Annals of oncology: official journal of the
`
`_no. 7 (July 2013)
`eral Collection
`AN617D
`
`2013-07-26 08:43:10 ISSN 0923-7534 (print)
` aS
`Oncology
`
`ISSN 1569-8041 (online)
`
`aeae
`
`040571 ANNALS OF ONCOLOGY - ENGLISH EDITION
`=|
`|iIlIUlPGR2019-00002
`Genome z Co. v. Univ. of Chicago
`
`=
`
`Sean to view this journal
`on your mobile device
`
`=
`
`ees — ae
`
`Va morte OF THE
`boty NATIONAL
`
`LIBRARY OF
`MEDICINE
`
`Www.annonc.oxfordjournals.org
`AOA Nn AL OG oOorda
`
`2013 VOLUME 24 ISSUE ?
`SISAC
`
`Waihe
`
`UNIV. CHICAGO EX. 2042
`
`

`

`Annals of Oncology
`
`-
`
`Ss wn fe)
`
`Official Journal of the
`EuropeanSociety for Medical Oncology and the Japanese Society of Medical Oncology
`
`GOOD SCIENCE
`
`= | BETTER MEDICINE
`BEST PRACTICE
`European Society for Medical Oncology
`
`Volume 24 | No, 7 | July 2013
`
`editorials
`
`“All action notalk’: the role of HER2/neuin adjuvant
`therapy choice for gastric cancer
`D. Santini, B. Vincenzi,
`FP, Pantano, G. Schiavon &
`G. Tonini
`
`Therapeutic windows and opportunity cost cast upon
`prostate cancers fatal shore
`A. Goldkorn, A. M. Aparicio & D. I. Quinn
`
`1715
`
`1717
`
`reviews
`
`Statins are associated with reduced risk of gastric cancer: a
`systematic review and meta-analysis
`1721
`P. P. Singh & S. Singh
`‘Targeted therapies andthe treatmentof non-clearcell renal
`cell carcinoma
`]. Bellmunt e J. Dutcher
`Active immunotherapy in HER2 overexpressing breast
`cancer: current status and future perspectives
`A. Milani, D. Sangiolo, F. Montemurro, M. Aglietta &
`1740
`G. Valabrega
`The volume effect in paediatric oncology: a systematic review
`R. R. G. Knops, E. C. van Dalen, R. L. Mulder, E. Leclercq,
`S. L. Knijnenburg, G. J. L. Kaspers, R. Pieters, H. N. Caron &
`L. C. M. Kremer
`1749
`
`1730
`
`original articles
`
`gastrointestinal tumors
`
`FOLFOX4 plus cetuximab administered weekly or every
`second weekin the first-line treatment of patients with
`KRASwild-type metastatic colorectal cancer: a randomized
`phase If CECOGstudy
`T. Brodowicz, T. E. Ciuleanu, D, Radosavljevic,
`E, Shacham-Shmueli, D. Vrbanee, S. Plate,
`Z. Mrsic-Krmpotic, M, Dank, G. Purkalne,
`D. Messinger & C. C, Zielinski
`
`1769
`
`A randomized, placebo-controlled phase 2 study of
`ganitumabor conatumumab in combination with FOLFIRI
`for second-line treatment of mutant KRAS metastatic
`colorectal cancer
`A. L. Cohn, J. Tabernero, J. Maurel, EF. Nowara, J. Sastre,
`B. Y. 8. Chuah, M. V. Kopp, D. D. Sakaeva, E. P. Mitchell,
`$. Dubey, S, Suzuki, Y.-J. Hei, F. Galimi, I. McCaffery,
`Y. Pan, R. Loberg, S, Cottrell & S.-P. Choo
`
`1777
`
`Sorafenib combined withtransarterial chemoembolization
`for the treatment of advanced hepatocellular carcinoma: a
`large-scale multicenter study of 222 patients
`Y. Zhao, W. J. Wang, 8. Guan, H. L. Li, R. C. Xu, J. B. Wu,
`J. S. Liu, H. P. Li, W. Bai, Z. X. Yin, D. M. Fan, Z. L. Zhang
`e& G. H. Han
`1786
`
`Global, multicenter, randomized, phase II trial of
`gemcitabine and gemcitabine plus AGS-1C4D4in patients
`with previously untreated, metastatic pancreatic cancer
`B. M. Wolpin, E. M. O'Reilly, Y. J. Ko, L. 8. Blaszkowsky,
`M. Rarick, C. M. Rocha-Lima, P. Ritch, E. Chan, }. Spratlin,
`T. Macarulla, E. McWhirter, D. Pezet, M. Lichinitser,
`L. Roman, A. Hartford, K. Morrison, L. Jackson, M. Vincent,
`L, Reyno & M. Hidalgo
`1792
`
`Assessment of HER2 gene amplification in
`adenocarcinomasof the stomach or gastroesophageal
`junction in the INT-0116/SWOG9008clinicaltrial
`M. A, Gordon, H. M. Gundacker, J. Benedetti,
`J. 8. Macdonald, J. C. Baranda, W.J. Levin, C. D. Blanke,
`W.Elatre, P. Weng, J. Y. Zhou, H. J. Lenz & M. PF. Press 1754
`
`Evaluation of short-course radiotherapy followed by
`neoadjuvant bevacizumab, capecitabine, and oxaliplatin and
`subsequentradical surgical treatment in primary stage IV
`rectal cancer
`T. H. van Dijk, K. Tamas, J. C. Beukema, G. L. Beets,
`A. J. Gelderblom, K. P. de Jong, I. D. Nagtegaal, H. J. Rutten,
`C.J. van de Velde, T. Wiggers, G. A. Hospers &
`K. Havenga
`
`1762
`
`urogenital tumors
`
`Clinical activity of abiraterone acetate in patients with
`metastatic castration-resistant prostate cancer progressing
`after enzalutamide
`K. L. Noonan, S. North, R. L. Bitting, A. J. Armstrong,
`S. L. Ellard e& K. N. Chi
`
`1802
`
`Antitumouractivity of abiraterone acetate against metastatic
`castration-resistant prostate cancer progressing after
`docetaxel and enzalutamide (MDV3100)
`Y. Loriot, D. Bianchini, E. Ileana, 8. Sandhu, A. Patrikidou,
`C. Pezaro, L. Albiges, G. Attard, K. Fizazi, J. 8. De Bono &
`C. Massard
`1807
`
`Continuedoverleaf
`
`

`

`Ipilimumab alone or in combinationwith radiotherapy in
`metastatic castration-resistant prostate cancer: results from
`an open-label, multicenter phaseI/II study
`5. F. Slovin, C. 8. Higano, O. Hamid, S. Tejwani,
`A. Harzstark,J. J. Alumkal, H. I. Scher, K. Chin, P. Gagnier,
`M. B. McHenry & T. M. Beer
`1813
`
`lung cancer
`
`ROS! fusions in Chinese patients with non-small-cell lung
`cancer
`W. Cai, X. Li, C. Su, L. Fan, L. Zheng, K. Fei, C. Zhou,
`C. Manegold & G, Schmid-Bindert
`
`1822
`
`breast cancer
`
`1834
`
`A randomized phase II study comparing capecitabine alone
`with capecitabine and oral cyclophosphamide
`in patients with advanced breast cancer-cyclox I]
`V. |. Harvey, K. J. Sharples, R. J. Isaacs, M. B. Jameson,
`G. M.Jeffery, B. R. McLaren, S. Pollard, G. A. Riley,
`A. B. Simpson, V. A. Hinder, J. N. Scott, M. V, Dzhelali &
`M. P. Findlay
`1828
`{s adjuvant trastuzumaba cost-effective therapy for HER-2/
`neu-positive TIbNO breast cancer?
`C. Skedgel, D. Rayson & T. Younis
`A phaseII study ofixabepilone andtrastuzumab
`for metastatic HER2-positive breast cancer
`S. M. Tolaney, J. Najita, J. Sperinde, W. Huang, W. Y. Chen,
`]. Savoie, M. Fornier, E. P. Winer, C. Bunnell &
`I. E. Krop
`Breast cancer phenotype, nodal status and palpability
`may be useful in the detection of overdiagnosed
`screening-detected breast cancers
`O. Brouckaert, A. Schoneveld, C. Truyers, E. Kellen,
`C. Van Ongeval, I. Vergote, P. Moerman, G. Floris,
`H. Wildiers, M. R. Christiaens, E. Van Limbergen &
`1847
`P. Neven, on behalf of MBCLeuven, Belgitum
`Attitudes of patients with metastatic breast cancer toward
`research biopsies
`D. 8. Seah, S. M. Scott, J. Najita, T. Openshaw,
`K. Krag, E. Frank, J. Sohl, Z. K, Stadler, M. Garrett,
`S. G. Silverman, J. Peppercorn, E. P. Winer, S. E. Come &
`N. U. Lin
`1853
`
`1841
`
`Effect of low-dose tamoxifen after surgical excision ofductal
`intraepithelial neoplasia: results ofa large retrospective
`monoinstitutional cohort study
`A, Guerrieri-Gonzaga, M. Lazzeroni, E. Botteri, D. Serrano,
`N. Rotmensz, M.-C. Varricchio, M. Cazzaniga, G. Bollani,
`5. Mora, C. Montefrancesco, G. Pruneri, G. Viale, M. Intra,
`V. Galimberti, A, Goldhirsch, V. Bagnardi, B. Bonanni &
`A. DeCensi
`1859
`
`translational research
`
`Genome-wide discovery ofgenetic variants affecting tamoxifen
`sensitivity andtheir clinical and functional validation
`L, Weng, D, Ziliak, H. K. Im, E. R. Gamazon,S. Philips,
`A. T. Nguyen, Z. Desta, I. C. Skaar,
`the Consortium on Breast
`Cancer Pharmacogenomics (COBRA), D. A. Flockhart &
`ROS. Huang
`
`1867
`
`hematologic malignancies
`
`Granulocytetransfusions in hematologic malignancy
`patients with invasive pulmonary aspergillosis: outcomes
`and complications
`LL Raad, A. M. Chaftari, M. M. Al Shuaibi, Y. Jiang,
`W. Shomali, J. E. Cortes, B. Lichtiger & R. Y. Hachem 1873
`Impact of chemotherapy regimenandrituximabin adult
`Burkitt lymphoma: a retrospective population-based study
`from the Nordic Lymphoma Group
`T. Wasterlid, P. N. Brown, O, Hagberg, H. Hagberg,
`L, M. Pedersen, F. D'Amore & M. Jerkeman
`
`1879
`
`quality of life and supportive care
`
`Prevalence ofiron deficiency across different tumors andits
`association with poor performancestatus, disease status and
`anemia
`H. Ludwig, E. Miildiir, G. Endler & W. Hiibl
`
`1886
`
`Comparing normalsaline versus diluted heparin to lock
`non-valved totally implantable venous access devices in
`cancer patients: a randomised, non-inferiority, open trial
`G. A. Goossens, M. Jérome, C. Janssens, W. FE. Peetermans,
`S. Fieuws, P. Moons, }. Verschakelen, K. Peerlinck,
`M. Jacquemin e& M. Stas
`
`1892
`
`phase | and pharmacokinetics
`
`Temsirolimus combined with sorafenib in hepatocellular
`carcinoma: a phase | dose-finding trial with
`pharmacokinetic and biomarker correlates
`R. K. Kelley, H. S. Nimeiri, P. N. Munster, M. T. Vergo,
`Y. Huang, C.-M,Li, J. Hwang, M. F. Muleahy, B. M. Yeh,
`P. Kuhn, M. 8, Luttgen, J. A. Grabowsky, L. Stucky-Marshall,
`W. M. Korn, A, H. Ko, E. K, Bergsland, A, B, Benson II] &
`A. P. Venook
`1900
`
`epidemiology
`
`Prevalence and risk factors of extrapancreatic malignancies
`in a large cohort of patients with intraductal papillary
`mucinous neoplasm (IPMN)ofthe pancreas
`A. Larghi, N. Panic, G. Capurso, E. Leoncini, D, Arzani,
`R. Salvia, M. Del Chiaro, L. Frulloni, P. G. Arcidiacono,
`A. Zerbi, R. Manta, C. Fabbri, M. Ventrucei, I. Tarantino,
`M. Piciuechi, A. Carnuccio, U. Boggi, G. Costamagna,
`G. Delle Fave, R. Pezzilli, C. Bassi, M. Bulajic, W. Ricciardi
`e& S. Boccia
`1907
`
`Continued overleaf
`
`

`

`Coffee consumptionandrisk oflocalized, advanced and
`fatal prostate cancer: a population-based prospective study
`A. Discacciati, N. Orsini, 8-O. Andersson, O. Andrén,
`1912
`.-E. Johansson, C. 8. Mantzoros & A. Wolk
`Cruciferous vegetables consumptionandthe risk of female
`lung cancer: a prospective study and a meta-analysis
`Q. |. Wu, L. Xie, W. Zheng, E. Vogtmanit, H. L. Li, G. Yang,
`B. T. Ji, Y. T. Gao, X. O. Shu & Y. B. Xiang
`1918
`
`sarcomas
`
`Advancedsoft-tissue sarcomain elderly
`patients: patterns ofcare and survival
`D. Garbay, R. G. Maki,J. Y. Blay, N. Isambert, 5. Piperno
`Neumann, C. Blay, E. Zanardi, P. Boudou-Rouquette,
`L. Bozec, F. Duffaud, F. Bertucci & A. Italiano
`PhaseII study on lapatinib in advanced EGFR-positive
`chordoma
`S. Stacchiotti, BE, Tamborini, 5. Lo Vullo, F. Bozzi,
`A. Messina, C. Morosi, A. Casale, F. Crippa, E, Conca,
`T. Negri, E. Palassini, A. Marrari, E. Palmerini, L. Mariani,
`A. Gronchi, S. Pilotti & P.G. Casali
`1931
`
`1924
`
`clinical trials
`
`Performance of multinomial designs in comparison with
`response-based designs in non-randomized phaseII trials of
`targeted cancer agents
`R. Jamal, R. A. Geodwin, D. Tu, W. Walsh, D. Lacombe &
`E. A, Eisenhauer
`1936
`
`Non-inferiorily cancerclinical trials: scope and purposes
`underlying their design
`R. P. Riechelmann, A. Alex, L. Cruz, G. M. Bariani &
`P. M. Hoff
`
`1942
`
`letters to the editor
`
`Improving the chance of cure offollicular lymphoma by
`combining immunotherapy and radioimmunotherapy based
`on anti-CD20 antibodies?
`F, Buchegger, J.-P. Mach, O. W. Press, A. BischofDelaloye,
`5. M. Larson, ]. O. Prior & N. Ketterer
`1948
`
`Spin andbias: the tip of the iceberg
`V. W. Berger
`Spin andbias: the tip of the iceberg
`FE. Vera-Badillo & LF. Tannock
`
`1949
`
`1949
`
`

`

`subscriptions
`
`A subscription to Annals of Oncology comprises 12 issues plus supplements in
`each volume. Prices include postage, and for subscribers outside the UK deliy-
`ery is by Standard Air.
`
`Annual Subscription Rate (Volume 24, 12 issues, 2013)
`
`Group Office, Oxford (bank sort code 20-65-18) (UK), overseas only Swift code
`BARC GB
`22
`(GBE
`Sterling
`to
`account
`no,
`70299332,
`IBAN
`GBS89BARC20651870299332; US$ Dollars to account no. 66014600,
`IBAN
`GB27BARC20651866014600; EUC Euros
`to account no. 78923655,
`IBAN
`GBI6BARC20651878923655).
`(iii) Credit card (Mastercard, Visa. Switch or
`American Express).
`
`Annals of Oncology (ISSN 0923-7534)
`is published monthly hy Oxford
`Institutional—Academic / Nonprofit only
`University Press. Oxford, UK. The US annual print subscription or price 1s
`Print and Online £1319,00/$2639,.00/¢ 1980.00
`$2513.00. Airfreight and mailing in the USA byagent named Air Business Ltd,
`Online Only £1044.00/$2089.00/0 1568.00
`clo Worldnet Shipping Inc, 156-15, 146th Avenue, tnd Floor, Jamaica, NY
`Print Only £1209.00/$2419.00/C1815.00
`11434, USA. Periodicals postage paid at Jamaica NY 11431.
`
`Institutional — Corporate
`Print and Online £1649.00/$3299.00/02475,00
`Online Only £1305.00/5261 1.00/6 1959.00
`Print Only £151 1.00/53024.00/62269,00
`
`Personal
`Print and Online £1144.00/$2288.00/€17 17.00
`Please note: US$ rate applies to US & Canada, Euros applies to Europe, UKE
`applies to UK and Rest of World.
`
`There may be other subscription rates available, for a complete listing please
`visit wwwannone.oxtordjournals.org/subscrptions
`
`is required for all orders. Orders are
`Full prepayment, in the correct currency,
`regarded as firm and payments are not refundable, Subscriptions are accepted
`and entered on a complete volume basis. Claims cannot be considered more
`than FOUR months after publication or date of order, whichever is later. All
`subscriptions in Canada are subject
`to GST. Subscriptions in the EU may be
`subject
`to European VAT. If registered, please supply details to avoid: unneces-
`sary charges. For subscriptions that include online versions, a proportion of the
`subscription price may be subject to UK VAT. Personal rate subscriptions are
`onlyavailable if payment is made by personal chequeor credit card and deliv-
`ery is toa private address.
`
`issues are available from Oxford
`The current year and two previous years’
`Journals. Previous volumes can be obtained from the Periodicals Service
`Company at http://www.periodicalscom/oxtord.html or Periodicals Service
`Company, 11 Main Street, Germantown, NY 12526, USA, Email: psc@periodi-
`cals. com. Tel: (518) 537-4700. Fax: (518) 537-5899
`
`Service
`Journals Customer
`contact:
`please
`information,
`further
`For
`Department, Oxford University Press, Great Clarendon Street, Oxford OX2
`6DP, UK. Email: jnis,cust.serv@oup.com, Tel (and answerphone outside normal
`
`working hours): +44 (0)1865 353907. Fax: +44 (0)1865 353485, In the US,
`please contact:
`Journals Customer Service Department, Oxford University
`Press, 2001 Evans Road, Cary, NC 27513, USA. Email:
`jnlorders@oup,.com,
`‘Tel (and answerphoneoutside normal working hours): 800 852 7323 (toll-free
`in USA/Canada). Fax: 919 677 1714.
`In Japan, please contact:
`Journals
`Customer Service, Oxford University Press, 4-5-10-8F Shiba, Minato-ku, Tokyo
`108-8386, Japan. Tel. +81 3 5444 5858. Pax. +81 3 3454 2929, E-mail: custserv,
`jp@oup.com
`
`DOI: For information about DOIs andto resolve them, please visit http://www.
`doiorg
`
`to
`(i) Cheque (payable to Oxford University Press,
`Methods of payment.
`Oxford University Press, Cashiers Office, Great Clarendon’ Street, Oxford
`OX2 6DP, UK) in GBESterling (drawn on a UK bank), USS Dollars (drawn on
`a US bank), or EU€ Euros. (ii) Bank transfer to Barclays Bank Ple, Oxford
`
`Subscription records are maintained at Oxford University Press, Oxford, UR.
`
`supplements, reprints and corporate sales
`For requests from industry and companies regarding supplements, bulk article
`
`reprints,
`sponsored subseriptions,
`translation opportunities
`for previously
`published material, and corporate online opportunities, please email: special.
`sales@oup.com,fax: +44 (0) 1865 353774 or visit www.oxtordjournals.org/sales,
`
`permissions
`For information on howto request permissions to reproduce articles/intorma-
`tion fromthis journal, please visit www.oxfordjournals.org/permissions.
`
`advertising
`Advertising, inserts and artwork enquiries should be addressed to Advertising
`and Special Sales, Oxford Journals, Oxford University Press, Great Clarendon
`Street, Oxford, OX2 6DP, UK.
`‘Tel: +44 (0)1865 354767; Fax +44 (0)1865
`353774; E-mail: jnlsadvertising@oup.com
`
`environmental and ethical policies
`is committed to
`Oxford Journals, a division of Oxford University Press,
`working with the global community to bring the highest quality research tothe
`widest possible audience. Oxford Journals will protect
`the environment by
`implementing environmentally friendly policies and practices wherever possible,
`Please see http://www-.oxfordjournals.org/ethicalpolicies.html for further infor-
`mation on environmental andethical policies.
`
`drug disclaimer
`All reasonable precautions have been taken by the authors, editors and publisher
`to verify drug names and doses, theresults of experimental work and the clinical
`findings published in this journal, The opinions expressed are those of the
`authors, and not necessarily those ofthe editors or publisher, The ultimate res-
`ponsibility for the use and dosage of drugs mentioned in Annals of Oncology
`and in the interpretation of published material lies with the medical practitioner,
`The editors and publisher can accept noliability whatsoever in respect of any
`claim for damagesarising therefrom. Please informthe editors of any errors.
`
`© The European Society for Medical Oncology 2013
`
`All rights reserved; no part of this publication may be reproduced, stored in a
`retrieval system, or transmitted in any form or by any means, electronic, mech-
`anical, photocopying, recording, or otherwise without prior written: permission
`of the Publishers, or a licence permitting restricted copying issued in the UK by
`the Copyright Licensing Agency Ltd, 90 ‘Tottenham Court Road, London WIP
`SHE, or in the USA by the Copyright Clearance Center, 222 Rosewood Drive,
`Danvers, MA 01923,
`
`Typeset by Techset Composition Ltd, Salisbury, UR.
`Printed by Bell and Bain Lid., Glasgow, UK.
`
`
`MIX
`Paper from
`responsible sources
`For? Cnn77AR6
`
`FSC
`
`

`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`
`Annals of Oncology
`
`Annals of Oncology 24: 1813-1821, 2013
`dot: 10. 1093/annone/mal to?
`Published online 27 March 2013
`
`Ipilimumab alone or in combination with radiotherapyin
`metastatic castration-resistant prostate cancer: results
`from an open-label, multicenter phase I/II study
`S. F. Slovin™, C. S. Higano?, O. Hamid, S. Tejwani*, A. Harzstark®, J. J. Alumkal®, H.
`K. Chin’, P. Gagnier’, M. B. McHenry’ & T. M. Beer®
`'Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York: Department of Medicine, Seattle Cancer Care Alliance, University of Washington, Seattle;
`‘Department of Translational Research/Immunotherapy, The Angeles Clinic and Research Institute, Santa Monica: ‘Department of Hematology-Oncolagy, Henry Ford
`Health System, Detroit; “Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University af California, San Francisco; “Division of Hematology and
`Medical Oncology, Knight Cancer institute, Oregon Health and Science University, Portland;
`‘Department of Oncology Global Clinical Research, Bristol-Myers Squibb,
`Wallingford, USA
`
`|. Scher’,
`
`Received 15 November 2012; revised 4 February 2013; accepted 5 February 2013
`
`Background:This phase1/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored
`ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic
`antitumoractivity between anti-CTLA-4 antibody andradiotherapy.
`Patients and methods:In dose escalation, 33 patients (=>6/cohort) received ipilimumab every 3 weeks x 4 doses at
`3, 5, or 10 mg/kg orat 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expandedto 50
`patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs),
`prostate-specific antigen (PSA) decline, and tumor response.
`Results: Common immune-related AEs(irAEs) among the 50 patients receiving 10 mg/kg + radiotherapy were diarrhea
`(54%), Colitis (22%), rash (82%), and pruritus (20%); grade 3/4 irAEs includedcolitis (16%) andhepatitis (10%). One
`treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg +radiotherapy, eight had PSA
`declines of >50%(duration: 3-13+ months), one had complete response(duration: 11.3+ months), and six had stable
`disease (duration: 2.8-6.1 months).
`Conclusions:In mCRPCpatients,ipilimumab 10 mg/kg + radiotherapy suggestedclinical antitumor activity with
`disease control and manageable AEs. Two phaseIll trials inmCRPCpatients evaluatingipilimumab 10 mg/
`kg + radiotherapy are ongoing.
`ClinicalTrials.gov identifier; NCTO0323882.
`Key words:ipilimumab, metastatic castration-resistant prostate cancer, phase I/II trial, prostate-specific antigen and
`radiotherapy, immunotherapy
`
`introduction
`:
`pe
`se
`OE
`‘
`4
`Cancer immunotherapy, based on active immunization with
`tumorantigens, can induce antitumor immune responses and
`has been widelytested in prostate cancer [1]. Sipuleucel-T, an
`immunot herapy targeting prostatic acid phosphatase,
`demonstrated improvement in overall survival (OS) in patients
`with metastatic castration-resistant prostate cancer (mCRPC),
`with no demonstrable effects on the serum prostate-specific
`antigen (PSA) level or tumorgrowth in phaseIII trials [2].
`This andothertreatments, including docetaxel, cabazitaxel,
`
`-
`“Correspondenceto; Dr S. F. Slovin, Department of Medicine, Sidney Kimmel Genter for
`Prostate and ahi Cancers, igal loanKetlering Cancer Center, fare ere
`Avenue, New York, NY 10065, USA. Tel
`4 1-646-429-4470; Fax: +1-212-988-0701;
`E:mail: slovirs@mskes.org
`
`abiraterone, enzalutamide, and radium-223 chloride, showed
`only incremental OS improvements [3-7], so there is a need
`for novel therapeutic approaches providing durable disease
`control:
`Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative
`regulatorof T=coll uctivation, be emergedas a target for
`cancer immunotherapy [8-10]. Ipilimumab,afully human
`monoclonalantibody, specifically blocksthe binding of CTLA-
`4 to its ligands (CD80/CD86) andthereby augments ‘T-cell
`activation andproliferation and tumorregression [11-15].
`Early clinical trials with ipilimumabshowedclinical activityin
`several cancers including melanoma, renal cell carcinoma, non-
`Hodgkin lymphoma, pancreatic adenocarcinoma, lung and
`ovarian cancer [16 24 |. Two randomized phase Ill trials
`7
`demonstrated OS improvements and durable objective
`
`©The Author 2013. Published by Oxford University Press on behalf of the European Society lor Medical Oncology
`All rights reserved. For permissions, please email: journals.permissions@oup,corm
`
`

`

`responses in patients with metastatic melanoma [25, 26].
`Follow-up showedthat 19%-36%ofpatients with metastatic
`melanomatreated with ipilimumab had long-term (4-year) OS
`[27-29]. Adverse events (AEs) associated with ipilimumab
`were often immune-related and occurred mainly within the
`skin, gastrointestinal tract, and liver; these were generally
`managed byestablished treatment guidelines [25, 26, 30].
`Based on the antitumor immunity of the anti-CTLA-4
`antibody in preclinical models of prostate cancer {31, 32],
`several studies ofipilimumab in mCRPCpatients were carried
`out, Theseinitial studies showedthat ipilimumab 3 mg/kg
`given every 4 weeks for four doses had acceptable safety and
`preliminary antitumoractivity [33-35]. We chose to evaluate
`ipilimumab3, 5, or 10 mg/kg given every 3 weeks, because
`phase II data in melanomapatients showeda higher objective
`response rate (11,1%) at 10 mg/kg than at 3 mg/kg (4.2%) or
`0.3 mg/kg (0%) [18].
`Localized radiotherapy can cause immune-mediated tumor
`death and induce tumorregressionat sites distant fromthe
`primarysite of radiotherapy (abscopal effect) in an immune-
`mediated process [36, 37]. In murine models ofbreast and
`colon cancer, the combination ofthe anti-CTLA~-4 antibody
`and localized tumorirradiation resulted in the synergistic
`inhibition of metastases [38, 39]. Furthermore, the abscopal
`effect involving immuneresponse has been reported in two
`cases of metastatic melanoma treated with ipilimumab and
`localized radiotherapy [40, 41]. Therefore, we hypothesized
`that tumorantigensreleased during radiation-inducedcell
`death may enhance the antitumoractivity ofipilimumabin
`patients with mCRPC.Accordingly, we performed a phase I/II
`study in patients with mCRPCto systematically assess
`ipilimumabat various doses given alone orin combination
`with external-beamradiotherapy (XRT).
`
`patients and methods
`
`patients
`Mendiagnosed with mCRPC (rising PSA or progression on scans with a
`serum testosterone concentration of <50 ng/dl) andthe evidence of
`progressionafter the discontinuation ofantiandrogen therapy who had ne
`more thanoneprior chemotherapy were enrolled. Adenocarcinomaof the
`prostate was confirmedhistologically, andtheextent ofdisease was
`documented radiographically by bone scan and computed tomography.
`Patients hadalife expectancy of >12 weeks, an Eastern Cooperative
`Oncology Group (ECOG) performancestatus of 0 or 1, and adequate
`hematologic, hepatic, and renal functions. Patients with radiation-induced
`diarrhea within 12 months ofstudy entry or with prior colitis or irritable
`bowel syndrome were excluded. Other key exclusion criteria were
`autoimmunedisease (except for vitiligo) requiring systemic steroids or
`immunosuppressive agents, other prior malignancy within 5 years, active
`infection, bone pain severe enough to require routine narcotic analgesics,
`and prior treatment with antiCTLA-4therapies. All patients gave
`informed consent before enrollment. The study was conducted according
`to theprinciples of the Helsinki Declaration. The protocol was approved by
`Institutional Review Boards in all participating centers.
`
`study design and treatment
`‘This was a phase I/II, non-randomized, open-label, multicenter study
`(ClinicalTrials.gow identifier: NCT00323882). In the dose-escalation phase,
`
`Annals of Oncology
`
`eligible patients (>6 patients per cohort) receivedipilimumiabat 3, 5, or 10
`my/kg or at 3 or 10 mg/kg + XRT(Figure 1). Starting with the lowest
`monotherapydose, ipilimumab was administered intravenously once every
`3 weeks (days 1, 22, 43, and 64) ina cycle of upto four doses with a
`response assessment 3 weeks after the last dose (day 85), Dose escalation
`occurredafter all six patients in the preceding cohort received at least two
`doses ofipilimumab and were observedfor an additional 2 weeks with no
`more than one ofthe six patients experiencing a dose-limiting toxicity
`(DLT) during this 5-week period. The DLT was defined as a grade 3/4
`immune-related AE (irAE) or other grade 3/4 treatment-related AE, which
`requiredsurgical intervention or did not resolve to <grade 2 within 14 days
`ofthe start of immunosuppressive therapy. Dose escalation continued until
`the last monotherapy-dose cohort was enrolled or the maximum tolerated
`dose (MTD, defined as the highest dose at which no more than oneof the
`six patients experienced a DLT) was identified.
`Once the monotherapy cohorts werefully enrolled, patients were
`assigned to 3 mg/kg + XRT, and after completion ofaccrual in this arm, to
`10 mg/kg + XRT, Radiotherapy was given focally ata single dose of 8 Gy
`per target bonelesion for up to three bonelesions perpatient at 24-48 h
`betore thefirst ipilimumabdose. Single administration of 8 Gy has been
`shown to be therapeutically equivalent to fractionated regimens in terms of
`pain palliation andbetter tolerated [42]. Target lesions had to be >10 mm
`long in at least one direction when measuredby radiologic imaging. The
`liming of XRT delivery was designed to provide CTLA-4 blockade at a time
`whenantigen presentation due to radiation was expected to peak [43].
`For the phaseII portion, additional patients were assigned to
`monotherapy (at the MTD or at 10 mg/kg if the MT'D was not reached),
`andafter monotherapy accrual was completed, to combination therapy.
`Patients who progressed following aninitial response or stable disease
`could have received up to three additional cycles ofipilimumab, No
`retreatment with XRT was allowed, After the initial treatment period (days
`1-112), patients had follow-up visits every 4 weeks for 3 months and then
`every 12 weeks for 9 months or until disease progression, intolerance, or
`death, Patients who withdrewfromthe study due to disease progression or
`who completedall planned study visits were followed for survival every 3
`months for up to 5 years.
`
`assessments
`
`AEsincluding irAEs were based on assessments by investigators of patients
`treated between the first dose and 70 days after thelast ipilimumab dose.
`AnirAEwas defined as a treatment-related AE consistent with immune-
`mediated events, AEs, irAEs, and clinical laboratorytests were gradedusing
`the NCI Common ‘Terminology Criteria for Adverse Events, version 3.0.
`Theprotocol defined guidelines tor evaluation andtreatment of irAEs of
`the gastrointestinal tract, liver, skin, eye, and endocrine glands; irAE
`Management consisted of corticosteroids(e.g, prednisone or budesonide)
`given orally or intravenously. Additional immunosuppressive agents (e.g.
`infliximabfor colitis and mycophenolate mofetil for hepatic irAEs) and
`hormone replacement therapy for endocrine irAEs werealso usedat the
`investigator's discretion, No dose reductions were allowed, For a grade 2
`drug-related skin irAE or grade 3 skin irAF(regardless of causality),
`ipilimumab administration was delayed until its resolution to <grade|.
`Ipiimumab administration was permanently discontinued for any
`non-skin-related AE of >grade 3 or any other AE of Sprade 4.
`Antitumor effects were assessed by serum PSA status using criteria
`consistent with guidelines of the Prostate Cancer Clinical Trials Working
`Group | (PCWG1) [44], the standard when the study was being designed,
`and by tumor status using Response Evaluation Criteria in Solid ‘Tumors
`(RECIST) for soft tissue disease [45]. PSA assessments were performed on
`days 22, 43, 64, and 85 andevery month thereafter. Tumorassessments
`were carried oul on day 85 and every 3 months thereafter. This time
`
`

`

`Annals of Oncology
`
`Screening
`
`Dosing every 3 weeks
`up to 4 doses
`
`Follow-up or additional
`Ipilimumab doses
`
`+ XRT
`t
`a="
`24
`f
`
`Day: -28
`
`/
`Sla ———
`43
`64
`85
`'
`421
`22
`t
`f
`or PD
`j
`Ipilimumab dosing
`
`Design:
`* Phase 1 — Dose escalation: 3, 5 or 10 mg/kg Ipi, then 3 or 10 mg/kg Ipi + XRT
`(single dose of 8 Gy/lesion, up to 3 lesions per patient)
`* Phase 2 — Cohort expansion: 10 mg/kg + XAT cohorts
`Endpoints:
`* Safety
`* PSA response at Day 85, overall PSA response, and tumor response by RECIST
`Response assessments:
`* PSA: Days 22, 43, 64, 85, then monthly
`* Tumor: Day 85, then every 3 months
`
`Figure 1. The study schema. XRT, external-beamradiotherapy; PD, progressive disease; PSA, prostate-specific antigen.
`
`schedule was chosen, because responsesto ipilimumab have been observed
`weeks to months after therapyinitiation [46]. Both the decline in PSA to
`250% from baseline (PSA decline) and tumorresponse, as determined by
`investigators, were confirmedby repeat assessments at 4 weeksor laterafter
`theinitial assessments, The PSA decline was calculated by comparing the
`greatest decline in post-therapy PSA concentration to baseline. End points
`included PSAdecline by day 85, PSA declineat any time, tumorresponse
`al any time, time to and duration of tumor response, and OS.
`
`statistical considerations
`
`‘The primary objective ofthis study was to determine the safety of
`ipilimumabalone or in combination with a single dose of XRT. The
`secondaryobjective was to determineclinical antitumoractivity based on
`PSA andradiologic responses. For the phase II portion ofthest udy, the
`initial samplesize of 30 patients was based onthe designof the dose
`escalation for safety. For the phase I] portion ofthe study, there were to be
`16 assessable patients treated with ipilimumab monotherapy and32 treated
`with the combinationofipilimumab + XRT (chemotherapy-naive, 16;
`chemotherapy-experienced, 16). A sample size of 16 assessable patients was
`required to provide >80%power in a one-sample exact binomialtest at
`the significance level of 0.05, Data were summarized using descriptive
`statistics. The Kaplan-Meier product limit method was used to estimate
`the median OS,
`
`results
`
`patients
`Seventy-five patients were enrolled at ninesites in the United
`States: 71 wereeligible and received treatment between January
`2006 and September 2009. Forty-seven patients (66%)
`discontinued the study due to disease progression determined
`by either PCWGI criteria or RECIST (Table 1), Of eight
`discontinuations due to AEs, five were caused by irAEs (colitis,
`1; diarrhea, 3; hepatitis, 1). Of seven deaths causing
`discontinuation, one (5 mg/kg group) was dueto aspergillosis,
`after 4 months of immunosuppressive therapy required to
`control grade 3 colitis, and was thus considered treatment-
`related. ‘Three patients died from disease progression and one
`
`each from sepsis, pneumonia, and myocardial infarction; these
`deaths were deemedby investigators to be unrelated to
`treatment. The patient whodied ofsepsis (Clostridiumdifficile)
`received no immunosuppressives; no autopsy or endoscopy
`wascarried out to rule out colitis, but the presentation did not
`include diarrhea above grade 2. Two deaths (10 mg/kg + XRT:
`pneumonia, 1; progression, 1) occurred within 30days after
`the last ipilimumab dose,
`Patient demographics andbaseline disease characteristics are
`listed in Table 2, OF 50 patients in the expanded 10 mg/
`kg + XRTgroup, 27 received prior chemotherapy. Of21
`patients across other cohorts, 6 had prior chemotherapy.
`
`exposure
`There were 71 treated patients; 70 re