`
`ll
`
`The NEW ENGLAND
`
`
`
`JOURNAL of MEDICINE
`
`VOL. 363 N0. 8
`
`ESTABLISHED IN 1812
`NEJM.0RG
`
`AUGUST 19, 2010
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`
`
`710
`THISWEEKINTHEJOURNAL
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`PERSPECTIVE
`New Technology and Health Care Costs —
`The Case ofRobot—Assisted Surgery
`_
`G‘l' Bar-bash and S'A' Glied-
`_
`New Prlorities for Future Biomedical Innovations
`V'R‘ FUChS
`Facing the Wild West of Health Care Reform ——
`Donald Berwrck, Pioneer
`J'K‘ Iglehart
`ACGME Duty-Hour Recommendations —
`a National Survey of Residency Program
`Directors R.M. Antiel and Others
`
`
`704
`
`707
`
`e12
`
`711
`
`724
`
`733
`
`743
`
`ORIGINALARTICLES
`Improved Survival With Ipilimumab in 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:Teme| and Others
`A Randomized Trial ofTai Chi for Fibromyalgia
`C. Wang and Others
`
`755
`
`CLINICAL PRACTICE
`Emergency Treatment ofAsthma
`S.C. Lazarus
`Owned 8: published by theMAsSACHUSETrs MEDICAL SOCIETY© 2010.
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`IMAGES IN CLINICAL MEDICINE
`Acute Optic—Nerve Infarction in Carotid Dissection
`S.-B. KO and K. Lee
`Bladder Diverticula
`C.-C. Chang and K.-L. Liu
`CASE RECORDS OF THE MASSACHUSETTS
`G E N ERAL H 05 PITAL
`A Woman with Abdominal Pain and Shock
`M. S. Klempn er and Others
`E D ITo R I ALs
`_
`_
`Treating Cancer by Targeting the Immune System
`P. ku
`
`Palliative Care — A Shifting Paradigm
`A-S- Kelley and DE Meier
`Prescribing Tai Chi for Fibromyalgia — Are We
`Ihere YCt?
`G.Y. Yeh, TJ. Kaptchuk, and RH. Shmerling
`SPECIAL REPORT
`.
`.
`.
`HPV Vaccmation Mandates _ Lawmaking
`amid Political and Scientific Controversy
`J. Colgrove, S. Abiola, and MM. Mello
`CE," R Es?) T DE N c E
`h
`'d
`f , b
`E ecto .Va sartan on t e Incl ence 0 Dia etes
`Dutasteride and Prostate Cancer
`Ultrasound—Guided Internal Jugular Vein
`Cannulation
`.
`.
`.
`.
`.
`Mortahty among LlVlIlg Kldney Donors
`and Comparison populations
`
`798
`799
`
`CORRECHONs
`CONTINUING MEDICAL EDUCATION
`
`Genome & Co. v. Univ. of Chicago
`
`PGR2019-00002 UNIV. CHICAGO EX. 2052
`
`

`

`
`
`This material maybe protected by Copyright law (Title 17 U.S. Code)
`
`
`The NEW ENGLAND
`
`JOURNAL of MEDICINE
`
`
`
`ESTABLISHED IN 1812
`
`AUGUST 19, 2010
`
`VOL. 363 NO. 8
`
`Improved Survival with Ipilimumab in Patients
`with Metastatic Melanoma
`
`F. Stephen Hodi, M.D., Steven]. 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., AlfonsJM. 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., Ian Quirt, M.D.,
`Joseph L Clark, M.D.,Jedd D. Wolchok, M.D., Ph.D.,Jeffrey S. Weber, M.D., Ph.D.,Jason Tian, Ph.D.,
`Michael]. Yellin, M.D., Geoffrey M. Nichol, M.B., Ch.B., Axel Hoos, M.D., Ph.D., and Walter}. Urba, M.D., Ph.D.
`
`ABSTRACT
`
`Drs. Hodi and O’Day contributed equally
`to this article.
`
`The authors' affiliations and participating
`investigators are listed in the Appendix. Ad-
`dress reprint requests to Dr. Hodi at the
`Dana—Farber Cancer Institute, 44 Binney
`St., Boston, MA 02115, or at stephen_
`hodi@dfci.harvard.edu.
`
`This article (10.1056/NEJMoa1003466) was
`published onJune 5, 2010, and last updated
`on August 18, 2010, at NEJM.org.
`
`N EnglJ Med 2010;363:711-23.
`Copyright © 2010 Massachusetts Medical Society.
`
`BACKGROUND
`
`An improvement in 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 (gplOO) peptide vaccine was com-
`pared with gplOO alone in 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 median overall survival was 10.0 months among patients receiving ipilimumab
`plus gp100, as compared with 6.4 months among patients receiving gplOO alone
`(hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab
`alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone,
`0.66; P=0.003). No difference in overall survival was detected between the ipili-
`mumab groups (hazard ratio with ipilimumab plus gplOO, 1.04; P=0.76). Grade 3
`or 4 immune—related adverse events occurred in 10 to 15% of patients treated with
`ipilimumab and in 3% treated with gplOO alone. There were 14 deaths related to
`the study drugs (2.1%), and 7 were associated with immune—related adverse events.
`co N c L u s I o N s
`
`Ipilimumab, with or without a gp100 peptide vaccine, as compared with gplOO 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.)
`
`NENGLJMED363;8 NEJM.ORG AUGUST19,2010
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`The NEW ENGLAND JOURNAL 0f MEDICINE
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`HE INCIDENCE OF METASTATIC MELA-
`
`noma has increased over the past three de-
`cadres,L2 and the death rate continues to
`rise faster than the rate with most cancers.3 The
`
`World Health Organization (WHO) estimates that
`worldwide there are 66,000 deaths annually from
`skin cancer, with approximately 80% due to mel-
`anoma.4 In the United States alone, an estimated
`8600 persons died from melanoma in 2009.1 The
`median survival of patients with melanoma who
`have distant metastases (American Joint Com-
`mittee on Cancer stage IV) is less than 1 year.5v6
`No therapy is approved beyond the first-line ther—
`apy for metastatic melanoma, and enrollment in
`a clinical trial is the standard of care. No therapy
`has been shown in a phase 3, randomized, con—
`trolled trial to improve overall survival in patients
`with metastatic melanomafi'9
`
`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.10 Ipilimumab, a fully human
`monoclonal antibody (IgGl) that blocks CTLA-4
`to promote antitumor immunity,”14 has shown
`activity in patients with metastatic melanoma
`when it has been used as monotherapy in phase 2
`studies.15'17 Ipilimumab has also shown activity
`when combined with other agents,18’19 including
`cancer vaccines”)21 One well—studied cancer vac—
`cine comprises HLA-A*0201—restricted peptides
`derived from the melanosomal protein, glyco-
`protein 100 (gplOO). Monotherapy with this vac-
`cine induces immune responses but has limited
`antitumor activity.22 However,
`the results of a
`recent study suggest that gplOO may improve the
`efficacy of high—dose interleukin-2 in patients
`with metastatic melanoma.23 With no accepted
`standard of care, gp100 was used as an active
`control for our phase 3 study, which evaluated
`whether ipilimumab with or without gp100 im-
`proves overall survival, as compared with gplOO
`alone, among patients with metastatic melano-
`ma who had undergone previous treatment.
`
`METHODS
`
`PATIENTS
`
`Patients were eligible for inclusion in the study if
`they had a diagnosis of unresectable stage III or
`IV melanoma and had received a previous thera-
`
`peutic regimen containing one or more of the
`following: dacarbazine, temozolomide, fotemus-
`tine, carhoplatin, or interleukin—2. Other inclu-
`sion‘ criteria were age of at least 18 years; life ex—
`pectancy ofat least 4 months; Eastern Cooperative
`Oncology Group (ECOG) performance status of 0
`(fully active, able to carry on all predisease per-
`formance without restriction) or 1 (restricted in
`physically strenuous activity but ambulatory and
`able to carry out work of a light or sedentary na-
`ture, such as light housework or 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 been disease—free for less than 5 years
`(except treated and cured basal-cell or squamous—
`cell skin cancer, superficial bladder cancer, or
`treated carcinoma in situ of the cervix, breast, or
`bladder); primary ocular melanoma; previous re—
`ceipt of anti—CTLA-4 antibody or cancer vaccine;
`autoimmune disease; active, untreated metastases
`in the central nervous system; pregnancy or lac-
`tation; concomitant treatment with any nonstudy
`anticancer therapy or immunosuppressive agent;
`or long—term use of systemic corticosteroids.
`The protocol was approved by the institution-
`al review board at each participating institution
`and was conducted in accordance with 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 Mlb
`vs. Mlc, 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. The full 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
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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 gplOO peptide vaccine; ipi—
`limumab plus gp100 placebo; or gplOO plus ipi—
`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 of week 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
`weeks 4, 7, and 10. Patients in whom new lesions
`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 confirmed partial 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 response rate (i.e., the proportion of pa-
`tients with a partial or complete response). The
`primary 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-gplOO
`group and the gplOO—alone group. Prespecified
`secondary end points included a comparison of
`overall survival between the ipilimumab—alone
`and the gplOO—alone groups and between the
`two ipilimumab groups, the best overall 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. Mlc), 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 conformance of this report
`to the protocol, as amended. An initial 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 made the decision to submit
`the manuscript for publication. All the authors
`signed a confidentiality disclosure agreement
`with the sponsor.
`
`ASS as M E N 15
`
`For the assessment of a patient’s eligibility, each
`patient’s HLA-A*0201 status was determined at a
`central laboratory. Patients who met the study
`criteria were assigned to 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-
`formed at baseline, and all patients who did not
`have documented early disease progression and
`who had 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 WHO criteria to evaluate bidimension-
`
`ally measurable lesions.26
`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.15'17 Assigned doses were delayed in the case
`of nondermatologic immune—related adverse
`events of grade 2 or higher until the event im-
`
`NENGLJMED363;8 NE)M.ORG AUGU5T19,2010
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`The NEW ENGLAND JOURNAL anEDICINE
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`proved to grade 1 or lower; if the event did not
`improve to grade 1 or lower, treatment was dis—
`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 or stabilized.
`All patients,
`including those with low—grade
`changes in bowel frequency or stool 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 was in place: if 10% or more of the
`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 was attributable 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—
`pended until the sponsor and the data and safety
`monitoring committee had reviewed the events
`and determined the appropriate course of action.
`
`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 was re—
`vised with the new primary end point of overall
`survival. We estimated that with 385 events
`(deaths) among a total of 500 patients randomly
`assigned to the ipilimumab-plus-gplOO and the
`gplOO-alone groups,
`the study would have at
`least 90% power to detect a difference in overall
`survival, at a tvvo—sided alpha level of 0.05, with
`the use of a log-rank test. A total of 481 events
`were required in all three groups (assuming that
`the events were distributed in a 3:1:1 ratio in the
`ipilimumab-plus-gplOO,
`ipilimumab—alone, and
`gplOO-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 power anal—
`ysis showed that the 219 events observed among
`a total of 273 patients randomly assigned to the
`ipilimumab—alone and gplOO—alone groups pro—
`vided at least 80% power to detect a difference in
`overall 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 or
`death. Event—time distributions were estimated
`
`l
`
`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 confidence intervals
`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, 137 to receive ipilimumab alone, and
`136 to receive gplOO alone (control group) (Fig. 1
`in the Supplementary Appendix, available at
`NEJM.org). Included among these patients were
`82 patients who had metastases in the central
`nervous system at baseline, of whom 77 received
`the study drug. The baseline characteristics of
`the patients are shown in Table 1. Efficacy analy—
`ses were performed on the intention—to-treat
`population, which included all patients who had
`undergone randomization (676 patients). The
`safety population included all patients who had
`undergone randomization and who had received
`
`any amount of study drug (643 patients). Atotal
`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
`gplOO—alone group (57.4%) received all four ipi-
`limumab doses or 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.
`
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`NENGLJ MED363;3 NEJM.ORG AUGUST19, 2010
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`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`Table 1. Baseline Characteristits ofthe Patients.*
`
`Variable
`Mean age—yr
`
`Sex — no. (%)
`
`Male
`
`Female
`ECOG performance status — no. (%)‘i’
`
`0
`
`1
`2
`3
`
`I
`
`Unknown
`M stage — no. (%).1:
`
`M0
`
`Mla
`
`lpilimumab
`plus gp100
`(N =403)
`55.6
`
`lpilimumab
`Alone
`(N = 137)
`56.8
`
`gp100 Alone
`(N = 136)
`57.4
`
`247 (61.3)
`
`156 (38.7)
`
`232 (57.6)
`
`166 (41.2)
`4 (1.0)
`1 (0.2)
`
`0
`
`5 (1.2)
`
`37 (9.2)
`
`81 (59.1)
`
`56 (40.9)
`
`72 (52.6)
`
`64 (46.7)
`1 (0.7)
`0
`
`o
`
`1 (0.7)
`
`14 (10.2)
`
`73 (53.7)
`
`63 (46.3)
`
`70 (51.5)
`
`61 (44.9)
`4 (2.9)
`o
`
`1 (0.7)
`
`4 (2.9)
`
`11 (8.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Total
`(N =676)
`56.2
`
`401 (59.3)
`
`275 (40.7)
`
`374 (55.3)
`
`291 (43.0)
`9 (1.3)
`1 (0.1)
`
`1 (0.1)
`
`10 (1.5)
`
`62 (9.2)
`
`121 (17.9)
`
`
`
`
`
`
`
`
`
`Mlb
`
`Mlc
`
`Lactate dehydrogenase level .— no. (%)
`
`sUpper limit ofthe normal range
`
`>Upper limit ofthe normal range
`
`Unknown
`
`CNS metastases at baseline — no. (%)
`
`76 (18.9)
`
`285 (70.7)
`
`22 (16.1)
`
`100 (73.0)
`
`252 (62.5)
`
`149 (37.0)
`
`2 (0.5)
`
`46 (11.4)
`
`84 (61.3)
`
`53 (38.7)
`
`o
`
`15 (10.9)
`
`23 (16.9)
`
`98 (72.1)
`
`81 (59.6)
`
`52 (38.2)
`
`3 (2.2)
`
`21 (15.4)
`
`483 (71.4)
`
`417 (61.7)
`
`254 (37.6)
`
`5 (0.7)
`
`82 (12.1)
`
`
`
`
`
`
`
`
`
`Received study drug
`
`
`Had had previous treatment for CNS
`
`
`
`m etastases
`
`Previous systemic therapy for metastatic
`
`137 (100.0)
`136 (100.0)
`676 (100.0)
`
`403 (100.0)
`
`
`disease — no. (%)
`
`
`Previous interleukin-2 therapy — no. (%)
`89 (22.1)
`32 (23.4)
`33 (24.3)
`154 (22.8)
`
`
`
`
`
`42 (10.4)
`
`39 (9.7)
`
`15 (10.9)
`
`15 (10.9)
`
`20 (14.7)
`
`19 (14.0)
`
`77 (11.4)
`
`73 (10.8)
`
`* Percentages may not total 100 because of rounding. CNS denotes central nervous system.
`'i‘ The Eastern Cooperative Oncology Group (ECOG) status ranges from 0 to 5, with higher scores indicating greater im-
`pairment (5 indicates death).
`iThe metastasis (M) stage was classified according to the tumor—node—metastasis (TNM) categorization for melanoma
`ofthe 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—gplOO group,
`27.8 months in the ipilimumab—alone group, and
`17.2 months in the gplOO—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 gplOO-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
`gplOO, 1.04; P=‘0.76) (Fig. 1). Analyses of sur—
`vival showed that the rates of overall survival in
`
`the ipilimumab-plus-gplOO group, the ipilimu—
`mab-alone group, and the gplOO—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
`
`NENGLJ MED363;8 NEJM.ORG AUGUST19, 2010
`
`715
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`
`
`
`Ipi
` — Ipi plus gplOO
`---- gp100
`a e e Censored
`x x x Censored
`a a a Censored
`
`
`A Overall Survival
`
`
`
`
`
`OverallSurvival(%)
`
`“mounds—nieu-“n-uux
`"—1——
`
`
`‘31
`
`
`
` J I
`
`w‘--B~—--D--'Eula_a
`'l—I
`I
`|
`I—F-I
`I
`I—l—l
`
`
`16
`20
`24
`28
`32
`36 40
`44 48
`52
`56
`12
`
`
`
`Months
`
`
`No. at Risk
`
`lpiplusgplOO 403297223163 115 81
`54 42
`33
`24
`17
`6
`4
`
`
`Ipi
`137106 79
`55
`as 30
`24
`13
`13
`13
`a
`gp100
`136
`93
`58
`32
`23 17
`16
`7
`5
`5
`3
`
`O
`
`8
`
`4
`
`effect ofipilimumab 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 gplOO, 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 gplOO alone (hazard ratio, 0.64;
`P<0.001). The reduction in risk with ipilimumab
`plus gplOO 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 of the 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—alone group,
`9 of 15 patients (60.0%) maintained an objective
`response for at least 2 years (26.5 to 44.2 months
`[ongoing]), and in the ipilimumab-plus—gplOO
`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
`gplOO-alone group who had a partial response
`maintained the response for 2 years. Responses
`to ipilimumab continued to improve beyond week
`24: in the ipilimumab—plus-gplOO group, 3 pa—
`tients with disease progression improved to stable
`disease, 3 with stable disease improved to 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
`
`
`
` B Progression-free Survival
`100
`
`9‘0
`
`30
`
`3'0
`
`El}
`
`50
`40
`30
`EU
`10
`
`
` F"||Ir—l_l1
`
`12
`16
`20
`24
`28
`32
`36 40 44
`48
`52
`
`
`Months
`
`No. at Risk
`
`lpiplusgplOO 403 35
`52
`27
`17
`14
`1o
`3
`5
`4
`2
`2
`1
`o
`
`
`Ipi
`137 37
`26
`17
`13
`1o
`10
`9
`6
`4
`2
`1
`o
`o
`
`
`gplOO
`13618753222100000
`
`
`
`Figure 1. Kaplan—Meier Curves for Overall Survival and Progression-free
`Survival in the lntention-to-Treat Population.
` The median Follow-up for overall survival (Panel A) in the ipilimumab (Ipi)-
`plus-glycoprotein 100 (gp100) group was 21.0 months, and the median
`
`overall survival was 10.0 months (95% CI, 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% CI, 8.0 to 13.8); and in the gplOO-alone
`group. the median follow-up was 17.2 months, and the median overall sur-
`vival. 6.4 months (95% CI. 5.5 to 8.7). The median progressiomfree survival
`[Panel B} was 2.76 months (95% Cl, 2.73 to 2.?9) in the ipilimumab-plus-
`gplOO 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 2.33} in the gplOO-alone group.
`The rates of progression-free survival at week-12 were 49.1% (95% CI, 44.1
`to 53.9} in the ipilim‘umab-plus«gp100 group. 57.7% {95% CI. 48.9 to 65.5]
`in the ipilimumab-alone group, and 43.5% {95% Cl. 39.6 to 56.7} in the
`gplOO-alone group.
`
`
`
`
`
`Progression-freeSurvival(%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`716
`
`NENGLJ MED363;8 NEJM.ORG AUGUST19,201O
`
`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`
`
`gp100
`lpi plus gp100
`no. ofdeaths/no. randomized
`306/403
`119/136
`
`Hazard Ratio (95% Cl)
`
`0.69 (0.56—0.85)
`
`A
`
`Subgroup
`
`All patients
`Sex
`
`Male
`Female
`Age
`<65 yr
`265 yr
`M stage at study entry
`M0. Mla, Mlb
`M1:
`Baseline LDH
`
`sULN
`>ULN
`Prior use ofinterleukin-Z
`Yes
`No
`
`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
`
`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)
`
`1——o—1
`0.5
`
`1.0
`4—_—.-.
`
`1.5
`
`lpi plus gp100
`Better
`
`gp100
`Better
`
`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)
`
`
`
`
`
`
`
`Subgroup
`
`All patients
`Sex
`
`Male
`Female
`Age
`<65 yr
`265 yr
`M stage at study entry
`M0, Mla, Mlb
`M1:
`Baseline LDH
`5U LN
`>ULN
`Prior use ofinterleukin-Z
`Yes
`No
`
`gp100
`lpi
`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
`
`Figure 2. Subgroup Analyses ovaeralI Survival.
`The prespecified analyses of overall survival among subgroups of patients. as defined by baseline demographic
`characteristics and stratification factors (metastasis [M] stage, classified according to the tumor-node—metastasis
`[TN M] categorization for melanoma ofthe American Joint Committee on Cancer; and receipt or nonreceipt ofinter-
`leukin-2 therapy), showed that hazard ratios were lower than 1 (indicating a lower risk ofdeath) for each subgroup
`in the ipilimumab (Ipi)-plus-g|ycoprotein 100 (gp100) group as compared with the gplOO-alone group (Panel A) and
`for each subgroup in the ipilimumab-alone group as compared with the gplOO-alone group (Panel B). Hazard ratios
`were 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 ofthe normal range.
`
`
`N ENGLJ MED363;8 NEJM.ORG AUGUST19, 2010
`
`717
`
`

`

`
`
`
`Response and Time to Event
`Overall survival
`
`Total no. ofdeaths
`Comparison with gplOO alone
`
`Hazard ratio (95% Cl)
`P value by log-rank test
`Comparison with ipilimumab alone
`
`Hazard ratio (95% Cl)
`P value by log-rank test
`
`Evaluation oftherapy
`Induction
`
`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
`
`_
`~—
`
`119
`
`—
`-——
`
`—
`—
`
`Best overall response — no. (%)
`
`Complete response
`Partial response
`Stable disease
`Progressive disease
`Not evaluated
`Best overall response rate — % (95% CI)
`P value for comparison with gplOO alone
`
`1 (0.2)
`22 (5.5)
`58 (14.4)
`239 (59.3)
`83 (20.6)
`5.7 (3.7—8.4)
`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
`
`P value for comparison with ipilimumab alone
`
`0.04
`
`—
`
`0
`2 (1.5)
`13 (9.6)
`89 (65.4)
`32 (23.5)
`1.5 (0.2—5.2)
`-—
`
`—
`
`Disease control rate — % (95% Cl)'i'
`P value for comparison with gp100 alone
`
`20.1 (16.3—24.3)
`0.02
`
`28.5 (21.1—36.8)
`<0.001
`
`11.0 (6.3—17.5)
`—
`
`P value for comparison with ipilimumab alone
`Time to event — mo
`
`0.04
`
`—
`
`—
`
`Time to progression — median (95% Cl)
`
`Time to response — mean (95% Cl)
`
`Duration ofresponse— median (95% CI)
`Reinductioni
`
`Best overall response— no./tota| no. (%)
`
`2.76 (2.73—2.79)
`
`2.86 (2.76—3.02)
`
`2.76 (2.73—2.83)
`
`3.32 (2.91—3.74)
`
`3.18 (2.75—3.60)
`
`11.5 (5.4—NR)
`
`NR (28.1—NR)
`
`2.74 (2.12—3.37)
`NR (2.0—NR)
`
`
`
`
`
`
`The NEW ENGLAND JOURNAL ofMEDICINE
`
`
`
`Table 2. Best Response to Treatment and Time-to-Event Data.*
`
`
`
`lpilimumab
`lpilimumab
`plris gplOO
`Alone
`gp100 Alone
`"(N =403)
`(N =137)
`(N =136)
`
`
`
`
`
`
`
`
`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 may not total 100 because of round-
`ing. NR denotes not reached.
`1' The disease control rate is the percentage of patients with a partial or complete response or stable disease.
`15A total 01°40 patients (29 in the lpilimumab-plus—gplflfl group; 9 in the ipilimumab-alone group, and 2 in the gp100-
`alone group) were given reinduction therapy. but 3 were not included in the efficacy analysesz3 had major protocol vio-
`lations and 5 were not eligible owing to die fact that they had had a best overall response of progressive disease during
`induction and were glven rein'd uction therapy inadvertently,
`
`
`718
`
`NENGLJ MED363;8 NEJM.0RG AUGUST19,2010
`
`

`

`IPILIMUMAB FOR METASTATIC MELANOMA
`
`immun