Ipilimumab Monotherapy Study

8/10/2019 Ipilimumab Monotherapy Study

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n engl j med 363;8 nejm.org august 19, 2010 711

The new englandjournal of medicineestablished in 1812 august 19, 2010 vol. 363 no. 8

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

F. Stephen Hodi, M.D., Steven J. ODay, M.D., David F. McDermott, M.D., Robert W. Weber, M.D., Jeffrey A. Sosman, M.D., John B. Haanen, M.D., Rene Gonzalez, M.D., Caroline Robert, M.D., Ph.D.,

Dirk Schadendorf, M.D., Jessica C. Hassel, M.D., Wallace Akerley, M.D., Alfons J.M. van den Eertwegh, M.D., Ph.D., Jose Lutzky, M.D., Paul Lorigan, M.D., Julia M. Vaubel, M.D., Gerald P. Linette, M.D., Ph.D., David Hogg, M.D.,

Christian H. Ottensmeier, M.D., Ph.D., Celeste Lebb, M.D., Christian Peschel, M.D., Ian Quirt, M.D., Joseph I. Clark, M.D., Jedd D. Wolchok, M.D., Ph.D., Jeffrey S. Weber, M.D., Ph.D., Jason Tian, Ph.D.,

Michael J. Yellin, M.D., Geoffrey M. Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D., and Walter J. Urba, M.D., Ph.D.

A b s t r a c t

Drs. Hodi and ODay contributed equallyto this article.

The authors aff iliations and participatinginvestigators are listed in the Appendix. Ad-dress reprint requests to Dr. Hodi at theDanaFarber Cancer Institute, 44 BinneySt., Boston, MA 02115, or at [email protected].

This article (10.1056/NEJMoa1003466) waspublished on June 5, 2010, and last updatedon September 1, 2010, at NEJM.org.

N Engl J Med 2010;363:711-23.Copyright 2010 Massachusetts Medical Society.

Background

An improvement in overall survival among patients with metastatic melanoma hasbeen an elusive goal. In this phase 3 study, ipilimumab which blocks cytotoxicT-lymphocyteassociated antigen 4 to potentiate an antitumor T-cell response administered with or without a glycoprotein 100 (gp100) peptide vaccine was com-pared with gp100 alone in patients with previously treated metastatic melanoma.Methods

A total of 676 HLA-A*0201positive patients with unresectable stage III or IV mela-

noma, whose disease had progressed while they were receiving therapy for meta-static disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plusgp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at adose of 3 mg per kilogram of body weight, was administered with or without gp100every 3 weeks for up to four treatments (induction). Eligible patients could receivereinduction therapy. The primary end point was overall survival.Results

The median overall survival was 10.0 months among patients receiving ipilimumabplus gp100, as compared with 6.4 months among patients receiving gp100 alone(hazard ratio for death, 0.68; P


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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 363;8 nejm.org august 19, 2010712

The incidence of metastatic mela-noma has increased over the past three de-cades, 1,2 and the death rate continues torise faster than the rate with most cancers. 3 TheWorld Health Organization (WHO) estimates that

worldwide there are 66,000 deaths annually fromskin cancer, with approximately 80% due to mel-anoma. 4 In the United States alone, an estimated8600 persons died from melanoma in 2009. 1 Themedian survival of patients with melanoma whohave distant metastases (American Joint Com-mittee on Cancer stage IV) is less than 1 year. 5,6 No therapy is approved beyond the first-line ther-apy for metastatic melanoma, and enrollment ina clinical trial is the standard of care. No therapyhas been shown in a phase 3, randomized, con-trolled trial to improve overall survival in patients

with metastatic melanoma. 6-9Regulatory pathways that limit the immune

response to cancer are becoming increasingly well characterized. Cytotoxic T-lymphocyteasso-ciated antigen 4 (CTLA-4) is an immune check-point molecule that down-regulates pathways ofT-cell activation. 10 Ipilimumab, a fully humanmonoclonal antibody (IgG1) that blocks CTLA-4to promote antitumor immunity, 11-14 has shownactivity in patients with metastatic melanoma

when it has been used as monotherapy in phase 2studies. 15-17 Ipilimumab has also shown activity

when combined with other agents, 18,19 includingcancer vaccines. 20,21 One well-studied cancer vac-cine comprises HLA-A*0201restricted peptidesderived from the melanosomal protein, glyco-protein 100 (gp100). Monotherapy with this vac-cine induces immune responses but has limitedantitumor activity. 22 However, the results of arecent study suggest that gp100 may improve theefficacy of high-dose interleukin-2 in patients

with metastatic melanoma. 23 With no acceptedstandard of care, gp100 was used as an activecontrol for our phase 3 study, which evaluated

whether ipilimumab with or without gp100 im-

proves overall survival, as compared with gp100alone, among patients with metastatic melano-ma who had undergone previous treatment.

Methods

Patients

Patients were eligible for inclusion in the study ifthey had a diagnosis of unresectable stage III orIV melanoma and had received a previous thera-

peutic regimen containing one or more of thefollowing: dacarbazine, temozolomide, fotemus-tine, carboplatin, or interleukin-2. Other inclu-sion criteria were age of at least 18 years; life ex-pectancy of at least 4 months; Eastern CooperativeOncology Group (ECOG) performance status of 0(fully active, able to carry on all predisease per-formance without restriction) or 1 (restricted inphysically strenuous activity but ambulatory andable to carry out work of a light or sedentary na-ture, such as light housework or office work) 24 ;positive status for HLA-A*0201; normal hemato-logic, hepatic, and renal function; and no system-ic treatment in the previous 28 days. Exclusioncriteria were any other cancer from which thepatient had been disease-free for less than 5 years(except treated and cured basal-cell or squamous-cell skin cancer, superficial bladder cancer, ortreated carcinoma in situ of the cervix, breast, orbladder); primary ocular melanoma; previous re-ceipt of antiCTLA-4 antibody or cancer vaccine;autoimmune disease; active, untreated metastasesin the central nervous system; pregnancy or lac-tation; concomitant treatment with any nonstudyanticancer therapy or immunosuppressive agent;or long-term use of systemic corticosteroids.

The protocol was approved by the institution-al review board at each participating institutionand was conducted in accordance with the ethi-cal principles originating from the Declarationof Helsinki and with Good Clinical Practice asdefined by the International Conference on Har-monization. All patients (or their legal represen-tatives) gave written informed consent beforeenrollment.

Study Design and Treatment

In this randomized, double-blind, phase 3 study, we enrolled patients at 125 centers in 13 coun-tries in North America, South America, Europe,and Africa. Between September 2004 and August2008, patients were randomly assigned to one of

three study groups, with stratif ication accordingto baseline metastasis stage (M0, M1a, or M1b vs. M1c, classified according to the tumornodemetastasis [TNM] categorization for melanomaof the American Joint Committee on Cancer), andreceipt or nonreceipt of previous interleukin-2therapy. The full original protocol, a list of amend-ments, and the final protocol, as well as the sta-tistical analysis plan, are available with the fulltext of this article at NEJM.org.

The New England Journal of MedicineDownloaded from nejm.org by ANDREW BAUM on August 16, 2013. For personal use only. No other uses without permission.

Copyright 2010 Massachusetts Medical Society. All rights reserved.


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Ipilimumab for meta static melanoma


Patients were randomly assigned, in a 3:1:1ratio, to treatment with an induction course ofipilimumab, at a dose of 3 mg per kilogram ofbody weight, plus a gp100 peptide vaccine; ipi-limumab plus gp100 placebo; or gp100 plus ipi-limumab placebo all administered once every3 weeks for four treatments. In the vaccinegroups, patients received two modified HLA-A*0201restricted peptides, injected subcutane-ously as an emulsion with incomplete Freundsadjuvant (Montanide ISA-51): a gp100:209-217(210M) peptide, 1 mg injected in the rightanterior thigh, and a gp100:280-288(288V) pep-tide, 1 mg injected in the left anterior thigh.Peptide injections were given immediately aftera 90-minute intravenous infusion of ipilimumabor placebo. Treatment began on day 1 of week 1,and if there were no toxic effects that could notbe tolerated, no rapidly progressive disease, andno significant decline in performance status,patients received an additional treatment during

weeks 4, 7, and 10. Patients in whom new lesionsdeveloped or baseline lesions grew were allowedto receive additional treatments to complete induc-tion. Patients with stable disease for 3 monthsduration after week 12 or a confirmed partial orcomplete response were offered additional coursesof therapy (reinduction) with their assigned treat-ment regimen if they had disease progression.

The original primary end point was the bestoverall response rate (i.e., the proportion of pa-tients with a partial or complete response). Theprimary end point was amended to overall sur-

vival (with the amendment formally approved on January 15, 2009) in the ongoing blinded study,on the basis of phase 2 data and in alignment

with another ongoing phase 3 trial of ipilimu-mab involving patients with metastatic melano-ma. 25 The primary comparison in overall sur-

vival was between the ipilimumab-plus-gp100group and the gp100-alone group. Prespecifiedsecondary end points included a comparison of

overall survival between the ipilimumab-aloneand the gp100-alone groups and between thetwo ipilimumab groups, the best overall responserate, the duration of response, and progression-free survival. Subgroup comparisons of overallsurvival were performed across five prespecifiedcategories: metastasis stage (M0, M1a, or M1b

vs. M1c), receipt or nonreceipt of previous inter-leukin-2 therapy, baseline levels of serum lactatedehydrogenase (less than or equal to the upperlimit of the normal range vs. higher than the

upper limit of the normal range), age (


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proved to grade 1 or lower; if the event did notimprove to grade 1 or lower, treatment was dis-continued permanently. Monitoring of adverseevents continued for at least 70 days after thelast dose of study drugs had been administeredor until any ongoing event resolved or stabilized.All patients, including those with low-gradechanges in bowel frequency or stool consistency,

were followed closely. A data and safety moni-toring committee provided independent over-sight of safety and the riskbenefit ratio.

During the study enrollment, the followingstopping rule was in place: if 10% or more of thepatients in any study treatment group, evaluatedcumulatively every 3 months, had a nondermato-logic-related toxic adverse event of grade 3 orhigher that was attributable to the investigationalagents and that could not be alleviated or con-trolled by appropriate care or corticosteroid ther-apy within 14 days after the initiation of sup-portive care or corticosteroid therapy, assignmentof patients to that study group would be sus-pended until the sponsor and the data and safetymonitoring committee had reviewed the eventsand determined the appropriate course of action.

Statistical Analysis

The original study sample size of 750 patients was determined on the basis of the primary endpoint of best overall response rate but was re-

vised with the new primary end point of overallsurvival. We estimated that with 385 events(deaths) among a total of 500 patients randomlyassigned to the ipilimumab-plus-gp100 and thegp100-alone groups, the study would have atleast 90% power to detect a difference in overallsurvival, at a two-sided alpha level of 0.05, withthe use of a log-rank test. A total of 481 events

were required in all three groups (assuming thatthe events were distributed in a 3:1:1 ratio in theipilimumab-plus-gp100, ipilimumab-alone, andgp100-alone groups, respectively). Therefore, all

patients who were randomly assigned in thestudy were to be followed until at least 481 eventshad occurred in the study. Enrollment was com-pleted on July 25, 2008, when more than 650 pa-tients had been enrolled. A post hoc power anal-

ysis showed that the 219 events observed amonga total of 273 patients randomly assigned to theipilimumab-alone and gp100-alone groups pro-

vided at least 80% power to detect a difference inoverall survival between the two groups, at a

two-sided alpha level of 0.05, with the assump-tion that ipilimumab alone has the same treat-ment effect as the combination regimen of ipili-mumab plus gp100.

Survival was defined as the time from ran-domization to death from any cause, and pro-gression-free survival as the time from random-ization to documented disease progression ordeath. Event-time distributions were estimated

with the use of the KaplanMeier method. Coxproportional-hazards models, stratified accord-ing to metastasis status and receipt or nonre-ceipt of previous interleukin therapy, were usedto estimate hazard ratios and to test for sig-nificance of the timing of events. All reportedP values are two-sided, and confidence intervalsare at the 95% level. Survival rates were based onKaplanMeier estimation, and confidence inter-

vals were calculated with the use of the boot-strap method. Descriptive statistics were usedfor adverse events.

R e s u l t s

Patients and Treatment

Among 676 patients enrolled in the study, 403 were randomly assigned to receive ipilimumabplus gp100, 137 to receive ipilimumab alone, and136 to receive gp100 alone (control group) (Fig. 1in the Supplementary Appendix, available atNEJM.org). Included among these patients were82 patients who had metastases in the centralnervous system at baseline, of whom 77 receivedthe study drug. The baseline characteristics ofthe patients are shown in Table 1 . Efficacy analy-ses were performed on the intention-to-treatpopulation, which included all patients who hadundergone randomization (676 patients). Thesafety population included all patients who hadundergone randomization and who had receivedany amount of study drug (643 patients). A totalof 242 of 403 patients in the ipilimumab-plus-

gp100 group (60.0%), 88 of 137 in the ipilimu-mab-alone group (64.2%), and 78 of 136 in thegp100-alone group (57.4%) received all four ipi-limumab doses or placebo infusions. The mostfrequent reason for discontinuation of therapy

was disease progression.

Efficacy

All the analyses of the efficacy end points re-ported here were prespecified as per protocol.




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Patients were followed for up to 55 months, withmedian follow-up times for survival of 21.0

months in the ipilimumab-plus-gp100 group,27.8 months in the ipilimumab-alone group, and17.2 months in the gp100-alone group. The me-dian overall survival in the ipilimumab-plus-gp100 group was 10.0 months (95% confidenceinterval [CI], 8.5 to 11.5), as compared with 6.4months (95% CI, 5.5 to 8.7) in the gp100-alonegroup (hazard ratio for death, 0.68; PUpper limit of the normal range 149 (37.0) 53 (38.7) 52 (38.2) 254 (37.6)

Unknown 2 (0.5) 0 3 (2.2) 5 (0.7)

CNS metastases at baseline no. (%) 46 (11.4) 15 (10.9) 21 (15.4) 82 (12.1)

Received study drug 42 (10.4) 15 (10.9) 20 (14.7) 77 (11.4)

Had had previous treatment for CNSmetastases

39 (9.7) 15 (10.9) 19 (14.0) 73 (10.8)

Previous systemic therapy for metastaticdisease no. (%)

403 (100.0) 137 (100.0) 136 (100.0) 676 (100.0)

Previous interleukin-2 therapy no. (%) 89 (22.1) 32 (23.4) 33 (24.3) 154 (22.8)

* Percentages may not total 100 because of rounding. CNS denotes central nervous system. The Eastern Cooperative Oncology Group (ECOG) status ranges from 0 to 5, with higher scores indicating greater im-

pairment (5 indicates death). The metastasis (M) stage was classified according to the tumornodemetastasis (TNM) categorization for melanoma

of the American Joint Committee on Cancer.




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effect of ipilimumab on overall survival was inde-pendent of age, sex, baseline serum lactate dehy-drogenase levels, metastasis stage of disease,and receipt or nonreceipt of previous interleu-kin-2 therapy (Fig. 2).

A 19% reduction in the risk of progression was noted with ipilimumab plus gp100, as com-pared with gp100 alone (hazard ratio, 0.81;P


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A

no. of deaths/no. randomized

B

1.0 1.5

gp100Better Ipi plus gp100 Better

All patientsSex

MaleFemale

AgeULN

Prior use of interleukin-2YesNo

Ipi plus gp100 Hazard Ratio (95% CI)gp100Subgroup

0.5 1.0 1.5

gp100Better

IpiBetter

All patientsSex

MaleFemale

AgeULN

Prior use of interleukin-2YesNo

Ipi Hazard Ratio (95% CI)gp100Subgroup

191/247115/156

219/291 87/112

78/118228/285

178/252127/149

68/89238/314

306/403 119/136

66/7353/63

81/9438/42

31/3888/98

66/8150/52

25/33 94/103

0.5

0.69 (0.560.85)

0.66 (0.500.87)0.72 (0.520.99)

0.70 (0.540.90)0.69 (0.471.01)

0.57 (0.380.87)0.74 (0.580.95)

0.70 (0.530.93)0.71 (0.510.98)

0.78 (0.491.24)0.66 (0.520.84)

no. of deaths/no. randomized

100/137

53/8147/56

69/9531/42

21/3779/100

52/8448/53

19/32 81/105

119/136

66/7353/63

81/9438/42

31/3888/98

66/8150/52

25/33 94/103

0.64 (0.490.84)

0.54 (0.370.77)0.81 (0.551.20)

0.65 (0.470.90)0.61 (0.380.99)

0.47 (0.270.82)0.72 (0.530.97)

0.56 (0.390.81)0.76 (0.511.13)

0.50 (0.280.91)0.69 (0.510.93)

Figure 2. Subgroup Analyses of Overall Survival.

The prespecified analyses of overall survival among subgroups of patients, as defined by baseline demographiccharacteristics and stratification factors (metastasis [M] stage, classified according to the tumornodemetastasis[TNM] categorization for melanoma of the American Joint Committee on Cancer; and receipt or nonreceipt of inter-leukin-2 therapy), showed that hazard ratios were lower than 1 (indicating a lower risk of death) for each subgroupin the ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group as compared with the gp100-alone group (Panel A) andfor each subgroup in the ipilimumab-alone group as compared with the gp100-alone group (Panel B). Hazard ratioswere estimated with the use of unstratified Cox proportional-hazards models. Horizontal lines represent 95% confi-dence intervals. LDH denotes lactate dehydrogenase, and ULN the upper limit of the normal range.




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Table 2. Best Response to Treatment and Time-to-Event Data.*

Response and Time to Event

Ipilimumabplus gp100(N = 403)

IpilimumabAlone

(N = 137)gp100 Alone

(N = 136)

Overall survival

Total no. of deaths 306 100 119

Comparison with gp100 aloneHazard ratio (95% CI) 0.68 (0.550.85) 0.66 (0.510.87)

P value by log-rank test


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immune-related events, which occurred in approx-imately 60% of the patients treated with ipilimu-mab and 32% of the patients treated with gp100.The frequency of grade 3 or 4 immune-relatedadverse events was 10 to 15% in the ipilimumabgroups and 3.0% in the gp100-alone group. Allimmune-related events occurred during the in-duction and reinduction periods; the immune-related adverse events most often affected theskin and gastrointestinal tract. The median timeto the resolution of immune-related adverseevents of grade 2, 3, or 4 was 6.3 weeks (95% CI,4.3 to 8.4) in the ipilimumab-plus-gp100 group,4.9 weeks (95% CI, 3.1 to 6.4) in the ipilimumab-alone group, and 3.1 weeks (95% CI, 1.1 to notreached) in the gp100-alone group.

The most common immune-related adverseevent was diarrhea, which occurred at any gradein 27 to 31% of the patients in the ipilimumabgroups. After the administration of corticoste-roids, the median time to the resolution of diar-rhea of grade 2 or higher was 2.0 weeks for 40of 44 patients in the ipilimumab-plus-gp100group and 2.3 weeks for 14 of 15 patients in theipilimumab-alone group. In addition to cortico-steroids, 4 patients received infliximab (antitumor necrosis factor antibody) for diarrhea ofgrade 3 or higher or colitis. Among the 94 per-sons who survived for 2 years, residual effects ofadverse events included those related to injection-site reactions (16 patients), vitiligo (12), diarrheaor colitis (e.g., proctocolitis with rectal pain) (4),and endocrine immune-related adverse events (e.g.,inflammation of the pituitary) that requiredhormone-replacement therapy (8). Ongoing eventsin the persons who survived for 2 years includedrash, pruritus, diarrhea, anorexia, and fatigue,generally of grade 1 or 2 (in 5 to 15% of thepatients) and grade 3 leukocytosis (in one pa-tient). There were 14 deaths related to the studydrugs (2.1%), of which 7 were associated withimmune-related adverse events.

Discussion

This phase 3 study showed that ipilimumab, ei-ther alone or with gp100, improved overall sur-

vival as compared with gp100 alone in patients with metastatic melanoma who had undergoneprevious treatment. More than 70% of the pa-tients had M1c disease (presence of visceral me-

tastases) and more than 36% had elevated lactatedehydrogenase levels, both of which are associ-ated with very poor survival. 27,28 The eligibilitycriteria for patients in this study included HLA-A*0201positive status, on the basis of the mech-anism of action of gp100. However, CTLA-4blockade by ipilimumab is independent of HLAstatus, as indicated by efficacy and safety out-comes in earlier clinical trials that were similarbetween HLA-A*0201positive and HLA-A*0201negative patients 21 (and unpublished data).

In our study, the efficacy of ipilimumab wasnot improved by the addition of gp100. It is un-likely that this is due to a lack of gp100 expres-sion in the tumors, because differentiation anti-gens have been shown to be strongly expressedin more than 90% of melanoma tumors, regard-less of stage. 29 Some studies of adjuvant therapyfor melanoma showed that patients who were ad-ministered nongp100 vaccines had shorter sur-

vival than did patients in the control groups. 30,31 In contrast, phase 3 trials showed that in sub-groups of patients with melanoma, vaccines hadclinical activity when used as either adjuvanttherapy or therapy for metastatic disease. 32,33 Cumulative data show that gp100-based vaccineshave immunologic activity, although clinical ac-tivity is minimal when gp100 vaccines are ad-ministered as monotherapy. 22 In a randomized,phase 3 study involving patients with metastaticmelanoma, a significant improvement in pro-gression-free survival and response rate, and anonsignificant improvement in overall survival,

were seen with gp100-plus-high-dose interleu-kin-2, as compared with interleukin-2 alone. 23 Although gp100 appeared to attenuate ipilimu-mab responses in our study, it is important toconsider the fact that some radiographic re-sponses of immunotherapeutic agents are notcaptured by standard response criteria. 34 Regard-less, such effects of gp100 did not translate intoa difference in overall survival between the two

ipilimumab groups.The data in this study are consistent with theresults of phase 2 trials of ipilimumab mono-therapy in the same patient population. 15-17 Thedata from phase 2 studies suggest that there isa long-term survival effect of ipilimumab mono-therapy; ipilimumab monotherapy at a dose of3 mg per kilogram resulted in 1-year and 2-yearsurvival rates of 39.3% and 24.2%, respectively. 16




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11/13



The long-term effect of ipilimumab in our studyis shown by survival analyses at late time points,

which showed 1-year and 2-year survival rates of45.6% and 23.5%, respectively. In recent, ran-domized, phase 3 trials involving patients withunresectable stage III or IV melanoma who hadreceived previous treatment, 1-year survival rates

were reported to be 22% to 38% with varioustreatment regimens. 35,36 The median overall sur-

vival in these studies ranged from 5.9 to 9.7months. Neither these nor other randomized,controlled trials had shown a significant im-provement in overall survival.

The adverse-event profile of ipilimumab inthis study is consistent with that reported inphase 2 trials, 15-17 with the majority of adverseevents being immune-related and consistent

with the proposed mechanism of action of ipi-limumab. 11-14 As shown in phase 2 studies,prompt medical attention and early administra-tion of corticosteroids are critical to the man-agement of immune-related adverse events. 15-17 Management guidelines (algorithms) for immune-related adverse events involve close patient follow-up and the administration of high-dose systemiccorticosteroids which were used as necessaryin our study for grade 3 or 4 events. 37,38

In conclusion, this randomized, controlledtrial showed that there was a significant improve-ment in overall survival among patients withmetastatic melanoma. In some patients, side ef-fects can be life-threatening and may be treat-ment-limiting. Reinduction with ipilimumab atthe time of disease progression can result in fur-ther clinical benefit. Overall, our findings suggestthat the T-cell potentiator ipilimumab may be use-ful as a treatment for patients with metastaticmelanoma whose disease progressed while they

were receiving one or more previous therapies.Supported by Medarex and Bristol-Myers Squibb.All study sites and institutions received funding from Med-

arex or Bristol-Myers Squibb to cover the expenses of the inves-tigators for undertaking this trial.

Dr. Hodi reports receiving consulting fees from Bristol-MyersSquibbMedarex, Novartis, and Genentech; Dr. ODay, receivingconsulting fees, grants, honoraria, and fees for participation inspeakers bureaus from Bristol-Myers Squibb; Dr. McDermott,receiving consulting fees from Bristol-Myers SquibbMedarex;Dr. Gonzalez, receiving honoraria from Bristol-Myers Squibb; Dr.Schadendorf, serving on a board for and receiving consultingfees, fees for expert testimony, and fees for participation in speak-ers bureaus from Bristol-Myers Squibb; Dr. van den Eertwegh,receiving consulting fees from and serving on a board for Bristol-Myers Squibb; Dr. Lutzky, receiving consulting fees and honorariafrom Bristol-Myers Squibb; Dr. Lorigan, receiving consulting feesfrom Bristol-Myers Squibb; Dr. Hogg, serving on a board for

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) .




12/13



Bristol-Myers Squibb (pending); Dr. Ottensmeier, receiving hono-raria and grant funding from Bristol-Myers Squibb; Dr. Lebb,serving on a board for Bristol-Myers Squibb; Dr. Wolchok, servingon a board for Bristol-Myers Squibb; Dr. J.S. Weber, receivingconsulting fees from Bristol-Myers Squibb; Drs. Tian, Yellin, andNichol being former employees of Medarex; Dr. Hoos being cur-rently employed by Bristol-Myers Squibb with stock or stock op-tions; and Dr. Urba, receiving consulting fees from Bristol-MyersSquibbMedarex. No other potential conflicts of interest relevant

to this art icle were reported.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org

We thank the patients who volunteered to participate in thisstudy and staff members at the study sites who cared for them;the members of the data and safety monitoring committee; andrepresentatives of the sponsors who were involved in data collec-tion and analyses (in part icular, Tai-Tsang Chen, Xiaoping Zhu,Marianne Messina, and Helena Brett-Smith). Editorial and writ-ing assistance was provided by Ward A. Pedersen of StemScien-

tif ic, funded by Bristol-Myers Squibb.

Appendix

The authors affiliations are as follows: The DanaFarber Cancer Institute (F.S.H.) and Beth Israel Deaconess Medical Center(D.F.M.) both in Boston; the Angeles Clinic and Research Institute, Los Angeles (S.J.O.); St. Marys Medical Center, San Fran-cisco (R.W.W.); Vanderbilt University Medical Center, Nashville (J.A.S.); Netherlands Cancer Institute (J.B.H.) and VU UniversityMedical Center (A.J.M.E.) both in Amsterdam; University of Colorado Cancer Center, Aurora (R.G.); Institut Gustave Roussy,Villejui f, France (C.R.); University Hospital Essen, Essen (D.S., J.M.V.), German Cancer Research Center, Universit y of Mannheim,Mannheim (J.C.H.), and Technical University Munich, Munich (C.P.) all in Germany; Huntsman Cancer Institute, Salt Lake City(W.A.); Mount Sinai Comprehensive Cancer Center, Miami (J.L.); Christie Hospital NHS Trust , Manchest er (P.L.), and SouthamptonUniversity Hospitals, Southampton (C.H.O.) both in the United Kingdom; Washington University School of Medicine, St. Louis(G.P.L.); Princess Margaret Hospital, Toronto (D.H., I.Q.); Saint Louis Hospital, Paris (C.L.); Loyola University Medical Center,Maywood, IL (J.I.C.); Memorial Sloan-Kettering Cancer Center, New York (J.D.W.); H. Lee Moffitt Cancer Center, Tampa, FL(J.S.W.); Medarex, Bloomsbury, NJ (J.T., M.J.Y., G.M.N.); Bristol-Myers Squibb, Wallingford, CT (A.H.); and the Earle A. ChilesResearch Institute, Portland, OR (W.J.U.).

In addition to the authors, the following investigators (listed by country in alphabetical order) participated in the study: Argentina: M. Chacn, L. Koliren, G.L. Lerzo, R.L. Santos all in Buenos Aires; Belgium: A. Awada (Brussels), V. Cocquyt (Ghent), J. Kerger(Yvoir), J. Thomas (Leuven), T. Velu (Brussels); Brazil: C. Barrios (Porto Alegre), C. Dzik (So Paulo), M. Federico (So Paulo), J. Ho-hmann (Barretos), M. Liberrati (Londrina), A. Lima (Santo Andr), G. Schwartsmann (Porto Alegre), J. Segalla (Ja); Canada: T. Baetz(Kingston, ON), T. Cheng (Calgary, AB), W. Miller (Montreal), S. Rorke (St. Johns, NL), S. Verma (Ottawa), R. Wong (Winnipeg, MB);Chile: H. Harbst (Santiago), P. Gonzalez-Mella (Via del Mar), P. Salman (Santiago); France: F. Cambazard (Saint-Etienne), O. Dereure(Montpellier), B. Dreno (Nantes), L. Geoffrois (Vandoeuvre-ls-Nancy), J-J. Grob (Marseille), T. Lesimple (Dunkerque), S. Ngrier(Lyon), N. Penel (Lille), A. Thyss (Nice); Germany: J.C. Becker (Wrzburg), C. Garbe (Tbingen), S. Grabbe (Molnz), U. Keilholz (Ber-lin), C. Loquai (Mainz), H. Naeher (Heidelberg), G. Shuler (Erlangen), U. Trefzer (Berlin), J. Welzel (Augsburg); Hungary: Z. Karolyi(Miskolc); Netherlands: R.L.H. Jansen (Maastricht); South Africa: G.L. Cohen (Pretoria), J.I. Raats (Panorama), D.A. Vorobiof (Morning-side); Switzerland: R. Dummer (Zurich), O. Michielin (Lausanne); United Kingdom: J. Barber (Cardiff), S. Danson (Sheffield), M. Gore(London), S. Houston (Surrey), C.G. Kelly (Newcastle-upon-Tyne), M. Middleton (Oxford), P.M. Patel (Nottingham), E. Rankin (Dundee,Scotland); United States: M. Adler (Vista, CA), T. Amatruda (Robbinsdale, MN), A. Amin (Charlotte, NC), C. Anderson (Columbia, MO),L. Blakely (Memphis, TN), E. Borden (Cleveland), S. Burdette-Radoux (Burlington, VT), R. Chapman (Detroit), J. Chesney (Louisville,KY), A. Cohn (Denver), F.A. Collichio (Chapel Hill, NC), G. Daniels (La Jolla, CA), J. Drabick (Hershey, PA), J.A. Figueroa (Lubbock, TX),

J. Fleagle (Boulder, CO), J. Goydos (New Brunswick, NJ), N. Haas (Philadelphia), E. Hersh (Tucson, AZ), H.L. Kaufman (New York), K.D.Khan (Indianapolis), A. Khurshid (Arlington, TX), J.M. Kirkwood (Pittsburgh), J.J. Kirshner (East Syracuse, NY), H. Kluger (New Haven,CT), D. Lawrence (Boston), D. Lawson (Atlanta), P.D. Leming (Cincinnati), K. Margolin (Seattle), M. Mastrangelo (Philadelphia), B.Mirtsching (Dallas), W. Paroly (San Diego, CA), A.L. Pecora (Hackensack, NJ), D. Pham (Jacksonville, FL), R. Rangineni (St. Joseph, MO),N. Rothschild (West Palm Beach, FL), W.E. Samlowski (Las Vegas), D. Schwartzentruber (Goshen, IN), M. Scola (Morristown, NJ), W.H.Sharfman (Lutherville, MD), J.J. Stephenson (Greenville, SC), N.S. Tchekmedyian (Long Beach, CA), J. Wade (Decatur, IL), M. Wax (Berke-ley Heights, NJ), A. Weeks (Collierville, TN), J.L. Zapas (Baltimore).

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