Smart Oncology May Issue 24ii, 2011

8/6/2019 Smart Oncology May Issue 24ii, 2011

1/15

Volume 4, Issue 5 Monthly Oncology E-newsletter | May 27, 2011

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INTELLIGENT INSIGHTS. SMART RESULTS

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CLICK HERE to visit SMARTANALYST The E-newsletter team: Dr. Geetha Vani Rayasam, Dr. Shirish Kumar, Sarika Manchanda,Dr. Vinamrata Bhatia, Dr. Erica Salerno, Kimberly Tully, Monica Tuli, and Courtenay Veenis.

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In the Spotlight:

Tumor of the Month

Reciprocal Feedback Regulation of PI3K andAndrogen Receptor Signaling in PTEN-deficientProstate Cancer

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Prostate cancers are associated with genetic alterations involving the PI3Kand androgen receptor (AR) pathways, both of which mediate survivalsignals in prostate cancer. Nearly 40% primary and 70% metastatic prostatecancers have genomic alterations in the PI3K-signaling pathway, mostlythrough loss of PTEN, which promotes resistance to castration. The criticalrole of PTEN in regulating flux through the PI3K-signaling pathway raises thepossibility that the PI3K pathway inhibitors might be effective in PTEN-deficient prostate cancer. Inhibitors of the PI3K pathway targeting variouscritical components of the pathway (PI3K, AKT, mTORC1/2) are in earlyclinical trials, and AR inhibitors confer clinical responses in most patients.However, these inhibitors rarely induce tumor regression in preclinicalmodels.

Melanoma is the most severe type ofskin cancer in which transformedmelanocytes, cells responsible forproducing pigmentation, form amalignant tumor that spreads andattacks nearby tissues. In the case of

metastatic melanoma, malignant cellsbreak from the primary tumor andspread to distant organs and bones.Melanoma is primarily caused byexposure to sun (ultraviolet radiation),but can also be caused by intrinsic

factors, such as inherited genotypes. During 2004-2008, the incidence rateof melanoma in the US was 26.7 per 100,000 men and 16.7 per 100,000women. Early signs of melanoma are generally evaluated by the ABCDE

1

Model of PI3K Pathway and AR Crosstalk

RTK (HER2/3)RTK (HER2/3) PI3K

PHLP

P AKT

mTORC1/2

AR

AR Target Genes (FKBP5)

Business News

Research Highlights

Clinical Development

Biomarkers

Regulatory

Astellas and MMRF Collaborate to AccelerateDrug Development for Myeloma

c-Raf, but Not B-Raf, Is Essential forDevelopment of K-Ras Oncogene-driven

NSCLC

Sanofi Reports Positive Phase III Resultsnd

with Aflibercept in 2 Line mCRC

+Tumor-infiltrating CD8 Lymphocytes PredictClinical Outcome in Breast Cancer

FDA Approves Afinitor for Patients withAdvanced Pancreatic NET

Read More...

Read More...

Read More...

Read More...

Read More...
http://www.smartoncology.com/http://www.smartanalyst.com/http://www.smartanalyst.com/http://www.smartoncology.com/


2/15

Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-deficientProstate Cancer

Prostate cancers are associated with genetic alterations involving the PI3K and androgen receptor (AR)pathways, both of which mediate survival signals in prostate cancer. Nearly 40% primary and 70% metastaticprostate cancers have genomic alterations in the PI3K-signaling pathway, mostly through loss of PTEN, whichpromotes resistance to castration. The critical role of PTEN in regulating flux through the PI3K-signalingpathway raises the possibility that the PI3K pathway inhibitors might be effective in PTEN-deficient prostatecancer. Inhibitors of the PI3K pathway targeting various critical components of the pathway (PI3K, AKT,mTORC1/2) are in early clinical trials, and AR inhibitors confer clinical responses in most patients. However,these inhibitors rarely induce tumor regression in preclinical models.

In a recent study published in Cancer Cell, Carver et al. evaluated the therapeutic efficacy of PI3K pathway

inhibition in preclinical models of prostate cancer with an aim to define the molecular mechanism of PI3K and ARfeedback regulation. They found that AR transcriptional output is decreased in human and murine tumors withPTEN deletion, and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HERkinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus,these two oncogenic pathways cross-regulate each other by reciprocal negative feedback. Inhibition of oneactivates the other, thereby maintaining tumor cell survival. Therefore, tumor cells can adapt and survive wheneither single pathway is inhibited pharmacologically. However, combined pharmacologic inhibition of PI3K andAR signaling caused near-complete prostate cancer regressions in a PTEN-deficient murine prostate cancermodel and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.This bidirectional crosstalk between two critical survival pathways in prostate cancer provides the molecularrationale for simultaneously targeting both pathways. The demonstration of profound tumor regressions withcombined pathway inhibition in preclinical prostate tumor models provides rationale for combination therapy inpatients. The success of clinical trials evaluating PI3K pathway inhibitors in prostate cancer could be optimizedby enrolling patients with documented activation of the PI3K pathway and treating in combination with

appropriate AR pathway inhibition.

Spotlight Report

Back to top of Spotlight Section Back to Top of Document 2

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Monthly Oncology E-newsletter | Volume 4, Issue 5 | May 27, 2011

Source: Cancer Cell. 2011 May 17;19(5):575-86.

Cancer Cell, 19, May 17, 2011

Model of PI3K Pathway and AR Crosstalk

RTK (HER2/3)RTK (HER2/3) PI3K

PHLP

P AKT

mTORC1/2

AR

AR Target Genes (FKBP5)
http://www.cell.com/cancer-cell/abstract/S1535-6108(11)00155-3http://www.cell.com/cancer-cell/abstract/S1535-6108(11)00155-3


3/15

Tumor of the Month - Melanoma

Back to top of Tumor of the Month Section Back to Top of Document 3

Melanoma is the most severe type of skin cancer in which transformed melanocytes, cells responsible forproducing pigmentation, form a malignant tumor that spreads and attacks nearby tissues. In the case ofmetastatic melanoma, malignant cells break from the primary tumor and spread to distant organs and bones.Melanoma is primarily caused by exposure to sun (ultraviolet radiation), but can also be caused by intrinsicfactors, such as inherited genotypes. During 2004-2008, the incidence rate of melanoma in the US was 26.7 per100,000 men and 16.7 per 100,000 women. Early signs of melanoma are generally evaluated by the ABCDEmnemonic:

Asymmetry - One-half of the skin growth or mole is different than the other

Border Irregularity - Irregular edges (i.e. ragged, notched, or blurred)

Color - Changes in color distribution and variations in pigmentation

Diameter - Mole or skin growth is larger than 6 mm

Evolution - Change in the size, shape, symptoms, surface and color

Later signs include pain or a break in a mole or lesion. Metastatic melanoma signs include swollen lymph nodes,colorless lumps, unexplained weight loss, gray skin, chronic cough, headaches, and seizures.

Once melanoma is diagnosed via tissue biopsy, further tests may be conducted to assess possible growth,specifically in the lymph nodes. If diagnosed and treated early, melanoma can be cured. The current early stagetreatment for patients with limited disease/resectable melanoma is surgical excision of the affected skin andpossible adjuvant treatment on clinical trial. In April 2011, the FDA approved Sylatron (Merck) peginterferonalpha-2b for adjuvant treatment of melanoma with microscopic or gross nodal involvement. Stage IV, alsoknown as metastatic melanoma, responds poorly to most treatments. Treatment options for patients whoseresection is incomplete or patients with disseminated, unresectable melanoma are determined on the basis ofbrain metastases. If brain metastases are present, surgery or stereotactic radiosurgery is used, depending onthe number of brain metastases. Temozolomide, a chemotherapeutic agent that crosses the blood-brain barrier,may also be administered. If a patient presents no brain mets, he/she may be placed on a clinical trial,immunotherapy, or administered a combination of systemic chemotherapeutic agents (including dacarbazine,temozolomide, cisplatin, vinblastine, paclitaxel-based regimens, with or without IL-2 or IFN-a). Patients with

unresectable or metastatic melanoma now have another option with the FDA approval of Yervoy (ipilimumab) inMarch 2011. Yervoy, an anti-CTLA-4 mAb manufactured by BMS, is the first of its kind approved drug formetastatic melanoma, demonstrating significant improvement in overall survival. By hindering CTLA-4 bindingto B7 on antigen-presenting cells, the T cell inhibitory signal is prevented, thus prolonging their activation,proliferation, and anti-tumor activity.

The future treatment of metastatic melanoma is evolving toward targeted and immunotherapeutic agents.Several agents are currently undergoing Phase III clinical trials for stage III or IV melanoma, including novelimmunotherapeutic agents and targeted agents.

The approval of Yervoy has cleared the path for immunotherapeutic agents within this indicationTremelimumab is another anti-CTLA-4 mAb being developed by Debiopharm (in collaboration with Pfizer).Immunostimulants such as allovectin-7 (Vical), thymalfasin (SciClone), and Provecta (Provectus) are currentlyin the pipeline, as well as darleukin (Philogen's immunocytokine) and astuprotimut-r (MAGE-A3, GSK) cancervaccine. Most recently (May 23), results of a Phase III trial involving Gentasense (oblimerson), a novel antisensebcl-2 agent developed by Genta, demonstrated that overall survival in melanoma patients was not significantly

higher than patients treated with chemotherapy alone.

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4/15

Tumor ofthe Month

(Cont'd)

4

smartoncology.com

Source: NCCN Guidelines Version 4.2011 melanoma; melanomacenter.com; clinicaltrials.gov,

Trial Trove; www.webmd.com, www.seer.cancer.gov,

http://www.advancedmcode.org/home/wp-content/uploads/2011/04/melanoma.gif(picture) andcompany websites

US Treatment Algorithm for Metastatic Melanoma (Stage IV)

resectable

(limited disease)

unresectable

(disseminated disease)

Possible adjuvant

treatment

On clinical trial

Surgerysystemic therapy

(clinical trial,

or SOC)

Incomplete resection,

residual disease

Brain mets?

Or systemic chemo

that crosses

bloodbrain barrier

(temozolomide)

# of mets Clinical trial; ipilimumab;Dacarbazine, temozolomide or highdose IL2;

Dacarbazine or temozolomide +

cisplatin + vinblastine

With or w/o IL2, IFNa;

Paclitaxelbased chemo

(single or w/cisplatin or carboplatin)

Noyes

Stereotactic

Radiosurgery

surgery

12

mets multiple

mets

relapsed

Best supportive care

Intolerable

to chemo

tolerable

to chemo

Sources: based on NCCN Guidelines Version 4.2011 melanoma and melanomacenter.com

Back to top of Tumor of the Month Section Back to Top of Document

http://www.webmd.com/http://www.seer.cancer.gov/http://www.advancedmcode.org/home/wp-content/uploads/2011/04/melanoma.gifhttp://www.advancedmcode.org/home/wp-content/uploads/2011/04/melanoma.gifhttp://www.seer.cancer.gov/http://www.webmd.com/


5/15

Business News

Back to top of Business Section Back to Top of Document 5

Astellas and MMRF Collaborate to Accelerate Drug Development for Myeloma

LLS and Acetylon Partner to Develop ACY-1215 for Multiple Myeloma

Merrimack Acquires European and Asian Rights to MM-398, Nanoliposomal Irinotecan

The Multiple Myeloma Research Foundation (MMRF) and Astellas Pharma Global Development (APGD) haveentered into a joint collaboration for the clinical development of OSI-906 in patients with relapsed multiplemyeloma. OSI-906 is a potent, selective tyrosine kinase inhibitor of both insulin-like growth factor-1 receptor(IGF-1R) and insulin receptor (IR), viewed as important therapeutic targets due to their involvement in thegrowth and proliferation of a variety of human cancers, including adrenocortical carcinoma, ovarian, and non-small cell lung cancers.

In support of this partnership, the MMRF and APGD have agreed to fund a Phase I trial evaluating OSI-906 as asingle agent and in combination with the proteasome inhibitor bortezomib for the treatment of relapsed multiplemyeloma. The trial will be conducted through the Multiple Myeloma Research Consortium (MMRC), whichaccelerates the development of novel and combination treatments for patients with multiple myeloma bypromoting and facilitating collaborative research between industry and academia. Partial funding for this trial ismade possible by the donor-supported MMRF Clinical Fund, which enables the MMRF to invest in the

development of industry-owned compounds whose development in multiple myeloma is delayed due to mattersof prioritization.

The Leukemia & Lymphoma Society (LLS) and Acetylon Pharmaceuticals will jointly support a Phase I/II clinicaltrial of Acetylon's oral selective HDAC6 inhibitor drug candidate ACY-1215 in multiple myeloma, both alone andin combination with proteasome inhibitors. Selective inhibition of HDAC6 is expected to reduce or eliminate thesevere side effects associated with non-selective HDAC inhibition, and may enable the development ofoptimized treatment regimens, including maximally effective combination drug therapies.

Under the terms of the agreement, Acetylon will conduct a three-part Phase I/II clinical trial of ACY-1215 inadults with relapsed and relapsed/refractory multiple myeloma to achieve human proof of concept for selective

HDAC6 inhibition. LLS will provide $4.85 million in non-dilutive, milestone-based, and conditionally repayablefunding, representing half of the projected costs of the clinical trial. The Phase Ia part of the trial involvingpatients with relapsed and relapsed/ refractory multiple myeloma is expected to begin in the next severalmonths.

Merrimack Pharmaceuticals has acquired the rights to develop and commercialize MM-398 in Europe and Asia.MM-398, originally developed by Hermes BioSciences that was acquired by Merrimack in 2009, is a highly stablenanoliposomal formulation of irinotecan. Previously, the development and commercialization rights to MM-398in Europe and Asia had been licensed to PharmaEngine. Merrimack held the rights to the product in North

America and all other territories across the world.Under the terms of the agreement, Merrimack and PharmaEngine will collaborate on the development of MM-398. PharmaEngine will receive an upfront payment of $10 million and is eligible to receive up to an additional$210 million upon achievement of certain development, regulatory, and sales milestones, as well as tieredroyalties on sales of MM-398 in Europe and Asia. Through this agreement, the worldwide rights to MM-398 havebeen reunited, with Merrimack now having the right to develop and commercialize MM-398 in all territories ofthe world with the exception of Taiwan, where PharmaEngine will retain its rights to develop and commercializeMM- 398.

Source: MMRF

Source: Acetylon Pharmaceuticals

Source: Merrimack Pharmaceuticals

smartoncology.com

http://www.themmrf.org/about-the-mmrf/powerful-news/press-releases/multiple-myeloma-research-foundation-mmrf-and-astellas-pharma-global-development-enter-into-joint-collaboration-to-accelerate-drug-development-for-myeloma-patients.htmlhttp://www.acetylon.com/news/press_releases/pdfs/Acetylon_LLS_PressRelease.pdfhttp://www.merrimackpharma.com/newsEvents/2011/MM-PharmaEngine%20agreement.pdfhttp://www.merrimackpharma.com/newsEvents/2011/MM-PharmaEngine%20agreement.pdfhttp://www.acetylon.com/news/press_releases/pdfs/Acetylon_LLS_PressRelease.pdfhttp://www.themmrf.org/about-the-mmrf/powerful-news/press-releases/multiple-myeloma-research-foundation-mmrf-and-astellas-pharma-global-development-enter-into-joint-collaboration-to-accelerate-drug-development-for-myeloma-patients.html


6/15


7/15

c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-driven NSCLC

Ras proteins are small GTPases that serve as mitogenic switches to convey information generated at the cellsurface to the nuclear transcriptional machinery through multiple effector cascades. K-RAS, the RAS oncogenemost frequently mutated in human cancer, has been implicated in one-fourth of non-small cell lung carcinomas(NSCLCs), one of the human tumors with the worst prognosis. Although K-RAS signals through a cascade ofdruggable kinases including the RAF, MEK1/2, and ERK1/2 kinases, it is not known how these individual kinasescontribute to tumor development. As yet, there are no approved targeted therapies to treat K-RAS-drivenNSCLC. This situation may stem from our limited knowledge of what effectors are directly responsible formediating K-RAS signaling in this tumor type and hence, serve as effective therapeutic targets.

Blasco et al., in a study published in Cancer Cell, systematically examined by genetic means the role ofindividual members of the Raf/Mek/Erk cascade of kinases in a mouse model of K-Ras-driven NSCLC. They usedstrains of mice carrying mutations within loci encoding Raf, Mek, and Erk kinases to investigate whether they areessential for tumor development. They demonstrated that ablation of Mek1/2 or Erk1/2 kinases completely

prevents tumor development, although their systemic elimination is incompatible with adult life. Ablation of Erk1or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet,elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mekkinases. The immediate Ras downstream effectors within the Raf/Mek/Erk pathway are the Raf kinases A-Raf,B-Raf, and c-Raf. Ablation of B-Raf had no significant effect on tumor development. In contrast, ablation of c-Rafcompletely prevented K-Ras-driven NSCLC without inducing deleterious effects when systemically eliminated inadult tissues, either alone or in combination with B-Raf. Thus, neither B-Raf nor A-Raf could compensate for thelack of c-Raf pointing to c-RAF as a suitable target for therapeutic intervention in K-RAS-driven NSCLC. Theseresults provide information that might be used in the future to design targeted therapies to block K-RAS-inducedNSCLC in human patients. The study indicates that c-Raf plays a unique role in mediating K-Ras signaling,making it a suitable target for therapeutic intervention.

Research Highlights

Back to top of Research Section Back to Top of Document 7


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8/15

Mechanistic Rationale for Inhibition of PARP in ETS Gene Fusion-positive Prostate Cancer

Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, includingprostate, breast, melanoma, and Ewing's sarcoma. In prostate cancer, recurrent gene fusions of the androgen-

regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG are present in nearly 50% prostatecancers. ETS gene fusions appear early in prostatic disease during the transition from high-grade prostaticintraepithelial neoplasia (PIN) lesions to invasive carcinoma. Once an ETS gene fusion is formed throughgenomic rearrangement, the subsequent over-expression of an ETS gene fusion protein can contribute to cancerprogression through several different mechanisms. Considering the functional consequences of ETS generearrangements in prostate cancer progression, it is critical to know if ETS gene fusions can be therapeutictargets, either directly or indirectly, though transcription factors such as the ETS genes have been notoriouslydifficult to target therapeutically.

Due to the difficulties in targeting nuclear transcription factors using conventional therapeutic strategies,Brenner et al., in a study published in Cancer Cell, hypothesized that associated enzymes critical for ERGfunction may instead serve as viable therapeutic targets to inhibit ETS-positive prostate cancer cell growth. Theworkers investigated the mechanisms by which ETS fusions mediate their effects and found that the product ofthe predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly(ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly,pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograftgrowth. They also found that over-expression of the TMPRSS2:ERG fusion induces DNA damage, which ispotentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency. This study shows that theETS:PARP1 interaction axis may represent a target for therapeutic intervention in cancers with ETS gene fusions.The findings also suggest that inhibition of cofactors necessary for function may represent a promising paradigmof the treatment for malignancies driven by oncogenic transcription factors. Furthermore, the results warrantthe assessment of ETS gene fusions as a potential biomarker of response in future clinical trials incorporating

PARP inhibitors into the treatment of prostate cancer and other ETS fusion-positive malignancies.

ResearchHighlights

(Cont'd)

Back to Top of Document 8


Back to top of Research Section

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TMPRSS2 ERG

ERGoverexpression

DNA-PKcs

ERGKu80

Ku70

PARP1

DNA Breaks

P

Transcriptional programInvasion

Metastasis

H2A.X

Olaparib

Proposed Model to Therapeutically Target ETS GeneFusions via Their Interacting Enzyme, PARP1




9/15

CH5424802, a Selective ALK Inhibitor Capable of Blocking the Resistant Gatekeeper Mutant

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers,following gene alterations such as chromosomal translocation, amplification, or point mutation. Because the

growth of these tumors is strongly addicted to ALK activity, suppression of ALK could be a potent therapeuticstrategy for patients with gene alterations of ALK. Small-molecule ALK inhibitors have not yet been approved asanticancer agents. CH5424802, an ALK inhibitor with high selective properties, and potential antitumor activityagainst the gatekeeper mutant L1196M in EML4-ALK, is currently being investigated in Phase I/II clinical trialsfor patients with ALK-positive NSCLC. A remarkable characteristic of CH5424802 is the high selectivity for ALKamong various types of kinases, including c-MET and INSR.

Due to the narrow therapeutic index caused by inhibition of multiple kinases and the emergence of resistant

mutants to other kinase inhibitors, Sakomoto et al., in a study published in Cancer Cell, studied CH5424802 as apotential candidate against ALK-addicted tumors such as NSCLC-expressing EML4-ALK, anaplastic large-celllymphoma (ALCL) expressing NPM-ALK, and ALK-amplified neuroblastoma. They found the drug to be a potent,selective, and orally available agent with a unique chemical scaffold, showing preferential antitumor activityagainst these cancer cells in vitro and in vivo. Studying tumor cells isolated from a patient with NSCLC who wasrefractory to the c-MET/ALK inhibitor, PF-02341066 (crizotinib), CH5424802 inhibited ALK L1196M, whichcorresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Potent ALK inhibitors effective against the gatekeeper mutants may offer clinicaladvantages in cancer treatment for patients with ALK-driven tumors. The results of this study support thepotential for clinical evaluation of CH5424802 for the treatment of patients with such ALK-driven tumors.

ResearchHighlights

(Cont'd)



Back to top of Research Section

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Overall Structure of ALK containing CH5424802

N-lobe

C-lobe

Gly-rich loop

C-helixL1196

hinge regionand ATP binding site



10/15

ndSanofi Reports Positive Phase III Results with Aflibercept in 2 Line mCRC

Phase III Trial of Oblimersen in Advanced Melanoma Did Not Show Significant Increase in OS

Bortezomib Improved Outcomes in Multiple Myeloma Patients after Transplant

Sanofi and Regeneron announced that a Phase III VELOUR trial evaluating the investigational agent Zaltrap(aflibercept), also known as VEGF Trap, in combination with the FOLFIRI chemotherapy regimen [folinic acid(leucovorin), 5-fluorouracil, and irinotecan] versus a regimen of FOLFIRI plus placebo met its primary endpoint

ndof improving OS in the 2 line treatment of metastatic colorectal cancer (mCRC).

The VELOUR study enrolled 1,226 patients with mCRC who previously had been treated with an oxaliplatin-based regimen, was a multinational, randomized, and double-blind trial. The primary endpoint wasimprovement in OS. The study had 90% power to detect a 20% reduction in the hazard rate for OS, using a two-sided log-rank test. Secondary endpoints included PFS, response to treatment, and safety. The most frequentadverse events reported with Zaltrap in combination with FOLFIRI were diarrhea, asthenia/fatigue, stomatitisand ulceration, nausea, infection, hypertension, GI and abdominal pains, vomiting, decreased appetite,decreased weight, epistaxis, alopecia, and dysphonia. Based upon these positive findings, Sanofi andRegeneron plan to submit regulatory applications for marketing approval to the FDA and the EMA in H2 2011.

Genta Incorporated announced that OS for patients treated with Genasense (oblimersen sodium) Injection pluschemotherapy in AGENDA, the Company's Phase III trial in patients with advanced melanoma, was notsignificantly superior compared with patients treated with chemotherapy alone. We are keenly disappointed inthis result, which terminates our 10-year effort to achieve a clinically meaningful benefit for patients withmelanoma, said Dr. Raymond P. Warrell., Jr., Genta's CEO.

AGENDA was a randomized, double-blind, placebo-controlled trial of dacarbazine administered with or withoutGenasense in patients who had not previously received chemotherapy. As defined in a prior randomized trial,AGENDA employed a biomarker to define patients who might maximally benefit from such treatment. In the

trial, median survival was 13.5 months in the Genasense group and 13.1 months in the chemotherapy-onlygroup. The durable response rate was 10.8% and 7.6%, respectively. The safety profile of Genasense inAGENDA was consistent with prior studies, as previously released.

Millennium: The Takeda Oncology Company reported the presentation of results of a randomized Phase III trialthat investigated the effect of consolidation with single-agent Velcade (bortezomib) for injection in newlydiagnosed multiple myeloma patients after autologous stem cell transplant (ASCT). The study showed thatconsolidation with Velcade led to significant improvement in response rates and PFS, while the OS rate was 87%in both arms after a median follow-up of 27 months.

In this study, 370 patients were randomized to either Velcade consolidation therapy or no consolidation therapy2 stfollowing ASCT. Velcade was given in a dose of 1.3 mg/m twice weekly in a 3-week schedule for the 1 twocycles. In the following four cycles, Velcade was given once weekly in a 4-week schedule for a total of 20injections over 21 weeks. The median PFS measured from the time of randomization was 27 months for patientsin the compared to 20 months for patients in the control group. In the Velcade arm, 45% patients achieved acomplete response/near complete response (CR/nCR), compared to 35% patients in the control group. Theestimated OS was 87% in both groups, after a median follow-up of 27 months. 6% patients in the Velcade armhad neuropathic pain of grade 3 or higher, compared with 0.5% patients in the control arm. 5% patients in theVelcade arm experienced peripheral sensory neuropathy of grade 3 or higher, compared with 2% patients in thecontrol arm.

Clinical Development

Back to top of Clinical Section Back to Top of Document 1

Source: Sanofi

Source: Genta

Source: Millennium: The Takeda oncology company

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http://en.sanofi.com/binaries/20110426_VELOUR_en_tcm28-31928.pdfhttp://www.genta.com/Press_Releases/2011/Phase_3_Trial_of_Genasense%EE%9F%A9n_Advanced_Melanoma_Does_Not_Show_Significant_Increase_in_Overall_Survival.htmlhttp://phx.corporate-ir.net/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=1560848&highlight=http://phx.corporate-ir.net/phoenix.zhtml?c=80159&p=irol-newsArticle&ID=1560848&highlight=http://www.genta.com/Press_Releases/2011/Phase_3_Trial_of_Genasense%EE%9F%A9n_Advanced_Melanoma_Does_Not_Show_Significant_Increase_in_Overall_Survival.htmlhttp://en.sanofi.com/binaries/20110426_VELOUR_en_tcm28-31928.pdf


11/15

Cixutumumab in Phase II Showed Greatest Benefit in Adipocytic Sarcoma; Least Benefit inRhabdomyosarcoma

Promising Interim Survival Data from Phase II Cotara Recurrent GBM Trial

Eli Lilly announced data from its Phase II study with cixutumumab (IGF-1 receptor antagonist) in five subtypes

of sarcoma. The trial assessed PFS as a primary endpoint in 113 patients with advanced or metastatic soft tissuesarcoma (STS) and the Ewing family of tumors. The five tiers evaluated included those with previously treated,advanced, or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma, andEwing sarcoma/peripheral primitive neuroectodermal. Patients received cixutumumab 10 mg/kg intravenouslyover one hour every other week, until disease progression or discontinuation for other reasons.

Patients were assessed at the completion of stage one (12 weeks). Stable disease (SD) was seen in 57% (n =21) patients with adipocytic sarcoma and one (n = 1) partial response (PR) was seen with this tumor type. Thestudy continued into stage two for the adipocytic sarcoma tier, which was fully enrolled (37 patients). Bycontrast, treatment for rest of the four tiers was ended at the completion of stage one because the pre-specifiedresponse rate threshold was not met. Partial responses were as follows: 41% in leiomyosarcoma; 35% insynovial sarcoma; 28% in the Ewing family of tumors, and 24% in rhabdomyosarcoma. Among all patientsenrolled in the trial, the most frequent treatment-related adverse events were hyperglycemia (5%) andasthenia (4%). Grade 3/4 events also included pain (6%) and thrombocytopenia (4%).

Peregrine Pharmaceuticals announced interim median overall survival of 8.8 months (38 weeks, 40 patients atfirst relapse) from a Phase II trial for Cotara in recurrent glioblastoma multiforme (GBM). Cotara is a targetedmonoclonal antibody linked to a radioisotope that is administered as a single-infusion therapy directly into thetumor, destroying the tumor from the inside out, with minimal exposure to the healthy tissue.

Peregrine's Phase II open-label, multicenter trial was designed to enroll 40 GBM patients at first relapse. Theprimary endpoint is safety and tolerability of the maximum tolerated dose, a single 25-hour interstitial infusionof 2.5 mCi/cc of Cotara. Secondary endpoints include OS, PFS, and proportion of patients alive at 6 months aftertreatments. The FDA has granted orphan drug status and fast track designation to Cotara for the treatment ofGBM and anaplastic astrocytoma.

ClinicalDevelopment

(Cont'd)


Source: Eli Lilly

Source: Peregrine

Back to top of Clinical Section

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https://investor.lilly.com/releasedetail.cfm?ReleaseID=579227http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=579150http://ir.peregrineinc.com/releasedetail.cfm?ReleaseID=579150https://investor.lilly.com/releasedetail.cfm?ReleaseID=579227


12/15

+Tumor-infiltrating CD8 Lymphocytes Predict Clinical Outcome in Breast Cancer

Tumor cells are often surrounded by infiltrating inflammatory cells, particularly lymphocytes and macrophages.+

Tumor antigens drive the development of tumor-specific adaptive immune responses. Cytotoxic CD8 Tlymphocytes are crucial components of tumor-specific cellular adaptive immunity. In the recent issue ofJCO,

+Mahmoud et al. analyzed the influence of density and distribution of CD8 cytotoxic lymphocytes on patientprognosis in a large, well-characterized series of patients with invasive breast cancer with a long follow-up.

+Tumor-infiltrating CD8 lymphocytes were assessed by immunohistochemical staining of tissue microarray cores

+from 1,334 unselected breast tumors from patients with a long-term follow-up. The number of CD8 T cells wascounted in tumor nests (intratumoral), in stroma adjacent to tumor cells and in stroma distant to tumor cells,and their relationship with clinical outcome was determined.

+The study findings showed that the total number of CD8 cells was positively correlated with tumor grade and

inversely correlated with patient's age at diagnosis, estrogen receptoralpha (ER-), and progesterone receptor(PgR). The total patient cohort was randomly divided into two separate training and validation sets beforeperforming univariate survival analysis. Applying univariate analysis to the training set, high total and distant

+stromal CD8 counts were associated with significantly longer breast cancer-specific survival. In multivariate

+analysis, the total CD8 T-cell count was an independent prognostic factor in both training and validation sets.The study results provide evidence of the prognostic importance of the cytotoxic T-cell population in breastcancer. This suggests that cytotoxic T cells have clinically significant antitumoral activity against human breastcarcinoma. Although initial results of breast cancer immunotherapeutic studies have been disappointing, theresults of this study support further investigation of this line of potential therapeutic intervention.

Biomarkers

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Source: JCO. 2011 May 20; 29(15):1949-55.

smartoncology.com

JCO, 29, May 20, 2011

+Survival Curves for Total Number and Distant Stromal CD8 Lymphocytes

BreastCancer-SpecificSurvival

Time (years)

P = .041

1.0

0.8

0.6

0.4

0.2

+CD8 (n=434; events, 129)_

CD8 (n=112; events, 49)

0 5 10 15 20 25

BreastCancer-SpecificSurvival

P< .001

Time (years)

+CD8 (n=372; events, 98)_

CD8 (n=174; events, 77)

0 5 10 15 20 25

1.0

0.8

0.6

0.4

0.2

Figure 1

Figure 2

+Figure 1-Total number of CD8 lymphocytes

+Figure 2- Distant stroma CD8 lymphocytes

http://jco.ascopubs.org/content/early/2011/04/11/JCO.2010.30.5037.abstracthttp://jco.ascopubs.org/content/early/2011/04/11/JCO.2010.30.5037.abstract


13/15

Clotting Factor Gene Polymorphisms and Colorectal Cancer Risk

Increased coagulation has been associated with cancer onset and progression. Mainly, small studies haveaddressed the association between clotting factor gene polymorphisms and the onset of colorectal cancer(CRC). A recent study published in JCO by Vossen et al. examined the association between six well-knownclotting factor (factor V Leiden, prothrombin G20210A, PAI-1 4G/5G, MTHFR 677C>T, fibrinogen gamma10034C>T, and factor XIII Val34Leu) gene polymorphisms and CRC risk in a large case-control study.

The clotting factors were genotyped in 1,801 patients with CRC and 1,853 healthy controls from a large Germanpopulation-based study. The risk of CRC associated with gene variants was determined by calculating oddsratios (ORs) and their 95% CIs using logistic regression. Evidence for an increased risk for CRC for homozygouscarriers of the prothrombotic factor V Leiden polymorphism was found. It showed a 5.8-fold increased risk forCRC compared to non-carriers. A 30% reduced risk was found for heterozygous carriers of factor V Leiden (OR =0.68) and prothrombin G20210A (OR = 0.69), implying an advantage for slightly increased thrombingeneration. Carriers of the antithrombotic factor XIII Val34Leu polymorphism showed a 15% reduced risk ofdeveloping CRC (OR = 0.85) compared to non-carriers. The results did not support the effect of PAI-1 4G/5G,MTHFR 677C>T, and fibrinogen gamma 10034C>T on CRC risk. The results support the role of factor V Leidenand prothrombin G20210A in the onset of CRC. Further research on the association between coagulation andcancer could lead to the discovery of novel drug targets for cancer prevention or treatment.

Biomarkers(Cont'd)

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Source: JCO. 2011 May 1;29(13):1722-7

smartoncology.com

http://jco.ascopubs.org/content/29/13/1722.abstract?sid=b99ddd3f-c95b-4df1-9d63-1858c1af27dbhttp://jco.ascopubs.org/content/29/13/1722.abstract?sid=b99ddd3f-c95b-4df1-9d63-1858c1af27db


14/15

Back to top of Regulatory Section Back to Top of Document 1

RegulatoryFDA Approves Afinitor for Patients with Advanced Pancreatic NET

ZYTIGA Receives FDA Approval for Treatment of Metastatic Prostate Cancer

SUTENT Receives FDA Approval for Advanced Pancreatic NET

Novartis announced that the FDA approved Afinitor (everolimus) tablets for the treatment of progressiveneuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced ormetastatic disease.

The approval was based on Phase III data from the RADIANT-3 (RAD001 In Advanced Neuroendocrine Tumors)trial examining the efficacy and safety of Afinitor plus best supportive care (BSC) versus placebo plus BSC in 410patients with advanced, low- or intermediate-grade pancreatic NET. The results showed that treatment withAfinitor more than doubled the time without tumor growth (median 4.6 to 11.0 months) and reduced the risk ofcancer progression by 65% when compared with placebo in patients with advanced pancreatic NET. Aconsistent improvement in PFS was seen with Afinitor in all patient subgroups. Novartis has also submittedmarketing applications for everolimus to the European Medicines Agency, for the treatment of patients withadvanced NET of gastrointestinal, lung, or pancreatic origin.

Centocor Ortho Biotech announced that the FDA has approved ZYTIGA (abiraterone acetate), an oral, once-daily medication for use in combination with prednisone for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.

ZYTIGA, in combination with prednisone, was evaluated in a pivotal Phase III, randomized, placebo-controlled,multicenter clinical study in patients who had received prior chemotherapy containing a taxane (N = 1,195).Patients were randomized 2:1 to receive ZYTIGA 1 gram daily in combination with prednisone 5 mg twice daily,or placebo in combination with prednisone 5 mg twice daily (control arm). The study results showed that at apre-specified interim analysis, treatment with ZYTIGA in combination with prednisone resulted in a 35%reduction in the risk of death (14.8 months vs. 10.9 months) and a 3.9-month difference in median survival

compared to placebo plus prednisone. In an updated analysis, results were consistent with those from theinterim analysis, with a 4.6-month difference between the two arms in median survival (15.8 months vs. 11.2months).

stPfizer announced the FDA has approved SUTENT (sunitinib malate) as the 1 anti-VEGF therapy to treatprogressive, well-differentiated pancreatic neuroendocrine tumors (NET) in patients with unresectable locallyadvanced or metastatic disease. The FDA approval was based on data from the SUN 1111 pivotal Phase III trial(n=171) evaluating single-agent SUTENT in patients with unresectable pancreatic NET. The primary endpointwas PFS. Other endpoints included OS, ORR and safety. The study results demonstrated that SUTENT provideda clinically significant improvement in PFS compared to placebo (10.2 versus 5.4 months. Treatment with

SUTENT also yielded a statistically significant improvement in tumor response, with an objective response rate(ORR) of 9.3%. No objective responses were observed with placebo. In addition, while overall survival (OS) wasnot mature at the time of final analysis, nine deaths were observed in patients enrolled in the SUTENT armversus 21 deaths in patients enrolled in the placebo arm. SUTENT has already been approved for advancedpancreatic NET in Europe

Source: Novartis

Source: Centocor Ortho Biotech Inc.

Source: Pfizer

smartoncology.com

http://www.novartis.com/newsroom/media-releases/en/2011/1513095.shtmlhttp://www.centocororthobiotech.com/cobi/viewDocumentByTitleAlias.html?title=PR_042811http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp#guid=20110520006117en&source=RSS_2011&page=1http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp#guid=20110520006117en&source=RSS_2011&page=1http://www.centocororthobiotech.com/cobi/viewDocumentByTitleAlias.html?title=PR_042811http://www.novartis.com/newsroom/media-releases/en/2011/1513095.shtml


15/15

NDA Submitted in US and Europe for Vemurafenib in Metastatic Melanoma

Pfizer Files NDA for Crizotinib with FDA for the Treatment of ALK-positive NSCLC

Roche and Daiichi Sankyo announced the submission of a new drug application (NDA) to the FDA and amarketing authorization application to the European Medicines Agency (EMA) for vemurafenib (RG7204,PLX4032), a proto-oncogene protein b raf inhibitor, for people with BRAF V600 mutation-positive metastaticmelanoma. Roche also submitted an application for the cobas 4800 BRAF V600 Mutation Test, a companiondiagnostic.

The submissions are based on results from two positive clinical studies (BRIM2 and BRIM3) that evaluatedvemurafenib in people with BRAF V600 mutation-positive metastatic melanoma, as determined by theinvestigational companion diagnostic test also being developed by Roche. Roche submitted a premarketapproval application (PMA) for the cobas 4800 BRAF V600 Mutation Test in the US. The test will also be

thregistered in Europe. Full data from BRIM2 and BRIM3 will be presented at the 47 Annual Meeting of theAmerican Society of Clinical Oncology (ASCO) on June 5, 2011, in Chicago.

Pfizer announced that its NDA for crizotinib, an oral first-in-class anaplastic lymphoma kinase (ALK) inhibitor, hasbeen accepted for filing and granted priority review status by the FDA. The proposed indication is for thetreatment of patients with ALK-positive advanced NSCLC.

Our ability to file applications for regulatory review in the U.S. and Japan simultaneously only three years afterbeginning worldwide clinical trials in patients with ALK-positive lung cancer is a testament to the hard work ofthe crizotinib team and the productive discussions that we have had with the respective regulatory agencies,said Garry Nicholson, President and General Manager, Pfizer Oncology Business Unit.

Regulatory(Cont'd)

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Source:

Source: Pfizer

Genentech,Daiichi Sankyo

smartoncology.com

http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp#guid=20110517005334en&source=RSS_2011&page=1http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=13387http://www.daiichisankyo.com/news/detail/004051.htmlhttp://www.daiichisankyo.com/news/detail/004051.htmlhttp://www.gene.com/gene/news/press-releases/display.do?method=detail&id=13387http://www.pfizer.com/news/press_releases/pfizer_press_releases.jsp#guid=20110517005334en&source=RSS_2011&page=1

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Smart Oncology May Issue 24ii, 2011