MAY 2011, VOL 4, NO 3

3rd ANNUAL REVIEW ISSUE

A Look at Recent Advances in Cancer Care

Breast CancerEribulin: A New Option for Metastatic Breast CancerGeorgia Litsas, RN, NP

Prostate CancerTranslating Basic Science into the Clinic: Approval of AbirateroneWilliam D. Figg, PharmD

Ovarian CancerDevelopments in the Management of Ovarian CancerMaurie Markman, MD

Gastrointestinal CancerAdvances in Treating Pancreatic Neuroendocrine CancerDori L. Klemanski, MS, RN, CNP

Follicular LymphomaEmerging Agents & Regimens for Follicular LymphomasElizabeth Reist, PharmD; Angie Elefante, PharmD, BCOP; Francisco Hernandez-Ilizaliturri, MD

Supportive CareVitamin and Supplement Use in Oncology PatientsMegan Hagerty, PharmD, BCOP©

Copyright

Big

sto

ck.c

om

/mangosto

ck

©iS

tockp

ho

to.c

om

/Seb

astia

n K

au

litzki

For Payers, Purchasers, & Oncology P&T Committees

©2011 Green Hill Healthcare Communications, LLC

MAY 2011 www.TheOncologyPharmacist.com VOL 4, NO 3

TOP_May 2011_4_TOP 5/13/11 9:28 AM Page Cov1

TOP_May 2011_4_TOP 5/13/11 9:28 AM Page Cov2

May 2011 I VOL 4, NO 3 3www.TheOncologyPharmacist.com

Editorial Board

EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman, RN,MSN, APRN,BC, AOCN Cleveland Clinic TaussigCancer InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C. Gammon, BSPhOncologyPharmacist.net Warwick, RI

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase Cancer CenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDIndiana UniversityHospitalIndianapolis, IN

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud,PharmD, BCOP,FASHPThe University of TexasM. D. Anderson CancerCenter

Houston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina College ofPharmacyColumbia, SC

Steve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Burt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

TOP_May 2011_4_TOP 5/13/11 9:36 AM

PUBLISHING STAFF

Senior Vice President, Sales & MarketingPhilip [email protected]

PublisherJohn W. [email protected]

Associate EditorDawn [email protected]

Quality Control DirectorBarbara Marino

Director, Client ServicesJoe [email protected]

Production ManagerStephanie Laudien

Business ManagerBlanche [email protected]

Executive AdministratorAndrea Boylston

Circulation [email protected]

Editorial Contact:Telephone: 732-992-1891 Fax: 732-656-7938

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2011 byGreen Hill Healthcare Communications LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrieval sys-tem, without written permission from the Publisher.Printed in the United States of America.

EDITORIAL CORRESPONDENCE should beaddressed to EDITORIAL DIRECTOR, The OncologyPharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp,NJ 08831. E-mail: [email protected]. YEARLYSUBSCRIPTION RATES: United States and posses-sions: individuals, $105.00; institutions, $135.00; singleissues, $17.00. Orders will be billed at individual rate untilproof of status is confirmed. Prices are subject to changewithout notice. Correspondence regarding permission toreprint all or part of any article published in this journalshould be addressed to REPRINT PERMISSIONSDEPARTMENT, Green Hill Healthcare Commun i -cations, LLC, 241 Forsgate Drive, Suite 205C, MonroeTwp, NJ 08831. The ideas and opinions expressed in TheOncology Pharmacist® do not necessarily reflect those of theEditorial Board, the Editorial Director, or the Publisher.Publication of an advertisement or other product mentionin The Oncology Pharmacist® should not be construed as anendorsement of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damage topersons or property arising out of or related to any use ofthe material contained in this periodical. The reader isadvised to check the appropriate medical literature and theproduct information currently provided by the manufac-turer of each drug to be administered to verify the dosage,the method and duration of administration, or contraindi-cations. It is the responsibility of the treating physician orother healthcare professional, relying on independent expe-rience and knowledge of the patient, to determine drugdosages and the best treatment for the patient. Every efforthas been made to check generic and trade names, and toverify dosages. The ultimate responsibility, however, lieswith the prescribing physician. Please convey any errors tothe Editorial Director. BPA Worldwide membershipapplied for April 2011.

For Payers, Purchasers, & Oncology P&T Committees

Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™

™

241 Forsgate Drive, Suite 205C

Monroe Twp, NJ 08831

4 May 2011 I VOL 4, NO 3 www.TheOncologyPharmacist.com

This month’s Third AnnualReview Issue of The OncologyPharmacist highlights some of

the top advances in cancer care overthe past year. Although a few sys-temic cytotoxic therapies emerged assome of last year’s winners—eribulin,sipuleucel-T, bevacizumab in ovari-an cancer—most of the practice-changing studies reflect the continued shift in oncology towardgreater personalization of care. With a combined 10,000-plus

abstracts submitted for the AmericanSociety of Clinical Oncology and

the American Society of Hematology annual meetingsalone, we just do not have the space to address everyimportant discovery from the past 12 months, althoughwe managed to include several of the most noteworthydevelopments. Many of those not included have been dis-cussed in previous issues and are likely to be featured in

upcoming issues as investigators release updated data fromongoing studies. Also this year, the role of the oncology pharmacist has

reached prominence in our community and with ourpatients. With this in mind, we tried to summarize key find-ings on new regimens, drug–drug interactions, and pharma-cy process changes. As we move farther into the era of per-sonalized care, our role also will travel into pharmacogenetictesting for optimal outcomes with the least possible toxicity.We would like to thank all the authors who contributed

to this important issue. Many were directly involved in thestudies presented and others are experts in the therapeuticarea discussed. All share a deep understanding of the subjectand a passion for improving care for patients with cancer. In addition to looking at what occurred in oncology

during the past year, we also took an opportunity to lookahead at what might happen in the coming year. Pleasetake a moment to read the article at the end of the issuereviewing investigational therapies that appear to be justover the horizon. As always, please send us your questionsand comments to [email protected]. �

Patrick Medina,PharmD, BCOPEditor-in-Chief

Breast Cancer Genome SequencedBy sequencing, then comparing the whole genomes oftumors with those of the patient’s healthy cells in 50women with breast cancer, researchers found more than1700 mutations, most of which were unique to theindividual. They identified 8 significantly mutated genes:PIK3CA, TP53, ATR, RUNX1, MYST3, PRSS8, ZNHIT2,and MAP3K1. Of these, PIK3CA (43%), TP53 (15.2%),and MAP3K1 (9.3%) were found to have the highest ratesof incidence.The novel gene MAP3K1 was found to be disabled in

estrogen receptor–positive breast cancers. This gene controlsprogrammed cell death, meaning that by being disabled, cellsthat should die continue to live. ATR and MYST3mutationsalso occurred in approximately 10% of breast cancers.“Cancer genomes are extraordinarily complicated. This

explains our difficulty in predicting outcomes and findingnew treatments,” said Matthew J. Ellis, MD, PhD, FRCP,of Washington University in St. Louis, during his presen-tation at the 102nd American Association for CancerResearch Annual Meeting. “To get through this experi-ment and find only 3 additional gene mutations at the10% recurrence level was a bit of a shock.”If a cancer’s genome can be sequenced before treatment

and mutations that are rare in breast cancer but commonin other cancers are identified, drugs may already exist totreat them. Ideally, the goal is to design treatment plans bysequencing the tumor genome when the cancer is firstdiagnosed, according to Ellis.

SQ Bortezomib as Effective as IV Delivery inRelapsed Multiple MyelomaUsing the recommended dose of 1.3 mg/m2 administered asa 3- to 5-second bolus intravenous (IV) injection on days1, 4, 8, and 11 of 21-day cycles, patients with relapsedmultiple myeloma after 1 to 3 previous lines of therapyachieved noninferior efficacy with subcutaneous (SQ)versus IV delivery of the drug when receiving up to 8 cycles.In addition, those in the SQ arm experienced improvementin their systemic safety profile.In a phase 3 randomized trial, Moreau and colleagues

found an overall response rate (ORR) of 42% after 4cycles (ORR difference –0.4%; 95% confidence interval

[CI], –14.3 to 13.5; P = .002). At 12 months, they foundno significant differences in time to progression (median10.4 months; 95% CI, 8.5-11.7 vs 9.4 months; 95% CI,7.6-10.6; P = .387) and 1-year overall survival (72.6%;95% CI, 63.1-80.0 vs 76.7%; 95% CI, 64.1-85.4; P = .504)with SQ versus IV administration. Noninferiority wasdefined as retaining 60% of the IV treatment effect. In the SQ group, adverse events grade 3 or higher

included thrombocytopenia (13%), neutropenia (18%),and anemia (12%). Less peripheral neuropathy of anygrade was experienced in the SQ arm compared with theIVarm (38% vs 53%; P = .044), grade 2 or worse (24% vs41%, respectively; P = .012), and grade 3 or worse (6% vs16%, respectively; P = .026).The researchers concluded that “subcutaneous adminis-

tration is a promising alternative to intravenous adminis-tration, particularly in patients with poor venous access orat increased risk of side effects.”

PhRMA Reinforces Its Commitment to Safety,Integrity, and Availability of Drugs“PhRMA’s member companies recognize the importance ofavoiding unexpected disruptions in the supply of neededmedicines to patients,” said Pharmaceutical Research andManufacturers of America (PhRMA) senior assistant generalcounsel Maya J. Bermingham in a May 2 statement regardingthe myriad factors that contribute to drug shortages. “Toachieve that goal,” Bermingham continued, “PhRMAcompanies are committed to maintaining good manufacturingpractices and working closely with the FDA, supply chainpartners, and providers when unexpected shortages occur.”PhRMA’s ongoing commitment to the safety, integrity,

and market availability of the drugs they manufactureincludes leading the RxResponse program, which coordi-nates the entire drug supply chain to ensure patients’ timelyaccess to medicines during a natural disaster, such as its newform to expedite applications for prescription medicine assis-tance for those patients affected by the tornadoes and floodsin the South. In addition, many PhRMA companies partici-pate in Rx360, a consortium working to develop and toimplement enhanced global quality systems and processes tohelp members ensure product quality and authenticitythroughout their supply chains. �

News Notes

From the Editor

TOP_May 2011_4_TOP 5/13/11 9:30 AM

TOP_May 2011_4_TOP 5/13/11 9:30 AM

Hematologic Malignancies

6 May 2011 I VOL 4, NO 3 www.TheOncologyPharmacist.com

Imatinib (Gleevec) revolutionized thetreatment of Philadelphia chromo-some–positive chronic myeloid

leukemia (CML) and established tar-geting and inhibiting BCR-ABL as thestandard of care.1 In 2009, 8-year fol-low-up data from the landmark phase 3IRIS (International Randomized Studyof Interferon Versus STI571) trial werepresented for the 553 patients withnewly diagnosed chronic-phase (CP)CML randomized to imatinib. Findingsshowed a cumulative best completecytogenetic response (CCyR) rate of83% and an estimated rate of overallsurvival (OS) of 93% (CML-relateddeaths only).2 Despite these positiveresults, 17% of patients treated withimatinib never achieve a CCyR, and10% of those who do subsequentlyrelapse. An additional 8% of patientsare imatinib-intolerant.2Second-generation tyrosine kinase

inhibitors (TKIs) are more potentinhibitors of BCR-ABL and have de m -onstrated efficacy in patients resistant toor intolerant of imatinib (Table 1).3-7The US Food and Drug Administrationhas approved dasatinib (Sprycel) andnilotinib (Tasigna) as first- and second-line options in CP-CML. Both drugs areactive against all BCR-ABL mutationsexcept T315I and have well-establishedsafety profiles.8,9 Their increased potencymakes them attractive candidates for usein the first-line setting.

NilotinibThree recent studies evaluated re -sponse to nilotinib in patients withnewly diagnosed CP-CML (Table 2).10-13All point to nilotinib as being an effec-tive and safe frontline option in thispatient population.A single-institution study at M. D.

Anderson Cancer Center reported that50 (98%) of the 51 evaluable patientstreated with 400 mg of nilotinib twicedaily for at least 3 months attained aCCyR and 39 (76%) attained a majormolecular response (MMR).10 The 3-month rate of CCyR was 96%, increas-ing to 98% at 6 months. The projectedevent-free survival (EFS) rate at 24months was 90%. Grade 3/4 hematolog-ic toxicities included neutropenia(12%) and thrombocytopenia (11%).Non hematologic toxicities were grade1/2 and manageable. Some patientsrequired treatment interruptions and/ordose reductions; the median dose at 12months was 800 mg. The phase 2 GIMEMA (Italian

Group for Hematological Malignanciesof the Adult) trial treated 73 patientswith a 400-mg dose of nilotinib twicedaily; median follow-up was 30months.11 Rates of CCyR, MMR, andcomplete molecular response (CMR)at 24 months were 92%, 82%, and12%, respectively. One patient pro-gressed to advanced disease and wasfound to have developed a T315I

mutation. The discontinuation ratedue to adverse events was 5%. ENESTnd (Evaluating Nilotinib

Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients), a phase 3,randomized, open-label, multicenterstudy, compared the efficacy and safetyprofiles of nilotinib and imatinib.12Patients were assigned 1:1:1 to receivenilotinib 300 mg twice daily (n = 282),nilotinib 400 mg twice daily (n = 281),or imatinib 400 mg once daily (n = 283).The MMR rate at 12 months—thestudy’s primary end point—was signifi-cantly higher in the nilotinib 300-mgarm and in the nilotinib 400-mg armthan in the imatinib arm (44% vs 43%vs 22%, respectively; P <.0001 for nilo-tinib vs imatinib comparisons). At 12months, the best cumulative rates ofMMR were also significantly higher forthe nilotinib 300-mg and 400-mg armsthan for the imatinib group (51% vs 50%vs 27%, respectively; P <.0001 for nilo-tinib vs imatinib comparisons), as werethe cumulative CCyR rates (80% vs78% vs 65%, respectively; P <.0001 fornilotinib vs imatinib comparisons). Nilotinib was associated with faster

responses, with a 6-month MMR rate of33% in the nilotinib 400-mg arm and30% in the nilotinib 300-mg group com-pared with 12% in the imatinib arm. At9 months, the MMR rate was 43% in thenilotinib 300-mg arm, 38% in the nilo-tinib 400-mg group, and 18% in the ima-

tinib arm. A greater proportion ofpatients achieved undetectable levels ofdisease (defined as a CMR ≤0.0032%BCR-ABL on the International Scale)with nilotinib 300-mg and 400-mg dosesthan with imatinib (13% vs 12% vs 4%,respectively), resulting in significantlyfewer cases of progression in the nilotinibarms than in the imatinib group. Grade 3/4 nonhematologic adverse

events were uncommon in theENESTnd trial; the only grade 3/4nonhematologic adverse event toaffect >1% of patients was rash, whichoccurred in 3% of patients treated withnilotinib 400 mg twice daily. None ofthe patients in the trial experiencedQTcF prolongation >500 msec. Grade3/4 laboratory abnormalities wereuncommon among patients takingnilotinib, although the nilotinib armshad higher rates of grade 3/4 thrombo-cytopenia than the imatinib group.Patients treated with imatinib weremore likely to experience grade 3/4anemia and neutropenia than thosegiven nilotinib, however. At a minimum of 24 months of follow-

up, nilotinib proved superior to imatinibacross all efficacy end points assessed,13with significantly higher rates of MMRin the nilotinib 300-mg and 400-mgarms than in the imatinib group (71% vs67% vs 44%, respectively; P <.0001 fornilotinib vs imatinib comparisons). Thenilotinib 400-mg and 300-mg arms con-

New Horizons in CML Therapy By A. Megan Cornelison, MSPADepartment of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston

Elias Jabbour, MD Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston

Table 1 Effectiveness of Second-Generation TKIs in Imatinib-Resistant or -Intolerant Patients with CML by Phase

Dasatinib Nilotinib Bosutinib

CP (N = 387)

AP (n = 174)

MyBP (n = 109)

LyBP (n = 48)

CP(n = 321)

AP (N = 137)

MyBP (N = 105)

LyBP (N = 31)

CP (N = 146)

AP (N = 51)

BC (N = 38)

Median follow-up, mo

15 14 12+ 12+ 24 9 3 3 7 6 3

Imatinibresistant, %

74 93 91 88 70 80 82 82 69 NR NR

Hematologicresponse, %

— 79 40 94 56 80 80 80 80 5.5 80

CHR 91 45 27 29 76 31 11 13 81 54 36

NEL — 19 7 6 — 12 1 0 — 0 0

CyR, % NR 44 36 52 NR NR NR NR — NR NR

CCyR 49 32 26 46 46 20 29 32 34 27 35

Partial 79 79 79 79 79 79 79 79 79 79 79

1-year OS, %(no.)

96 (15) 82 (12) 50 (12) 50 (5) 87 (24) 67 (24) 42 (12) 42 (12) 98 (12) 60 (12) 50 (10)

AP indicates accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; CHR, complete hematologic response; CML, chronic myeloid leukemia; CP, chronic phase; CyR, cytogenetic response; LyBP, lymphoid blast phase; MyBP, myeloid blast phase; NEL, no evidence of leukemia; NR, none reported; OS, overall survival; TKI, tyrosine kinase inhibitors. Sources: References 3-7.

TOP_May 2011_4_TOP 5/13/11 9:30 AM



tinued to demonstrate significantlyhigher rates of CMR (26% vs 21% vs10%, respectively) than the imatinibgroup (26% vs 21% vs 10%, respective-ly; nilotinib 400 mg vs imatinib, P<.0001; nilotinib 300 mg vs imatinib, P= .004). The safety and tolerability pro-files of nilotinib and imatinib remainedunchanged with longer follow-up.

DasatinibResponse to dasatinib also was evaluatedin 3 studies (Table 3).14-16 Investigatorsfor these studies concluded that dasatinibwas an effective approach to manag-ing CP-CML in the first-line setting,yielding high rates of CCyR andMMR. Adverse events were consid-ered manageable.

A phase 2 study randomized patientswith newly diagnosed CP-CML to 100mg of dasatinib once daily or 50 mg ofdasatinib twice daily in the first-linesetting.14 Median follow-up was 24months, with 50 patients observed forat least 3 months. Of these 50 patients,49 (98%) attained a CCyR and 41(82%) attained an MMR. At 6months, 94% of evaluable patients hadattained CCyR. The treatment armshad similar rates of response. In -vestigators projected the EFS rate at 24months would reach 88%. No signifi-cant differences were observed betweenthe study arms in toxicity rates. Grade3/4 hematologic toxicities included neu-tropenia (21%) and thrombocytopenia(10%). Nonhematologic toxicities weregenerally grade 1/2. Some patientsrequired treatment interruptions and/ordose reductions, and the actual mediandose at 12 months was 100 mg (range, 20-100 mg).

The randomized, phase 3, multicenterDASISION (Dasatinib versus ImatinibStudy in Treatment-Naïve CML-CPPatients) trial compared the efficacy andsafety of dasatinib with imatinib, and itsprimary end point was the rate of con-firmed CCyR at 12 months.15 Patientswith newly diagnosed CP-CML wereassigned 1:1 to 100 mg of dasatinib oncedaily (n = 259) or 400 mg of imatinibdaily (n = 260). At 12 months, the bestcumulative MMR rate was significantlyhigher in the dasatinib arm than in theimatinib group (46% vs 28%, respective-ly; P <.0001) as was the best cumulativerate of CCyR (83% vs 72%, respectively;P <.001). Fewer patients on dasatinibprogressed to accelerated phase or blastcrisis compared with imatinib (1.9% vs3.5%, respectively).

Grade 3/4 nonhematologic adverseevents were uncommon in both treat-ment arms. Approximately 10% ofpatients treated with dasatinib experi-enced pleural effusions, but these weremostly grade 1/2. Rates of grade 3/4 ane-

mia and thrombocytopenia were higherwith dasatinib than with imatinib. In thedasatinib arm, 5% of patients discontin-ued because of drug-related adverseevents compared with 4% of patients inthe imatinib arm.

Similar results were reported at amedian of 18 months of follow-up,16with a cumulative rate of CCyR of 85%in the dasatinib arm compared with80% in the imatinib group. Cumulativerates of MMR were also significantlyhigher in the dasatinib group comparedwith the imatinib group (57% vs 41%,respectively; P = .0002). A greater pro-portion of patients in the dasatinib armhad CMR ≤0.0032% BCR-ABL on theInternational Scale compared with theimatinib arm (13% vs 7%, respectively)at any time. Longer follow-up demon-strated similar safety and tolerabilityprofiles for dasatinib and imatinib.

The Southwest Oncology Group, theEastern Cooperative Oncology Group,the Cancer and Leukemia Group B, theNational Cancer Institute of CanadaClinical Trials Group collaborated on aphase 2 study comparing 100 mg ofdasatinib daily (n = 123) with 400 mg ofimatinib daily (n = 123) in patientswith newly diagnosed CP-CML.Dasatinib was associated with deepermolecular responses than imatinib.17 At12 months’ follow-up, patients in thedasatinib arm had achieved a median3.3 log reduction in BCR-ABL tran-script levels, which was significantlyhigher than the 2.8 log reduction seenwith imatinib (P = .048). Rates ofhematologic and cytogenetic responsesand OS did not differ significantlybetween the treatment groups.

BosutinibThe BELA (Bosutinib Efficacy andSafety in CML Trial), an international,multicenter, randomized, open-labelphase 3 study, compared the novel TKIbosutinib (n = 250) with imatinib (n =252) in the first-line setting.18 A superiorrate of CCyR at 12 months was the pri-mary end point, with a superior MMRrate at 12 months as a secondary endpoint. For analysis purposes, nonevalu-able patients at 12 months were catego-rized as nonresponders, and the studyfailed to meet its primary end point,demonstrating similar rates of CCyR inthe bosutinib arm and the imatinib arm(70% vs 68%, respectively; P = .601).Limiting the analysis to evaluablepatients indicated a significantly higherrate of CCyR with bosutinib comparedwith imatinib (78% vs 68%, respective-ly; P =.026). Bosutinib was also associat-ed with a significantly higher MMR ratethan imatinib in the intent-to-treat(39% vs 26%, respectively; P = .002) andthe evaluable populations (43% vs 27%,respectively; P <.001). More follow-up isneeded to determine whether patients’responses are durable and whether bosu-tinib is superior to imatinib.

ConclusionResults of trials investigating second-generation TKIs in the first-line set-ting show that these agents providefaster response rates and deeperresponses compared with imatinib.The newer TKIs are also associatedwith lower rates of progression toaccelerated phase/blast crisis. Nilo -tinib and dasatinib (and possiblybosutinib, if approved) should join

imatinib as acceptable first-lineoptions for patients with newly diag-nosed CP-CML. �

References1.Druker BJ, Guilhot F, O’Brien SG, et al. Five-year fol-low-up of patients receiving imatinib for chronicmyeloid leukemia. N Engl J Med. 2006;355:2408-2417.2. Deininger M, O’Brien SG, Guilhot F, et al.International randomized study of interferon vs STI571(IRIS) 8-year follow up: sustained survival and low riskfor progression or events in patients with newly diag-nosed chronic myeloid leukemia in chronic phase(CML-CP) treated with imatinib. Blood (ASH AnnualMeeting Abstracts). 2009;114:Abstract 1126. 3. Hochhaus A, Kantarjian HM, Baccarani M, et al.Dasatinib induces notable hematologic and cytogenet-ic responses in chronic-phase chronic myeloidleukemia after failure of imatinib therapy. Blood.2007;109:2303-2309. 4. Hochhaus A, Baccarani M, Deininger M, et al.Dasatinib induces durable cytogenetic responses inpatients with chronic myelogenous leukemia in chronicphase with resistance or intolerance to imatinib.Leukemia. 2008;22:1200-1206. 5. Shah NP, Kantarjian HM, Kim DW, et al.Intermittent target inhibition with dasatinib 100 mgonce daily preserves efficacy and improves tolerability inimatinib-resistant and -intolerant chronic-phase chron-ic myeloid leukemia. J Clin Oncol. 2008;26:3204-3212. 6. Kantarjian HM, Giles F, Gattermann N, et al.Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patientswith Philadelphia chromosome-positive chronic mye -logenous leukemia in chronic phase following imatinibresistance and intolerance. Blood. 2007;110:3540-3546. 7. Bruemmendorf TH, Cervantes F, Kim D, et al.Bosutinib is safe and active in patients (pts) with chron-ic phase (CP) chronic myeloid leukemia (CML) withresistance or intolerance to imatinib and other tyrosinekinase inhibitors. J Clin Oncol. 2008;26S:Abstract 7001.8. Sprycel (dasatinib) [package insert]. Princeton, NJ:Bristol-Meyers Squibb Company; 2010.9. Tasigna (nilotinib) [package insert]. East Hanover,NJ: Novartis Pharmaceuticals Corporation; 2010.10. Cortes JE, Jones D, O’Brien S, et al. Nilotinib asfront-line therapy for patients with chronic myeloidleukemia in early chronic phase. J Clin Oncol.2010;28:392-397.11. Rosti G, Castagnetti F, Gugliotta G, et al. Excellentoutcomes at 3 years with nilotinib 800 mg daily in earlychronic phase, Ph+ chronic myeloid leukemia (CML):results of a phase 2 GIMEMA CML WP clinical trial.Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 359.12. Saglio G, Kim DW, Issaragrisil S, et al; for theENESTnd Investigators. Nilotinib versus imatinib fornewly diagnosed chronic myeloid leukemia. N Engl JMed. 2010;362:2251-2259. 13. Hughes TP, Hochhaus A, Saglio G, et al. ENESTndupdate: continued superiority of nilotinib versus ima-tinib in patients with newly diagnosed chronic myeloidleukemia in chronic phase (CML-CP). Presented at:American Society of Hematology Annual Meeting andExposition; December 4-7, 2010; Orlando, FL.14. Cortes JE, Jones D, O’Brien S, et al. Results of dasa-tinib therapy in patients with early chronic-phase chron-ic myeloid leukemia. J Clin Oncol. 2010;28:398-404.15. Kantarjian H, Shah NP, Hochhaus A, et al.Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med.2010;362:2260-2270. 16. Shah N, Kantarjian H, Hochhaus A, et al.Dasatinib versus imatinib in patients with newly diag-nosed chronic myeloid leukemia in chronic phase(CML-CP) in the DASISION trial: 18-month follow-up. Blood (ASH Annual Meeting Abstracts). 2010;21:Abstract 206.17. Radich JP, Kopecky KJ, Kamel-Reid S, et al. A ran-domized phase II trial of dasatinib 100 mg vs imatinib400 mg in newly diagnosed chronic myeloid leukemia inchronic phase (CML-CP): the S0325 intergroup trial.Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract LBA-6. 18. Gambacorti-Passerini C, Kim DW, Kantarjian HM,et al. An ongoing phase 3 study of bosutinib (SKI-606)versus imatinib in patients with newly diagnosed chron-ic phase chronic myeloid leukemia. Blood (ASH AnnualMeeting Abstracts). 2010;116:Abstract 208.

Table 2 Response Rates with First-Line Nilotinib

Phase Patients, No. Dose CCyR, % MMR, %

2 67 400 mg twice daily 93 81

2 73 400 mg twice daily 93 85

3 846a 300 mg (n = 282)400 mg (n = 281)

8078

4443

CCyR indicates complete cytogenetic response; MMR, major molecular response.aThe remaining 283 patients received imatinib.Sources: References 10-13.

Table 3 Response Rates with First-Line Dasatinib

Study Patients, No. CCyR, % MMR, % PFS, % OS, %

MDACC 62 98 71 — —

DASISION 259 78a 57 94.9(at 18 mo)

96(at 18 mo)

S0325 123 82 59 99(at 12 mo)

100(at 12 mo)

CCyR indicates complete cytogenetic response; MMR, major molecular response; OS, overall survival; PFS, progression-free survival.aConfirmed CCyR.Sources: References 14-16.

TOP_May 2011_4_TOP 5/13/11 9:30 AM

www.TheOncologyPharmacist.com8 May 2011 I VOL 4, NO 3


Follicular lymphoma (FL) is one ofthe most common subtypes ofindolent non-Hodgkin lym-

phoma (NHL). Although FL is consid-ered incurable with currently availabletherapy, the introduction of mono-clonal antibodies has improved clinicaloutcomes for this group of patients.Ongoing research focuses on assistingpracticing oncologists with selectingthe proper therapeutic options for spe-cific clinical scenarios. This articlepresents some of the most recent andnovel approaches for treatment of FL,with regimens involving rituximab(Rituxan), bendamustine (Treanda),lenalidomide (Revlimid), and bortez -omib (Velcade).

Rituximab MaintenanceThis past January, the US Food and DrugAdministration approved rituximab formaintenance therapy in patients withpreviously untreated FL who achieved aresponse to rituximab in combinationwith chemotherapy.1 Updated resultsfrom the PRIMA (Primary Rituximaband Maintenance) trial (Table 1)showed sustained benefits from ritux-imab maintenance therapy in patientswith FL who had high tumor burden (n = 1193). In the observational arm,60.3% of patients achieved 3-year pro-gression-free survival (PFS) comparedwith 78.6% of patients in the mainte-nance arm (hazard ratio [HR], 0.55; 95%confidence interval [CI], 0.44-0.68).2,3Similar to what was observed in ritux-imab maintenance clinical trials in therelapsed/refractory setting, improve-ments in PFS did not translate intoimprovement in overall survival(OS).2,3For asymptomatic patients with non-

bulky FL, many clinicians believe watch-ful waiting is superior to chemotherapy.As research on less toxic and effectivetherapies such as rituximab continues toemerge, clinicians are questioning thewatchful waiting approach. For example,Ardeshna and colleagues reported resultsof a clinical trial comparing ri tuximabinduction therapy followed by rituximabmaintenance versus observation for non-bulky FL grades 1-3a (Table 1). Pre -liminary results are encouraging, with

patients in the rituximab arm achiev-ing a significant delay in the need toinitiate new therapy compared withthose in the watchful waiting arm (P<.001; 95% CI, 0.13-0.29).4 Im prove -ments in more clinically relevant endpoints, such as PFS and OS, have notyet been observed.The benefit of rituximab maintenance

in FL patients was further evaluated byVidal and associates in a meta-analysis ofclinical trials comparing rituximab main-tenance with observation in previouslyuntreated or relapsed/refractory FL.Results showed increased OS in the ri -tuximab maintenance arm for relapsed/refractory FL (HR, 0.75; 95% CI, 0.57-0.91) but no significant change in OSfor previously untreated patients (HR,0.83; 95% CI, 0.56-1.23).5 In theabsence of a clear benefit in OS, clini-cians must carefully weigh the benefitsand risk for individual patients of start-ing rituximab maintenance in the first-line or relapsed/refractory setting.

Rituximab in Combination withLenalidomideSeveral trials have evaluated the com-bination of rituximab and lenalido-mide in FL patients. Ahmadi and col-leagues treated rituximab-resistantrelapsed/refractory indolent or mantlecell lymphoma patients with ritux-imab, lenalidomide, and dexametha-sone (Table 2). Preliminary resultsshowed an overall response rate(ORR) of 60% for the subset of 18patients with FL, and 78% of allpatients were progression-free at 12months.6 Another study evaluated theability of lenalidomide to overcomethe negative impact of low affinity

FCGR3 genotype on rituximab activ-ity. Early analysis suggests thatpatients with the higher affinityFCGR3 genotype (158V/V) appear tohave significantly increased ORR andPFS compared with patients with thelow-affinity FCGR3 allele (158F)when treated with rituximab mono -therapy.7 Dutia and colleagues formallyevaluated whether lenalidomide couldimprove rituximab activity in FLpatients with FCGR3-158V/F orFCGR3-158F/F genotypes. Patients with relapsed/refractory

indolent lymphoma were treated witha combination of rituximab andlenalidomide. FcγRIIIA genotype wasdetermined in DNA isolated fromperipheral blood cells by polymerasechain reaction amplification followedby allele-specific restriction enzymedigestion. Preliminary results suggestan impressive ORR of 100% andmedian PFS of 14.85 months forpatients with the FCGR3-158V/Fpolymorphism and 8.31 months forpatients with the FCGR3-158F/Fpolymorphism. The subsets of patientswith other polymorphisms of theFCGR3 genotype were too small forresearchers to draw any preliminary

conclusions. Enrollment into thestudy continues, and final resultsmight support using lenalidomide incombination with rituximab to treatrelapsed/refractory lymphomas.8Rituximab and lenalidomide were

also tested in the first-line setting byFowler and colleagues in a single-armstudy that enrolled 30 patients withpreviously untreated NHL, including17 patients with FL (Table 2).9 TheORR was 86%; 79% of all patients and94% of FL patients achieved a com-plete response (CR). Grade 3/4 adverseevents consisted primarily of rash (6 patients), neutropenia (7 patients),and myalgia (4 patients). Other grade3/4 adverse events included neuropa-thy, infection, fatigue, and thrombosis,each of which affected 1 patient. Aftera median follow-up period of 14.1months, only 1 patient progressed.Based on these results, planned accrualwas increased to 110 patients.

Rituximab in Combination withBortezomibBortezomib plus rituximab has shownactivity in FL patients. Pre clinical datasuggest rituximab and bortezomibinteract biologically. Coiffier and asso-

Emerging Agents and Regimens in the Managementof Follicular LymphomasBy Elizabeth Reist, PharmDDepartment of Pharmacy, Roswell Park Cancer Institute, Buffalo, New York

Angie Elefante, PharmD, BCOPDepartment of Pharmacy, Roswell Park Cancer Institute, Buffalo, New York

Francisco Hernandez-Ilizaliturri, MDAssistant Professor of Medicine, Department of Medical Oncology; Assistant Professor of Immunology,

Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York

As research on less toxicand effective therapiessuch as rituximabcontinues to emerge,clinicians are questioningthe watchful waitingapproach.

Table 1 Rituximab Maintenance Studies

End Points by Study Maintenance Observation

PRIMA2 n = 505 n = 513

3-Year PFS, % 74.9 57.6

2-Year CR or uCR, No. (%) 361 (71.5) 268 (52.2)

Grade 3/4 AEs, No. (%) 121 (24) 84 (17)

Infections ≥grade 2, No. (%) 197 (39) 123 (24)

Ardeshna et al4 n = 192 n = 186

3-Year PFS, % 81 30

PR, % 36 6

PD, % 3 17No change, % 74 11

3-Year OS, % 96 96

No new treatment at 3 years, % 91 48

Time to new treatment, mo NR at 48 33

Serious AEs, No. 10 25AE indicates adverse event; CR, complete response; NR, none reported; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; uCR, unconfirmed complete response.

TOP_May 2011_4_TOP 5/13/11 9:30 AM



ciates presented the results of a phase 3clinical trial evaluating the efficacy ofbortezomib in combination with ritux-imab.10 Re lapsed rituximab-naïve or -sensitive FL patients were randomizedto single-agent rituximab or the com-bination regimen. Preliminary resultsindicated that the doublet of rituximaband bortezomib resulted in a higherORR than rituximab alone (63% vs49%, respectively; P = .039). Patientsreceiving the combination were alsomore likely to experience CR thanpatients in the monotherapy arm (25%vs 18%, respectively; P = .035) andalso demonstrated prolonged PFS (398 days vs 334 days, respectively; P <.001). At the time the data werepresented, median OS had not beenreached in either group. These findingssuggest that bortezomib is potentially

an active agent for patients with FL.Ongoing studies are seeking to betterdefine the role of bortezomib in treat-ing FL and to find ways to minimizethe treatment-related toxicities observedwhen using this agent.

Rituximab in Combination withBendamustineThe treatment of previously untreatedFL continues to change. The incorpo-ration of various chemotherapy agentsfocuses on improving clinical outcomeand minimizing drug-related toxicities.A recent phase 3 clinical trial com-pared rituximab combined with a regi-men of cyclophosphamide, doxoru-bicin, vincristine, and prednisone(CHOP) versus rituximab plus ben-damustine for patients with grade 1/2 FLwho required systemic chemo therapy (n

= 549). Although the ORR was similarbetween the 2 treatment arms, the CRrate was higher in the group of patientsreceiving rituximab plus bendamustinethan in the group of patients treatedwith rituximab-CHOP (40% vs 30%,respectively; P = .0323). In addition,median PFS was longer for patientstreated with rituximab plus bendamus-tine than for those patients receiving rituximab-CHOP (54.8 vs 34.8 mo,respectively; P = .0002). Although thesepreliminary results are interesting, it isimportant to stress that only patientswith grade 1/2 FL were included in thisstudy. Sym ptomatic patients with grade3a FL should be treated with rituximab-CHOP therapy.11

ConclusionResults of recently completed andongoing clinical studies are encourag-ing and suggest that several novelagents are someday likely to have aplace in the management of untreatedrelapsed/refractory FL patients. Thelargest “obstacle” facing cliniciansand re searchers today is determiningthe best way to streamline evaluationsof the large number of effective thera-pies and establishing the optimal useand sequencing of these agents. Over -coming these hurdles promises toimprove the quantity and quality oflife for FL patients today and in futuregenerations. �

References1. US Food and Drug Administration. Rituximab 2011.February 2011. www.fda.gov/AboutFDA/CentersOffices/CDER/ucm241928.htm. Accessed March 6, 2011.2. Salles GA, Seymour JF, Offner F. Rituximab mainte-nance for 2 years in patients with high tumour burden fol-

licular lymphoma responding to rituximab pluschemotherapy (PRIMA): a phase 3, randomised con-trolled trial. Lancet. 2010;377:42-51. 3. Salles GA, Catalano J, Feugier P, et al. Updated resultsof the PRIMA study confirms the benefit of 2-years rituximab maintenance in follicular lymphoma patientsresponding to immunochemotherapy. Blood (ASHAnnual Meeting Abstracts). 2010;116:Abstract 1788. 4. Ardeshna KR, Smith P, Qian W, et al. An intergrouprandomised trial of rituximab versus a watch and waitstrategy in patients with stage II, III, IV, asymptomatic,non-bulky follicular lymphoma (grades 1, 2 and 3a). Apreliminary analysis. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 6.5. Vidal L, Gafter-Gvili A, Salles G, et al. Rituximabmaintenance for the treatment of patients with follicularlymphoma: systematic review and meta-analysis of ran-domized trials—2010 update. Blood (ASH AnnualMeeting Abstracts). 2010;116:Abstract 1798. 6. Ahmadi T, Chong EA, Gordon A, et al. Phase II trialof lenalidomide-dexamethasone-rituximab in relapsed orrefractory indolent B-cell or mantle cell lymphomasresistant to rituximab. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 3962.7. Taverna CJ, Bassi S, Hits F, et al. Rituximab mainte-nance treatment for a maximum of 5 years in follicularlymphoma: safety analysis of the randomized phase IIItrial SAKK 35/03. Blood (ASH Annual Meeting Abstracts).2010;116:Abstract 1802.8. Dutia M, DeRoock IB, Reed-Pease C, Tuscano J.Lenalidomide overcomes FcgRIIIa-mediated resistance torituximab in patients with relapsed/refractory indolentnon-Hodgkin’s lymphoma (NHL): a correlative analysisof a phase 2 study. Blood (ASH Annual Meeting Abstracts).2010;116:Abstract 3967.9. Fowler NH, McLaughlin P, Hagemeister FB, et al.Complete response rates with lenalidomide plus ritux-imab for untreated indolent B-cell non-Hodgkin’s lym-phoma. J Clin Oncol. 2010;28(15S):Abstract 8036.10. Coiffier B, Osmanov E, Hong X, et al. A phase 3 trialcomparing bortezomib plus rituximab with rituximabalone in patients with relapsed, rituximab-naive or -sen-sitive follicular lymphoma. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 857. 11. Rummel MJ, Niederle N, Maschmeyer G, et al.Bendamustine plus rituximab is superior in respect of pro-gression free survival and CR rate when compared toCHOP plus rituximab as first-line treatment of patientswith advanced follicular, indolent, and mantle cell lym-phomas: final results of a randomized phase III study ofthe StiL (Study Group Indolent Lymphomas, Germany).Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 405.

Table 2 Lenalidomide and Rituximab Trials

End Points by Study Rituximab/Lenalidomide, %

Ahmadi et al (part II)6 N = 23; FL, n = 15

Overall ORR, % 60

FL-only ORR, % 57

1-Year PFS, % 78

Fowler et al9 N = 30; FL, n = 17

ORR 86

Overall CR/uCR, No. (%) 79

FL-only CR, No. (%) 94

PR, % 7

SD, % 14

CR indicates complete response; FL, follicular lymphoma; ORR, overall response rate; PFS, progression-free survival; PR, partial response; SD, stable disease; uCR, unconfirmedcomplete response.

Impaired Hydroxylation of 5-Methylcytosine in TET2-Mutated MyeloidMalignanciesThrough the use of 2 assays (1 developedspecifically for this study), researchersdemonstrated for the first time thatTET2 mutations in predicted catalyticresidues and other positions compro-mise TET2 function in patients withvarious myeloid malignancies. Follow -ing in vitro study, researchers usedmethylation arrays in 62 of the study’s102 patients to analyze methylationpatterns in patients with and withoutTET2 mutations, finding that an asso-ciated methylation signature wasskewed strongly toward hypo methyla-tion compared with hyper methylation.The researchers concluded that theirresults suggest that TET2 is involved in conversion of 5-methylcytosine to 5-hydroxymethylcytosine in DNA.Jankowska A, et al. Abstract 1.

Prophylactic Rituximab After ASCT Prevents Steroid-Requiring Chronic Graft-vs-Host DiseaseIn a phase 2 trial, rituximab at 3, 6, 9,and 12 months after allogeneic hema -topoietic stem cell transplantationreduced the rate of steroid-requir - ing chronic graft-versus-host disease(GVHD) in patients in remission with out active GVHD. At 1 year,researchers found that the cumulativeincidence of chronic GVHD requiringcorticosteroids was just more than halfof historical levels at their institution.They also identified very low numbersof CD19+ B-cells during the first yearafter transplant, and that patients with-out chronic GVHD trended towardenhanced B-cell recovery. BRAF levelsalso trended higher in those withoutchronic GVHD as well as in those withchronic GVHD who did not require cor-ticosteroid treatment. The re searchers

concluded that these findings predictthat this therapy could free patients fromor reduce the severity of chronic GVHD,but cautioned a randomized trial shouldconfirm their findings. Cutler C, et al.Abstract 214.

Brentuximab Vedotin (SGN-35)in Patients with Relapsed orRefractory Hodgkin LymphomaBrentuximab vedotin was observed toproduce tumor shrinkage in 94% of102 patients with relapsed or refractoryHodgkin lymphoma after autologousstem cell transplant. In a phase 2, sin-gle-arm study, this novel antibody–drug conjugate targeted to CD30 alsoproduced an objective response rate of75%, and a B symptom resolution rateof 83%. The agent was found to have amanageable adverse event profile.Because of the poor prognosis of thesepatients, the researchers concludedthat their results encourage further

study of brentuximab vedotin. Chen R,et al. Abstract 283.

Crizotinib in Advanced,Chemoresistant ALK-PositiveLymphoma PatientsThis report on 2 chemoresistantpatients with ALK-positive anaplasticlarge cell lymphoma suggests that thisdisease is sensitive to ALK inhibition,in these cases through treatment withcrizotinib. This agent, a competitivesmall-molecule inhibitor of the ALKand c-Met/HGF receptor tyrosinekinases with cellular IC50 values inNPM-ALK expressing cells comprisedbetween 24 and 60 nM, achievedregression of superficial adenopathies inboth patients with 8 days of treatment.Patient 1 achieved complete response,which is ongoing at 6 months. Patient 2 continues complete response at 5 months of treatment. Gambacorti-Passerini CB, et al. Abstract 2877. �

52nd American Society of Hematology Annual Meeting & Exposition

Abstracts of Interest

TOP_May 2011_4_TOP 5/13/11 9:30 AM

On April 28, 2011, the US Foodand Drug Administration(FDA) approved abiraterone

acetate (Zytiga, Johnson & Johnson) forthe treatment of metastatic castration-resistant prostate cancer (CRPC) forpatients who have failed docetaxel ther-apy. Prostate cancer is a leading cause ofcancer mortality and morbidity in theUnited States.1,2 Each year approxi-mately 215,000 men are diagnosed and32,000 men die of the disease.Androgen ablation is the cornerstonefor the treatment of metastatic prostatecancer, as a result of Huggins andHodges’ Nobel Prize–winning workpublished in 1941. Depletion of circu-lating androgens either through surgicalor medical castration is the first thera-peutic maneuver for men failing defini-tive therapy (radical prostatectomy orexternal beam radiation). For severaldecades it was believed that the progres-sion following androgen-deprivationtherapy (ADT) was resistant to furtherhormonal manipulations.3

This paradigm started to changewhen prostate cancer gene–expressionstudies found that androgen-receptoractivated genes, which are normallydownregulated during ADT, becomereactivated on transition to CRPC.4,5Furthermore, ADT strategies resulted incastrate concentrations of testosterone;however, it was found that low levels ofcirculating androgen persisted (mainlythrough peripheral conversion of adre-nal steroids). In addition, gene upregu-lation is involved in androgen biosyn-thesis, including CYP 17.6-8Intratumoral enzymes involved in theconversion of upstream precursors oftestosterone and dihydrotestosteronebecame a molecular target.

Clinical TrialsCytochrome p450c17 is involved inandrogen biosynthesis by 17-alpha-hydroxylation of C21 steroids andcleavage of C17,20 bond of C21steroids.3,9 These reactions are criticalin the biosynthesis of dehydroepiandro -

sterone and androstenedione. Abirate -rone is a potent, selective, irreversibleinhibitor of CYP 17A1.10 In the initial

phase 1 trial of abiraterone conductedin chemotherapy-naïve CRPC patients,the drug was well tolerated. The dose

(1000 mg/day) used in the phase 2 trialwas determined after a plateau in thepharmacodynamic effects was observed.


Solid Tumors

YERVOY™ (ipilimumab)

731US11AB08002 03/11 Printed in USA

Y

A

P

U

M

T

rash (29%), and colitis (8%).

Now Approved

INDICATIONYERVOY is indicated for the treatment of unresectable or metastatic melanoma.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Important Safety Information

11:22 AM

Translating Basic Science into the Clinic: Approval of AbirateroneBy William D. Figg, PharmDMolecular Pharmacology Section and the Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

The benefit wasobserved across multiplesubgroups, such asperformance status, sitesof metastatic disease,and number of previouschemotherapy regimensreceived.

TOP_May 2011_4_TOP 5/13/11 9:31 AM


Solid Tumors

For additional information, please visit

www.YERVOY.com/hcp©2011 Bristol-Myers Squibb, Princeton, NJ 08543 731US11AB08002 03/11 Printed in USAYERVOY is a trademark of Bristol-Myers Squibb. All rights reserved.

Important Safety Information (continued)Recommended Dose Modifications:Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.Permanently discontinue YERVOY for any of the following:

corticosteroid dose to 7.5 mg prednisone or equivalent per day.

administration of first dose.

Immune-mediated Enterocolitis:

threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred

abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients.

intestinal perforation, 4 (0.8%) died as a result of complications, and

diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).

endoscopic evaluation for persistent or severe symptoms.

Immune-mediated Hepatitis:

threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3–5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and

>2.5X but ≤5X the ULN or total bilirubin elevation >1.5X but ≤3X the ULN; Grade 2).

patients for signs and symptoms of hepatotoxicity before each dose of YERVOY.

Immune-mediated Dermatitis:

life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients.

– 1 (0.2%) patient died as a result of toxic epidermal necrolysis.

dermatitis.

and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Immune-mediated Neuropathies:

Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

and additional cases of Guillain-Barré syndrome have been reported.

unilateral or bilateral weakness, sensory alterations, or paresthesia.

Immune-mediated Endocrinopathies:

to life-threatening immune-mediated endocrinopathies (requiring

of daily living; Grade 3-4) occurred in 9 (1.8%). – All 9 patients had hypopituitarism and some had additional

concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism.

intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome.

endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.

adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism.

– Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease.

– Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms.

imaging studies through enlargement of the pituitary gland.

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Pregnancy & Nursing:

and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

mother to the developing fetus.

many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY.

Common Adverse Reactions:The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Boxed WARNING regarding immune-mediated adverse reactions, on following pages.

1-2 4 11:22 AM

When compared with baseline valuesduring an additional phase 1/2 trial ofabiraterone in chemotherapy-naïvepatients, 67% of the patients achieved adecline in prostate-specific antigen(PSA) ≥50% and the median time toPSA progression (TTPP) on abi-raterone alone for all phase 2 patientswas 225 days.11 Toxicities observed were

attributed to changes in mineralocorti-coid, which were manageable with low-dose corticosteroids.11,12The pivotal trial for abiraterone was

conducted in the postchemotherapysetting for men with CRPC. In COU-AA-301, a large randomized, double-blind, placebo-controlled phase 3study, chemotherapy-refractory meta -

static patients were treated witheither abiraterone plus low-dose pred-nisone (n = 797) or prednisone plusplacebo (n = 398). The median over-all survival, the primary end point forthis study, was 15.8 months and 11.2months, respectively, after 775 events(hazard ratio, 0.740; 95% confidenceinterval, 0.638-0.859), and the benefit

was observed across multiple subgroups,such as performance status, sites ofmetastatic disease, and number of previ-ous chemotherapy regimens received.Other trial end points, including PSAchange, TTPP, and radiographic progres-sion-free survival (PFS), also resulted insuperior outcomes. Patients on abi-raterone achieved a PSA decline of

TOP_May 2011_4_TOP 5/13/11 9:31 AM

>50% in 38% of the patients comparedwith 10% for placebo (P <.0001), had asignificant delay in TTPP (10.2 vs 6.6mo, P <.0001), and radiographic PFS(5.6 vs 3.6 mo, P <.0001). Although theincidence of adverse events was higher inpatients receiving placebo, there weremore patients who experienced grade 3and 4 toxicities on the treatment arm

(fluid retention, hypo kalemia, andhypertension).13

An Additional OptionTreatment options for men with CRPCare limited, but abiraterone/ prednisone isa welcomed addition to the armamentar-ium. With this addition, we now have 5FDA-approved regimens for the treat-

ment of this disease (sipuleucel-T, doc-etaxel plus prednisone, cabazitaxel plusprednisone, and mitoxantrone plus pred-nisone). The real question is whether cli-nicians will move this treatment to theprechemo therapy setting. Abira-terone isa novel agent that inhibits androgen syn-thesis by selectively blocking CYP 17.The role of prednisone is of some con-

cern, especially with prolonged use.None theless, this is a true example oftranslating basic laboratory observationsinto clinic advances. �

References1. Howlader N, Noone AM, Krapcho M, et al; eds.SEER cancer statistics review, 1975-2008. April 15,2011. www.seer.cancer.gov/csr/1975_2008/index.html.Accessed May 3, 2011.


Solid Tumors

YERVOY™ (ipilimumab) Injection, for intravenous infusion

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information]

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions]

INDICATIONS AND USAGE

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning]

Immune-mediated Enterocolitis

In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.

The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.

Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.

Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Hepatitis

In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Dermatitis

In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.

Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information]

For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.

Immune-mediated Neuropathies

In Study 1, one case of fatal Guillain-Barré syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Endocrinopathies

In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.

Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations

The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

[see Warnings and Precautions].






Selected Adverse Reactions in Study 1

P

I

S

I

Bristol-Myers Squibb Company P

IP-B0001A-03-11 Issued: March 2011

3-4 4 11:22 AM

TOP_May 2011_4_TOP 5/13/11 9:31 AM

2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin. 2010;60:277-300.3. Mohler JL, Pantuck AJ. Use of abiraterone forprostate cancer. J Urol. 2011;185:783-786.4. Molina A, Belldegrun A. Novel therapeutic strate-gies for castration resistant prostate cancer: inhibition ofpersistent androgen production and androgen receptormediated signaling. J Urol. 2011;185:787-794.5. Scher HI, Sawyers CL. Biology of progressive, castra-tion-resistant prostate cancer: directed therapies target-ing the androgen-receptor signaling axis. J Clin Oncol.2005;23:8253-8261.

6. Chung BC, Picado-Leonard J, Haniu M, et al.Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testiscDNAs indicates the same gene is expressed in both tis-sues. Proc Natl Acad Sci U S A. 1987;84:407-411.7. Picado-Leonard J, Miller WL. Cloning and sequenceof the human gene for P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): similarity with the geneP250c21. DNA. 1987;6:439-448.8. Stanbrough M, Bubley GJ, Ross K, et al. Increasedexpression of genes converting adrenal androgens to

testosterone in androgen-independent prostate cancer.Cancer Res. 2006;66:2815-2825.9.Auchus RJ. The genetics, pathophysiology, and man-agement of human deficiencies of P450c17. EndocrinolMetab Clin North Am. 2001;30:101-119, vii.10. Barrie SE, Potter GA, Goddard PM, et al.Pharmacology of novel steroidal inhibitors ofcytochrome P450(17) alpha (17 alpha-hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol. 1994;50:267-273.11.Attard G, Reid AH, A’Hern R, et al. Selective inhi-

bition of CYP17 with abiraterone acetate is highlyactive in the treatment of castration-resistant prostatecancer. J Clin Oncol. 2009;27:3742-3748.12. Attard G, Reid AH, Yap TA, et al. Phase I clinicaltrial of a selective inhibitor of CYP17, abirateroneacetate, confirms that castration-resistant prostate can-cer commonly remains hormone driven. J Clin Oncol.2008;26:4563-4571.13. Pal SK, Sartor O. Phase III data for abiraterone inan evolving landscape for castration-resistant prostatecancer. Maturitas. 2011;68:103-105.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

Table 1: Selected Adverse Reactions in Study 1

Percentage (%) of Patientsa

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100

n=380

gp100 n=132

System Organ Class/ Preferred Term

Any Grade

Grade3–5

Any Grade

Grade3–5

Any Grade

Grade 3–5

Gastrointestinal Disorders Diarrhea ColitisSkin and Subcutaneous Tissue Disorders Pruritus RashGeneral Disorders and Administration Site Conditions Fatigue

328

3129

41

55

02

7

375

2125

34

43

<12

5

202

118

31

10

00

3

a Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.

Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1

Percentage (%) of Patients

YERVOY3 mg/kgn=131

YERVOY3 mg/kg+gp100

n=380

Any Immune-mediated Adverse ReactionEnterocolitisa,b

Hepatotoxicitya

Dermatitisa

Neuropathya

Endocrinopathy Hypopituitarism Adrenal insufficiencyOther Pneumonitis Meningitis Nephritis Eosinophiliac

Pericarditisa,c

157121440

00110

12723

<1111

<1<100

<1

a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established.

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Immunogenicity

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab).

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information]

In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes.

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Nursing Mothers

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

Pediatric Use

Safety and effectiveness of YERVOY have not been established in pediatric patients.

Geriatric Use

Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Renal Impairment

No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

Hepatic Impairment

No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

OVERDOSAGE

There is no information on overdosage with YERVOY.

PATIENT COUNSELING INFORMATION

See MEDICATION GUIDE in Full Prescribing Information.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1281558A2 IP-B0001A-03-11 Issued: March 2011


Solid Tumors

Serum Albumin AffectsMethotrexate Level Variabilityand Methotrexate ToxicityThis retrospective study of patientsreceiving high-dose methotrexate foundthat serum albumin level predictsmethotrexate toxicity and explains thevariability in pharmacokinetic parame-ters in different courses of methotrexate.Nonparametric Spearman rank correla-tion analysis showed an associationbetween de creased albumin level andincreased methotrexate level that mayindicate toxicity. Based on their findings,pharmacists in Egypt now order albumintesting routinely in these patients, as wellas monitor the methotrexate levels andgive recommendations based on the lev-els putting the albumin level into con-sideration. Kamal S. Abstract 17.

Pharmacist-Derived MedicationHistory Provides MoreInformation than GeriatricCancer Patient–CompletedMedication ListBy taking a comprehensive medica-tion history at geriatric (70-82 years)cancer patients’ first outpatient ap p oint- ments, Australian pharmacists creat-ed more accurate medication histo-ries and demonstrated that in some(2/27) patients these histories wereclinically important. The structured,comprehensive medication historyconsisted of asking patients to bringall their medications to their firstappointment, followed by pharmacistreview of prescribed and nonpre-scribed medications for interactionswith chemo therapy and sup portivemedications. Concerns were commu-nicated to the oncologist. They founda patient-reported omission rate of29.7%, primarily composed of anal-gesics, laxatives, complimentary andalternative medications, and ophthal-mologic medications. Lees J, Tohn V.Abstract 32. �

The XII Symposiumof the InternationalSociety of OncologyPharmacyPractitioners


TOP_May 2011_4_TOP 5/13/11 9:31 AM


Solid Tumors

When initial androgen-depriva-tion therapy (ADT) fails to control progression of

metastatic prostate cancer, the diseaseis redefined as castration-resistant pros -tate cancer (CRPC). Studies haveshown that using docetaxel and pred-nisone to treat men with CRPC onlymodestly extends median overall sur-vival (OS) to ~19 months. In addition,only 18.6% of patients who receive thiscombination survive 3 years.1,2 Re cently,cabazitaxel (Jevtana), a novel taxane,was found to extend median OS in pro-gressive metastatic CRPC following pre-vious docetaxel, but only modestly com-pared with mitoxantrone (15.1 vs12.7 mo, P <.0001).3 Novel and moretolerable options are needed to man-age prostate cancer in this populationof mostly elderly men, who often havemultiple comorbidities. Sipuleucel-T(Provenge), an autologous dendriticcell–based vaccine approved by theUS Food and Drug Administration(FDA) in 2010, is one such option.Studies show that it prolongs OS in

men with metastatic CRPC and is welltolerated.4

Rationale for Immunotherapy inMetastatic CRPCHumoral (antibody) and cellular (Tcells, natural killer cells, macrophages)immune responses are involved incombating malignancies, with cellularimmunity thought to play a moreprominent role. Antigen-presentingcells (APCs), which include dendriticcells, are able to activate T lympho-cytes by efficiently presenting them toT-cell receptors. Activation of T cellssubsequently enhances B-lymphocyteresponse. Prostate cancer provides anexcellent opportunity for applyingimmunotherapy, because it is relativelyindolent and expresses several essen-tially organ-specific tumor-associatedantigens, such as prostatic acid phos-phatase (PAP) and prostate-specificantigen (PSA).

A Novel VaccineThe sipuleucel-T vaccine, which con-sists of autologous APCs manufacturedby processing the leukapheresis productand manipulating it to enhance thepresentation of tumor antigens, hasbeen evaluated extensively, culminatingin FDA approval.5-7 The vaccine con-tains APCs pulsed with PA2024, afusion protein of PAP-granulocytemacrophage colony-stimulating factor.8In an initial small randomized trialenrolling 127 previously untreated menwith asymptomatic, metastatic CRPC,sipuleucel-T prolonged median OScompared with placebo (25.9 vs 21.4months, P = .01).9Subsequently, the larger IMPACT

(Immunotherapy Prostate Adeno car -cinoma Treatment) trial randomized512 men with asymptomatic metastaticCRPC at a 2:1 ratio to sipuleucel-T orplacebo; the study’s primary end pointof OS.4 Men with visceral metastasiswere excluded. About 85% of patientswere chemotherapy-naïve, and the 15%of men who received chemotherapypreviously were required to have com-pleted the treatment at least 3 monthsprior to enrollment. ADT was contin-ued in all patients.Treatment included 3 leukapheresis

procedures (at weeks 0, 2, and 4).Approximately 3 days after each proce-dure, patients received a 60-minuteinfusion of sipuleucel-T or placebo fol-lowing premedication with acetamino-phen and an antihistamine. Eventhough the trial allowed patientsassigned to placebo to crossover, medianOS was still significantly improved inthe sipuleucel-T arm compared with theplacebo arm (25.8 vs 21.7 mo, respec-tively; P = .02). The probability of 3-year survival was also better with sip-uleucel-T than placebo (31.7% vs23.0%, respectively). Approximately55% of men in both groups receivedsubsequent docetaxel at a median of 12to 13 months after on-study therapy, butanalyses did not suggest that the differ-ences in the frequency of or timeelapsed to docetaxel treatment couldaccount for the differences in outcomes.Notably, the time to disease progres-

sion was similar in the 2 groups and noclear early evidence of activity wasobserved. Confirmed PSA declines≥50% were observed in only 8 of 311(2.6%) patients in the sipuleucel-Tgroup and in 2 of 153 (1.3%) patientsin the placebo group. Sipuleucel-T wasassociated with mild and manageablegrade 1 and 2 infusion-related adverseevents, including fever (22.5%) andchills (51.2%). Antibody responseagainst PAP or PA2024 (antibody titerexceeding 400) was observed in 66.2%of patients in the sipuleucel-T groupand correlated with survival benefit. T-cell responses to the immunizing anti-gen also were observed but were notassociated with survival.

ConclusionSipuleucel-T provides a modest exten-sion of survival coupled with an excel-lent toxicity profile in generallychemotherapy-naïve and relativelyasymptomatic patients without visceralmetastases. Sipuleucel-T was highlytolerable, and no long-term anddelayed adverse immune phenomenahave been observed. Given the costand a modest survival benefit, it isimportant to select patients appropri-ately based on the eligibility criteriaused in the IMPACT trial. Several other novel immunotherapeu-

tic agents are being evaluated in clinicaltrials. Poxvirus-based vaccines andimmune-checkpoint inhibitors of cyto-toxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1)appear promising. In addition, multipleemerging novel androgen-pathway in -hibitors (abiraterone acetate, TAK700,MDV3100) are likely to expand thetherapeutic armamentarium in the nearfuture.10 Therefore, the proper sequenceof therapeutic agents and appropriateselection of patients likely to benefitfrom specific agents will assume greatimportance. �

DisclosuresGuru Sonpavde is a speaker for DendreonCorp, and his institution receives researchfunding from Bellicum Pharmaceuticals.Toni K. Choueiri has nothing to disclose.Philip W. Kantoff is a consultant forDendreon Corp, Bellicum Pharmaceuticals,and BN ImmunoTherapeutics Inc.

References1. Berthold DR, Pond GR, Soban F, et al. Docetaxelplus prednisone or mitoxantrone plus prednisone foradvanced prostate cancer: updated survival in the TAX327 study. J Clin Oncol. 2008;26:242-245.2. Petrylak DP, Tangen CM, Hussain MH, et al.Docetaxel and estramustine compared with mito -xantrone and prednisone for advanced refractoryprostate cancer. N Engl J Med. 2004;351:1513-1520.3. de Bono JS, Oudard S, Ozguroglu M, et al; for theTROPIC Investigators. Prednisone plus cabazitaxel ormitoxantrone for metastatic castration-resistant prostatecancer progressing after docetaxel treatment: a ran-domised open-label trial. Lancet. 2010;376:1147-1154.4. Kantoff PW, Higano CS, Shore ND, et al; for theIMPACT Study Investigators. Sipuleucel-T im muno -therapy for castration-resistant prostate cancer. N Engl JMed. 2010;363:411-422.5. Sonpavde G, Slawin KM, Spencer DM, Levitt JM.Emerging vaccine therapy approaches for prostate can-cer. Rev Urol. 2010;12:25-34.6. Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ.Dendritic cell immunotherapy: mapping the way. NatMed. 2004;10:475-480.7. Drake CG. Prostate cancer as a model for tumourimmunotherapy. Nat Rev Immunol. 2010;10:580-593.8. Small EJ, Fratesi P, Reese DM, et al. Immunotherapyof hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000;18:3894-3903.9. Small EJ, Schellhammer PF, Higano CS, et al.Placebo-controlled phase III trial of immunologic ther-apy with sipuleucel-T (APC8015) in patients withmetastatic, asymptomatic hormone refractory prostatecancer. J Clin Oncol. 2006;24:3089-3094.10. De Bono J LC, Logothetis CJ, Fizazi K, et al; for theCOU-AA-301 investigators. Abiraterone acetate pluslow dose prednisone improves overall survival inpatients with metastatic castration resistant prostatecancer who have progressed after docetaxel-basedchemotherapy: results of COU-AA-301, a randomizeddouble-blind placebo-controlled phase III study. AnnOncol. 2010;21(suppl 8):LBA5.

Sipuleucel-T Immunotherapy forCastration-Resistant Prostate Cancer By Guru Sonpavde, MDTexas Oncology Cancer Center, Houston; Michael E. DeBakey Veterans Affairs Medical Center;

the Baylor College of Medicine, Houston, Texas

Toni K. Choueiri, MD, MSDana-Farber Cancer Institute; Harvard Medical School, Boston, Massachusetts

Philip W. Kantoff, MDDana-Farber Cancer Institute; Harvard Medical School, Boston, MassachusettsGuru Sonpavde, MD

Toni K. Choueiri, MD, MS

Philip W. Kantoff, MD

TOP_May 2011_4_TOP 5/13/11 9:31 AM

Single Vial

Docetaxel Injection(10 mg/mL concentration)

• Larger 160 mg Multiple Dose Vial

• More convenient 80 mg Multiple Dose Vial

• Requires NO dilution with a diluent prior to adding to the infusion solution

Exclusive Onco-Tain™ packaging for safe handling1

Clarity of glass

Barrier sheath

PVC reinforced bottom

P11-3247-10.875x13.125-Apr., 11 � only

Docetaxel Injection is a microtubule inhibitor indicated for:

Breast Cancer (BC):single agent for locally advanced metastatic BC after chemotherapy failure; and with doxorubicin and cyclophosphamide as adjuvant treatment of operable node-positive BC

Non-Small Cell Lung Cancer (NSCLC): single agent for locally advanced or metastatic NSCLC after platinum therapy failure; and with cisplatin for unresectable, locally advanced or metastatic untreated NSCLC

Hormone Refractory Prostate Cancer (HRPC): with prednisone in androgen independent (hormone refractory) metastatic prostate cancer

1. Data on fi le at Hospira

Indications and Usage Safety Information

Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fl uid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

See brief Prescribing Information on reverse side.

WARNING: Toxic Deaths, Hepatotoxicity, Neutropenia, Hypersensitivity Reactions, and Fluid RetentionSee full prescribing information for complete boxed warning

• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2

• Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy

• Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80

• Severe fl uid retention may occur despite dexamethasone

TOP_May 2011_4_TOP 5/13/11 9:31 AM

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

Docetaxel Injection,For intravenous infusion only.Initial U.S. Approval: 1996

––––––––––––––––––––––––––––––––––––– CONTRAINDICATIONS –––––––––––––––––––––––––––––––––––––––––• Hypersensitivity to docetaxel or polysorbate 80 (4)• Neutrophil counts of <1500 cells/mm3 (4)

–––––––––––––––––––––––––––––––––– WARNINGS AND PRECAUTIONS ––––––––––––––––––––––––––––––––––––• Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed

myelodysplasia or myeloid leukemia (5.6)• Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may

occur. Severe skin toxicity may require dose adjustment (5.7)• Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory

symptoms require dose adjustment or discontinuation if persistent. (5.8)• Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9)• Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should

be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1)–––––––––––––––––––––––––––––––––––––– ADVERSE REACTIONS –––––––––––––––––––––––––––––––––––––––––Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia,hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention,asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 orwww.fda.gov/medwatch

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION

See full prescribing information for complete boxed warning• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC

and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) • Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase >

2.5 × ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before eachtreatment cycle (8.6)

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor forneutropenia (4)

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who receiveddexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection andadministration of appropriate therapy (5.4)

• Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate80 (4)

• Severe fluid retention may occur despite dexamethasone (5.5)

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, AustraliaManufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, IndiaDistributed by: Hospira, Inc., Lake Forest, IL 60045 USA Reference EN-2761

TOP_May 2011_4_TOP 5/13/11 9:31 AM


Soild Tumors

Clear cell (CC)-renal cell carci-noma (RCC), the predominanthistologic type of RCC, is high-

ly dependent on angiogenesis, via thevascular endothelial growth factor(VEGF) pathway.1 The mammalian tar-get of rapamycin (mTOR) pathway alsoappears to play a role in VEGF produc-tion, as well as directly promote tumorcell growth.

First-Line ManagementSunitinib (Sutent), a multitargeted oraltyrosine kinase inhibitor (TKI) target-ing VEGF receptors and multiple othermolecular targets, yielded a greatermedian overall survival (OS) thaninterferon (IFN)-α in a landmark phase3 trial (26.4 vs 21.8 mo, respectively; P = .051).2 After censoring patients’crossing over from IFN-α to sunitinib,the difference was statistically signifi-cant. Median progression-free survival(PFS) was 11 months for sunitinib compared with 5 months for IFN-α(P <.001); objective response rate(ORR) was 47% for sunitinib comparedwith 12% for IFN-α (P <.001). Themost common sunitinib-related grade 3adverse events included hypertension(12%), fatigue (11%), diarrhea (9%),and hand-foot syndrome (9%). All 3Memorial Sloan-Kettering Cancer

Center clinical risk groups (good, inter-mediate, and poor) appeared to benefit,although ~93% of patients had good- orintermediate-risk disease. In a presenta-tion at the Genitourinary CancersSymposium this past February, the renalEFFECT trial demonstrated that theconventional regimen of 50-mg daily 4 weeks on treatment/2 weeks off treat-ment was statistically superior to 37.5mg daily given continuously on thecomposite end point of death, progres-sion, and patient-reported outcomes.3A phase 3 placebo-controlled study

of pazopanib (Votrient), a VEGF recep-tor TKI, enrolled 435 patients with CC-RCC who were treatment-naïve or hadreceived previous cytokine-based thera-py.4 Median PFS was 9.2 months in thepazopanib group compared with 4.2months in the placebo group (P<.0001). When analyzed according toprior therapy, median PFS for treat-ment-naïve patients was 11.1 monthscompared with 2.8 months for placebo(P <.0001); and for cytokine-treatedpatients, median PFS was 7.4 monthsversus 4.3 months for placebo (P<.001). The ORR was 30% for thepazopanib arm and 3% for the placebogroup. Common pazopanib-relatedadverse events included diarrhea,hypertension, hair depigmentation,

nausea, anorexia, and vomiting.Elevated levels of alanine aminotrans-ferase and aspartate aminotransferasewere noteworthy laboratory abnormali-ties, and these were occasionally severe.Results from the completed phase 3COMPARZ trial comparing pazopanibwith sunitinib are eagerly awaited.The AVOREN (Avastin and Roferon

in Renal Cell Carcinoma) trial random-ized 649 patients with CC-RCC to first-line IFN-α-2a plus placebo or IFN-α-2aplus bevacizumab (Avastin), a mono-clonal antibody against VEGF, whichwas administered intravenously every 2weeks.5 Adding bevacizumab to IFN-α-2a significantly prolonged median PFS (10.2 vs 5.4 mo, respectively; P <.0001) and ORR (30.6% vs 12.4%,respectively; P <.0001). A trend towardimproved OS was also observed withthe addition of bevacizumab (P =.3360), but the availability of otheractive agents confounded the survivalanalysis. The contribution of IFN-α-2ato the efficacy of the combination isunclear, and the poor-risk subgroupmight not benefit from the doublet. Asimilar Cancer and Leukemia Group Btrial demonstrated a comparable exten-sion in median PFS with the combina-tion of bevacizumab and IFN.6Temsirolimus, an mTOR inhibitor

administered via weekly intravenousinfusion, prolonged median OS com-pared with IFN-α (10.9 vs 7.3 mo,respectively; P = .008) in patients withpoor-risk RCC, defined as ≥3 poor riskfactors by Memorial Sloan-Ketteringrisk classification.7 Thus, the standardof care has changed relatively rapidlywith the advent of these targeted bio-logic agents, which have generally sup-planted cytokines as conventional ther-apy. High-dose (HD) interleukin (IL)-2may retain a role in selected patients(good-risk CC-RCC, alveolar featuresand the absence of papillary or granularfeatures, high CAIX expression, genom-ic signatures) with good performancestatus as a result of an ~7% durablecomplete remission and apparentcures.8,9 The severe cardiovascular, pul-monary, and renal toxicities of HD IL-2render it as an option only for relativelyyoung patients without significant

comorbidities. Unfortunately, the re -cent prospective SELECT (Seleniumand Vitamin E Cancer PreventionTrial) was unable to validate tumorCAIX expression as a predictive factorfor response.To summarize, sunitinib, pazopanib,

or bevacizumab-IFN are preferred first-line agents for good- and intermediate-risk CC-RCC, whereas temsirolimus ispreferred for patients with poor-risk dis-ease. HD IL-2 retains its role in a well-selected, good-risk subset. Phase 3 trialsunder way include tivozanib versussorafenib (Nexavar) and axitinib versussorafenib. Other ongoing studies areevaluating adjuvant therapy withVEGF and mTOR inhibitors.

Salvage TherapyFor salvage therapy after relapsed/refractory cytokine-based regimens, theevidence supports using pazopanib orsorafenib, although the other approvedagents also demonstrate activity in thissetting.10,11 The TARGET (TreatmentApproaches in Renal Cancer Global

Recent Advances in the Management of Advanced Kidney Cancer By Guru Sonpavde, MDTexas Oncology Cancer Center, Houston; Michael E. DeBakey Veterans Affairs Medical Center;

Baylor College of Medicine, Houston, Texas

C. Lance Cowey, MDMichael E. DeBakey Veterans Affairs Medical Center; Baylor College of Medicine, Houston, Texas

Thomas E. Hutson, DO, PharmDBaylor Sammons Cancer Center, Dallas, Texas

Management Algorithm for Advanced Clear Cell-Renal Cell Carcinoma

Treatment Setting TherapyTreatment-naïve, good-risk, intermediate-risk

Clinical trialBevacizumab plus IFN-α-2a5

HD IL-28,9

Pazopanib4

Sunitinib2

Treatment-naïve, poor-risk Clinical trialTemsirolimus7

Cytokine refractory Clinical trialPazopanib4

Sorafenib10

Prior VEGF inhibitor Clinical trialAxitinib (evidence emerging)Everolimus13

Prior mTOR inhibitor Clinical trial

HD IL-2 indicates high-dose interleukin-2; IFN-α-2a, interferon-α-2a; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.

Guru Sonpavde, MD

C. Lance Cowey, MD

Thomas E. Hutson, DO, PharmD

TOP_May 2011_4_TOP 5/13/11 9:31 AM


Soild Tumors

Evaluation Trial) trial was limited togood- and intermediate-risk patientsand demonstrated superior median PFSfor sorafenib compared with placebo(5.5 vs 2.8 mo, respectively; P<.000001).10 The 13.5% improvementin median OS seen with sorafenib overpazopanib was not significant (17.8 vs15.2 mo, respectively; hazard ratio[HR], 0.88; P = .146). Secondaryanalysis censoring crossover datashowed a significant OS benefit withsorafenib (HR, 0.78; P = .0287).Diarrhea, rash, fatigue, and hand-footskin reactions were the most common adverse events associated withsorafenib; hypertension and cardiacischemia were rare. A smaller random-ized phase 2 trial in the first-line set-ting failed to demonstrate improvedoutcomes with sorafenib versus IFN-α.12 Given the lack of robust frontlinedata, sorafenib increasingly is beingreserved for salvage therapy followingother agents.Everolimus (Afinitor), an orally

administered mTOR inhibitor, wasrecently approved in RCC based onfindings from the RECORD (RenalCell Cancer Treatment with OralRAD001 Given Daily)-1 trial, whichshowed improved outcomes in patientspreviously treated with sunitinib and/orsorafenib.13 Everolimus was associatedwith significant improvement in medi-an PFS compared with placebo (4.0-1.9mo; HR, 0.30; P <.001). The probabili-ty of 6-month PFS was 26% witheverolimus versus 2% with placebo,though the RECIST response rate witheverolimus was only 1%. Stomatitis,rash, and fatigue were the most com-mon adverse events, but were mostlymild or moderate in severity. Observed

class-specific toxicities consisted ofinterstitial pneumonitis, hyperlipi-demia, and hyperglycemia.For therapy following previous treat-

ment with mTOR inhibitors, no defini-tive data exist demonstrating improvedoutcomes with currently availableagents. There is evidence of incompletecross-resistance between the newlyapproved agents discussed, with modestactivity when switching agents.14,15 Lackof complete cross-resistance occurs whensequentially administering the differentantiangiogenic agents; for example,sorafenib → sunitinib, sunitinib →sorafenib, bevacizumab → sunitinib andsorafenib → axitinib.14-17 A phase 3 trialcomparing second-line sorafenib withaxitinib in patients treated previouslywith sunitinib reported prolonged PFSwith axitinib, but the data have not yetbeen presented formally. An ongoingphase 3 trial is comparing sorafenib withtemsirolimus following previous treat-ment with sunitinib.

Prognostic and Predictive FactorsKnown prognostic factors associatedwith outcomes in advanced RCC treat-ed with IFN-α include performance status, disease-free interval, number ofmetastatic sites, hemoglobin, calcium,and lactate dehydrogenase (LDH).18Recent analysis from trials with anti-VEGF agents shows these factors contin-ue to be of major importance, althoughnotably neutrophilia and thrombocytosisreplaced LDH in the newly created(2009) model.19 Future prognostic mod-els will attempt to incorporate molecularmarkers with clinical variables to refineprognosis prediction in patients withmetastatic CC-RCC treated with novelantiangiogenic agents.

ConclusionDespite providing important incre-mental improvements in outcomes, thenovel antiangiogenic agents have notyielded complete responses or curesand are associated with significant tox-icities, implying there is ample roomfor improvement and the need for con-tinued commitment to clinical trials.Biomarkers potentially predictive ofresponse are emerging and need to beincorporated into the clinical develop-ment of agents. Furthermore, the eval-uation of adjuvant therapy usingVEGF and mTOR inhibitors is ongo-ing after surgery. �

DisclosuresGuru Sonpavde receives research supportfrom Pfizer, Bristol-Myers Squibb,Cephalon, Celgene, and Bellicum and is onthe speakers’ bureau for GlaxoSmithKline,Novartis, and sanofi-aventis. Thomas E.Hutson receives research support fromBayer/Onyx, Pfizer, GlaxoSmithKline; isan advisory board/consultant for Bayer/Onyx, Pfizer, Den dreon, and sanofi-aven-tis; and is on the speakers’ bureau forBayer/Onyx, Pfizer, Amgen, sanofi-aven-tis, Novartis, and Genentech. C. LanceCowey has nothing to disclose.

References1. Erber R, Thurnher A, Katsen AD, et al. Combinedinhibition of VEGF and PDGF signaling enforces tumorvessel regression by interfering with pericyte-mediatedendothelial cell survival mechanisms. FASEB J.2004;18:338-340.2. Motzer RJ, Hutson TE, Tomczak P, et al. Overall sur-vival and updated results for sunitinib compared withinterferon alfa in patients with metastatic renal cell car-cinoma. J Clin Oncol. 2009;27:3584-3590.3.Motzer RJ, Hutson TE, Olsen MR, et al. Randomisedphase II multicenter study of the efficacy and safety ofsunitinib on the 4/2 versus continuous dosing scheduleas first-line therapy of metastatic renal cell carcinoma(Renal EFFECT Trial). J Clin Oncol. 2011;29(suppl7):LBA308.4. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib

in locally advanced or metastatic renal cell carcinoma:results of a randomized phase III trial. J Clin Oncol.2010;28:1061-1068.5. Escudier B, Bellmunt J, Négrier S, et al. Phase III trialof bevacizumab plus interferon alfa-2a in patients withmetastatic renal cell carcinoma (AVOREN): final analy-sis of overall survival. J Clin Oncol. 2010;28:2144-2150.6. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumabplus interferon alfa compared with interferon alfamonotherapy in patients with metastatic renal cell carci-noma: CALGB 90206. J Clin Oncol. 2008;26:5422-5428.7. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus,interferon alfa, or both for advanced renal-cell carcino-ma. N Engl J Med. 2007;356:2271-2281.8. Fyfe G, Fisher RI, Rosenberg SA, et al. Results oftreatment of 255 patients with metastatic renal cell car-cinoma who received high-dose recombinant inter-leukin-2 therapy. J Clin Oncol. 1995;13:688-696.9. McDermott DF, Regan MM, Clark JI, et al.Randomized phase III trial of high-dose interleukin-2versus subcutaneous interleukin-2 and interferon inpatients with metastatic renal cell carcinoma. J ClinOncol. 2005;23:133-141.10. Escudier B, Eisen T, Stadler WM, et al. Sorafenib fortreatment of renal cell carcinoma: final efficacy andsafety results of the phase III Treatment Approaches inRenal Cancer Global Evaluation Trial. J Clin Oncol.2009;27:3312-3318.11. Hutson TE, Davis ID, Machiels JP, et al. Pazopanib(GW786034) is active in metastatic renal cell carcino-ma (RCC): interim results of a phase II randomized discontinuation trial (RDT). J Clin Oncol. 2007;25(18S):Abstract 5031.12. Escudier B, Szczylik C, Hutson TE, et al. Randomizedphase II trial of first-line treatment with sorafenib versusinterferon alfa-2a in patients with metastatic renal cellcarcinoma. J Clin Oncol. 2009;27:1280-1289.13. Motzer RJ, Escudier B, Oudard S, et al; for theRECORD-1 Study Group. Efficacy of everolimus inadvanced renal cell carcinoma: a double-blind, ran-domised, placebo-controlled phase III trial. Lancet.2008;372:449-456.14. Tamaskar I, Garcia JA, Elson P, et al. Antitumoreffects of sunitinib or sorafenib in patients with meta -static renal cell carcinoma who received prior anti -angiogenic therapy. J Urol. 2008;179:81-86.15. Sablin MP, Negrier S, Ravaud A, et al. Sequentialsorafenib and sunitinib for renal cell carcinoma. J Urol.2009;182:29-34.16. Rini BI, Michaelson MD, Rosenberg JE, et al.Antitumor activity and biomarker analysis of sunitinibin patients with bevacizumab-refractory metastaticrenal cell carcinoma. J Clin Oncol. 2008;26:3743-3748.17. Rini BI, Wilding G, Hudes G, et al. Phase II studyof axitinib in sorafenib-refractory metastatic renal cellcarcinoma. J Clin Oncol. 2009;27:4462-4468.18.Motzer RJ, Bacik J, Murphy BA, Russo P, MazumdarM. Interferon-alfa as a comparative treatment for clini-cal trials of new therapies against advanced renal cellcarcinoma. J Clin Oncol. 2002;20:289-296.19. Heng DY, Xie W, Regan MM, et al. Prognostic fac-tors for overall survival in patients with metastatic renalcell carcinoma treated with vascular endothelial growthfactor-targeted agents: results from a large, multicenterstudy. J Clin Oncol. 2009;27:5794-5799.

Over the past year, data regarding2 specific ovarian cancer man-agement strategies have gener-

ated considerable interest within theclinical gynecologic cancer communityamong patients, clinicians, and re -searchers. One strategy involves the useof bevacizumab (Avastin), and theother approach centers on poly(ADP-ribose) polymerase (PARP) inhibitors.

BevacizumabPreliminary results from 2 eagerly await-ed phase 3 randomized studies examin-ing a potential role for the antiangio-genic agent bevacizumab in the primarymanagement of advanced ovarian can-

cer were presented at separate interna-tional cancer meetings (Table).1,2 Thefirst study was presented at the 2010annual meeting of the AmericanSociety of Clinical Oncology. In -vestigators with the GynecologicOncology Group (GOG) sought toassess the utility of this drug combinedwith standard cytotoxic agents as an ini-tial therapeutic strategy or as part of aninitial strategy and then continued asmaintenance therapy. Patients were randomized to 1 of 3 arms: standardchemotherapy with carboplatin andpaclitaxel (the control arm); initial ther-apy with bevacizumab, carboplatin, andpaclitaxel but no maintenance therapy;

and initial therapy with bevacizumabplus the same 2 chemotherapy agentsfollowed by 16 cycles of bevacizumabalone as a maintenance strategy.1 Theadministration of bevacizumab with car-boplatin/paclitaxel followed by beva-cizumab monotherapy for 12 months of

maintenance therapy following chemo -therapy discontinuation resulted in sta-tistically significant improvement inprogression-free survival (PFS) com-pared with chemotherapy alone.Considering this provocative out-

come, it was somewhat surprising to find

Developments in the Management of Ovarian CancerBy Maurie Markman, MDCancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, Pennsylvania

One strategy involves the use of bevacizumab, andthe other approach centers on poly(ADP-ribose)polymerase (PARP) inhibitors.

TOP_May 2011_4_TOP 5/13/11 9:31 AM


Soild Tumors

that patients in this trial randomized totreatment with chemotherapy plusbevacizumab who discontinued theantiangiogenic drug after completingchemotherapy experienced no im -provement in PFS compared withpatients in the control arm. At thetime these data were presented, finalinformation on overall survival (OS)was not available, but preliminaryanalyses of the median OS and the 1-year OS rate suggested no differencesamong the 3 study arms.

Data from ICON 7, the secondfrontline bevacizumab ovarian cancerstudy, were reported by an internation-al team of investigators from theEuropean Organisation for Researchand Treat ment of Cancer (EORTC) atthe 35th European Society of MedicalOncology Congress in 2010. Patientswere randomized to a control arm ofcarboplatin plus paclitaxel or an inves-tigational regimen of the 2 cytotoxicagents plus bevacizumab.2 In this study,bevacizumab was administered concur-rently with chemotherapy and as a sin-gle-agent maintenance strategy follow-ing discontinuation of chemotherapy.Unlike the study discussed previously,ICON 7 did not include an arm ofpatients who received only the initialtreatment regimen of bevacizumab,carboplatin, and paclitaxel, withoutany maintenance therapy.

Similar to the data reported fromGOG, this study revealed a statistical-ly significant improvement in PFSassociated with adding bevacizumab tothe cytotoxic regimen. At the time ofthis preliminary report, no statisticallysignificant difference in OS wasobserved between the study arms.

It is important to note several majordistinctions between the protocols forthese 2 studies. The GOG trial wasplacebo-controlled, whereas theEORTC study made no attempt toconceal from participants or investiga-tors which patients were receiving theantiangiogenic drug. It is reasonable toquestion, however, whether blindingin the GOG study was effective con-sidering the frequency with whichbevacizumab’s well-recognized adverseeffect of significant hypertension wasobserved.

The GOG trial used a 15-mg/kg doseof bevacizumab in the initial chemo -therapy regimen and in the mainte-nance phase, whereas the EORTC trialused a 7.5-mg/kg dose of bevacizumabthroughout the study. It remains to bedetermined whether this difference indrug dose, associated with differences intreatment cost, will affect the ultimateoutcome of therapy.

On the question of OS, it is conceiv-able that the studies will ultimatelyreach different conclusions, potentiallybecause of the general—but by no

means universal—availability of beva-cizumab in the United States as a sin-gle-agent treatment for platinum-resis-tant ovarian cancer. Third parties haveprovided financial coverage for beva-cizumab use in this country based ondata reported from several well-designed and well-conducted phase 2trials. These studies have demonstratedthat the overall clinical activity of sin-gle-agent bevacizumab is comparable tothe activity seen with a number of otherdrugs routinely employed as monother-apy in this difficult clinical setting (eg,pegylated liposomal doxorubicin, topo -tecan, and altretamine).3,4

As a result of far more restrictive pay-ment policies in European countries, itis less likely that a patient from the con-trol arm of the EORTC study, treatedwith a carboplatin/paclitaxel regimen,will have access to bevacizumab at thetime of disease progression comparedwith a patient in the control arm of theGOG study. How this factor mightinfluence the ability to assess the levelof benefit in OS seen with bevacizumabin the 2 studies is not clear.

PARP InhibitorsThe second category of agents of par-ticular interest in ovarian cancer isPARP inhibitors. Recently reporteddata reveal as many as one-third ofovarian cancer patients with either aBRCA1 or a BRCA2 mutation achievean objective response when treatedwith a single agent from this novelclass of drugs in the second-line set-ting.5,6 The hypothesis supporting thisstrategy is that women with BRCAabnormalities have an underlyingdefect in DNA repair, so using aninhibitor to interfere with PARP—asecond relevant DNA repair mecha-nism—should seriously impair the sur-vival of malignant cells.

As exciting as these data appear tobe, germline BRCA mutations are onlyfound in approximately 5% to 10% ofall women with ovarian cancer, limit-ing the potential applicability of thisnovel approach. Recent data suggest,however, that up to an additional 10%to 20% of patients might possesssomatic (nongermline) molecularabnormalities in their tumors thatclosely resemble the genetic defectsobserved in women with hereditarycancers.7 If appropriately designed andconducted clinical studies ultimatelydemonstrate that cancers with this so-called “BRCAness” profile are as sensi-tive to PARP inhibition as patientswith germline mutations appear to be,it could substantially increase the pro-portion of women who stand to deriveclinical benefit from this managementstrategy. The results of trials exploringthe utility of this class of drugs in this

specific patient population are keenlyanticipated.

ConclusionPreliminary data from single-arm orrandomized phase 2 trials regarding thepotential efficacy of quite a number ofnovel traditional cytotoxic agents andmore targeted antineoplastic agents inovarian cancer were reported at sever-al international meetings during thepast year. Additional follow-up dataand publication of these results in thepeer-reviewed literature are neededbefore we can make a meaningfulassessment of the possible role thesestrategies might play in the futuremanagement of ovarian cancer. It isnot unreasonable to anticipate, how-ever, that at least 1 of these approach-es will someday find a place in thestandard treatment of this hard-to-treat neoplasm. �

References1. Burger RA, Brady MF, Bookman MA, et al. Phase IIItrial of bevacizumab in the primary treatment ofadvanced epithelial ovarian cancer, primary peritonealcancer, or fallopian tumor cancer: a GynecologicOncology Group study. J Clin Oncol. 2010;28(185):Abstract LBA1.2. Perren T, Swart AM, Pfisterer J, et al. ICON 7: a phaseIII Gynecologic Cancer Intergroup (GCIG) trial ofadding bevacizumab to standard chemotherapy in womenwith newly diagnosed epithelial ovarian, primary peri-toneal or fallopian tube cancer. Presentation at: 35thESMO Congress; October 8-12, 2010; Milan, Italy.3. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JL.Phase II trial of bevacizumab in persistent or recurrentepithelial ovarian cancer or primary peritoneal cancer: aGynecologic Oncology Group study. J Clin Oncol.2007;25:5165-5171.4. Cannistra SA, Matulonis UA, Penson RT, et al. PhaseII study of bevacizumab in patients with platinum-resis-tant ovarian cancer or peritoneal serous cancer. J ClinOncol. 2007;25:5180-5186.5. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribosepolymerase inhibition: frequent durable responses inBRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28:2512-2519.6. Audeh MW, Carmichael J, Person RT, et al. Oralpoly(ADP-ribose) polymerase inhibitor olaparib inpatients with BRCA1 or BRCA2 mutations and recurrentovarian cancer: a proof-of-concept trial. Lancet.2010;376:245-251.7. Hennessy BT, Timms KM, Carey MS, et al. Somaticmutations in BRCA1 and BRCA2 could expand thenumber of patients that benefit from poly(ADP-ribose)polymerase inhibitors in ovarian cancer. J Clin Oncol.2010;28:3570-3576.

[ICON 7] revealed astatistically significantimprovement in PFSassociated with addingbevacizumab to thecytotoxic regimen.

Table Phase 3 Trials Examining Bevacizumab in Advanced Ovarian Cancer

PFS, mo (median) OS, % (1 year) OS, mo (median)Gynecologic Oncology Group Trial1

Upfront carboplatin/paclitaxel (control arm) 10.3 90.6 39.3

Upfront carboplatin/paclitaxel + bevacizumab (no maintenance)

11.2HR, 0.098

90.4 38.7

Upfront carboplatin/paclitaxel + bevacizumab followed by maintenance withsingle-agent bevacizumab

14.1HR, 0.717; P <.0001

91.3 39.7

ICON 7 Trial2

Upfront carboplatin/paclitaxel (control arm) 17.3 93 NR

Upfront carboplatin/paclitaxel + bevacizumab followed by maintenance with single-agent bevacizumab

19.0 HR, 0.81; P = .0041

95 NR

HR, hazard ratio; NR, not reported; OS, overall survival; PFS, progression-free survival.

Germline BRCA mutations are only found inapproximately 5% to 10% of all women with ovariancancer, limiting the potential applicability of [PARPinhibition].

TOP_May 2011_4_TOP 5/13/11 9:31 AM


Soild Tumors

Pancreatic neuroendocrine tumor(PNET) refers to several tumortypes located in the pancreas.

These tumors are classified as function-al or nonfunctional depending on pro-duction and secretion of bioactive hor-mones. Functional PNETs causeclinical symptoms associated with theirtumor classification. Some examplesinclude gastrinomas, which are associ-ated with gastrointestinal ulcers anddiarrhea; glucagonomas, which areassociated with diabetes, skin rash, anddiarrhea; and vasoactive intestinalpolypeptide tumors, which may pro-duce extreme watery diarrhea, abdom-inal pain, and flushing.1,2 Because non-functional PNETs do not producebioactive hormones and do not causeclinical symptoms, these tumor types(eg, pancreatic polypeptidoma) arediagnosed at a more advanced stage,often presenting with symptoms relat-ed to mass effect or metastasis (eg,abdominal pain, obstructive jaundice,or weight loss).3,4 PNET is relativelyrare, with an incidence of <1 in100,000.5 Most diagnoses occur inpatients aged >40 years, with equalgender distribution.5 Causation ofPNET is sporadic but associated lesscommonly with genetic syndromes (eg,multiple endocrine neoplasia type 1 orvon Hippel-Lindau).1

The malignant potential for PNETis determined by clinical symptomsand presence of metastatic diseaserather than a specific immunohisto-chemistry profile. In addition, neu-roendocrine tumors (NETs) are clas-sified according to their degree ofpathologic differentiation. Well-dif-ferentiated NETs typically includelow and intermediate grades, whereaspoorly differentiated NETs are con-sidered biologically aggressive.6Historically, staging of PNETs usedthe classification system of the WorldHealth Organization, in whichPNETs were considered (1) well-dif-ferentiated of benign or uncertainbehavior, (2) well-differentiated withlow malignant potential, or (3) poor-ly differentiated with high-grademalignant potential based on the pro-liferation index of the Ki67 marker.6,7

The European Neuro endocrineTumor Society (ENETS) developed asystem of grading that uses both theKi67 proliferation index and thenumber of mitoses per high-powerfield.1,6 More recently, ENETS andthe American Joint Committee onCancer each proposed a TNM stagingsystem.2,3,7

Treatment of PNETTreatment of PNET is dependent onfunctional status as well as the absenceor presence of metastatic disease.Optimal therapy for PNET includesmedications (eg, somatostatin analogs,proton pump inhibitors) to controlclinical symptoms followed by surgicalresection, such as pancreaticoduo-denectomy (also known as theWhipple procedure) or distal pancrea-tectomy, of the primary tumor.2,3,8,9

Surgical resection of hepatic metas-tases from PNET has a low morbidityand mortality rate10,11 and is recognizedas the recommended treatment modal-ity if >90% of a patient’s tumor burdenis resectable.2,3

Metastatic disease is not alwaysamenable to surgical resection andrequires alternative treatments, such asregional hepatic therapy (eg, radiofre-quency ablation, arterial embolization,chemoembolization, and radioem-bolization) or peptide receptor radio -nucleotide therapy, which is currentlyonly used outside the United States.2,3

These treatments are not curative butmay be used for symptom palliation ordisease control.12-16 Orthotopic livertransplantation has been attempted ina small subset of patients, but it has notreceived empirical support.2,3,17-21

Effectiveness of ChemotherapyLimitedAn additional treatment modality is theuse of systemic chemotherapeutics.Traditionally effective chemotherapycombinations for well-differentiatedPNET have included streptozocin com-bined with doxorubicin, fluorouracil, orboth.1,3,22-25 Cisplatin and etoposidehave been effective for short durationsin poorly differentiated PNET.26-28

Recent clinical trials have indicatedthe potential use of temozolomide(Temodar), an alkylating agent thatcauses apoptosis through damage to thetumor’s DNA, alone or in combination

with capecitabine (Xeloda) or thalido-mide (Thalomid).29-31 Patients withhigh expression levels of the DNArepair enzyme O6-methylguanineDNA-methyltransferase demonstratevirtually no response to temozolomide.32

Biotherapies Show PromiseNewer biologic agents are being used totreat PNET. Somatostatin analogs (eg,octreotide and lanreotide), which havelong been used to mitigate the effects offunctional PNETs, have recently beenfound to increase the effectiveness ofoctreotide acetate injection long-acting release (Sandostatin LAR) inpatients with minimal hepatic tumorburden and delay disease progression.Preliminary data from the PROMIDstudy revealed a median progression-free survival (PFS) of 14 months inpatients who received octreotide LARcompared with 6 months for patientsin the placebo group. Final results fromthe phase 3 trial, which aims to deter-mine the effect of lanreotide autogelon nonfunctional PNETs, have notbeen published [clinicaltrials.gov iden-tifier: NCT0035496].

Molecular genetic investigation intoPNET suggests that the deactivation oftumor suppressor genes such as TSC2and PTEN activates the mammaliantarget of rapamycin (mTOR) pathway.33This pathway promotes angiogenesisand cell growth and proliferation inPNETs.1,9,33 Two trials, RADIANT(RAD001 in Advanced Neuro en do -crine Tumors)-1 and RADIANT-3,demonstrated that 10 mg daily of themTOR inhibitor everolimus (Afinitor)might be an effective treatment optionfor patients with advanced PNET.34,35 Inthe phase 2 RADIANT-1 trial, patientswho received everolimus plus octreotideLAR demonstrated PFS of 16.7 monthscompared with 9.7 months for thosegiven only everolimus. Clinical benefit,defined as stable disease and partialremission, was observed in both arms ofthe study.34 The phase 3 RADIANT-3trial reported longer PFS witheverolimus than with placebo (11 vs 4.6mo, respectively) and minimal treat-ment-related adverse effects.35

Another promising therapy is suni-tinib malate, a tyrosine kinase inhibitorthat inhibits vascular endothelialgrowth factor (VEGF) and platelet-derived growth factor. One phase 3 trialdemonstrated a median PFS of 11.4months in patients with well-differenti-ated PNET who received a 37.5-mgdaily dose of sunitinib compared with amedian PFS of 5.5 months for patients

who took placebo.36 Additional trialsinvestigating sunitinib in poorly differ-entiated NETs are planned.37

Bevacizumab (Avastin), a monoclon-al antibody targeting VEGF receptors,has also been used to treat neuroen-docrine cancers in clinical trials.Patients on stable doses of octreotideLAR were given bevacizumab or pegy-lated interferon-α-2b separately for 18weeks, with treatment discontinued ear-lier if disease progression was ob -served.38 After the initial trial phase,patients were started on a combinationof bevacizumab and pegylated interferon-α-2b. At 18 weeks, the beva-cizu mab monotherapy arm demonstrat-ed a higher rate of PFS than thepegylated interferon-α-2b group (95%vs 68%, respectively). As a result ofthese findings, an ongoing phase 2 trialis actively recruiting patients with local-ly advanced or metastatic PNET tostudy the effects of using a combinationof everolimus and octreotide with orwithout bevacizumab [clinicaltrials.govidentifier: NCT01229943]. Severalother phase 2 clinical trials in progressare evaluating the effects of bevacizu -mab combined with many of the thera-pies previously discussed.39

ConclusionPNET is a rare tumor type for whichsurgical resection combined with cyto-toxic chemotherapy has been the main-stay of treatment. Traditionally, the pur-pose of using medical therapies was tocontrol clinical symptoms associatedwith functional PNETs. Chemo -therapeutic agents such as streptozocin,cisplatin, and etoposide have beenfound to have minimal impact on dis-ease survival, and recent clinical trialshave investigated the efficacy and safe-ty of biotherapies. Studies have shownthat everolimus, sunitinib, and beva-cizumab effectively prolong PFS, gener-ating optimism that these and othernew therapies might alter the diseasetrajectory for patients with PNET. �

References1. Öberg K. Pancreatic endocrine tumors. Semin Oncol.2010;37:594-561.2. National Comprehensive Cancer Network. ClinicalPractice Guidelines in Oncology: Neuroendocrine Tumors.V.2.2010. www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed April 7, 2011.3. Kulke MH, Anthony LB, Bushnell DL, et al; for theNorth American Neuroendocrine Tumor Society.NANETS treatment guidelines: well-differentiatedneuroendocrine tumors of the stomach and pancreas.Pancreas. 2010;39:735-752.4. Elaraj D, Sturgeon C. Neuroendocrine tumors of thepancreas. In: ACS Surgery: Principles and Practice.Philadelphia, PA: BC Decker, Inc; 2010. http://129.49.170.167/Volumes/ACSCD+March+2010/ACSCD/pdf/ACS0540.pdf. Accessed April 7, 2011.5. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM.

Pancreatic Neuroendocrine CancerBy Dori L. Klemanski, MS, RN, CNPThe Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital

and Richard J. Solove Research Institute, Columbus, Ohio

Studies have shown thateverolimus, sunitinib, andbevacizumab effectivelyprolong PFS, generatingoptimism that these andother new therapiesmight alter the diseasetrajectory for patientswith PNET.

TOP_May 2011_4_TOP 5/13/11 9:31 AM


Soild Tumors

Pancreatic neuroendocrine tumors (PNETs): incidence,prognosis and recent trend toward improved survival.Ann Oncol. 2008;19:1727-1733.6. International Agency for Research on Cancer. WHOClassification of Tumours of the Digestive System. 2000.www.iarc.fr/en/publications/pdfs-online/pat-gen/bb2/BB2.pdf. Accessed April 7, 2011.7. Klimstra DS, Modlin IR, Coppola D, et al. Thepathologic classification of neuroendocrine tumors: areview of nomenclature, grading, and staging systems.Pancreas. 2010;39:707-712.8. Franko J, Feng W, Yip L, et al. Non-functional neu-roendocrine carcinoma of the pancreas: incidence,tumor biology, and outcomes in 2,158 patients. J Gastrointes Surg. 2010;14:541-548.9. Fazio N, Cinieri S, Lorizzo K, et al. Biological target-ed therapies in patients with advanced enteropancreat-ic neuroendocrine carcinomas. Cancer Treat Rev.2010;36(suppl 3):S87-S94.10. Hemming AW, Magliocca JF, Fujita S, et al.Combined resection of liver and pancreas for malignan-cy. J Am Coll Surg. 2010;210:808-816.11. Glazer ES, Tseng JF, Al-Refaie W, et al. Long-termsurvival after surgical management of neuroendocrinehepatic metastases. HPB (Oxford). 2010;12:427-433.12. Gamblin TC, Christians K, Pappas SG. Radio -frequency ablation of neuroendocrine hepatic metasta-sis. Surg Oncol Clin N Am. 2011;20:273-279.13. Akyildiz HY, Mitchell J, Milas M, et al.Laparoscopic radiofrequency thermal ablation of neu-roendocrine hepatic metastases: a long-term follow-up.Surgery. 2010;148:1288-1293.14. King J, Quinn R, Glenn DM, et al. Radio -embolization with selective internal radiation micro -

spheres for neuroendocrine liver metastases. Cancer.2008;113:921-929.15. Kennedy AS, Dezarn WA, McNeillie P, et al.Radioembolization for unresectable neuroendocrinehepatic metastases using resin 90Y-microspheres: earlyresults in 148 patients. Am J Clin Oncol. 2008;31:271-279.16. Varker K, Martin EW, Klemanski D, et al. Repeattransarterial chemoembolization (TACE) for progres-sive hepatic carcinoid metastases provides results similarto first TACE. J Gastrointest Surg. 2007;11:1680-1685.17. Pascher A, Klupp J, Neuhaus P. Endocrine tumoursof the gastrointestinal tract. Transplantation in themanagement of metastatic endocrine tumours. BestPract Res Clin Gastroenterol. 2005;19:637-648.18. Le Treut YP, Grégoire E, Belghiti J, et al. Predictorsof long-term survival after liver transplantation formetastatic endocrine tumors: an 85-case French multi-centric report. Am J Transplant. 2008;8:1205-1213.19. Olausson M, Friman S, Herlenius G, et al.Orthotopic liver or multivisceral transplantation astreatment of metastatic neuroendocrine tumors. LiverTranspl. 2007;13:327-333.20. Grégoire E, Le Treut YP. Liver transplantation forprimary or secondary endocrine tumors. Transplant Int.2010;23:704-711.21. Stauffer JA, Steers JL, Bonatti H, etal. Liver trans-plantation and pancreatic resection: a single-centerexperience and a review of the literature. Liver Transpl.2009;15:1728-1737.22. Moertel CG, Hanley JA, Johnson LA. Streptozocinalone compared with streptozocin plus fluorouracil inthe treatment of advanced islet-cell carcinoma. N EnglJ Med. 1980;303:1189-1194.23. Moertel CG, Lefkopoulo M, Lipsitz S, et al.

Streptozocin-doxorubicin, streptozocin-fluorouracil orchlorozotocin in the treatment of advanced islet-cellcarcinoma. N Engl J Med. 1992;326:519-523.24. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil,doxorubicin, and streptozocin in the treatment ofpatients with locally advanced and metastatic pancreaticendocrine carcinomas. J Clin Oncol. 2004;22:4762-4771.25. Turner NC, Strauss SJ, Sarker D, et al. Chemo -therapy with 5-fluorouracil, cisplatin and streptozocinfor neuroendocrine tumours. Br J Cancer. 2010;102:1106-1112.26. Moertel CG, Kvols LK, O’Connell MJ, Rubin J.Treatment of neuroendocrine carcinomas with com-bined etoposide and cisplatin. Evidence of major thera-peutic activity in the anaplastic variants of these neo-plasms. Cancer. 1991;68:227-232.27. Mitry E, Baudin E, Ducreux M, et al. Treatment ofpoorly differentiated neuroendocrine tumours withetoposide and cisplatin. Br J Cancer. 1999;81:1351-1355.28. Fjallskog ML, Granberg DP, Welin SL, et al.Treatment with cisplatin and etoposide in patients withcisplatin and etoposide in patients with neuroendocrinetumors. Cancer. 2001;92:1101-1107.29. Ekeblad S, Sundin A, Janson ET, et al.Temozolomide as monotherapy is effective in treatmentof advanced malignant neuroendocrine tumors. ClinCancer Res. 2007;13:2986-2991.30. Strosberg JR, Fine RL, Choi J, et al. First-linechemotherapy with capecitabine and temozolomide inpatients with metastatic pancreatic endocrine carcino-mas. Cancer. 2011;117:268-275.31. Kulke MH, Stuart K, Enzinger PC, et al. Phase IIstudy of temozolomide and thalidomide in patients withmetastatic neuroendocrine tumors. J Clin Oncol.2006;24:401-406.

32. Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-methylguanine DNA methyltransferase deficiency andresponse to temozolomide-based therapy in patientswith neuroendocrine tumors. Clin Cancer Res.2009;15:338-345.33. Missiaglia E, Dalai I, Barbi S, et al. Pancreaticendocrine tumors: expression profiling evidences a rolefor AKT-mTOR pathway. J Clin Oncol. 2010;28:245-255.34. Yao JC, Phan AT, Chang DZ, et al. Efficacy ofRAD001 (everolimus) and octreotide LAR inadvanced low- to intermediate-grade neuroendocrinetumors: results of a phase II study. J Clin Oncol.2008;26:4311-4318.35. Yao JC, Shah MH, Ito T, et al; for the RAD001 inAdvanced Neuroendocrine Tumors, Third Trial(RADIANT-3) Study Group. Everolimus for advancedpancreatic neuroendocrine tumors. N Engl J Med.2011;364:514-523.36. Raymond E, Dahan L, Raoul JL, et al. Sunitinibmalate for the treatment of pancreatic neuroendocrinetumors. N Engl J Med. 2011;364:501-513.37. Faivre S, Sablin MP, Dreyer C, Raymond E. Novelanticancer agents in clinical trials for well-differentiatedneuroendocrine tumors. Endocrinol Metab Clin NorthAm. 2010;39:811-826.38. Yao JC, Phan A, Hoff PM, et al. Targeting vascularendothelial growth factor in advanced carcinoid tumor:a random assignment phase II study of depot octreotidewith bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316-1323.39. Raymond E, Hobday T, Castellano D, et al. Therapyinnovations: tyrosine kinase inhibitors for the treatmentof pancreatic neuroendocrine tumors. Cancer MetastasisRev. 2011;30(suppl 1):19-26.

Breast cancer is the most commoncancer among women. In 2010,there were an estimated 207,090

new cases and 39,840 deaths.1 Despitemany improvements in the treatmentof breast cancer, about 20% to 30% ofwomen with the disease will progressto metastatic breast cancer (MBC).Although MBC remains incurable, avariety of treatment options are avail-able. The US Food and Drug Ad -ministration (FDA) recently approvederibulin (Halaven), providing anexciting new option for women withheavily pretreated MBC.

Eribulin is a synthetic analog of hali-chondrin B, a nontaxane microtubuledynamics inhibitor originally isolatedfrom a sea sponge. Eribulin inhibits thegrowth phase of microtubules andsequesters tubulin into nonproductiveaggregates, resulting in G2/M cell-cycle block, by disrupting mitotic spin-dles. It exerts its action at a site on thecellular level that is distinct from thattargeted by taxanes, vinca alkaloids,and other existing microtubulininhibitors.

FDA approval was based on datafrom the international, phase 3EMBRACE (Eisai Metastatic BreastCancer Study Assessing Physician’sChoice Versus Eribulin) clinical trial,which had a primary end point of over-all survival (OS). To be eligible, all thewomen had to have been treated with 2

to 5 prior chemotherapy regimens andto have experienced disease progressionwithin 6 months of completing theirmost recent chemotherapy regimen. Ofthe regimens administered previously inthe adjuvant or metastatic setting, atleast 1 had to have been anthracyclinebased and 1 had to have been taxanebased to be eligible for enrollment.Patients were required to have anEastern Cooperative Oncology Group(ECOG) performance status ≤2, andpatients with preexisting neuropathy>grade 2 were ineligible.

Investigators randomized 762 patientswith MBC at a 2:1 ratio to eribulin (n =508) or a single-agent therapy selectedby their physician prior to randomization(n = 254). Randomization was stratifiedby geographic region, HER2 status, andprior capecitabine exposure. The physi-cian’s choice of treatment consisted ofany single agent, whether a chemothera-py, hormonal, or biologic therapy, or sup-portive care only. Randomization wasstratified by geographic region, HER2

status, and prior capecitabine exposure.Eribulin 1.4 mg/m2 was administered ondays 1 and 8 every 21 days, with dosereductions and delays for predeterminedtoxicities. The control arm therapiesconsisted of the following agents:vinorelbine (Navelbine; 26%), gemcitabine (Gemzar; 18%), a taxane(16%), capecitabine (18%), an anthra-cycline (9%), other chemo therapy(10%), and hormonal therapy (3%).

Median OS was significantly pro-longed for patients randomized to receiveeribulin compared with those whoreceived the physician’s choice of treat-ment (13.1 vs 10.6 mo, respectively; haz-ard ratio, 0.809; 95% confidence inter-val, 0.660-0.991; P = .041).

Eribulin treatment had a manage-able safety profile. The most commonadverse reactions in the eribulin arm,occurring in >25% of patients, wereneutropenia, anemia, asthenia/fatigue,alopecia, peripheral neuropathy, nau-sea, and constipation. The most com-mon treatment-related adverse reac-tions ≥grade 3 experienced by >5% ofpatients were neutropenia (57%),asthenia/fatigue (10%), and peripheralneuropathy (8%). The most commonserious adverse reactions reported ineribulin-treated patients were febrileneutropenia (4%) and neutropenia(2%). The most common toxicity lead-ing to discontinuation of eribulin wasperipheral neuropathy (5%).

These results were discussed at the2010 ASCO Annual Meeting and pub-lished in The Lancet in March 2011.2These results are especially noteworthybecause this is the first time a singleagent has demonstrated survival benefitin this population.

The recommended dosage of eribulinis 1.4 mg/m2 administered intravenouslyover 2 to 5 minutes on days 1 and 8 of a21-day cycle. Eribulin may be adminis-tered undiluted or diluted in 100 mL of0.9% sodium chloride injection, USP.The drug should not be administeredthrough an intravenous line that is deliv-ering a dextrose-containing solution.3

Eribulin offers new promise forwomen with heavily pretreated MBC.The results of the EMBRACE trialdemonstrate that cytotoxic therapiesdirected at a well-defined targetremain a viable area of continuedstudy. Given the favorable results ofthe EMBRACE trial, future studies willexamine the use of eribulin in theadjuvant setting and also as frontlinetherapy in the metastatic setting. It isimportant for nurses to be aware of theFDA’s approval of eribulin, its mecha-nism of action, and its safety profile.Nurses are in a pivotal position toadvocate for their patients, to provideconsistent patient education, and tomonitor adverse reactions. �

References 1. Breast cancer overview. American Cancer Society.http://www.cancer.org/Cancer/BreastCancer/OverviewGuide/breast-cancer-overview-key-statistics. Up datedSeptember 2010. Accessed April 12, 2011.2. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulinmonotherapy versus treatment of physician’s choice inpatients with metastatic breast cancer (EMBRACE): aphase 3 open-label randomized study. Lancet. 2011;377(9769):914-923. 3. Halaven [package insert]. Woodcliff Lake, NJ: Eisai,Inc.; 2010.

Eribulin: A New Option in the Treatmentof Metastatic Breast CancerBy Georgia Litsas, RN, NPDana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts

Median OS wassignificantly prolonged forpatients randomized toreceive eribulin.

TOP_May 2011_4_TOP 5/13/11 9:31 AM

Poly(ADP-ribose) polymerase(PARP) are a group of enzymesthat are essential for base excision

repair.1 There are several members ofthe PARP family, of which PARP1 isthe most extensively studied.1,2 PARP1only detects single-stranded DNAbreaks and initiates repair; withoutPARP1, a single-stranded break is con-verted into a double-stranded break andrepaired by homologous repair.1 PARPinhibition shows promise in BRCA1/2-deficient tumors, which lack homolo-gous repair capability, causing syntheticlethality (decrease in repair of both sin-gle- and double-stranded DNA breaks,leading to cell death).3 Synergy has alsobeen demonstrated when PARPinhibitors are combined with severaltraditional cytotoxic agents includingtemozolomide (Temodar), cyclophos-phamide, topotecan, paclitaxel, cis-platin, gemcitabine (Gemzar), andirinotecan.4-12 Several PARP inhibitorsare in development, with iniparib (BSI-201), veliparib (ABT-888), and olaparib(AZD2281) being the furthest along. Inthe past year, PARP inhibitors haveshown activity as single agents and incombination with chemotherapy, anddata have been published in journals andpresented as abstracts in meetings.

IniparibO’Shaughnessy and colleagues evaluatedthe efficacy of the intravenous small-molecule PARP inhibitor, iniparib, inwomen with triple-negative (estrogenreceptor-, progesterone receptor-, andHER2-negative) metastatic breast can-cer.4 In this open-label phase 2 study, 123patients were randomized to gem citabine(1000 mg/m2) and carboplatin (AUC 2)on days 1 and 8 of a 21-day cycle withor without iniparib, which was admin-istered to patients in that group ondays 1, 4, 8, and 11. Up to 2 priorchemotherapy regimens for meta staticdisease were permitted. The studyallowed for patients in the control armto cross over to the iniparib group atthe time of progression.

The overall response rate (ORR) was52% in the iniparib arm versus 32% in the chemotherapy-only group (P =.002). The median progression-free sur-vival (PFS) was 5.9 months for patientstaking iniparib compared with 3.6months for those on chemotherapyalone (P = .01). No significant differ-ences were observed in the frequency ofadverse events between the groups.

For the 51% of patients in the control

group who crossed over, iniparib demon-strated only minimal antitumor activity.The authors noted that the results areprone to biases and are being confirmedin a randomized phase 3 trial.

Earlier this year, sanofi-aventisannounced that a phase 3 study of ini-parib failed to meet its primary endpoints of significant improvement inoverall survival (OS) and PFS but didnot offer detailed findings.13 A prespeci-fied analysis of patients treated with iniparib in the second- and third-line set-tings reportedly demonstrated improve-ment in OS and PFS “consistent withwhat was seen in the phase 2 study,” butspecific data will not be offered until theupcoming annual meeting of theAmerican Society of Clinical On cology.It will be interesting to view data on thesurvival advantage for these patients andfor those with a BRCA1/2 mutation.

OliparibTwo articles published in The Lancetevaluated the novel oral PARPinhibitor olaparib in patients withBRCA1/2 mutations and advancedbreast cancer or recurrent ovarian can-cer.14,15 Both studies compared a 400-mg twice-daily dose (cohort 1) with a100-mg twice-daily dose (cohort 2). Inpatients with breast cancer, the ORRwas 42% in cohort 1 and 25% incohort 2. The median PFS also seemedto be lower in cohort 2 than in cohort1 (2.8 vs 5.7 mo, respectively).

Patients progressing after platinumchemotherapy rarely had a confirmedresponse when treated with oliparib.This was also seen in patients with ovar-ian cancer who received olaparib 400 mgtwice daily. Response was confirmed in38% of platinum-sensitive patients ver-sus 30% of platinum-resistant patients.

The most common toxicities seenwith oliparib in these trials were nau-sea and fatigue. It is important to notethat the cohorts were not randomized;hence, one has to exercise caution ininterpreting the response rates.

ConclusionAdditional novel PARP inhibitors arebeing investigated in early-phase trialsfor breast and ovarian cancer and othersolid tumors. In 2010, several abstractswere presented from early-stage trialsthat combine PARP inhibitors withcytotoxic chemotherapy agents. Forexample, a phase 2 study evaluated theefficacy of veliparib in combination withtemozolomide in patients with metastat-

ic breast cancer8 and reported 1 completeresponse, 2 partial responses, 7 patientswith stable disease (all unconfirmed),and 14 patients whose disease progressed.A number of phase 1 trials were also pre-sented. Updated data from these andother trials could help determine thefuture rule for PARP inhibitors inbreast cancer. �

References1. Underhill C, Toulmonde M, Bonnefoi H. A review ofPARP inhibitors: from bench to bedside. Ann Oncol.2011;22:268-279. 2. Ame JC, Splenlehauer C, de Murcia G. The PARPsuperfamily. BioEssays. 2004;26:882-893.3. Leung M, Rosen D, Fields S, et al. Poly(ADP-ribose)polymerase-1 inhibition: preclinical and clinical devel-opment of synthetic lethality. Mol Med. 2011. [Epubahead of print.]4. O’Shaughnessy J, Osborne C, Pippen JE, et al.Iniparib plus chemotherapy in metastatic triple-nega-tive breast cancer. N Engl J Med. 2011;364:205-214.5. Blakeley JO, Ye X, Grossman SA, et al. Poly (ADP-ribose) polymerase-1 (PARP1) inhibitor BSI-201 incombination with temozolomide (TMZ) in malignantglioma. J Clin Oncol. 2010;28(15S):Abstract 2010.6. Dent RA, Lindeman GJ, Clemons M, et al. Safetyand efficacy of the oral PARP inhibitor olaparib(AZD2281) in combination with paclitaxel for the first-or second-line treatment of patients with metastatictriple-negative breast cancer: results from the safetycohort of a phase I/II multicenter trial. J Clin Oncol.2010;28(15S):Abstract 1018.7. Giaccone G, Rajan A, Kelly RJ, et al. A phase I com-bination study of olaparib (AZD2281; KU-0059436) andcisplatin (C) plus gemcitabine (G) in adults with solidtumors. J Clin Oncol. 2010;28(15S):Abstract 3027.

8. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase IItrial of the PARP inhibitor veliparib (ABT888) andtemozolomide for metastatic breast cancer. J Clin Oncol.2010;28(15S):Abstract 1019.9. Ji JJ, Kummar S, Chen AP, et al. Pharmacodynamicresponse in phase I combination study of ABT-888 andtopotecan in adults with refractory solid tumors andlymphomas. J Clin Oncol. 2010;28(15S):Abstract 2514.10. Kummar S, Chen AP, Ji JJ, et al. A phase I study ofABT-888 in combination with metronomic cyclophos-phamide in adults with refractory solid tumors and lym-phomas. J Clin Oncol. 2010;28(15S):Abstract 2605.11. Moulder S, Mita M, Bradely C. A phase 1b studyto assess the safety and tolerability of the PARPinhibitor iniparib (BSI-201) in combination withirinotecan for the treatment of patients with metastat-ic breast cancer (MBC). In: Proceedings from the 33rdAnnual CTRC-AACR San Antonio Breast CancerSymposium; December 8-15, 2010; San Antonio, TX.Abstract P6-15-01.12. Tan AR, Givvon MN, Stein RA, et al. Preliminaryresults of a phase I trial of ABT-888, a poly(ADP-ribose) polymerase (PARP) inhibitor, in combinationwith cyclo phosphamide. J Clin Oncol. 2010;28(15S):Abstract 3000.13. Sanofi-aventis reports top-line results from phaseIII study with iniparib (BSI-201) in metastatic triple-negative breast cancer [press release]. Bridgewater, NJ:sanofi-aventis; January 27, 2011. http://sanofi-aventis.mediaroom.com/index.php?s=43&item=310.Accessed April 1, 2011.14. Tutt A, Robson M, Garber JE, et al. Oralpoly(ADP)-ribose polymerase inhibitor olaparib inpatients with BRCA1 or BRCA2 mutations andadvanced breast cancer: a proof-of-concept trial.Lancet. 2010;376:235-244.15. Audeh MW, Carmichael J, Penson RT, et al. Oralpoly(ADP)-ribose polymerase inhibitor olaparib inpatients with BRCA1 or BRCA2 mutations and recur-rent ovarian cancer: a proof-of-concept trial. Lancet.2010;376:245-251.


Soild Tumors

Update on PARP Inhibitors in Breast Cancer, 2010-2011By Sarah Hopps, PharmDCollege of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City

Shubham Pant, MDUniversity of Oklahoma Health Sciences Center, Oklahoma City

Neoadjuvant Comparisonbetween Letrozole, Anastrozole,and Exemestane forPostmenopausal Women withEstrogen Receptor–Rich Stage2/3 Breast CancerACOSOG Z1031 investigators identi-fied 2 data sets that will help inform thedesign of larger adjuvant endocrine trials.One finding will help in the selection of agents: Letrozole, anastrozole, andexemestane showed no difference in effi-cacy in the neoadjuvant setting for post-menopausal women with estrogen recep-tor–rich (Allred 6-8) clinical stage 2/3breast cancer. The other finding will helpin patient selection: Patients with pre-treatment intrinsic subtype luminal B had more favorable preoperativeendocrine prognostic in dex scores thanpatients with subtype luminal A. Thisfinding suggests that because approxi-mately one-third of women with subtypeluminal A may be able to avoid chemo -

therapy, they are not suitable for largeradjuvant en docrine trials. Ellis M, et al.Abstract S1-2.

Lapatinib vs Trastuzumab inCombination with NeoadjuvantAnthracycline-Taxane–BasedChemotherapyIn the GEPARQUINTO study’s ongo-ing head-to-head comparison of lapa-tinib versus trastuzumab added toanthracycline/taxane-based neoadju-vant chemotherapy in early breast can-cer, investigators confirmed that patho-logic complete response (pCR) rate canbe used as a surrogate marker for long-term outcome after treatment. To date, ahigher pCR rate has been observed withtrastuzumab (50%) compared with lapa-tinib (35%). Final analysis of efficacydata has not yet been reported. Safetydata was reported previously. Untch M,et al; for the German Breast Group.Abstract S3-1. �

33rd Annual San Antonio BreastCancer Symposium


TOP_May 2011_4_TOP 5/13/11 9:31 AM

THANK YOU FORMAKING US#1Source: © Kantar Media, Custom Study of Oncology Pharmacy Publications among The Oncology Pharmacist Circulation (June 2010)

��

�� The Oncology Pharmacist��

The #1* Read

Oncology Pharmacy

Tabloid Publication

In a recent survey, oncology pharmacists said thatthey read The Oncology Pharmacist 1.5 times more*than its closest competitor in the pharmacy market.

� � � �� TOP_May 2011_4_TOP 5/13/11 9:31 AM


Supportive Care

After a diagnosis of cancer,patients often initiate orincrease their use of vitamins

and dietary supplements, and their useis prevalent among the 11.7 millionadults in the United States living withcancer. Whereas 50% of healthy adultstake 1 or more dietary supplements,between 64% and 81% of cancer sur-vivors report that they use vitamin ordietary supplements.1 Reasons offeredfor using these alternative therapiesinclude strengthening the immune sys-tem, increasing the chance to be cured,and gaining a sense of control over theirdisease.

Although the American CancerSociety says, “A daily, multivitaminsupplement in amounts equivalent to100% of the [US Department ofAgriculture Recommended] DailyValue is a good choice for anyone…who cannot eat a healthful diet,”2 sup-plements do not come without risks.Because of limited US Food and DrugAdministration regulations and pub-lished experience, little is known abouthow supplements interact with cancersand their treatments. For example,antioxidants might reduce the efficacyof radiation and chemo therapy byblocking reactive oxygen species3 andsome vitamins could stimulate cancercell growth.4

More than half of cancer patientstaking supplements do not inform theirphysician.1 It is therefore important forall healthcare practitioners to be famil-iar with the current literature address-ing vitamin and dietary supplementuse in this patient population so theycan assist physicians and help mitigaterisks. In 2010, research literatureincluded studies on multivitamins,selenium, and vitamin D. Cautionshould be taken when evaluating andapplying literature to clinical practice.In addition to inconsistencies amongthese trials, some published reports relyon early-phase data.

Multivitamin UseTo evaluate the effects of multivitaminuse on survival in patients with stage IIIcolon cancer, a prospective, observa-tional study was conducted as a com-panion study to CALGB 89803.5Patients were asked to complete a dietand lifestyle questionnaire midwaythrough therapy and again 6 monthsafter treatment ended. During treat-ment, 49.9% (518/1038) of patientssaid they used multivitamins. Useremained consistent after treatment,with 51.4% (416/810) of patientsreporting that they took multivitamins.

The hazard ratio (HR) for disease-freesurvival for multivitamin users com-pared with nonusers was 0.94 (95%confidence interval [CI], 0.77-1.15).Multivitamin use during or followingchemotherapy was not associated with asignificant increase in recurrence-freesurvival (multivariate HR, 0.93; 95%CI, 0.75-1.15) or overall survival (mul-tivariate HR, 0.92; 95% CI, 0.74-1.16).Women, patients with higher house-hold incomes, and physically activepatients were more likely to report mul-tivitamin use.

SeleniumThe proposed anticancer effects of sele-nium include supporting antioxidantstatus, increasing activity of proteinsinvolved in apoptosis, and inhibitingtranscription factors associated withcarcinogenesis, such as nuclear factorkappa-light-chain-enhancer of activat-ed B cells (NF-κB) and activator pro-tein-1.6,7 Common adverse effects ofselenium supplementation includebrittle nails and hair, liver and kidney function test abnormalities, andcataracts. Previous trials have shownconflicting results regarding the abilityof selenium to reduce the risk of devel-oping cancer.8,9

Stratton and colleagues conducted aphase 2 trial to assess whether seleni-um supplementation reduces prostatecancer progression as measured byprostate-specific antigen (PSA) veloc-ity.10 A total of 140 patients with local-ized non–high-grade prostate cancerwere randomized to receive dailyplacebo (n = 46), selenium 200 µg (n =46), or selenium 800 µg (n = 47). Afteradjusting for confounders, PSA veloci-ty did not differ significantly betweenthe 3 groups. A subgroup analysis forthe quartile of men with the highestbaseline selenium levels who were ran-domized to the selenium 800-µg armshowed that they had significantlyhigher PSA velocity than men takingplacebo (P = .018). The authors con-cluded that selenium did not demon-strate a protective effect on PSA veloc-ity and that high-dose seleniumsupplementation might negativelyaffect PSA velocity.

Vitamin DVitamin D is a unique supplement,because daily intake is derived fromdiet and sun exposure. This nutrientregulates calcium and skeletal homeo -stasis and behaves like a hormone, reg-ulating transcription of more than 200genes. It is theorized that vitamin Dmight help prevent cancer by inducingcellular differentiation, inhibitingangiogenesis, and causing apoptosis.Observational studies have demon-strated a link between low levels ofvitamin D and increased cancer inci-dence or poorer cancer prognosis.11-13

In November 2010, the Institute ofMedicine (IOM) released a report pro-posing increases in the dietary refer-ence intake values for calcium andvitamin D.14 IOM tripled the recom-mended daily allowance of vitamin Dfor adults aged 31 to 50 years andincreased it by 50% for adults aged 51to 70 years, advising that all healthy,noninfant children and adults aged≤70 years get 600 IU daily of vitaminD. The IOM said evidence of im provedbone health was the only health condi-tion that informed the suggestedincreases and cited mixed and incon-clusive research about the use of vita-min D in the prevention and treat-ment of cancer.

A single-arm, phase 2 trial evaluatedthe palliative benefit of high-dose vita-min D3 (cholecalciferol) on pain scoresand bone resorption markers in 38patients with breast cancer and evi-dence of bone metastases.15 Every dayfor 4 months, patients took 10,000 IUof oral vitamin D3 and 1000 mg of calcium. Pain response was measuredusing 2 validated questionnaires,which were administered at baselineand repeated monthly. All patientscontinued on previously prescribed bis-phosphonate therapy. No significantchanges from baseline in pain score ordaily morphine-equivalent analgesiause were observed, although there wasa significant reduction in number ofpain sites. In addition, daily use ofhigh-dose vitamin D3 and calcium didnot significantly reduce levels of uri-nary bone resorption markers. Theauthors concluded that although the

combination of daily high-dose vita-min D3 and calcium appeared safe, itdid not offer significant palliation orreduce bone resorption.

Your RoleVitamin and mineral supplementationare often used to treat oncologypatients. Emerging literature suggests arole for vitamin D in the preventionand treatment of cancer, but studieshave failed to show any benefit withmultivitamin and selenium use. Vita -min supplementation remains a promis-ing area for research, but because of therisks and the inconsistent and conflict-ing data, it is important for healthcareprofessionals to evaluate the informa-tion carefully. This, in turn, allows med-ical professionals to assist cancer sur-vivors in making appropriate treatmentdecisions. �

References1. Velicer CM, Ulrich CM. Vitamin and mineral sup-plement use among US adults after cancer diagnosis: asystematic review. J Clin Oncol. 2008;26:665-673.2. Doyle C, Kushi LH, Byers T, et al; for the 2006Nutrition, Physical Activity and Cancer SurvivorshipAdvisory Committee; American Cancer Society.Nutrition and physical activity during and after cancertreatment: an American Cancer Society guide forinformed choices. CA Cancer J Clin. 2006;56:323-353.3. Lawenda BD, Kelly KM, Ladas EJ, et al. Should sup-plemental antioxidant administration be avoided duringchemotherapy and radiation therapy? J Natl Cancer Inst.2008;100:773-783.4. Giovannucci E, Chan AT. Role of vitamin and min-eral supplementation and aspirin use in cancer sur-vivors. J Clin Oncol. 2010;28:4081-4085.5. Ng K, Meyerhardt JA, Chan JA, et al. Multivitaminuse is not associated with cancer recurrence or survivalin patients with stage III colon cancer: findings fromCALGB 89803. J Clin Oncol. 2010;28:4354-4363.6. Stratton MS, Reid ME, Schwartzberg G, et al.Selenium and inhibition of disease progression in mendiagnosed with prostate carcinoma: study design andbaseline characteristics of the “Watchful Waiting”Study. Anticancer Drugs. 2003;14:595-600.7. Thompson IM. Chemoprevention of prostate cancer:agents and study designs. J Urol. 2007;178(3 pt 2):S9-S13.8. Lippman SM, Klein EA, Goodman PJ, et al. Effect ofselenium and vitamin E on risk of prostate cancer andother cancers: the Selenium and Vitamin E CancerPrevention Trial (SELECT). JAMA. 2009;301:39-51.9. Clark LC, Combs GF Jr, Turnbull BW, et al. Effects ofselenium supplementation for cancer prevention inpatients with carcinoma of the skin. A randomized con-trolled trial. Nutrition Prevention of Cancer StudyGroup [published correction appears in JAMA.1997;277:1520]. JAMA. 1996;276:1957-1963.10. Stratton MS, Algotar AM, Ranger-Moore J, et al.Oral selenium supplementation has no effect onprostate-specific antigen velocity in men undergoingactive surveillance for localized prostate cancer. CancerPrev Res (Phila). 2010;3:1035-1043.11. Chung M, Balk EM, Brendel M, et al. Vitamin D andCalcium: A Systematic Review of Health Outcomes.Evidence Report no. 183. Rockville, MD: Agency forHealthcare Research and Quality; 2009. AHRQ publi-cation no. 09-E015.12. Drake MT, Maurer MJ, Link BK, et al. Vitamin Dinsufficiency and prognosis in non-Hodgkin’s lym-phoma. J Clin Oncol. 2010;28:4191-4198.13. Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N.Prognostic effects of 25-hydroxyvitamin D levels inearly breast cancer. J Clin Oncol. 2009;27:3757-3763.14. Institute of Medicine. Dietary reference intakes forcalcium and vitamin D. Washington, DC: NationalAcademies Press; 2011.15. Amir E, Simmons CE, Freedman OC, et al. A phase2 trial exploring the effects of high-dose (10,000IU/day) vitamin D3 in breast cancer patients with bonemetastases. Cancer. 2010;116:284-291.

Vitamin and Supplement Use in Oncology PatientsBy Megan Hagerty, PharmD, BCOPDepartment of Pharmacy Practice, Purdue University College of Pharmacy, Indianapolis, Indiana

Emerging literature suggests a role for vitamin D in theprevention and treatment of cancer, but studies havefailed to show any benefit with multivitamin andselenium use.

TOP_May 2011_4_TOP 5/13/11 9:31 AM

�� Editor in ChiefSagar Lonial, MDAssociate Professor of Hematology and Oncology Emory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Section of HematologyRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Therapy• Transplant-Eligible Patients• Retreatment• Transplant-Ineligible Patients• Cytogenetics• Side-Effect Management• Bone Health

Newsletter Series

��

��

Topics include:• Hodgkin Lymphoma• Follicular Lymphoma• Mantle Cell Lymphoma• Waldenstrom’s Macroglobulinemia• Diffuse Large B-Cell Lymphoma• T-Cell Lymphoma

��

��

Target AudienceThese activities were developed for physicians, nurses, and pharmacists.

AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided.For complete learning objectives and accreditation information, please refer to each activity.

This activity is jointly sponsored by Global Education Groupand Medical Learning Institute, Inc.

Coordination for this activity provided by Center of Excellence Media, LLC.

��

YOUR QUESTIONS ANSWERED

COEKsize40611MM

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or [email protected].

This activity is supported by educational grant from Cephalon Oncology,Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

� �� TOP_May 2011_4_TOP 5/13/11 9:31 AM


Drug Pipeline

Areview of promising investiga-tional drugs at the annualHematology/Oncology Phar -

macy Association meeting shows thepharmaceutical industry is respondingto the call for more targeted agents inoncology. While a few drugs in thepipeline offer little survival advantageover current standards of care, clinicaltrials suggest their greater selectivityresults in less toxicity. Robert T. Dorr,PhD, RPh, a professor of pharmacologyat the Ar i zona Cancer Center inTucson, expects a handful of new agentsto come to market in the United Statesin the next year.

Prostate Cancer PipelineMDV3100 is an emerging therapy formetastatic castration-resistant prostatecancer, but Dorr said abiraterone’s suc-cess has hindered recruitment for thephase 3 trials needed to support themanufacturer’s New Drug Application.Pre liminary study data show that theandrogen-receptor antagonist producedfairly high rates of prostate-specific anti-gen response in chemotherapy-naiveand previously treated patients, and hebelieves it will ultimately receive FDAapproval.

Breast Cancer TherapiesTDM-1, a novel agent for HER2-posi-tive breast cancer, suffered a setbackwhen the FDA deferred approving thedrug pending stronger evidence of its effi-cacy. TDM-1 combines tras tuzumab anda derivative of the microtubule antibodymaytansine, and Dorr considers it superi-or to trastuzumab. He ex pects forth-coming trial data to provide the FDAwith enough evidence that TDM-1im proves re sponse and overall sur-vival (OS) to warrant approval. “At the highest dose [with TDM-1],

you actually get regression with thisconstruct.… In some breast tumors, youcan get near-total suppression,” he said.Although trastu zumab inhibits tumorgrowth, it does not typically spur tumorregression. Phase 2 studies suggest thatTDM-1 is far less toxic than trastuzum-ab. “This is a big improvement forpatients, that you can get the same out-come with markedly reduced toxicity,”he said.

Crizotinib in Lung CancerCrizotinib, which Dorr called “a homerun,” is another drug he expects to seeapproved soon. Crizotinib is an oralsmall-molecule inhibitor, effective forthe 5% of patients with non–small celllung cancer who have chromosomalrearrangements of anaplastic lymphomakinase. Phase 1/2 trial (N = 82) results

published in the New England Journal ofMedicine last year by Kwak and col-leagues disclosed that 80% of heavilypretreated patients achieved partialresponse (PR), complete response (CR),or stable disease (SD). A follow-up analysis slotted for the

upcoming annual meeting of theAmerican Society of Clinical Oncologyis expected to show responses were fair-ly durable and is likely to reportimprovement in OS. Crizotinib appearsto be relatively safe, with most toxicities≤grade 1. “The only grade 3 toxicitieswe are seeing is AST [alanine amino-transferase] and ALT [aspartate amino-transferase] elevations, and 80% ofthese patients could go down to 200 mgtwice daily,” said Dorr. He added thatdose-limiting fatigue was seen at a doseof 300 mg twice daily. Approval couldbe delayed if the FDA does not approvethe companion diagnostic test submit-ted for consideration at the same time.

Drugs in Hematologic MalignanciesThe pace of drug development in chron-ic myeloid leukemia (CML) does notappear to be slowing. Of the most prom-ising investigational agents, bosutinib(SKI-606) is probably the furthestalong. Like the currently approvedtyrosine kinase inhibitors imatinib,dasatinib, and nilotinib, bosutinib isnot effective in patients with a T315Imutation. Bosutinib’s primary targetsare ABL, SRC, and CAMK26, and ithas a maximum tolerated dose of 500mg once daily. Bosutinib has demon-strated activity in phase 2 trials, which

have reported CRs and major molecu-lar response in nearly three-quarters(74%) of patients resistant to orunable to tolerate imatinib and inpatients resistant to dasatinib or nilo-tinib. Trials report low rates of grade3/4 toxicities, with diarrhea, neutrope-nia, and hypomagnesemia among themost common. “The problem that happened with

bosutinib is that the so-called pivotal3000 trial that was supposed to show asuperior cytogenetic response rate[over imatinib] at 1 year did not reachits primary end point,” he said. Despitethis, the manufacturer filed a NewDrug Application with the FDA in thehopes that it might be approved as asecond- or third-line agent, whichDorr believes is likely.Dorr discussed 2 agents progressing

down the multiple myeloma pipeline.Carfilzomib is a proteasome inhibitorundergoing investigation in a large,closely watched, phase 3 trial enrollingpatients refractory to bortezomib. Heexpressed skepticism as to whether itwould prove superior to existing agentsin terms of efficacy but praised its lowertoxicity profile. An added benefit ofcarfilzomib is that patients do not needsteroid treatment while taking it. Pomalidomide is another promising

drug for refractory multiple myeloma. Itis an oral immunomodulatory agent,and preliminary phase 1/2 trial data pre-sented by Lacy and associates at theAmerican Society of Hematology meet-ing in December 2010 indicated that itwas highly active in patients with heav-ily pretreated disease. They reported anoverall response rate (ORR) of 62%,and Dorr said 24% of PR fell into the“very good” category. One-third ofpatients experienced neutropenia≥grade 3, which might be something towatch for in future analyses.

Is Axitinib Next in Kidney Cancer?Patients with renal cell carcinoma(RCC) refractory to sorafenib couldhave a new option soon. A 2007 phase2 trial of the oral drug axitinib, whichDorr described as a “pure” inhibitor of

vascular endothelial growth factor(VEGF) 1, 2, and 3, demonstrated a44% ORR using RECIST criteria, timeto progression of 15.7 months, andmedian OS of 29.9 months. Rini andcolleagues enrolled 62 heavily pre-treated patients with refractory me ta -static RCC in a single-arm trial of axi-tinib and found that most patientsexperienced PR or SD. Grade 3/4adverse events included hand-foot syn-drome, which he noted is a class effectof VEGF inhibitors.“I think RCC is turning out to be a

little like CML. You’ll start on a drugand ultimately fail on it, move toanother one and then another one,and there’s a possibility you can latergo back to an original drug and getresponse,” said Dorr.

BRAF a Target in MelanomaConstitutively active BRAFV600E muta-tions are found in 60% of patients withmelanoma. PLX4032 (also known as RG7204), a

powerful inhibitor of BRAFV600E, is thefurthest along in development. Early trialresults in advanced melanoma showedthat most patients with a BRAFV600E

mutation achieved PR or CR and that81% of patients saw their tumors shrinkby at least 30%, which prompted numer-ous headlines touting PLX4032 as a pos-sible cure. Many patients ultimatelybecome refractory to the drug, however,and some researchers are looking atwhether combining it with a MET in -hibitor might provide more durableresponses. A January 2011 press releaseby the companies making PLX4032an nounced that upcoming preliminarydata would show improved OS andprogression-free survival for patientstaking PLX4032 as part of a phase 3trial. “I think the molecular drug willprobably be approved some- time nextyear,” Dorr said.Dorr predicted that in the coming

year, we would likely see many morenovel targeted agents making their wayout of the crowded oncology pipeline.He expects a number of RET and METinhibitors and drugs that affect RASsignaling to start generating interest.We have “maybe 15 or 16 kinase in -hibitors in the armamentarium now,” hesaid, but with more than 500 proteinkinases identified in humans, a tre -mendous amount of room remains forfuture discovery. �

Robert T. Dorr receives a salary fromAmpliMed Corporation, for which he ischief executive officer; owns interest instock in AmpliMed; and has received roy-alties from Clinovel.

A Review of Investigational Drugs at HOPABy Christin Melton

“At the highest dose [with TDM-1],you actually get regression withthis construct.… In some breasttumors, you can get near-totalsuppression.”

—Robert T. Dorr, PhD, RPh

Crizotinib is effective forthe 5% of patients withnon–small cell lung cancerwho have chromosomalrearrangements ofanaplastic lymphomakinase.

TOP_May 2011_4_TOP 5/13/11 10:10 AM

��

��

To use 2D barcodes, download the ScanLife app:• Text “scan” to 43588• Go to www.getscanlife.com

on your smartphone’s web browser, and select “Download”

• Visit the app store for your smartphone

Scan Here to Register.

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

Current activities atwww.COEXM.com include:

Pushing Your Limits

COEKsize2711CE©iStockphoto.com/altaykaya

� �� TOP_May 2011_4_TOP 5/13/11 9:31 AM

TOP_May 2011_4_TOP 5/13/11 9:31 AM

MAY 2011, VOL 4, NO 3

Documents

Transcript of MAY 2011, VOL 4, NO 3