Annals of oncology: official journal of the
`v. 24, no. 10 (Oct. 2013)
`General Collection
`W1 AN617D
`2013-11-12 06:34:15
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`JANNALS OF ONCOLOGY - ENGLISH EDITION
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`Annals of Oncology
`
`Ji, ESMD ==
`
`European Society lor Medical Oncology
`Official Journal of the
`European Society for Medical Oncology and the Japanese Society of Medical Oncology
`
`
`
`Volume 24 | No. 10 | October 2013
`
`editorials
`
`Information to womeninvited to mammography screening
`S. H. Njor & M. von Euler-Chelpin
`2467
`Cancerpatients and survivors: changing wordsor changing
`culture?
`A. Surbone, M. A. Annunziata, A. Santoro, U. Tirelli &
`2468
`P. Tralongo
`Equipoise abandoned? Randomization andclinicaltrials
`R. Kurzrock e& D. J. Stewart
`2471
`
`reviews
`
`The impact of the granulocyte colony-stimulating factor
`on chemotherapy doseintensity and cancer survival: a
`systematic review and meta-analysis of randomized
`controlled trials
`G. H. Lyman, D.C. Dale, E. Culakova, M. S. Poniewierski,
`D. A. Wolff, N. M. Kuderer, M. Huang & J. Crawford
`2475
`Neoadjuvant treatment of borderline resectable and non-
`resectable pancreatic cancer
`V. Heinemann, M. Haas & S. Boeck
`
`2484
`
`Emerging approachesfor treating HER2-positive metastatic
`breast cancer beyond trastuzumab
`W. J. Gradishar
`
`2492
`
`original articles
`
`breast cancer
`
`Likelihoodof early detection of breast cancer in relation to
`false-positive risk in life-time mammographic screening:
`population-based cohort study
`]. D. M. Otten, J. Fracheboud, G. J. den Heeten, S. J. Otto,
`R. Holland, H. J, de Koning, M. ]. M. Broeders &
`A. L. M. Verbeek
`
`2501
`
`Obesity, diabetes, and survival outcomes in a large cohort of
`early-stage breast cancer patients
`S. Jiralerspong, E. S. Kim, W. Dong, L. Feng,
`G. N. Hortobagyi & S. H. Giordano
`
`2506
`
`Clinical relevance of cancer stem cells in bone marrow of
`early breast cancer patients
`A. Giordano, H. Gao, E, N. Cohen, $8. Anfossi, J. Khoury,
`K. Hess, 8. Krishnamurthy, S. Tin, M. Cristofanilli,
`G. N. Hortobagyi, W. A, Woodward, A, Lucci &
`J. M. Reuben
`
`2515
`
`Functional proteomics characterization ofresidual triple-
`negative breast cancerafter standard neoadjuvant
`chemotherapy
`J. Sohn, K. A. Do, S. Liu, H. Chen, G. B. Mills,
`G. N. Hortobagyi, F. Meric-Bernstam & A. M. Gonzalez-
`Angulo
`2522
`
`A comparison of hormonal profiles between breast cancer
`and benign breast disease: a case-control study
`P. Lagiou, E. Samoli, A. Lagiou, P. Zourna, A, Barbouni,
`C. Georgila, A. Tsikkinis, D. Vassilarou, P. Minaki, C. Sfikas,
`E, Spanos & D. Trichopoulos
`2527
`Prognostic value of the trichorhinophalangeal syndrome-1
`(TRPS-1), a GATA family transcription factor, in early-stage
`breast cancer
`J. Q. Chen, Y. Bao, J. Lee, J. L. Murray, J. K. Litton, L. Xiao,
`R. Zhou, Y. Wu, X. Y. Shen, H. Zhang, A. A. Sahin,
`R. L. Katz, M. L. Bondy, N. L. Berinstein, G. N. Hortobagyi
`e L. G. Radvanyi
`2534
`
`Randomized phase II study of lonaprisan as second-line
`therapy for progesterone receptor-positive breast cancer
`W.Jonat, T. Bachelot, T. Ruhstaller, I. Kuss, U. Reimann &
`J. FR. Robertson
`2543
`
`N0539 phaseII trial of fulvestrant and bevacizumabin
`patients with metastatic breast cancer previously treated
`with an aromatase inhibitor: a North Central Cancer
`Treatment Group (now Alliance)trial
`W. W. Tan, A. C. Dueck, P. Flynn, P. Steen, D. Anderson,
`K. Rowland, D. Northfelt & E. A. Perez
`2548
`
`gastrointestinal tumors
`
`Primary tumorlocation and bevacizumabeffectivenessin
`patients with metastatic colorectal cancer
`M. K. Boisen, J. S. Johansen, C. Dehlendorff, J. 8. Larsen,
`K. Osterlind, J. Hansen,S. E. Nielsen, P. Pfeiffer,
`L. 8. Tarpgaard, N. H. Hollander, N. Keldsen, T. F. Hansen,
`B. B. Jensen & B. V. Jensen
`2554
`
`Impact ofexcision repair cross-complementing gene |
`(ERCC1) onthe outcomesofpatients with advanced gastric
`cancer: correlative study in Japan Clinical Oncology Group
`Trial JCOG9912
`Y. Yamada, N. Boku, T. Nishina, K. Yamaguchi, T, Denda,
`A, Tsuji, Y. Hamamoto, K, Konishi, Y. Tsuji, K. Amagai,
`S. Ohkawa, Y. Fujita, H. Nishisaki, H. Kawai, A. Takashima,
`J. Mizusawa, K. Nakamura e& A, Ohtsu
`2560
`
`Continued overleaf
`
`Volume 24 | No, 10 | October 2013
`
`This material was copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`

`

`A simple prognostic scoring system for patients receiving
`transarterial embolisation for hepatocellular cancer
`L. Kadalayil, R. Benini, L. Pallan, J. O'Beirne, L. Marelli,
`D. Yu, A. Hackshaw, R. Fox, P. Johnson, A. K. Burroughs,
`D. H. Palmer & T. Meyer
`2565
`
`‘TNF-o@ gene promoter polymorphisms andrisk of venous
`thromboembolismin gastrointestinal cancer patients
`undergoing chemotherapy
`M. Roselli, P. Ferroni, C. Rolfo, M. Peeters, R. Palmirotta,
`V. Formica, G. Ludovici, A. Laudisi, M. L. De Marchtis,
`F. La Farina, A, Russo & F. Guadagni
`2571
`Multicenter phaseII trial to investigate safety andefficacy of
`gemcitabine combined with cetuximab as adjuvant therapy
`in pancreatic cancer (ATIP)
`H. Fensterer, C. Schade-Brittinger, H. -H. Miiller, S. Tebbe,
`J. Fass, U. Lindig, U. Settmacher, W. E. Schmidt,
`A, Marten, M. P. Ebert, M. Kornmann, R. Hofheinz,
`E, Endlicher, C. Brendel, P. J. Barth, D. K. Bartsch, P. Michl
`e& T. M. Gress for the Arbeitsgemeinschaft Internistische
`Onkologie (AIO)
`2576
`
`Prognostic role of microRNA polymorphisms in advanced
`gastric cancer: a translational study ofthe
`Arbeitsgemeinschaft Internistische Onkologie (AIO)
`L. Stenholm, J. Stoehlmacher- Williams, S. E. AL-Batran,
`N. Heussen, S. Akin, C. Pauligk, $. Lehmann, T. Senf,
`R, D. Hofheinz, G. Ehninger, M. Kramer e& E. Goekkurt 2581
`
`lung cancer
`
`Diagnostic value ofa novel fully automated
`immunochemistry assay for detection of ALK
`rearrangement in primary lung adenocarcinoma
`J. Ying, L. Guo, T. Qiu, L. Shan, Y. Ling, X. Liu &
`N. Lu
`
`2589
`
`Distinct outcomeofstage | lung adenocarcinoma with
`ACTN4cell motility gene amplification
`R. Noro, K. Honda, K. Tsuta, G. Ishii, A. M. Maeshima,
`N. Miura, K. Furuta, T. Shibata,
`tH. Tsuda, A, Ochiai,
`T. Sakuma, N. Nishijima, A, Gemma, H, Asaniura, K. Nagai
`e& T. Yamada
`2594
`A phaseI/II study ofsepantronium bromide (YM155,
`survivin suppressor) with paclitaxel and carboplatin in
`patients with advanced non-small-cell lung cancer
`R. J. Kelly, A. Thomas, A. Rajan, G. Chun, A, Lopez-Chavez,
`FE. Szabo, S. Spencer, C. A. Carter, U. Guha, 8. Khozin,
`S. Poondru, C. Van Sant, A. Keating, S. M. Steinberg,
`2601
`W. Figg & G. Giaccone
`Red meat, Mediterraneandiet and lung cancerrisk among
`heavy smokers in the COSMOSscreening study
`P. Gnagnarella, P. Maisonneuve, M. Bellomi, C. Rampinelli,
`R. Bertolotti, L. Spaggiari, D. Palli & G. Veronesi
`2606
`
`hematologic malignancies
`
`Lymphomaoccurring in patients over 90 years ofage:
`characteristics, outcomes, and prognostic factors. A
`retrospective analysis of 234 cases from the LYSA
`A. Trebouet, T. Marchand, R. Lemal, E. Gyan, F. Broussats-
`Guillaumot, Y. Guillermin, H. Monjanel, G, Salles, 8. Le
`Gouill, P. Godmer, C. Fruchart, G. Damaj, P. Feugier,
`C. Thieblemont, M, Maynadié, A. Monnereau, X, Trotssard,
`D. Rossille, T. Lamy & R. Houot
`2612
`
`Comparison of pixantrone-based regimen (CPOP-R) with
`doxorubicin-based therapy (CHOP-R) for treatment of
`diffuse large B-cell lymphoma
`R. Herbrecht, P. Cernohous, A. Engert, S. Le Gouill,
`D. Macdonald, C. Machida, H. Myint, A. Saleh, J. Singer,
`M. Wilhelm & R. van der Jagt
`2618
`
`head and neck cancer
`
`Expression and mutational status of treatment-relevant
`targets and key oncogenes in 123 malignantsalivary gland
`tumours
`
`|. Cros, E, Sbidian, 8. Hans, H. Roussel, F. Scotte, E. Tartour,
`D, Brasnu, P. Laurent-Puig, P. Bruneval, H. Blons &
`C. Badoual
`
`2624
`
`quality oflife and supportive care
`
`Health-related quality-of-life assessment in
`CLEOPATRA, a phaseIT study combining
`pertuzumab with trastuzumab and docetaxel in
`metastatic breast cancer
`}. Cortés, J. Baselga, Y.-H. Im, S.-A. Im, X. Pivot, G. Ross,
`E. Clark, A, Knott & 8. M. Swain
`2630
`
`Informal caregiving to older cancer patients: preliminary
`research outcomes and implications
`G, Goldzweig, 5. Merims, R. Ganon,
`L, Baider
`
`‘I. Peretz, A. Altman e&
`2635
`
`oncology practice
`
`Attitude of employees of a university clinic to
`complementary andalternative medicine in oncology
`A. Trimborn, B. Senf, K. Muenstedt, J. Buentzel, O. Micke,
`R. Muecke, FP. J. Prott, 5. Wicker & |, Huebner, on behalf of
`Working group Prevention and Integrative Oncology (PRIQ)
`ofthe German Cancer Society
`2641
`
`Continuedoverleaf
`
`Thi
`terial
`ied
`adnettliandaanta
`Subject US Copyright Laws
`
`Volume 24 | No. 10 | October 2013
`
`

`

`epidemiology
`
`Dietary intake of acrylamide and pancreatic cancer risk in
`the European Prospective Investigation into Cancer and
`Nutrition (EPIC) cohort
`M, Obon-Santacana, N. Slimani, L. Lujan-Barroso,
`N. Travier, G. Hallmans, H. Freisling, P. Ferrari,
`M. C. Boutron-Ruault, A, Racine, F. Clavel, C. Saieva,
`V. Pala, R. Tumino, A. Mattiello, P. Vineis, M. Argiielles,
`E, Ardanaz, P. Amiano, C. Navarro, M. J. Sanchez,
`E. Molina Montes, T. Key, K.-T. Khaw, N. Wareham,
`P.H, Peeters, A, Trichopoulou, C. Bamia, D. Trichopoutlos,
`H. Boeing, R. Kaaks, V. Katzke, W. Ye, M, Sund, U. Ericson,
`E. Wirfalt, K. Overvad, A. Tjonneland, A, Olsen, G. Skeie,
`L. A. Asli, E. Weiderpass, E. Riboli, H. B. Bueno-de-Mesquita
`ec E. J. Duell
`2645
`
`Family history of cancer and the risk of cancer: a network of
`case-control studies
`F. Turati, V. Edefonti, C. Bosetti, M. Ferraroni, M, Malvezzi,
`S. Franceschi, R. Talamini, M. Montella, F. Levi, L. Dal
`Maso, D. Serraino,J. Polesel, E. Negri, A. Decarli & C. La
`Vecchia
`2651
`
`Cancer mortality in Europe, 2005-2009, and an overview of
`trends since 1980
`
`C. Bosetti, P. Bertuccio, M. Malvezzt, F. Levi, L. Chatenoud,
`E. Negri & C. La Vecchia
`2657
`
`sarcomas and melanoma
`
`Results of a phase II pilot study of moderate dose
`radiotherapy for inoperable desmoid-type fibromatosis—
`an EORTC STBSG and ROG study (EORTC 62991-22998)
`R. B. Keus, R. A. Nout, J.-Y. Blay, J. M. de Jong, 1, Hennig,
`F. Saran, J. T. Hartmann, M. P. Sunyach, 8. ]. Gwyther,
`M. Ouali, A. Kirkpatrick, P. M. Poortmans,
`2672
`P. C. W. Hogendoorn & W. T. A. van der Graaf
`Limbpreservation surgery with extracorporealirradiation in
`the management of malignant bone tumor: the oncological
`outcomes of 101 patients
`A. M. Hong, S. Millington, V. Ahern, G. McCowage,
`R. Boyle, M. Tattersall, L. Haydu & P. D, Stalley
`
`2676
`
`Correlation between overall survival and growth modulation
`index in pre-treated sarcoma patients: a study from the
`French Sarcoma Group
`S. Cousin, J. Y. Blay, F. Bertucci, N. Isambert, A. Italiano,
`E. Bompas, I. Ray-Coquard, D. Perrot, M. Chaix, B. Bui-
`Nguyen, L. Chaigneau, N, Corradini & N, Penel
`2681
`A phaseIB study on intravenous syntheticmRNA
`electroporated dendritic cell immunotherapyin pretreated
`advanced melanomapatients
`5. Wilgenhof, A, M. T. Van Nuffel, D. Benteyn, J. Corthals,
`C. Aerts, C. Heirman, 1. Van Riet, A. Bonehill,
`K. Thielemans & B. Neyns
`
`2686
`
`Efficacy andsafety ofipilimumab in metastatic melanoma
`patients surviving more than 2 years following treatment in
`a phase III trial (MDX010-20)
`D. McDermott, J. Haanen, T.-T. Chen, P. Lorigan &
`S. O'Dayfor theMDX010-20 investigators
`
`2694
`
`cancerprevention
`
`Tobacco smoking and the risk of subsequent primary cancer
`among cancer survivors: a retrospective cohort study
`T. Tabuchi, Y. Ito, A. loka, T. Nakayama, I. Miyashiro &
`H, Tsukuma
`2699
`
`letter to the editor
`
`Detection of aberrant methylation of 10 genes in genomic
`DNAoflung tumors
`R. Sheikhnejad, M. Zohri, M, B, Shadmelhr, M, Rahmani-
`Khalili, N. Doozande, Z. Farsad & K. Sheikhzade
`2705
`
`corrigenda
`
`Needs regarding care and factors associated with unmet
`needs in disease-free survivors ofsurgically treated lung
`cancer
`2707
`
`Relationship amongcirculating tumorcells, CEA
`andoverall survival in patients with metastatic
`colorectal cancer:
`
`2708
`
`sa
`O¢
`,
`.
`ania
`This material was copied
`
`Volume 24|No. 10 | October 2013 atthe NUMand maybe
`
`Subject US Copyright Laws
`
`

`

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`
`Annals of Oncology
`
`Annals of Oncology 24; 2694-2698, 2013
`dor 10, (O9S/annonc/meal2o 4
`Published online 13 August 2013
`
`Efficacy and safety of ipilimumab in metastatic
`melanomapatients surviving more than 2 years
`following treatmentin a phaseIII trial (MDX010-20)
`D. McDermott", J. Haanen?, T.-T. Chen’, P. Lorigan* & S. O’Day®for the MDX010-20 investigators
`
`' Division of f fematology/Oncology, Beth Israel Deaconess
`; Medical Center, Boston, USA; “Department of immunology, Netherlands Cancer Institute, Amsterck WT),
`
`The Netherlands; “Oncology Biostatistics, Bristol-Myer
`quibb, Vvallingtord, USA: “Department of Medical Oncology, Christie Hospital NES Trust, Manchester, LIK:
`Department of Medical Oncology, Los Angeles Skin CancerInstitute, The Beverly Hills Cancer Genter, BeverlyHills, USA
`
`Received 23 January 2013; revised 21 June 2013; accepted 28 June 2013
`
`Background:In a phaseIll trial (ClinicalTrials.gov registration 1D: NCT00094653), ipilimumabsignificantly improved
`survival versus a vaccine control in pretreated patients with metastatic melanoma. Here, we characterize outcomes of
`those patients who survived 2 years.
`: 1) to receiveipilimumab 3 mg/kg + gp 100 vaccine,ipilimumab
`1
`Methods:Patients were randomized(3 :
`3 mg/kg + placebo, or gp100 vaccine alone. Baseline demographic data, duration of survival, responses, andsafety
`among patients with >2 years’ survival were analyzed,
`Results: Among 676 randomizedpatients, 474 and 259 patients hadat least 2 or 3 years of potential follow-up,
`respectively, andwereeligible for analysis. Among these, 94 (20%) and 42 (16%) survived >2 and >3years,respectively,
`Survival rates at 2 and 3 years were 25% (24 of 95) and 25% (13 of 53) with ipilimurmab alone and 19%(54 of 284) and
`5%(24 of 156) with ipilimumab plus gp 100. Safety amongpatients with >2 years’ survival was comparablewith the
`overall study population, with the onset of newipilimumab-related toxic effect (all graces) reported in 6 of 78 (8%)
`patients.
`Conclusions: |pilimurnabresults in survival of =2 yearsin one-fifth of pretreated patients with 2 years potential follow-up
`in a phaselll trial. New onset, low-grade events starting after administration of the last dose wereinfrequent.
`Trial Registration ID: NC 100094655
`Key words:ipilimumab, long-term survivors, ralanorma, salety, survival analysis
`
`introduction
`
`Beforetheavailabilityofipilimumab, approved treatment
`options for patients with metastatic melanoma werelimited and
`despite concerted efforts over many decades, overall survival
`(OS) remaineddisappointing[1].
`Ipilimumab, a monoclonal antibody against cytotoxic
`T-lymphocyte-associated antigen-4 (CTLA-4) that augments
`‘T-cell activation andproliferation to enhancethe immune
`responseagainst tumors, wasthefirst agent to showa survival
`benefit in patients with metastatic melanomaenrolled ina
`phase IT trial (2]. Ipilimumab3 me/kg significantly improved
`survival in patients with previouslytreated, metastatic
`melanoma comparedwith a vaccine control [hazardratio (HR):
`0.66; P = 0.003], with estimated 1- and2-yearsurvivalrates of
`45.6%versus 25.3% and 23.5%versus 13.7%, respectively [2]. In
`2011, ipilimumabwas approvedat a doseof3 mg/kg for
`
`
`
` yndence to; Dr Dawid MeDermatt, Division of Hematology/Oncology, Beth Israel
`
`#5 Medical Center, 375 Longwood Ave, Boste in, MA 02215, USA,
`
`O. E-maik: dmedernmoabicimne.narvard ecu
`Tel: +1-617-632-9270; Fax: +1-617-639-9%
`
`pretreated andtreatment-naive adult patients with metastatic
`melanoma.
`By contrast with chemotherapy, where responsesare typically
`transient, clinical benefit with ipilimumab tends to be durable,
`lasting months and even years in somepatients, Extended
`follow-up from phaseIL trials consistently show a plateauin
`survival Curves with a meaningful proportion of patients
`surviving 5 or more years from the start of treatment | 3}.
`Ipilimumab also differs from chemotherapyin that it
`is
`associaled with characteristic spectrum ol adverse events (AEs)
`resulting from increased orexcessive immuneactivity, likely to
`berelated to its mechanism of action. Immune related ALs
`(irAEs), which can besevereorlife-threatening, may involve the
`gastrointestinal (G1), liver, skin, nervous, endocrine, or other
`organ systems. However, they are mostly mild and generally
`manageable with appropriate treatment, including the useof
`systemic high-dosecorticosteroids in patients with severe
`(grade 3 or 4) irAEs,
`Improved understanding ofthesafety profile ofpatients
`treated with ipilimumabis very important. Somedata suggest
`that developing an irAE maybe associated with clinical benefit
`andthat patients who develop irAEs maysurvive longer;
`
`The Author 2013, Published by Oxford University Press on behalf of the European Sociely for Medical Oncok xy
`Allrights reserved. For permissions, please email: journals, permissions@ioup.com
`
`

`

`Annals of Oncology
`
`however, other studies have shown no correlation between
`efficacy andtoxiceffect [4, 5]. In addition, little is known
`regarding the types and impactoftoxiceffects that occur
`beyondtheinitial dosing periodorlate, new-onsetevents that
`are observedafixed timeafterthelast dose.
`‘Theobjectiveofthis analysis is to describethesafety andlong-
`termefficacy ofipilimumab amongpatients from the pivotal
`phase IIT MDX010-20study whosurvived2 years orlonger.
`
`methods
`
`Full details of the phase [I] MDX010-20 study (trial registration [D:
`NC 100094653), including the study design, inclusion and exclusion criteria,
`treatment, responseassessment, endpoints, andstatistical analysis methods
`have been published previously [2]. Brietly, a total of 676 patients with
`unresectable stage [Hor [LV melanoma who had been treated previously with
`chemotherapyor interleukin-2 (IL-2) were randomized 2: 1:1 to receive
`ipilimumab plus gp100vaccine, ipilimumabaloneor gp100aloneevery
`3 weeks for fourdoses.
`
`‘Tumor responses wereassessed using modified World Health
`Organization responsecriteria and AEs were graded accordingto the
`National CancerInstitute’s Common ‘Terminology Criteria for Adverse
`Events, version 3.0 [2]. [rAEs were definedas anyevent associated with
`study drug exposure that was consistent with an immune phenomenon.
`Patients with an objective tumorresponse orstable disease of >3 months’
`duration wereeligible for retreatment with theirassigned treatment regimen
`upon evidenceofdisease progression (2, 6].
`
`results
`
`efficacy
`Of 676 patients treated in MDX010-20, 474 were randomizedat
`least 2 years before the study cut-off date and wereeligible for
`this analysis. Ofthe 474 patients, 94 (20%) survived >2 years,
`
`Table 1. Analysis of actual survival in subsets oftotal trial population
`
`comprising 54 of 284 (19%) patients treated with ipilimumab
`plus gp 100, 24 of 95 (25%) treated with ipilimumab alone, and
`16 of 95 (17%) treated with vaccine alone. Of these 94 patients,
`5 (5%) had brain metastases comprising 3 patients treated with
`ipilimumabplus gp100, and 1 patient treated with ipilimumab
`alone or gp100alone, respectively. Among patients who
`survived >2 years, 42 of 94 (45%) survivedat least >3 years
`(Table 1).
`Of38 ipilimumab-treated patients who achieved complete or
`partial tumorresponsesas their best on-study response [7], 25
`(66%) survived >2 years, and of82 patients whohadstable
`disease (SD) as their best on-studyresponse, 31 (38%) survived
`for 2 years or longer. Among, 309patients whosebest on-study
`response wasprogressive disease (PD), 21 (7%) survived
`>2 years (Table 2).
`Baseline characteristics of the patients whosurvived >2 years
`were comparable across thethreetreatment groups (‘Table3).
`However, when comparedwith patients who survived <1 year
`(Table 4), some baseline characteristics appeared to be
`associated with longer survival. For example, ofthe 81 patients
`treated withipilimumabalone whosurvived<1 year, 66 (82%)
`had Mle diseaseat baseline compared with 12 (50%) ofthe
`24 patients whosurvived more than2 years. Similarly,for
`patients treated withipilimumabplus gp100 or gp100 alone,
`80%and 74%ofpatients surviving <1 year had M1c disease,
`respectively, compared with 56% and 63%patients surviving >2
`years. Comparedwith patients whosurvived <1 year,a higher
`percentageofpatients who had received priortreatment with
`IL-2, had an ECOG PS of0, or hadlactate dehydrogenase
`(LDH) levels belowthe upperlimit of normal (ULN), survived
`>2 years.
`
`Actual survival
`
`22 years
`
`gp100 + placebo
`
`16 of 95 (17)
`
`Total
`
`94 (20)
`
`N (%)
`Ipilimumab+ placebo
`Ipilimumab + gp100
`?atients randomized 22 years before studysurvival cut-offdate (N= 474)
`54 of284 (19)
`24 of 95 (25)
`Patients randomized >3 years before study survival cut-off date (N= 259)
`
`
`24 of 156 (15) 13 of 53 (25) 5 of 50 (10)23 years 42 (16)
`
`
`
`
`
`Table 2. Response anddisease control rates for on-studypatients during the inductionperiod (from first treatment until week 24), andin patients with at least
`2 years’ survival
`
` Ipilimumab+gp1000 Ipilimumab + placebo
`n=403—
`n=54
`n=137
`n=24
`On-study response
`Survived >2years
`On-study response
`Survived >2 years
`
`gp100 + placebo
`n= 136
`On-study response
`
`n=16
`Survived 22 years
`
`Response, 1 (%)
`0
`0
`2 (8.3)
`2 (1.5)
`1 (1.9)
`1 (0.2)
`CR
`0
`2 (1.5)
`10 (41.7)
`13 (9.5)
`12.(22.2)
`22 (5.5)
`PR
`7 (43.7)
`13 (9.6)
`8 (33.3)
`24 (17.5)
`23 (42.6)
`58 (14.4)
`sD
`9 (56,3)
`89 (65,4)
`4(16.7)
`7O(51L.1)
`17 (31.5)
`239 (59.3)
`PD
`0
`32 (23.5)
`0
`28 (20.4)
`1 (1.9)
`83 (20.6)
`Not evaluable
`43.8
`11.0
`83.3
`28.5
`66,7
`20.1
`Disease contral rate* (%)
`
`CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
`“CR4PR+ SD.
`
`Volume 24 | No. 10 | October 2013
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`doi:10.1093/annone/mdt291 | 2695
`
`

`

`Table 3. Characteristics of patients from MDX010-20 survivingat least
`2 years
`
`Table 4. Characteristics of patients from MDX010-20 surviving at least
`| year
`
`Annals of Oncology
`
`Ipilimumab
`+p100,
`n=54
`
`—Ipilimumab
`+placebo,
`n=24
`
`—_—_— gp100
`+ placebo,
`n=16
`
`57
`
`50
`50
`
`59
`
`75
`25
`
`56
`
`44
`56
`
`Age(years)
`Mean
`Gender (%)
`Male
`Female
`
`28
`17
`56
`
`72
`28
`
`65
`35
`
`82
`17
`3
`
`2)
`29
`50
`
`54
`46
`
`79
`21
`
`87
`13
`1
`
`M stage (%)
`Mla
`MIb
`Mic
`Prior IL-2 (%)
`No
`Yes
`ECOG PS (h)
`0
`|
`LDH? (%)
`<ULN
`>ULN
`Patients with brain
`metastases (1m)
`
`ECOG PS, Eastern Cooperative Oncology Group performancestatus; IL-2,
`interleukin-2; LDH, lactate dehydrogenase; ULN, upperlimit of normal.
`“Datafor one patient not reported.
`
`19
`19
`63
`
`56
`44
`
`56
`44
`
`87
`13
`1
`
`safety
`AEs were monitored from thefirst induction dose until at least
`70 daysafter thelast induction dose ofipilimumab had been
`administered. During this period, safety in patients with
`22 years’ survival was comparable to that in the overall study
`population. Amongthe78 ipilimumab-treated patients,
`11 (14%) had a high gradeirAE betweenthefirst induction dose
`and70daysafter last induction dose, comprising 7 patients
`treated with ipilimumabplus gpl00 and 4 patients treated with
`ipilimumabalone. This was similarto the overall study
`population, where high grade irAEs occurred in 43 (11%)
`patients treated with ipilimumab plus gp 100 and 20 (15%)
`patients treated with ipilimumabalone.
`Seven patients (7%) had irAEs that occurred morethan
`70daysafter thelast dose, comprising 5 patients treated with
`ipilimumabplus gp100, and1 treated with ipilimumabaloneor
`gp 100alone, respectively, With the exception ofone incidence
`ofgrade 3 colitis, all new cases were low-grade events, including
`grade 1 vitiligo and diarrhea and grade 2 hypogonadism and
`proctitis (Table 5). In the overall study population, 6 of
`45 patients (14%) experienced a grade >2 irAE morethan
`3 monthsafterthe last induction dose.
`
`discussion
`
`[pilimumab therapy was associated with survivalofat least
`2 years in approximately one-fifth ofqualifying patients
`enrolled in MDXO010-20. Patients who received ipilimumab with
`
`Ipilimumab
`+ gp100,
`n=240
`
`Ipilimumab.
`+placebo,
`n=B8L
`
`gp100.
`+ placebo,
`n=104
`
`6
`13
`80
`
`82
`18
`
`48
`50
`
`9
`9
`82
`
`80
`20
`
`41
`58
`
`M stage (%)
`Mla
`Mlb
`Mle
`Prior LL-2 (%)
`No
`Yes
`ECOGPS (%)
`0
`l
`LDH(%)
`53
`47
`50
`<ULN
`45
`53
`50
`>ULN
`
`ECOG PS, Eastern Cooperative Oncology Group performance status; IL-2,
`interleukin-2; LDH, lactate dehydrogenase; ULN, upper limit of normal.
`
`5
`\7
`Fe
`
`7
`23
`
`46
`49
`
`gp 100 vaccine and whosurvived for >2 years represent 19%of
`patients who had2 years ofpotential follow-up, and among
`patients whowere followedfor 3 years, 15%were still alive at >3
`years. Correspondingactual survival for the ipilimumab
`monotherapy subgroup was 25%at both timepoints.
`The differences in survival outcome between the two
`ipilimumab groups described above,albeit small, together with
`data fromthe overall MDX010-20 study population and a recent
`phase I] adjuvant trial of ipilimumab, suggests the addition of
`the gp 100 peptide does not improve ipilimumabefficacy.
`However, in a separate phaseIII trial, adding the vaccine to IL-2
`significantly improved response rates andresulted in longer OS
`compared with [L-2 alone. ‘This disparity may point to the
`distinct mechanisms ofaction ofdifferent immunotherapies,
`andrequires furtherinvestigation in prospectivetrials [2, 8, 9].
`The2- and 3-year survival rates from this analysis benchmark
`favorablyagainst long-termsurvival reportedafterfirst-line
`dacarbazine (11%at >1.5 years and 5%at 3 years), or high-dose
`IL-2 bolus regimen (15%at 2 years) or continuous infusion
`regimen (6%at 3 years) [10-13]. However, survival rates
`reported here are binomial and only determinedin patients
`with the potential to live at least 2 or 3 years, In thetrials
`described above, survival rates wouldlikely have been
`determined by Kaplan-Meieranalysis of the entire study
`population. Although useful to reference against historical data,
`thesurvival rates cannot be compareddirectly and should be
`considered accordingly.
`Importantly, long-term survival occurredin the absence of
`continuedipilimumabtreatment. Unlike cytotoxic
`chemotherapy or mol