The primary end point, time totreatment failure, which included patients without a response after four cycles as an event, was significantly prolonged inpatients receiving R-CVP versus CVP. Improvements in all other end points, including overall and complete response rates,time to progression (TTP), response duration, time to next antilymphoma treatment, and OS (OS; 4-year OS: 83% v 77%;) wereachieved with R-CVP versus CVP alone. This report confirms that the benefits of the addition of rituximab to first-linechemotherapy continue to be observed with long-term follow-up and reinforces the notion that rituximab containingchemotherapy should be the current standard of care for patients with FL requiring treatment.Source: Genentech, JCO

BiovaxID®, Anti-Cancer Vaccine Prolongs Cancer-Free SurvivalBiovest International, a majority-owned subsidiary of Accentia Biopharmaceuticals, reported clinically and statisticallysignificant data on its personalized, anti-cancer vaccine, BiovaxID® from its randomized controlled pivotal Phase III Fast-Tracked clinical trial for the treatment of indolent follicular non-Hodgkin’s lymphoma (NHL). After a recent meeting with theFDA, the Company closed the clinical trial, unblinded the patients, and analyzed the disease-free survival in both armsthrough June 30, 2008. Originally, the study was intended to follow patients in both arms after unblinding for the purposeof determining OS, but based on the trial results, the Company now believes that it would be unethical to withhold BiovaxIDfrom control patients, and therefore the study is closed.

The study population comprised of newly diagnosed patients with follicular NHL. Randomization required thatpatients achieve a complete clinical remission following chemotherapy. The intent-to-treat analysis from the point ofrandomization for all patients in the trial who received at least one dose of BiovaxID or control vaccination showed that themedian duration of complete remission in the BiovaxID arm of the study was 44.2 months which is clinically and statisticallysignificant compared to the control arm, median duration of cancer-free survival of 30.6 months. BiovaxID prolonged thecancer-free survival by 13.6 months or 44% with a median follow up of 56.6 months.The time point at which the differencein disease-free survival between the two arms was greatest was approximately 36 months. At 36 months, 61% of BiovaxIDpatients and 37% of control patients were cancer-free, indicating that BiovaxID patients were 65% more likely to becancer-free than were the control patients.Source: Accentia Biopharmaceuticals

ClinicalDevelopment(cont’d)

Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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Efficacy of Axitinib and Sorafenib in Refractory Thyroid CancerHistorically, thyroid cancers have receivedrelatively little attention from the medicaloncology community. Limited interest indevelopmental therapeutics for thyroidmalignancies is due to the natural history ofthyroid carcinomas, traditional managementparadigms, and the limitations of availablechemotherapies. In this background, theresults of two Phase II studies reported in therecent issue of the JCO evaluating differenttargeted therapies in patients with advancedthyroid cancer have special significance.

The multicenter trial from Cohen et al.1

assessed the activity and safety of axitinib, anoral, potent, and selective inhibitor ofvascular endothelial growth factor receptors

(VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer of any histology that was resistant or not appropriate for 131I.The study enrolled 60 patients into a single-arm Phase II trial to receive axitinib orally. Partial responses were observed in18 patients, yielding an objective response rate (ORR) of 30%. Stable disease lasting for 16 weeks was reported in 38%patients. Objective responses (OR) were noted in all histologic subtypes. Median PFS was 18.1 months.The study concluded0that axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advancedthyroid cancer.

Another study from Gupta-Abramson et al.2 evaluated the efficacy of the oral agent, sorafenib which inhibits not onlyangiogenesis, but also RAF and RET kinases, which are important targets in thyroid cancers. The study enrolled 30 patientswith metastatic, iodine-refractory thyroid carcinoma who received sorafenib orally twice daily for a minimum of 16 weeks.23% patients had a partial response lasting 18+ to 84 weeks. 53% had stable disease lasting 14 to 89+ weeks. Seventeen (95%)of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulinlevels with a mean decrease of 70%. The median PFS was 79 weeks. These findings highlighted that sorafenib has clinicallyrelevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefitrate and an overall acceptable safety profile.Source: JCO 1,2

ClinicalDevelopment(cont’d)

Time (weeks)

Kaplan-Meier Estimate of PFS for Patients on SorafenibPr

ogre

ssio

n-Fr

eeSu

rviv

al(%

)

1.00

0.75

0.50

0.25

0 20 40 60 80 100

Median PFS was79 weeks

JCO 26 Oct 10 2008JCO, 26, Oct 10, 2008

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Genetic Variability in VEGF and VEGFR-2 as a Biomarker for BevacizumabDrugs that target vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) have made a major impact in cancertherapy.Recently,E2100,aPhaseIII studydemonstratedanimprovement inresponserateandPFSwiththeadditionofbevacizumabto paclitaxel in the first-line metastatic setting of breast cancer. Although these drugs are regarded as targeted therapy, but it isdifficult to identify which patients will benefit most from them.There is substantial inherited genetic variability within VEGF andVEGFR-2, including multiple single nucleotide polymorphisms.Thus, genetic variability in VEGF andVEGFR-2 represents a logicalcandidate to study as a potential biomarker for bevacizumab.Therefore, in this study published in JCO, Schneider et al. evaluatedthe association of VEGF genotype with efficacy and toxicity in E2100 trial. DNA was extracted from tumor blocks of patients fromE2100 and genotyping was performed for selected polymorphisms in VEGF and VEGF receptor 2.

This study showed that VEGF-2578 AA genotype and the VEGF-1154 AA genotype had a superior median OS compared withpatients with alternative genotypes. Two additional genotype, VEGF-1498 TT and VEGF-634 CC were largely protected from seriousgrade 3 or 4 hypertension in the combination arm when compared with alternate genotypes combined.The high blood pressureinduced by bevacizumab can be a troubling toxicity, resulting in need for therapeutic intervention and even discontinuation forsome. The ability to anticipate this toxicity could allow for either close monitoring with early intervention or even possiblyprophylactic antihypertensive therapy. These findings support an association between VEGF genotype and median OS as wellas grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer.Source: JCO

OPN Plasma Levels as a Biomarker in Chemotherapy-Treated Patients with Unresectable NSCLCIdentification of prognostic and/or predictivebiomarkersforchemotherapyoutcomescouldenhancetherapeutic decision making. Secreted osteopontin(OPN), a phosphorylated acidic glycoprotein, interactswith members of the integrin family and variants ofCD44, stimulating a variety of downstream processesassociated with tumor progression or cellulartransformation. In a study published in JCO, Mack et al.hypothesized that plasma levels of OPN and two otherbiomarkers associated with tumor hypoxia and earlyprogression, plasminogen activator inhibitor-1 (PAI-1)and VEGF, would correlate with patient outcomes. Thishypothesis was evaluated in advanced-stage NSCLCpatients in S0003, a Southwest Oncology Group trial ofcarboplatin/paclitaxel with or without tirapazamine.

The study showed that low plasma concentrations of OPN were a highly significant marker of superior patient outcome,regardlessoftreatmentarm.PatientswithlowerOPNlevels(belowthemedian)hadasignificantlysuperiorOScomparedwithpatientswith higher levels. A similar correlation was observed for PFS. Patients with lower plasma OPN levels were significantly more likelyto have tumor response. No significant association between OPN plasma levels and tumor expression as measured byimmunohistochemistry could be demonstrated. One explanation for this observation is that nonmalignant cells may be contributingto plasma OPN concentrations. Although PAI-1 andVEGF levels were inter-related and declined after therapy, neither was associatedwith patient outcomes. These findings suggest that OPN plasma level may prove to have utility as a prognostic biomarker inchemotherapy-treated patients with unresectable NSCLC.Source: JCO

BiomarkersOv

eral

lSur

viva

l(%

)

Time After Registration (months)

0

100

80

60

40

20

24 48 7212 36 60 84

MedianN Events (months)

≤ 592 78 71 12.6> 592 78 77 7.5P = .002

Survival by Baseline OPN Plasma Level

JCO, 26, Oct 10, 2008

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Bi-weekly Oncology E-newsletter | Volume 1, Issue 22 | October 22, 2008

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TP53 Gene Mutations in DLBCL and FL Predicts Clinical OutcomeMutations in TP53 are frequent in hematologicalmalignancies where they correlate with unfavorableprognosis and chemotherapy resistance. In a studypublished in Blood, O’Shea et al. investigated theprognostic value of TP53 mutation at diagnosis in FLby analyzing heterozygous DNA from 185 untreatedpatients with FL. TP53 mutation was detected in12 of 185 (6%) cases of diagnostic FL. Multivariateanalyses confirmed that TP53 mutation waspredictive for shorter PFS and OS. TP53 mutationwas more frequent in older patients.

In another study,Young et al. demonstrated that themutational status of the TP53 gene in diffuse largeB-cell lymphoma (DLBCL) had a large impact on OSin this patient cohort. The study showed that 24%

of the cohort that contained TP53 mutations had a poor OS. The relative risk of death from DLBCL after standard CHOP orCHOP-like chemotherapy for patients with TP53 mutations in exons 5 to 8 was 2-fold higher than for patients withWT- TP53.Moreover, the location of the mutation in the p53 gene was also important. TP53 mutations in the DNA-binding domainswere associated with a significantly worse OS than mutations in non–DNA-binding domains. The consistent and strongresults in both studies suggest that analysis of the type of p53 mutation in a lymphoma could be very useful prognosticinformation with utility for treatment decisions.Source: Blood 1, 2

Biomarkers(cont’d)

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Progression Free Survival by TP53 Mutational Status in Follicular Lymphoma%

Prog

ress

ion

Free

Time (Years)

Blood, 112, October 15, 2008

Roche Lowers Price of Tarceva to Get UK ApprovalRoche's lung cancer drug Tarceva® (erlotinib) has been recommended for use on Britain's state-funded health service afterthe Swiss drug maker agreed to cut the price of the medicine. Roche and the National Institute for Health and ClinicalExcellence (NICE) announced they had reached a deal for Tarceva to be supplied at the same overall treatment cost asSanofi-Aventis's Taxotere®.

NICE had previously recommended against Tarceva, arguing that buying the costly drug was not a good use of NationalHealth Service (NHS) resources. The new price for a 125-day course of treatment is £6,128 ($10,830), compared with aprevious typical cost of £6,800.Tarceva is indicated for the treatment of patients with locally advanced or metastatic NSCLCafter failure of at least one prior chemotherapy regimen.Source: NICE

Regulatory

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EpiCept Receives Ceplene® Marketing Approval in EuropeEpiCept announced that the European Commission has granted a full marketing authorization in the form of a positiveCommission Decision, for Ceplene® (histamine dihydrochloride) for the remission maintenance and prevention of relapsein adult patients with Acute Myeloid Leukemia (AML) in first remission. Ceplene is to be administered in conjunction withlow-dose interleukin-2 (IL-2). The approval allows Ceplene to be marketed in the 27 member states of the EU, as well as inIceland, Liechtenstein and Norway.

The approval by the European Commission is based, in part, on the results of the pivotal 320-patient Phase III trial forCeplene in conjunction with IL-2. The primary result of this trial was that treatment with Ceplene/IL-2 significantly reducedthe occurrence of relapse among AML patients in complete remission. The improvement of long-term leukemia-freesurvival in patients receiving Ceplene/IL-2 exceeded 50%. Moreover, Ceplene was well tolerated in this patient populationand conferred an acceptable risk benefit profile for AML patients.Source: EpiCept

NICE Rejects GSK's Tyverb as too ExpensiveTyverb® (lapatinib) has been deemed too expensive for use by the UK's NHS, despite an offer from drug major GSK toprovide it free to each patient for the first 12 weeks. In its second appraisal consultation document, the NICE agreed with theverdict of an earlier draft recommendation that the oral, dual targeted therapy is too expensive. Given our involvement, itis difficult to comment without the appearance of self interest, however we strongly believe that the wrong decision hasbeen made for patients, doctors and the NHS,” said Simon Jose, GM for GSK UK Pharmaceuticals. We therefore remaincommitted to working with the NHS and NICE to make this innovative medicine available," he added.

The NICE is expected to make its final decision at a meeting on November 19. Tyverb, in combination with capecitabine, isindicated for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express ErbB2. Patientsshould have progressive disease following prior therapy which must include anthracyclines and taxanes and therapy withtrastuzumab in the metastatic setting.Source: GSK

FDA Grants Full Approval to ONTAK® in CTCLEisai Corporation of North America announced that the FDA has approved an efficacy supplemental biologics licenseapplication (sBLA) for ONTAK® (denileukin diftitox) solution for intravenous injection for the treatment of patients withpersistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of theinterleukin (IL)-2 receptor. A separate efficacy supplement that included data from patients with CTCL whose malignantcells did not test positive for the CD25 component of the IL-2 receptor received a complete response letter.

The FDA's action, following a priority review, marks the conversion of an accelerated approval indication to full approvaland is based on data from a Phase III clinical trial that evaluated the overall efficacy and safety of ONTAK in patients with CTCL.The study met its primary endpoint of overall response rate (ORR).The ORR was 46% for the 18 mcg/kg/day dose of ONTAKand 37% for the 9 mcg/kg/day dose vs. 15% for placebo. In addition, analysis of a secondary endpoint, PFS, suggested a 73%reduction in risk of disease progression in the 18 mcg/kg/day group and a 58% reduction in risk of disease progression inthe 9 mcg/kg/day group compared to placebo.Source: Eisai

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