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`The NEW ENGLAND
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`792 eeRev,: alba h
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`eDiab
`Effect o i sartan on the Incidence of Diabetes
`Dutasteride and Prostate Cancer
`Ultrasound-Guided Internal Jugular Vein
`Cannulation
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`711
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`743
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`ORIGINAL ARTICLES
`Improved Survival with Ipilimumabin Patients
`with Metastatic Melanoma
`F.S. Hodi and Others
`Racial Variation in Medical Outcomes
`among Living Kidney Donors
`K.L. Lentine and Others
`Early Palliative Care for Patients with Metastatic
`Non-Small-Cell Lung Cancer
`J.S:Temel and Others
`A Randomized Trial ofTai Chi for Fibromyalgia
`C. Wang and Others
`CLINICAL PRACTICE
`Emergency Treatment ofAsthma
`755
`S.C. Lazarus
`Owned & published by the MASSACHUSETTS MEDICALSOCIETY© 2010.
`All rights reserved. ISSN 0028-4793.
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`This material may be protected by Copyrightlaw (Title 17 U.S. Code)
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`
`
`The NEW ENGLAND
`JOURNAL of MEDICINE
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`ESTABLISHED IN 1812
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`AUGUST 19, 2010
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`VOL. 363 NO.8
`
`Improved Survival with Ipilimumab in Patients
`with Metastatic Melanoma
`
`F. Stephen Hodi, M.D., Steven J. O'Day, 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 Lebbé, M.D., Christian Peschel, M.D., lan Quirt, M.D.,
`Joseph|. 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.
`ABSTRACT
`
`Drs. Hodi and O'Daycontributed equally
`to this article.
`
`The authors’affiliations and participating
`investigatorsare listed in the Appendix. Ad-
`dress reprint requests to Dr. Hodi at the
`Dana-Farber CancerInstitute, 44 Binney
`St., Boston, MA 02115, or at stephen_
`hodi@dfci.harvard.edu.
`
`This article (10.1056/NEJMoal003466) was
`published on June 5, 2010, and last updated
`on August18, 2010, at NEJM.org.
`
`N Engl J Med 2010;363:711-23.
`Copyright © 2010 Massachusetts Medical Society,
`
`BACKGROUND
`
`An improvementin overall survival among patients with metastatic melanoma has
`been an elusive goal. In this phase 3 study, ipilimumab — which blocks cytotoxic
`T-lymphocyte—associated antigen 4 to potentiate an antitumor T-cell response —
`administered with or without a glycoprotein 100 (gp100) peptide vaccine was com-
`pared with gp100 alonein patients with previously treated metastatic melanoma.
`METHODS
`
`A total of 676 HLA-A*0201-positive 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 plus
`gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab,at a
`dose of 3 mg per kilogram of body weight, was administered with or without gp100
`every 3 weeks for up to four treatments (induction). Eligible patients could receive
`reinduction therapy. The primary end point was overall survival.
`RESULTS
`
`The medianoverall survival was 10.0 months amongpatients receiving ipilimumab
`plus gpi00, as compared with 6.4 months amongpatients receiving gp100 alone
`(hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab
`alone was 10.1 months (hazardratio for death in the comparison with gp100alone,
`0.66; P=0.003). No difference in overall survival was detected between theipili-
`mumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3
`or 4 immune-related adverse events occurred in 10 to 15%ofpatients treated with
`ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to
`the study drugs (2.1%), and 7 were associated with immune-related adverse events.
`CONCLUSIONS
`
`Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone,
`improved overall survival in patients with previously treated metastatic melanoma.
`Adverse events can be severe, long-lasting, or both, but most are reversible with ap-
`propriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov
`number, NCT00094653.)
`
`N ENGL] MED 363;8 NEJM.ORG AUGUST 19, 2010
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`HE INCIDENCE OF METASTATIC MELA-
`nomahasincreased over the past three de-
`cades,+? and the death rate continues to
`rise faster than the rate with mostcancers.3 The
`World Health Organization (WHO)estimatesthat
`worldwidethere are 66,000 deaths annually from
`skin cancer, with approximately 80%due to mel-
`anoma.* In the United States alone, an estimated
`8600 persons died from melanomain 2009.1 The
`mediansurvival of patients with melanoma who
`have distant metastases (American Joint Com-
`mittee on Cancer stage IV) is less than 1 year.5.°
`Notherapyis approved beyondthefirst-line ther-
`apy for metastatic melanoma, and enrollmentin
`a clinicaltrial is the standard ofcare. No therapy
`has been shownin a phase 3, randomized, con-
`trolled trial to improveoverall survivalin patients
`with metastatic melanoma.*®
`Regulatory pathways that limit the immune
`response to cancer are becoming increasingly
`well characterized. Cytotoxic T-lymphocyte—asso-
`ciated antigen 4 (CTLA-4) is an immune check
`point molecule that down-regulates pathways of
`T-cell activation.?° Ipilimumab, a fully human
`monoclonal antibody (IgG1) that blocks CTLA-4
`to promote antitumor immunity,1*4* has shown
`activity in patients with metastatic melanoma
`when it has been used as monotherapy in phase 2
`studies.’5*7 Ipilimumab has also shownactivity
`when combined with other agents,1*9 including
`cancer vaccines.?°?1 One well-studied cancer vac-
`cine comprises HLA-A*0201-restricted peptides
`derived from the melanosomalprotein, glyco-
`protein 100 (gp100). Monotherapy with this vac-
`cine induces immuneresponses but has limited
`antitumoractivity.22 However,
`the results of a
`recent study suggestthat gp100 may improve the
`efficacy of high-dose interleukin-2 in patients
`with metastatic melanoma.?? With no accepted
`standard of care, gp100 was used as an active
`control for our phase 3 study, which evaluated
`whetheripilimumab with or without gp100 im-
`proves overall survival, as compared with gp100
`alone, among patients with metastatic melano-
`ma who had undergone previous treatment.
`
`METHODS
`
`PATIENTS
`
`Patients wereeligible for inclusion in the study if
`they had a diagnosis of unresectable stageIII or
`IV melanomaand hadreceived a previous thera-
`
`peutic regimen containing one or more of the
`following: dacarbazine, temozolomide, fotemus-
`tine, carboplatin, or interleukin-2. Other inclu-
`sion criteria were age ofat least 18 years;life ex-
`pectancyofat least 4 months; Eastern Cooperative
`Oncology Group (ECOG) performancestatus of 0
`(fully active, able to carry on all predisease per-
`formance withoutrestriction) or 1 (restricted in
`physically strenuousactivity but ambulatory and
`able to carry out workofa light or sedentary na-
`ture, such as light houseworkor office work)?*;
`positive status for HLA-A*0201; normal hemato-
`logic, hepatic, and renal function; and no system-
`ic treatment in the previous 28 days. Exclusion
`criteria were any other cancer from which the
`patient had beendisease-free for less than 5 years
`(except treated and cured basal-cell or squamous-
`cell skin cancer, superficial bladder cancer, or
`treated carcinomainsitu of the cervix, breast, or
`bladder); primary ocular melanoma;previousre-
`ceipt of anti-CTLA-4 antibody or cancervaccine;
`autoimmunedisease; active, untreated metastases
`in the central nervous system; pregnancyorlac-
`tation; concomitant treatmentwith any nonstudy
`anticancer therapy or immunosuppressive agent;
`or long-term use of systemic corticosteroids.
`The protocol was approvedbytheinstitution-
`al review board at each participating institution
`and was conducted in accordancewith the ethi-
`cal principles originating from the Declaration
`of Helsinki and with Good Clinical Practice as
`defined by the International Conference on Har-
`monization. All patients (or their legal represen-
`tatives) gave written informed consent before
`enrollment.
`
`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 August
`2008, patients were randomly assigned to one of
`three study groups, with stratification according
`to baseline metastasis stage (MO, Mla, or M1b
`vs. Mic, classified according to the tumor—node—
`metastasis [TNM] categorization for melanoma
`ofthe American Joint Committee on Cancer), and
`receipt or nonreceipt of previous interleukin-2
`therapy. Thefull original protocol, a list ofamend-
`ments, and the final protocol, as well as the sta-
`tistical analysis plan, are available with the full
`text of this article at NEJM.org.
`
`712
`
`N ENGLJ MED 363;8 NEJM.ORG AUGUST 19, 2010
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`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`Patients were randomly assigned, in a 3:1:1
`ratio, to treatment with an induction course of
`ipilimumab, at a dose of 3 mg per kilogram of
`body weight, plus a gp100 peptide vaccine; ipi-
`limumab plus gp100 placebo; or gp100 plusipi-
`limumab placebo — all administered once every
`3 weeks for four treatments. In the vaccine
`groups, patients received two modified HLA-
`A*0201-restricted peptides, injected subcutane-
`ously as an emulsion with incomplete Freund’s
`adjuvant
`(Montanide
`ISA-51):
`a gp100:209-
`217(210M) peptide, 1 mg injected in the right
`anterior thigh, and a gp100:280-288(288V) pep-
`tide, 1 mg injected in the left anterior thigh.
`Peptide injections were given immediately after
`a 90-minute intravenous infusion of ipilimumab
`or placebo. Treatment began on day 1 ofweek 1,
`and if there were no toxic effects that could not
`be tolerated, no rapidly progressive disease, and
`no significant decline in performance status,
`patients received an additional treatment during
`weeks4, 7, and 10. Patients in whom newlesions
`developed or baseline lesions grew were allowed
`to receive additional] treatments to complete induc-
`tion. Patients with stable disease for 3 months’
`duration after week 12 or a confirmedpartial or
`complete response were offered additional courses
`of therapy (reinduction) with their assigned treat-
`ment regimen if they had disease progression.
`The original primary end point was the best
`overall responserate (i.e., the proportion of pa-
`tients with a partial or complete response). The
`primary end point was amendedto 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-
`mabinvolving patients with metastatic melano-
`ma.?> The primary comparison in overall sur-
`vival was between the ipilimumab-plus-gp100
`group and the gp100-alone group. Prespecified
`secondary end points included a comparison of
`overall survival between the ipilimumab-alone
`and the gpl00-alone groups and between the
`two ipilimumab groups, the bestoverall response
`rate, the duration of response, and progression-
`free survival. Subgroup comparisons of overall
`survival were performed across five prespecified
`categories: metastasis stage (M0, Mla, or M1b
`vs. Mic), receipt or nonreceipt of previous inter-
`leukin-2 therapy, baseline levels of serum lactate
`dehydrogenase (less than or equal to the upper
`limit of the normal range vs. higher than the
`
`upper limit of the normal range), age (<65 years
`vs. 265 years), and sex.
`The trial was designed jointly by the senior
`academic authors and the sponsors, Medarex
`and Bristol-Myers Squibb. Data were collected by
`the sponsors and analyzed in collaboration with
`the senior academic authors, who vouch for the
`completeness and accuracy of the data and
`analyses and for the conformanceofthis report
`to the protocol, as amended. Aninitial draft of
`the manuscript was prepared by six of the aca-
`demic authors in collaboration with the sponsor
`and a professional medical writer paid by the
`sponsor. All the authors contributed to subse-
`quent drafts and madethe decision to submit
`the manuscript for publication. All the authors
`signed a confidentiality disclosure agreement
`with the sponsor.
`
`ASSESSMENTS
`
`For the assessmentofa patient’s eligibility, each
`patient’s HLA-A*0201 status was determined at a
`central laboratory. Patients who met the study
`criteria were assignedto receive treatment within
`35 days after HLA typing and within 28 days af
`ter diagnostic imaging. Computed tomography
`with contrast material or magnetic resonance.
`imaging of the brain, chest, abdomen, pelvis,
`and other anatomical regions, as clinically indi-
`cated, was performed. Cutaneous lesions were
`photographed. Tumor assessments were per-
`formedat baseline, and all patients who did not
`have documented early disease progression and
`whohad stable disease or better at week 12 had
`confirmatory scans at weeks 16 and 24 and every
`3 months thereafter. Tumor responses were de-
`termined by the investigators with the use of
`modified WHOcriteria to evaluate bidimension-
`ally measurable lesions.Ӣ
`Adverse events were graded according to the
`National Cancer Institute’s Common Terminol-
`ogy Criteria for Adverse Events, version 3.0. An
`immune-related adverse event was defined as an
`adverse event that was associated with exposure
`to the study drug and that was consistent with
`an immune phenomenon. Protocol guidelines
`for the management of immune-related adverse
`events included the administration of cortico-
`steroids (orally or intravenously), a delay in a
`scheduled dose, or discontinuation of thera-
`py-+577 Assigned doses were delayed in the case
`of nondermatologic immune-related adverse
`events of grade 2 or higher until the event im-
`
`N ENGLJ MED 363;8 NEJM.ORG AUGUST 19, 2010
`
`713
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`proved to grade 1 or lower; if the event did not
`improve to grade 1 or lower, treatment wasdis-
`continued permanently. Monitoring of adverse
`events continued for at least 70 days after the
`last dose of study drugs had been administered
`or until any ongoing event resolved orstabilized.
`All patients,
`including those with low-grade
`changesin bowel frequencyorstool consistency,
`were followed closely. A data and safety moni-
`toring committee provided independent over-
`sight of safety and the risk-benefit ratio.
`During the study enrollment,
`the following
`stopping rule wasin place: if 10% or moreofthe
`patients in any study treatment group, evaluated
`cumulatively every 3 months, had a nondermato-
`logic-related toxic adverse event of grade 3 or
`higher that wasattributable to the investigational
`agents 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, assignment
`of patients to that study group would be sus-
`pendeduntil the sponsor and the data and safety
`monitoring committee had reviewed the events
`and determined the appropriate course ofaction.
`
`STATISTICAL ANALYSIS
`The original study sample size of 750 patients
`was determined on the basis of the primary end
`point of best overall response rate but wasre-
`vised with the new primary end pointofoverall
`survival. We estimated that with 385 events
`(deaths) amonga total of 500 patients randomly
`assigned to the ipilimumab-plus-gp100 and the
`gp100-alone groups,
`the study would have at
`least 90% powerto detect a difference in overall
`survival, at a two-sided alphalevel of 0.05, with
`the use of a log-ranktest. A total of 481 events
`were requiredin all three groups (assuming that
`the events were distributed in a 3:1:1 ratio in the
`ipilimumab-plus-gp100,
`ipilimumab-alone, and
`gp100-alone groups,respectively). Therefore,all
`patients who were randomly assigned in the
`study were to be followed until at least 481 events
`had occurred in the study. Enrollment was com-
`pleted on July 25, 2008, when more than 650 pa-
`tients had been enrolled. A post hoc poweranal-
`ysis showed that the 219 events observed among
`a total of 273 patients randomly assigned to the
`ipilimumab-alone and gp100-alone groups pro-
`videdat least 80% powerto detect a differencein
`overall survival between the two groups, at a
`
`two-sided alphalevel of 0.05, with the assump-
`tion that ipilimumab alone has the sametreat-
`ment effect as the combination regimenofipili-
`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 or
`death. Event-time distributions were estimated
`with the use of the Kaplan-Meier method. Cox
`proportional-hazards models, stratified accord-
`ing to metastasis status and receipt or nonre-
`ceipt of previous interleukin therapy, were used
`to estimate hazard ratios and to test for sig-
`nificance of the timing of events. All reported
`P values are two-sided, and confidenceintervals
`are at the 95%level. Survival rates were based on
`Kaplan-Meier estimation, and confidence inter-
`vals were calculated with the use of the boot-
`strap method. Descriptive statistics were used
`for adverse events.
`
`RESULTS
`
`PATIENTS AND TREATMENT
`
`Among 676 patients enrolled in the study, 403
`were randomly assigned to receive ipilimumab
`plus gp100, 137to receive ipilimumabalone, and
`136 to receive gp100 alone (contro! group) (Fig. 1
`in the Supplementary Appendix, available at
`NEJM.org). Included amongthese patients were
`82 patients who had metastases in the central
`nervous system at baseline, ofwhom 77 received
`the study drug. The baseline characteristics of
`the patients are shownin Table 1. Efficacy analy-
`ses were performed on the intention-to-treat
`population, which includedall patients who had
`undergone randomization (676 patients). The
`safety population included all patients who had
`undergone randomization and who hadreceived
`any amountof study drug (643 patients). A-total
`of 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 the
`gp100-alone group (57.4%) received all four ipi-
`limumab dosesor placebo infusions. The most
`frequent 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.
`
`714
`
`N ENGLJ MED 363;8 NEJM.ORG AUGUST 19, 2010
`
`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`
`
`
`
` Table 1. Baseline Characteristics ofthe Patients.*
`
`
`Ipilimumab
`Ipilimumab
`plus gp100
`Alone
`gp100 Alone
`Total
`Variable
`(N=403)
`(N=137)
`(N=136)
`(N=676)
`
`
`Mean age — yr
`55.6
`56.8
`57.4
`56.2
`
`
`
`
`
`
`
`
`
`
`
`Sex — no. (%)
`Male
`Female
`ECOGperformance status — no. (%){
`
`0
`1
`2
`3
`Unknown
`M stage — no. (%)t
`
`\
`
`247(61.3)
`156 (38.7)
`
`232 (57.6)
`166 (41.2)
`4 (1.0)
`1 (0.2)
`0
`
`81 (59.1)
`56 (40.9)
`
`72 (52.6)
`64 (46.7)
`1 (0.7)
`0
`0
`
`73 (53.7)
`63 (46.3)
`
`70 (51.5)
`61 (44.9)
`4 (2.9)
`0
`1 (0.7)
`
`401 (59.3)
`275 (40.7)
`
`374 (55.3)
`291 (43.0)
`9 (1.3)
`1 (0.1)
`1 (0.1)
`
`
`
`
`
`
`
`
`
`
`Mo
`Mla
`M1b
`Mic
`Lactate dehydrogenaselevel — no. (%)
`<Upper limit of the normal range
`>Upper limit of the normal range
`Unknown
`CNS metastases at baseline — no. (%)
`Received study drug
`Had had previous treatment for CNS
`metastases
`
`5 (1.2)
`37 (9.2)
`76 (18.9)
`285 (70.7)
`
`1 (0.7)
`14 (10.2)
`22 (16.1)
`100 (73.0)
`
`4 (2.9)
`11 (8.1)
`23 (16.9)
`98 (72.1)
`
`10 (1.5)
`62 (9.2)
`121 (17.9)
`483 (71.4)
`
`
`
`252 (62.5)
`149 (37.0)
`2 (0.5)
`46 (11.4)
`42 (10.4)
`39 (9.7)
`
`84 (61.3)
`53 (38.7)
`0
`15 (10.9)
`15 (10.9)
`15 (10.9)
`
`81 (59.6)
`52 (38.2)
`3 (2.2)
`21 (15.4)
`20 (14.7)
`19 (14.0)
`
`417 (61.7)
`254 (37.6)
`5 (0.7)
`82 (12.1)
`77 (11.4)
`73 (10.8)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Previous systemic therapy for metastatic
`137 (100.0)
`136 (100.0)
`676 (100.0)
`403 (100.0)
`disease — no. (%)
`
`
`
`
`
` 154 (22.8)
`
`Previous interleukin-2 therapy — no. (%)
`89 (22:1)
`32 (23.4)
`33 (24.3)
`* 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 tumor—-node—metastasis (TNM) categorization for melanoma
`of the American Joint Committee on Cancer.
`
`Patients were followed for up to 55 months, with
`median follow-up times for survival of 21.0
`months in the ipilimumab-plus-gp100 group,
`27.8 monthsin the ipilimumab-alone group, and
`17.2 months in the gp100-alone group. The me-
`dian overall survival
`in the ipilimumab-plus-
`gp100 group was 10.0 months (95% confidence
`interval [CI], 8.5 to 11.5), as compared with 6.4
`months (95% CI, 5.5 to 8.7) in the gp100-alone
`group (hazard ratio for death, 0.68; P<0.001).
`The median overall survival in the ipilimumab-
`alone group was 10.1 months (95%CI, 8.0 to
`
`13.8) (hazard ratio for death with ipilimumab
`alone as compared with gp100 alone, 0.66;
`P=0.003). No difference in overall survival was
`detected between the two ipilimumab groups
`(hazard ratio for death with ipilimumab plus
`gp100, 1.04; P=0.76) (Fig. 1). Analyses of sur-
`vival showed that the rates of overall survival in
`the ipilimumab-plus-gp100 group, the ipilimu-
`mab-alone group, and the gp100-alone group,
`respectively, were 43.6%, 45.6%, and 25.3%at 12
`months, 30.0%, 33.2%, and 16.3% at 18 months,
`and 21.6%, 23.5%, and 13.7% at 24 months. The
`
`N ENGLJ MED 363;8 NEJM.ORG AUGUST 19, 2010
`
`715
`
`

`

`
`
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`---- Ipi
`—-7— gp100
`86 e@ Censored
`xxx Censored
`sae Censored
`
`
`
` —— Ipi plus gp100
`
`A Overall Survival
` Overall
`(%) = a=Hitt OE—~1= = ale === =X
`Survival
`
`
`
`4
`
`
`be cc ce ec AO
`
`T
`rT 0 T at T
`tar
`7
`
`
`8
`12
`16
`20
`24
`28
`32
`36 40
`44 48
`52
`56
`Months
`
`No.at Risk
`
`
`Ipi plus gpl00 403 297 223 163 115 81
`54 42
`33
`24
`17
`7
`6
`4
`O
`Ipi
`137 106
`79
`56
`38 30
`24
`18
`13
`13
`8
`5
`2
`1
`«0
`136
`93
`58
`32 23:17 16
`7
`5
`5
`3
`1
`0
`0
`
`
`
`
` B Progression-free Survival
`
`100
`
`90
`
`80
`
`70
`
`60:
`
`50
`
`40
`
`30
`
`20
`10
`
`
`
`
`
`Progression-freeSurvival(%)
`
`
`
`
`Months
`
`No.at Risk
`
`
`
`
`
`Ipiplus gpl00 403 85
`52
`27
`17
`14
`10
`8
`5
`4
`2
`2
`1
`0
`Ipi
`137 37
`26
`17
`13
`10
`10
`9
`6
`4
`2 10 0
`
`
`136037 aon ee ee,
`©
`© OW
`
`
`
`
` Figure 1. Kaplan—Meier Curves for Overall Survival and Progression-free
`Survival in the Intention-to-Treat Population.
`
` The median follow-up for overall survival (Panel A)in theipilimumab(Ipi)-
`
`plus-glycoprotein 100 (gp100) group was 21.0 months, and the median
`
`
`overall survival was 10.0 months (95% Cl, 8.5 to 11.5); in the ipilimumab-
`alone group, the median follow-up was 27.8 months, and the median over-
`all survival, 10.1 months (95% Cl, 8.0 to 13.8); and in the gp100-alone
`group, the median follow-up was 17.2 months, and the median overall sur-
`vival, 6.4 months (95% Cl, 5.5 to 8.7). The median progression-free survival
`(Panel B) was 2.76 months (95% Cl, 2.73 to 2.79) in the ipilimumab-plus-
`gpl00 group, 2.86 months (95% Cl, 2.76 to 3,02) in the ipilimumab-alone
`group, and 2.76 months (95% Cl, 2.73 to 2.83) in the #p100-alone group.
`The rates of progression-free survival at week12 were 49.1% (95% Cl, 44.1
`to 53.9) in the ipilimumab-plus-gp100 group, 57.7% (95% Cl, 48.9 to 65.5)
`in the ipilimumab-alone group, and 48.596 (95% Cl, 39.6 to 56.7) in the
`#p100-alone group.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`effect ofipilimumab onoverall survival was inde-
`pendentof 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<0.05), and a 36%reduction in risk of progres-
`sion was seen with ipilimumab alone as com-
`pared with gpl00 alone (hazard ratio, 0.64;
`P<0.001). The reduction in risk with ipilimumab
`plus gp100 was less than that with ipilimumab
`alone (hazard ratio with ipilimumab plus gp100,
`1.25; P=0.04). The median values for progres-
`sion-free survival were similar in all groups at
`the time ofthe first assessment of progression
`(week 12), after which there was a separation
`between the curves(Fig. 1B).
`The highest percentage of patients with an
`objective response or stable disease was in the
`ipilimumab-alone group (Table 2);
`this group
`had a best overall response rate of 10.9% and a
`disease control rate (the proportion of patients
`with a partial or complete response or stable
`disease) of28.5%. In the ipilimumab-alonegroup,
`9 of 15 patients (60.0%) maintained an objective
`responseforat least 2 years (26.5 to 44.2 months
`[ongoing]), and in the ipilimumab-plus-gp100
`group, 4 of 23 patients (17.4%) maintained the
`response for at least 2 years (27.9 to 44.4 months
`{ongoing]). Neither of the two patients in the
`gp100-alone group whohada partial response
`maintained the response for 2 years. Responses
`to ipilimumab continued to improve beyond week
`24: in the ipilimumab-plus-gp100 group, 3 pa-
`tients with disease progression improvedto stable
`disease, 3 with stable disease improvedto a par-
`tial response, and 1 with a partial response im-
`proved to a complete response; in the ipilimu-
`mab-alone group, 2 patients with stable disease
`improved to a partial response and 3 with a
`partial response improved to a complete re-
`sponse. Among 31 patients. given reinduction
`therapy with ipilimumab, a partial or complete
`response or stable disease was achieved by 21
`(Table 2).
`
`ADVERSE EVENTS
`
`:
`
`The adverse events reported in the safety popu-
`lation are listed in Table 3. The most common
`adverse events related to the study drugs were
`
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`N ENGL J MED 363;8 NEJM.ORG AUGUST 19, 2010
`
`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`
`
`A
`
`Subgroup
`
`All patients
`Sex
`
`Male
`Female
`Age
`<65 yr
`265 yr
`M stageat study entry
`MO, Mla, M1b
`Mlc
`Baseline LDH
`
`sULN
`>ULN
`Prior use ofinterleukin-2
`
`No
`
`gp100
`|pi plus gp100
`no. ofdeaths/no. randomized
`306/403
`119/136
`
`191/247
`115/156
`
`219/291
`87/112
`
`78/118
`228/285
`
`178/252
`127/149
`
`68/89
`238/314
`
`66/73
`53/63
`
`81/94
`38/42
`
`31/38
`88/98
`
`66/81
`50/52
`
`25/33
`94/103
`
`Hazard Ratio (95% Cl)
`
`0.69 (0.56~0.85)
`
`0.66 (0.50-0.87)
`0.72 (0.52—0.99)
`
`0.70 (0.54—0.90)
`0.69 (0.47-1.01)
`
`0.57 (0.38-0.87)
`0.74 (0.58-0.95)
`
`0.70 (0.53-0.93)
`0.71 (0.51-0.98)
`
`0.78 (0.49-1.24)
`0.66 (0.52-0.84)
`
`gp100
`Ipi plus gp100
`
` Better Better
`
`0.5
`
`1.0
`————————
`
`15
`
`dence intervals. LDH denotes lactate dehydrogenase, and ULN the upperlimit of the normal range.
`
`Subgroup
`
`All patients
`Sex
`
`Male
`Female
`Age
`<65 yr
`265 yr
`M stageat study entry
`MO, Mla, M1b
`Mlc
`Baseline LDH
`<ULN
`>ULN
`Prior use ofinterleukin-2
`
`gp100
`Ipi
`no. ofdeaths/no. randomized
`100/137
`119/136
`
`53/81
`47/56
`
`69/95
`31/42
`
`21/37
`79/100
`
`52/84
`48/53
`
`19/32
`81/105
`
`66/73
`53/63
`
`81/94
`38/42
`
`31/38
`88/98
`
`66/81
`50/52
`
`25/33
`94/103
`
`Hazard Ratio (95% Cl)
`
`
`
`0.64 (0.49-0.84)
`
`0.54 (0.37-0.77)
`0.81 (0.55—1.20)
`
`0.65 (0.47-0.90)
`0.61 (0.38-0.99)
`
`0.47 (0.27-0.82)
`0.72 (0.53-0.97)
`
`0.56 (0.39—0.81)
`0.76 (0.51-1.13)
`
`0.50 (0.28-0.91)
`0.69 (0.51-0.93)
`
`
`
`Figure 2. Subgroup Analyses of Overall Survival.
`The prespecified analyses of overall survival among subgroupsofpatients, as defined by baseline demographic
`characteristics and stratification factors (metastasis [M] stage, classified according to the tumor—node—metastasis
`[TNM] categorization for melanoma of the American Joint Committee on Cancer; and receipt or nonreceiptof inter-
`leukin-2 therapy), showed that hazard ratios were lower than 1 (indicating a lower risk of death) for each subgroup
`in the ipilimumab (Ipi)-plus-glycoprotein 100 (gp100) group as compared with the gp100-alone group (Panel A) and
`for each subgroup in the ipilimumab-alone group as compared with the gp100-alone group (Panel B). Hazard ratios
`were estimated with the use of unstratified Cox proportional-hazards models. Horizontal lines represent 95% confi-
`
`N ENGL) MED 363;8 NEJM.ORG AUGUST 19, 2010
`
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`
`Table 2. Best Response to Treatmentand Time-to-Event Data.*
`
`Responseand Timeto Event
`Overall survival
`
`Total no. of deaths
`Comparison with gp100 alone
`Hazardratio (95% Cl)
`P value by log-rank test
`Comparisonwith ipilimumab alone
`Hazardratio (95% Cl)
`P value by log-rank test
`Evaluation oftherapy
`Induction
`
`Bestoverall response — no. (%)
`Complete response
`Partial response
`Stable disease
`Progressive disease
`Notevaluated
`Best overall response rate — % (95% Cl)
`P value for comparison with gp100 alone
`P value for comparison with ipilimumab alone
`Disease control rate — % (95% Cl)+
`P value for comparison with gp100 alone
`P value for comparisonwith ipilimumab alone
`Time to event — mo
`
`Ipilimumab
`plus gp100
`“(N=403)
`
`Ipilimumab
`Alone
`(N=137)
`
`306
`
`100
`
`0.68 (0.55-0.85)
`<0.001
`
`0.66 (0.51-0.87)
`0.003
`
`1.04 (0.83-1.30)
`0.76
`
`==
`—
`
`1 (0.2)
`22 (5.5)
`58 (14.4)
`239 (59.3)
`83 (20.6)
`5.7 (3.7-8.4)
`0.04
`0.04
`20.1 (16.3-24.3)
`0.02
`0.04
`
`2 (1.5)
`13 (9.5)
`24 (17.5)
`70 (51.1)
`28 (20.4)
`10.9 (6.3-17.4)
`0.001
`—
`28.5 (21.1-36.8)
`<0.001
`—
`
`gp100 Alone
`(N=136)
`
`119
`
`=
`—
`
`=
`—
`
`0
`2 (1.5)
`13 (9.6)
`89 (65.4)
`32 (23.5)
`1.5 (0.2-5.2)
`—
`—
`11.0 (6.3-17.5)
`—
`-
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.76 (2.73-2.79)
`
`3.32 (2.91-3.74)
`11.5 (5.4-NR)
`
`2.86 (2.76—3.02)
`
`2.76 (2.73-2.83)
`
`3.18 (2.75—3.60)
`NR (28.1-NR)
`
`2.74 (2.12-3.37)
`NR (2.0-NR)
`
`Time to progression — median (95% Cl)
`Time to response — mean (95% Cl)
`Duration of response — median (95% Cl)
`Reinductiont
`Bestoverall response — no./total no. (%)
`0
`1/8 (12.5)
`0
`Complete response
`0
`2/8 (25.0)
`3/23 (13.0)
`Partial response
`0
`3/8 (37.5)
`12/23 (52.2)
`Stable disease
`
`1/1 (100.0)
`2/8 (25.0)
`8/23 (34.8)
`Progressive disease
`
`* Ofthe 143 patients who could not be evaluated for a response, 33 patients did not receive any study drug and 110 pa-
`tients did not have baseline or week-12 tumor assessments (or both). Percentages maynottotal 100 because of round-
`ing. NR denotes not reached.
`T The disease control rate is the percentage ofpatierits with a partial or complete response orstable disease.
`{A total of 40 patients (29 in the Ipilimumab-plus-gp100 group; 9 in the ipilimumab-alone group, and 2 in the gp100-
`alone group) were given reinduction therapy, but 8 were not included in the efficacy analyses: 3 had major protocolvio-
`lations and 5 were not eligible owing to the fact that they had had a bestoverall response of progressive disease during
`induction and were given reiriduction therapy inadvertently.
`
`
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`N ENGLJ MED 363;8 NEJM.ORG AUGUST 19, 2010
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`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`immune-related events, which occurred in approx-
`imately 60%of the patients treated with ipilimu-
`mab and 32%ofthe patients treated with gp100.
`The frequency of grade 3 or 4 immune-related
`adverse events was 10 to 15%in the ipilimumab
`groups and 3.0%in the gp100-alone group. All
`immune-related events occurred during the in-
`duction and reinduction periods; the immune-
`related adverse events most often affected the
`ski