The incidence of melanoma, the most serious

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1 Efectiveness nd sfety of ipilimumb therpy in dvnced melnom: evidence from clinicl prctice sites in the US Kim A Mrgolin, MD, Ahmd Trhini, MD, PhD, b Sumti Ro, PhD, c Monic Ktyl, JD, MPH, d I-Fen Chng, PhrmD, c Dougls B Johnson, MD, e Sekwon Jng, MD, f Joseph I Clrk, MD, g nd Dvid McDermott, MD h University of Wshington, Settle, Wshington; b University of Pittsburgh, Pittsburgh, Pennsylvni; c Bristol-Myers Squibb, Plinsboro, New Jersey; d Medicl Dt Anlytics, Prsippny, New Jersey; e Vnderbilt University Medicl Center, Nshville, Tennessee; f Wshington Cncer Institute t MedStr Wshington Hospitl Center, Wshington, DC; g Loyol University Medicl Center, Crdinl Bernrdin Cncer Center, Mywood, Illinois; nd h Beth Isrel Deconess Medicl Center, Boston, Msschusetts Bckground Ipilimumb ws pproved in 2011 by the US Food nd Drug Administrtion in 2011 for the tretment of unresectble or metsttic (dvnced) melnom, lthough pivotl dt using the pproved 3 mg/kg monotherpy q3w 4 were vilble only for ptients with previously treted disese. Objective To investigte ptient nd disese chrcteristics, survivl outcomes, nd sfety in tretment-nïve ptients receiving ipilimumb therpy. Methods Adult ptients with tretment-nïve dvnced melnom who received 1 dose of ipilimumb 3 mg/kg during April 2011-Sept 2012, with 12 months hving elpsed since the strt of tretment, were identifed from 34 US sites. Personnel from ech study site retrospectively bstrcted existing dt from individul ptient medicl records, which were collected nd vlidted by n independent reserch orgniztion. Results In ll, 273 ptients were included in the study. The medin ge of the totl study popultion ws 64 yers (rnge, 26-91), nd 64.8% were men. At dignosis, 56.0% were stge IV M1c, nd 12.1% hd brin metstses. 50 ptients hd BRAF muttion, 181 were BRAF wild-type, nd BRAF sttus ws not known for % of ptients received ll 4 plnned doses of ipilimumb. Medin survivl from initition of ipilimumb tretment ws 14.5 months (95% confdence index [CI], ). The overll one-yer survivl rte ws 59.2% (95% CI, ); nd 71.0% nd 54.9% for ptients with BRAF-mutted nd wild-type tumors, respectively. Adverse events of ny grde, grde 3, nd grde 4 occurred in 164 ptients (60.1%), 45 (16.5%), nd 8 (2.9%), respectively. The most common grde 3 or 4 dverse events were colitis (4.0%), ftigue (2.9%), nd dirrhe (1.5%). Drugrelted dverse events were primrily immune-relted nd occurred in 147 ptients (53.8%), including grde 3/4 in 15.7% of ptients (13.9% nd 1.8%, respectively). No deths were ttributed to ipilimumb. Conclusions This observtionl study provides rel-world, clinicl prctice evidence supporting improved survivl with the pproved ipilimumb 3 mg/kg monotherpy in ptients with tretment-nïve dvnced melnom, including prolonged survivl in some ptients. The sfety profle ws consistent with tht reported in clinicl trils. Funding/sponsorship Bristol-Myers Squibb. Dr Johnson is supported by NIH trining grnt K12 CA The incidence of melnom, the most serious form of skin cncer, is rising globlly. 1,2 Although most ptients re dignosed nd treted t n erly stge of the disese nd hve good prognosis, survivl mong ptients with unresectble or metsttic (dvnced) melnom remins poor. In the United Sttes, n estimted 9,940 deths from melnom will occur in 2015; 1 in Europe, melnom ccounts for n estimted 20,000 deths nnully. 2 Ptients with dvnced melnom historiclly hd disml prognosis, with medin survivl of less thn yer. 3,4 In met-nlysis of 2,100 ptients with dvnced melnom from 42 phse 2 coopertive group clinicl trils with ccrul closing between 1975 nd 2005, the medin overll survivl (OS) ws 6.2 months (95% confdence intervl [CI], ), with 25.5% (95% CI, ) live t 1 yer. 3 Another recent systemtic review estimted medin OS for stge IV melnom of bout 8 months, Accepted for publiction Mrch 13, Correspondence: Sumti Ro, PhD; sumti.ro@bms.com. Disclosures: Drs Ro nd Chng re employees of Bristol-Myers Squibb. Dr Clrk receives grnts nd spekers bureu fees from Bristol-Myers Squibb. Dr McDermott reports compenstion from Bristol-Myers Squibb for dvisory bord ttendnce. Dr Trhini reports grnts received nd compenstion from Bristol-Myers Squibb for dvisory bord ttendnce. Dr Mrgolin nd Ms Ktyl receive grnts from Bristol-Myers Squibb. Dr Jng nd Dr Johnson report nothing to disclose. JCSO 2015;13: Frontline Medicl Communictions. DOI /jcso Volume 13/Number 4 April 2015 g THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 131

2 with bout 10% of ptients surviving more thn 5 yers. 4 Beginning in 2010, however, phse 3 studies of severl novel gents showed sttisticlly improved OS in ptients with dvnced melnom. 5-7 Tese fndings further vlidted the use of immunotherpy nd introduced moleculrly trgeted therpy for the tretment of dvnced melnom, resulting in the vilbility of severl new gents for use in routine clinicl prctice. 8 Te frst of these new gents ws the frst-in-clss immune checkpoint inhibitor ipilimumb, humn monoclonl ntibody. Ipilimumb trgets the cytotoxic T-lymphocyte ssocited ntigen 4 (CTLA-4) receptor, blocking its inhibitory mechnisms nd thereby ugmenting T-lymphocyte medited ntitumor immune responses. Ipilimumb monotherpy, 3 mg/kg every 3 weeks for 4 doses, ws pproved in 2011 by the US Food nd Drug Administrtion on the bsis of signifcnt improvements in OS demonstrted in 2 pivotl, phse 3 rndomized, double-blind trils in ptients with dvnced melnom. Te frst study ws conducted in previously treted ptients; ipilimumb 3 mg/kg prolonged OS, whether dministered s monotherpy (medin, 10.1 months) or combined with glycoprotein 100 (gp100) peptide vccine (medin, 10.0 months), over gp100 lone (medin, 6.4 months; hzrd rtio [HR] for deth for ipilimumb lone vs gp100 lone, 0.66; P =.003). 5 Furthermore, there were 20.3% (45.6 vs 25.3) nd 9.8% (23.5 vs 13.7) more ptients live in the ipilimumb-only rm thn in the gp100 rm t 1 yer nd 2 yers, respectively. In the second tril, ptients with tretment-nïve disese who received concurrent regimen of ipilimumb 10 mg/kg nd dcrbzine hd improved OS over single-gent dcrbzine (medin, 11.2 vs 9.1 months; HR, 0.72; P <.001). 6 Higher survivl rtes were lso seen in this tril in the ptients treted with ipilimumb-dcrbzine compred with dcrbzine lone: 47.3% vs 36.3% t 1 yer, 28.5% vs 17.9% t 2 yers, nd 20.8% vs 12.2% t 3 yers. In both trils, ipilimumb ws well tolerted nd ssocited with mngeble sfety profle. Adverse events were primrily immune-relted in nture, consistent with the mechnism of ction of ipilimumb. Observtions from these nd other clinicl trils with ipilimumb resulted in product-specifc guidelines for mnging dverse events to mitigte the impct of immune-relted dverse events. 9 When new drugs re pproved, dt from use in clinicl prctice settings my hve considerble utility in confrming observtions obtined within the controlled setting of phse 3 clinicl trils. Te present study (CA ), multisite observtionl chrt review, ws initited to gther such dt, specifclly on frst-line tretment with ipilimumb in ptients with dvnced melnom in rel-world US tretment setting. Key objectives were to evlute survivl outcomes nd sfety in ptients for whom t lest 12 months of follow-up from the strt of ipilimumb therpy ws vilble, which provides study popultion tht is generlly similr to tht treted in the ipilimumb phse 3 trils. Although this report provides results t medin 1 yer of follow-up, the study protocol includes yerly updtes of survivl for this cohort out to 4 yers. Methods Study design Te study ws n observtionl chrt review study cross 34 US sites nd 15 Cytokine Working Group (CWG) nd 19 cdemic/community non-cwg centers, ech heded by medicl oncologist physicin investigtor (PI). Prticipting sites were instructed to sequentilly identify ll ptients who were treted with ipilimumb nd who met study inclusion nd exclusion criteri. Te PIs nd/or their supervised clinicl reserch stf bstrcted nd trnsferred existing (retrospective) ptient dt from medicl records onto prequlifed, stndrdized cse report forms. Dt collection, mngement, nd vlidtion ctivities were conducted by Medicl Dt Anlytics, contrct reserch orgniztion (Prsippny, New Jersey). Te study protocol ws pproved by either the institutionl review bord (IRB) of the individul prticipting institution or centrlized review bord (New Englnd IRB, Newton, Msschusetts). Te need for ptient informed consent ws determined on site-by-site bsis ccording to site IRB requirements. If site required ptient consent, then ll ptients who were still live nd eligible for the study were consented. Ptients Eligible ptients could hve unresectble stge III or metsttic (stge IV, M1, b, or c) melnom of ll primry types, including cutneous, noncutneous, nd unknown/unidentifble. Tey hd to be 18 yers or older, t dvnced dignosis, nd hd to hve initited frst-line commercil ipilimumb monotherpy (3 mg/kg q3w 4) during April 2011-September Of note, ptients with brin metstses t the time of inititing or continuing ipilimumb were eligible. Key exclusion criteri included ny previous systemic tretment for dvnced melnom, current or pending prticiption in clinicl tril or expnded ccess progrm, nd concurrent use of therpy for cncer other thn melnom. Ptients who were decesed or live t the time of dt collection were eligible. Ptients could hve received dditionl locl nd/or systemic nticncer therpies, including surgery, rdiotherpy, or non-ipilimumb systemic therpy, following the strt of ipilimumb tretment, provided these were not initited t the sme time s ipilimumb. Study vribles Te following study vribles were collected nd re reported in this nlysis: 132 THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g April

3 Mrgolin et l g Ptient demogrphics nd disese chrcteristics t dignosis of dvnced melnom nd bseline (ipilimumb initition); g Detils of ipilimumb dosing, including number of doses dministered, doses completed, dose delys, tretment discontinutions, nd resons for delys nd discontinution; g Concomitnt nticncer therpy initited fter the strt of nd dministered during ipilimumb tretment nd nticncer therpy provided subsequent to the lst dose of ipilimumb initil tretment, including retretment with ipilimumb; g Survivl-relted dt, including ll-cuse deth dte nd dte lst known to be live; nd g All dverse events scribed to disese or tretment (ipilimumb or other nticncer drugs). Dt on dverse events included type of event nd whether the event ws drug-relted, serious, or ssocited with tretment discontinution. Adverse events were coded using the Medicl Dictionry for Regultory Activities (MedDRA) version 16.1 nd grded ccording to the Common Terminology Criteri for Adverse Events, version Sttisticl nlysis Demogrphic nd disese chrcteristics t bseline, ipilimumb dosing informtion, nd sfety profle dt were summrized for ll ptients. Ctegoricl dt were described using counts with percentges nd continuous dt by medins with rnges. Te primry endpoint for evlution of efectiveness ws OS in months from the dte of ipilimumb initition. Te event of interest ws ll-cuse deth; ptients who were live t lst follow-up were censored. Medin OS nd survivl rte t 1 yer from the dte of ipilimumb initition were estimted for ll ptients using the Kpln-Meier method. Corresponding 95% CI for medin OS were clculted using the method of Brookmeyer nd Crowley, 11 nd the 95% CI for OS rtes t 1 yer were clculted using the log-log trnsformtion. Overll survivl ws computed in d hoc, explortory nlyses for specifc subgroups, including ptients with n Estern Coopertive Oncology Group Performnce Sttus (ECOG PS) of 0 or 1, without brin metstses t dvnced dignosis, with cutneous primry site t dignosis, nd by BRAF muttion sttus. Sttistics on d hoc results were not performed becuse study ws observtionl. All of the nlyses were conducted using SAS version 9 (SAS Institute Inc, Cry, NC). Results A totl of 273 ptients were included in this study. Dt collection ws completed during December 2012-Jnury Te medin times from initil melnom dignosis to dvnced melnom dignosis nd from dvnced melnom dignosis to frst dose of ipilimumb were 16.6 months (rnge, 0-312) nd 1.2 months (rnge, 0-72), respectively. Te medin ge ws 64 yers (rnge, 26-91) nd 64.8% of ptients were men (Tble 1). At the time of dignosis of dvnced disese, 12.1% of ptients hd unresectble stge III disese, 56.0% hd stge IV M1c disese, nd 12.1% hd brin metstses. Te primry site ws cutneous in 88.3% of ptients. Before receiving ipilimumb, 38.1% nd 42.5% of ptients hd ECOG PS 0 or 1, respectively, nd 36.6% hd serum lctte dehydrogense levels greter thn the institutionl upper limit of norml. BRAF muttion sttus ws known for 231 ptients, of whom 50 (21.6%) hd V600 muttion, nd 181 (78.4%) were BRAF wild-type. In ll, 78% of ptients received ll 4 plnned doses of ipilimumb (Supplementl dt). Te most common resons for discontinuing dosing were disese progression (10.3%), drug toxicity (7.0%), nd ptient request (3.7%). Ipilimumb dosing ws delyed once in 14 ptients (5.1%), with the most frequent resons given being fever (1.1%), hypotension (0.7%), nd pruritus (0.7%). No ptient experienced more thn 1 dose dely. Additionl nticncer therpy during ipilimumb tretment ws dministered to 8.4% of ptients, with rdiotherpy being the most frequent type (6.6%; Supplementl dt). Forty-one percent of ptients lso received supportive cre gents, including prednisone (16.1%), ntiemetics (15.0%), nlgesics (13.9%), ntipruritics (10.6%), nd ntimotility gents (6.6%). Tree ptients (1.1%) received levothyroxine for thyroiditis, nd 1 ptient (<1%) received infiximb in ddition to prednisone for dirrhe/colitis. Subsequent to the lst dose of ipilimumb, 126 ptients (46.2%) received dditionl non-ipilimumb nticncer therpy including surgery (9.9%), rdiotherpy (23.1%), cytotoxic chemotherpy (17.9%), trgeted therpy (7.7%), nd non-ipilimumb immunotherpy (4.4%). Eighteen ptients (6.6%) were retreted with ipilimumb ccording to stndrd guidelines nd prctice for retretment, which generlly require ptients to hve experienced n objective response or stbility lsting t lest 3 months nd to hve hd no serious tretment-relted toxicity. Overll, 28.9% of ptients received non-ipilimumb systemic therpy subsequent to the lst dose of ipilimumb. Twenty-nine percent of ptients chieved durble therpeutic beneft nd did not receive ny further ipilimumb; other ptients did not receive further ipilimumb becuse their performnce sttus worsened (12.8%) or they died (24.2%). At medin follow-up of 12.2 months (interqurtile rnge, ), 142 (52.0%) ptients hd died. Medin OS from the strt of ipilimumb tretment ws 14.5 months (95% CI, ), nd 1-yer survivl ws 59.2% (95% CI, ) (Tble 2, Figure 1). Medin Volume 13/Number 4 April 2015 g THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 133

4 OS vlues derived from the d hoc, explortory OS nlyses for ptient subgroups were 21.5 (95% CI, 16.8-not reched) nd 12.8 months (95% CI, ) for ptients with ECOG PS 0 or 1, respectively; 17.5 months (95% CI, ) for ptients without brin metstses; nd 16.8 months (95% CI, ) for ptients with cutneous primry site of dignosis. One-yer survivl rtes for BRAF-mutted, wild-type, nd untested ptients were 71.0% (95% CI, ), 54.9% (95% CI, ), nd 63.6% (95% CI, ), respectively. Adverse events during ipilimumb tretment were reported in 164 ptients (60.1%; Tble 3); these were considered drug-relted nd serious in 53.8% nd 18.7% of ptients, respectively. Te most frequently observed dverse events were skin-relted (29.3%), with rsh, pruritus, nd dermtitis most commonly reported, nd gstrointestinlrelted (27.5%), the most frequent being dirrhe (Tble 4). Drug-relted dverse events were grde 3/4 in 15.7% of ptients (13.9 nd 1.8, respectively), nd there were no toxic deths. Drug-relted dverse events led to discontinution of tretment in 10.6% of ptients, most often becuse of colitis (2.9%), dirrhe (1.8%), nd/or enterocolitis (1.5%). Of the 48 deths (17.6%) tht occurred during tretment, 45 were owing to progressive melnom, 1 ws from nondrug-relted congestive hert filure/myocrdil infrction, 1 from pulmonry embolism, nd 1 from unknown cuses. Discussion Tis multisite observtionl chrt review study is the lrgest study to dte of ipilimumb dministered s pproved for frst-line systemic therpy in ptients with dvnced melnom. It is expected tht ptients treted outside of the controlled setting of rndomized clinicl tril my exhibit greter heterogeneity in demogrphic nd disese chrcteristics thn those in clinicl tril cohort. As with ny recently pproved gent, it ws therefore importnt to ssess the efectiveness nd sfety of ipilimumb observed in routine clinicl prctice. Tis rel-world study ddresses this need nd lso provides vluble dt on the use of ipilimumb t its pproved dose nd schedule in ptients with tretment-nïve dvnced melnom. Clinicl tril experience with ipilimumb 3 mg/kg monotherpy in tretment-nïve ptients with dvnced melnom is limited to 2 phse 2 trils. In the frst, 32 ptients who were chemotherpy-nïve hd medin OS of 11.4 months nd 1-yer survivl of 45%, 12 nd in the second, 40 ptients hd medin OS of 12.9 months nd 1-yer survivl of 60.9%. 13 In the ipilimumb-contining rms of the 2 pivotl phse 3 trils, the medin OS rnge ws months, nd the 1-yer survivl rte rnge ws 45.6%- 47.3%. 5,6 In the present study, the observed medin OS of 14.5 months nd 1-yer survivl rte of 59.2% suggest tht survivl outcomes with ipilimumb in routine clinicl prc- TABLE 1 Ptient demogrphics nd disese chrcteristics Chrcteristic No. of ptients (%) (N = 273) Mle 177 (64.8) Medin ge: 64 yers, rnge tice re consistent with those shown in the controlled phse 3 clinicl tril setting. Of note, the plnned yerly survivl updtes of this observtionl cohort will provide rel-world dt on whether long-term survivl is lso consistent with the durble long-term survivl (>3-5 yers) now shown for 20%-26% of ptients in extended follow-up cross the ipi- Treted t CWG center 162 (59.3) Rce White Blck Asin Unknown Primry site b Cutneous Noncutneous Oculr Mucosl Stge c Stge III (M0) Stge IV (M1) M1 M1b M1c ECOG PS Unknown 260 (95.2) 9 (3.3) 3 (1.1) 1 (<1) 241 (88.3) 32 (11.7) 12 (4.4) 5 (1.8) 33 (12.1) 240 (87.9) 30 (11.0) 57 (20.9) 153 (56.0) 104 (38.1) 116 (42.5) 16 (5.9) 3 (1.1) 34 (12.5) Brin metstses c 33 (12.1) LDH, n (%) d Elevted Norml Not tested BRAF muttion sttus e Positive Negtive Not tested 100 (36.6) 127 (46.5) 46 (16.8) 50 (18.3) 181 (66.3) 42 (15.4) CWG, Cytokine Working Group; Estern Coopertive Oncology Group Performnce Sttus, ECOG PS; LDH, serum lctte dehydrogense At strt of ipilimumb tretment unless otherwise noted. b At initil dignosis of melnom. c At dignosis of dvnced melnom. d Site-defned s >upper limit of norml. e At ny melnom dignosis. 134 THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g April

5 Mrgolin et l TABLE 2 Effccy of frst-line ipilimumb Effccy objective Primry, ll ptients (N = 273) b Vlue Medin OS, mo (95% CI) 14.5 ( ) 1-yer survivl, % (95% CI) 59.2 ( ) Explortory, for subgroups (d hoc nlyses) b ECOG PS 0 (n = 104), medin OS, mo (95% CI) ECOG PS 1 (n = 116), medin OS, mo (95% CI) Without brin metstses (n = 240), medin OS, mo (95% CI) Cutneous primry site of dignosis (n = 241), medin OS, mo (95% CI) BRAF muttion sttus, 1-yer survivl, % (95% CI) c 21.5 (16.8-nr) 12.8 ( ) 17.5 ( ) 16.8 ( ) Positive (n = 50) 71.0 ( ) Wild-type (n = 181) 54.9 ( ) Not tested (n = 42) 63.6 ( ) Estern Coopertive Oncology Group Performnce Sttus, ECOG PS; LDH, serum lctte dehydrogense; OS, overll survivl; PS, performnce sttus Approved 3 mg/kg monotherpy q3w 4. b Medin follow-up, 12.2 months (interqurtile rnge, months). c Frequency of BRAF muttions not representtive of typicl frst-line ptient popultion, nd my refect physicins preference to only tret specifc BRAF mutted ptients with ipilimumb (eg, ptients with less ggressive disese or longer life expectncy). TABLE 3 Overll sfety with frst-line ipilimumb Adverse events Ptients with worst grde, n (%) b (N = 273) Any grde Grde 3 Grde 4 Totl c 164 (60.1) 45 (16.5) 8 (2.9) Drug-relted 147 (53.8) 38 (13.9) 5 (1.8) Serious 51 (18.7) 33 (12.1) 7 (2.6) Drug-relted 38 (13.9) 26 (9.5) 5 (1.8) Leding to discontinution 31 (11.4) 18 (6.6) 4 (1.5) Drug-relted 29 (10.6) 18 (6.6) 3 (1.1) Approved 3 mg/kg monotherpy q3w 4; restricted to dverse events reported between the frst ipilimumb dose nd erliest of 70 dys fter the lst initil dose or, if ipilimumb ws given gin, the dy before the strt of retretment. b Common Terminology Criteri, Version 3.0; there were no Grde 5 dverse events. c Ptients my hve experienced more thn one dverse event. limumb clinicl trils. 14 As expected, the d hoc, explortory OS nlyses of subgroups in this study showed higher OS for ptients with ECOG PS 0, without brin metstses, nd with cutneous primry site. BRAF muttion sttus did not seem to fect survivl. Tese results must be interpreted with cution, however, becuse this ws n observtionl study with inherent limittions. Indeed, it should be noted tht the frequency of BRAF muttions reported here (21.6%) is lower thn the 40%-60% expected in popultion of ptients with primrily cutneous melnoms. 7 Tis fnding my refect the prctice of preferentilly treting ptients with BRAF-mutted tumors with BRAF inhibitors, prticulrly ptients with unfvorble clinicl chrcteristics. In ddition, during the time period covered in this study, clinicl trils of BRAF inhibitors in frst-line therpy for melnom were ongoing nd probbly cptured some ptients who might otherwise hve been treted frst-line with ipilimumb. It remins uncertin whether ptients with BRAF mutted tumors should receive MAPK inhibitors or ipilimumb s frst-line systemic therpy while prospective studies re ongoing to inform clinicl prctice. 15 Retrospective dt suggest tht response to BRAF inhibitor is similr pre- nd post-ipilimumb, but response to ipilimumb my be improved before BRAF inhibitor compred with fter BRAF inhibitor. 16 On the bsis of tht evidence, the use of ipilimumb before BRAF inhibitor hs been recommended, prticulrly in n initil setting of symptomtic or low-volume disese. In the future, however, potentil strtegy my be to strt with trgeted therpy nd then to switch to immunotherpy t the time of best response (before filure occurs). 16,17 Ptients with melnom in the US re treted in both cdemic nd community centers, but ptients with dvnced melnom in the Europen Union nd mny other regions re treted primrily in centrlized cdemic centers. Although the present study ws limited to centers in the US, they were primrily specilized centers (CWG or CWG-flited). Tus, ptients in this cohort were treted by cdemic clinicins who hd clinicl tril experience with ipilimumb tretment, selection of pproprite ptients, nd mnging immune-relted dverse events, nd who were supported by similrly experienced nd dedicted clinicl nd reserch tems. Tis rgubly mkes the study results generlizble to the verge tretment-nïve ptient with dvnced melnom who might be treted with frst-line ipilimumb therpy in centrlized cdemic centers in the Europen Union nd other regions. In contrst to the primrily cdemic setting of our study, the community setting (McKesson Specilty Helth/US Oncology Network) ws exclusively the source of ptients for nother US multisite, retrospective, observtionl cohort study tht ws conducted with the sme objectives during the sme timefrme. 18 In this second study, medin OS ws 11.5 months (95% CI, ) nd 1-yer survivl ws Volume 13/Number 4 April 2015 g THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 135

6 Medin OS 14.5 months (95% CI: ) Proportion live yer survivl 59.2% (95% CI: ) Months Ptients t risk FIGURE 1 Overll survivl from strt of frst-line ipilimumb. N = 273; medin follow-up, 12.2 months (interqurtile rnge: 6.6, 15.9 months). Circles indicte censored observtions. 46.7% (95% CI, ) for the 157-ptient cohort with tretment-nïve dvnced melnom who received ipilimumb monotherpy. Fewer ptients in this community setting cohort received ll 4 cycles of the frst-line ipilimumb (53.8% vs 77.7% in the present study) nd this popultion lso hd higher proportion of ptients with brin metstses (34.4% vs 12.1% in the present study); both of those diferences could hve contributed to the lower survivl observed in the second study. Despite the diferences, the results of these 2 observtionl studies re independently consistent with those from the ipilimumb clinicl trils, which strongly suggest tht improved survivl cn be chieved with ipilimumb in the rel-world tretment settings of both cdemic nd community prctice. Ipilimumb seemed to be well tolerted in this tretment-nïve cohort, with nerly 80% of ptients ble to receive ll 4 of the prescribed doses of ipilimumb. Tis therpy ws lso ssocited with sfety profle similr to tht observed in clinicl trils of ipilimumb t this dose nd schedule. In those trils, the most frequent dverse events occurred in the skin nd gstrointestinl systems. Grde 3/4 drug-relted dverse events were reported in 15.7% (13.9% nd 1.18%, respectively) of ptients in the present study, nd in 17.4%-22.9% ( nd ) of previously treted ptients receiving ipilimumb 3 mg/ kg in the frst pivotl phse 3 study. 6 Of note is tht there were no dverse event-relted deths or gstrointestinl perfortions reported in this study, which possibly refects creful ptient selection nd vigilnt use of the ipilimumb dverse event mngement guidelines, which cll for rigorous monitoring nd prompt intervention with immunosuppressive therpy. 9 Tis intervention, strting with glucocorticosteroids nd sometimes requiring the ddition of djunctive immunosuppressnts such s infiximb (in ptients whose immune-relted dverse events re not well controlled by steroids or to spre ptients the risks inherent with long-term nd/or high-dose glucocorticosteroid therpy), ws shown to prevent the worsening of immunerelted events nd to tret them efectively in nerly ll cses in the phse 3 trils. 5,6 Te results suggest tht the use of these dverse event-mngement guidelines in relworld setting yields mngeble sfety profle similr to tht observed in the ipilimumb clinicl trils. Tis study is limited by its observtionl nture nd the heterogeneity of ptients vilble for inclusion in the report. On the one hnd, the inclusion here of ptients typiclly excluded from most ipilimumb clinicl studies (eg, those with brin metstses) nd others who would lso be expected to hve poorer prognosis (eg, with oculr or mucosl melnom) could unfvorbly fect the ppr- 136 THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g April

7 Mrgolin et l TABLE 4 Adverse events occurring in more thn 5% of ptients with frst-line ipilimumb Adverse event Ptients with worst grde, n (%) b (N = 273) Grde 1 Grde 2 Grde 3 Grde 4 Unknown Any Grde Any c 42 (15.4) 67 (24.5) 45 (16.5) 8 (2.9) 2 (0.7) 164 (60.1) Skin 49 (17.9) 24(8.8) 5 (1.8) 0 2 (0.7) 80 (29.3) Rsh 27 (9.9) 11 (4.0) 2 (0.7) (14.7) Pruritus 22 (8.1) 12 (4.4) 1 (0.4) 0 1 (0.4) 36 (13.2) Dermtitis 17 (6.2) 7 (2.6) 2 (0.7) 0 1 (0.4) 27 (9.9) Gstrointestinl 25 (9.2) 26 (9.5) 21 (7.7) 2 (0.7) 1 75 (27.5) Dirrhe 20 (7.3) 16 (5.9) 4 (1.5) (14.7) Colitis 2 (0.7) 6 (2.2) 10 (3.7) 1 (0.4) 0 19 (7.0) Nuse 8 (2.9) 5 (1.8) 1 (0.4) (5.1) Ftigue 16 (5.9) 31 (11.4) 8 (2.9) (20.1) Nervous system d 9 (3.3) 10 (3.7) 5 (1.8) 2 (0.7) 1 (0.4) 27 (9.9) Endocrine e 2 (0.7) 8 (2.9) 6 (2.2) 1 (0.4) 0 17 (6.2) Approved 3 mg/kg monotherpy q3w 4; restricted to dverse events reported between the frst ipilimumb dose nd erliest of 70 dys fter the lst initil dose or, if ipilimumb ws given gin, the dy before the strt of retretment. bcommon Terminology Criteri, Version 3.0; there were no Grde 5 dverse events. cptients my hve experienced more thn one dverse event. dmost common dverse event of ny grde ws peripherl neuropthy in 12 (4.4%) ptients. Hedche ws the most common Grde 3 dverse event, occurring in 3 (1.1%) ptients. emost common Grde 3 or 4 dverse events were drenl insuffciency nd hypophysitis in 3 (1.1%) ptients ech. ent ctivity nd toxicity experience with ipilimumb. On the other hnd, the exclusion of ptients receiving previous therpy for dvnced disese could fvorbly bis the dt. Further limittions re imposed by the incomplete nture of some dt, loss to follow-up, nd possible overor under-reporting of selected outcomes, especilly dverse events. For the OS nlysis, the censoring of ptients not known to hve died by the time of the dt lock reduces the relibility of the OS results with incresing time; its impct is expected to decline with longer follow-up in this cohort. Finlly, the OS results re confounded by the unknown contribution of dditionl nticncer therpy provided during nd subsequent to initil ipilimumb therpy, including ipilimumb retretment. In conclusion, this report expnds our knowledge of the clinicl profle of ipilimumb in ptients with dvnced melnom who received the drug s frst-line therpy in rel-world clinicl prctice setting. To our knowledge, it is the lrgest study of frst-line ipilimumb for ptients with dvnced melnom treted outside of clinicl tril to dte, nd it included ptients cross ll primry subtypes of melnom, including noncutneous subtypes nd those with brin metstses, for whom clinicl tril dt re limited. 19,20 Te observed medin OS of 14.5 months nd 1-yer survivl rte of 59.2% provide evidence tht the improved survivl outcomes ssocited with ipilimumb tretment in the pivotl clinicl trils re chievble in rel-world clinicl setting. Although these results re subject to the limittions of dt obtined from observtionl studies, they support the efectiveness nd sfety of ipilimumb used t the indicted 3 mg/kg dose nd schedule s frst-line therpy for ptients with dvnced melnom. Acknowledgments Tis study ws presented in prt t the 2013 Europen Cncer Congress, October 2013, nd the 2013 Society for Melnom Reserch Interntionl Congress, November Te uthors tke full responsibility for the content of this publiction nd confrm tht it refects their viewpoint nd medicl expertise. Dt collection, reserch opertions, nd nlytics support were provided by Schifon L Wong, Mrinne Messin, nd John R Penrod of Bristol-Myers Squibb; by nd Pete Wolthof, Cynthi Mchilig, nd Scott Merrill of Medicl Dt Anlytics. Professionl medicl writing ssistnce ws provided by Jennifer Wietzke nd Wrd A. Pedersen t StemScientifc, n Ashfeld Compny, funded by Bristol-Myers Squibb. References 1. Americn Cncer Society, Cncer Fcts & Figures Accessed Mrch 19, Forse AM, Del Mrmol V, de Vries E, Biley EE, Geller AC Biley. Melnom incidence nd mortlity in Europe: new estimtes, persistent disprities. Br J Dermtol. 2012;167: Korn EL, Liu PY, Lee SJ, et l. Met-nlysis of phse II coopertive group trils in metsttic stge IV melnom to determine progression-free nd overll survivl benchmrks for future phse II trils. J Clin Oncol. 2008;26: Grbe C, Eigentler TK, Keilholz U, Huschild A, Kirkwood JM. Systemtic review of medicl tretment in melnom: current sttus nd future prospects. Oncologist. 2011;16: Hodi FS, O Dy SJ, McDermott DF, et l. Improved survivl with ipilimumb in ptients with metsttic melnom. N Engl J Med. 2010;363: Robert C, Toms L, Bondrenko I, et l. Ipilimumb plus dcrbzine for previously untreted metsttic melnom. N Engl J Med. 2011;364: Chpmn PB, Huschild A, Robert C, et l. Improved survivl Volume 13/Number 4 April 2015 g THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY 137

8 with vemurfenib in melnom with BRAF V600E muttion. N Engl J Med. 2011;364: Luke JJ, Hodi FS. Ipilimumb, vemurfenib, dbrfenib, nd trmetinib: synergistic competitors in the clinicl mngement of BRAF mutnt mlignnt melnom. Oncologist. 2013;18: Weber JS, Khler KC, Huschild A. Mngement of immune-relted dverse events nd kinetics of response with ipilimumb. J Clin Oncol. 2012;30: Cncer Terpy Evlution Progrm. Common Terminology Criteri for Adverse Events (CTCAE). Version 3.0, DCTD, NCI, NIH, DHHS. August 9, Accessed Mrch 1, Brookmeyer R, Crowley J. A confdence intervl for the medin survivl time. Biometrics. 1982;38: Hersh EM, O Dy SJ, Powderly J, et l. A phse II multicenter study of ipilimumb with or without dcrbzine in chemotherpy-nïve ptients with dvnced melnom. Invest New Drugs. 2011;29: Hmid O, Schmidt H, Nissn A, et l. A prospective phse II tril exploring the ssocition between tumor microenvironment biomrkers nd clinicl ctivity of ipilimumb in dvnced melnom. J Trns Med. 2011;9: Schdendorf D, Hodi FS, Roberts C, et l. Pooled nlysis of longterm survivl dt from phse II nd phse III trils of ipilimumb in unresectble or metsttic melnom. J Clin Oncol. 2014: submitted Mrch Jng S, Atkins MB. Which drug, nd when, for ptients with BRAFmutnt melnom? Lncet Oncol. 2013;14:e60-e Ackermn A, Klein O, McDermott DF, et l. Outcomes of ptients with metsttic melnom treted with immunotherpy prior to or fter BRAF inhibitors. Cncer. 2014; 120: Ascierto PA, Mrgolin K. Ipilimumb before BRAF inhibitor tretment my be more benefcil thn vice vers for the mjority of ptients with dvnced melnom. Cncer. 2014;120: Ptt D, Rembert D, Bhor M, Bhowmik D, Ro S. A rel-world observtionl study of ptients with dvnced melnom receiving frst-line Ipilimumb in community prctice setting. J Cncer Ter. 2014: submitted Mrch Mrgolin K, Ernstof MS, Hmid O, et l. Ipilimumb in ptients with melnom nd brin metstses: n open-lbel, phse 2 tril. Lncet Oncol. 2012;13: Di Gicomo AM, Ascierto PA, Pill L, et l. Ipilimumb nd fotemustine in ptients with dvnced melnom (NIBIT M1): n openlbel, single-rm phse 2 tril. Lncet Oncol. 2012;13: THE JOURNAL OF COMMUNITY AND SUPPORTIVE ONCOLOGY g April