The ~EW ENG-LAND
`JOURNAL of MEDICINE
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`VOL. 372
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`PERSPECTIVE
`Treating Millions for HIV - The Adherence Clubs
`of Khayelitsha
`EW. Campion
`Demedicalizing AIDS Prevention and Treatment
`in Africa
`1. Ellman
`Foreseeable Risks? Informed Consent
`within the Standard of Care
`CA. Sacks and CE. Warren
`Bridging the Hospitalist-Primary Care Divide through
`Collaborative Care A.H. Goroli and D.P. Hunt
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`for Studies
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`ARTICLES
`ORIGINAL
`PD-l Blockade with Nivolumab in Relapsed
`or Refractory Hodgkin's Lymphoma
`S.M. Ansell and Others
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`Nivolumab in Previously Untreated Melanoma
`without BRAF Mutation
`C Robert and Others
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`Causes and Timing of Death in Extremely
`Premature
`Infants
`from 2000 through 2011
`R.M. Pateland Others
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`TBX6Null Variants and a Common Hypomorphic
`Allele in Congenital Scoliosis
`N. Wu and Others
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`REVIEW ARTICLE
`Origins of Cystic Fibrosis Lung Disease
`and M.J. Welsh
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`IMAGES IN CLINICAL MEDICINE
`Bilateral Lower Palpebral MALT Lymphoma
`I. Lalya and H. Mansouri
`Acute Colonic Pseudo-Obstruction
`F. Alahdab and S. Saligram
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`CASE RECORDS OF THE MASSACHUSETTS
`GENERAL
`HOSPITAL
`A Woman with Abdominal Pain, Dyspnea,
`and Diplopia
`W.S. David and Others
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`EDITORIAL
`Release the Hounds! Activating the T-Cell Response
`to Cancer
`M. Sznol and D.L. Longo
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`POLICY REPORT
`HEALTH
`Institute of Medicine Report on GME - A Call
`for Reform
`J.K. Iglehart
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`IMPLICATIONS
`CLINICAL
`A Biologic Velcro Patch
`J. Tolar andJ.E. Wagner
`
`OF BASIC RESEARCH
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`CORRESPONDENCE
`Rituximab or "AzathIoprine Maintenance
`in ANCA-Associated Vasculitis
`Cost-Effectiveness
`of CT Screening
`in the National Lung Screening Trial
`Integration
`of Acid-Base and Electrolyte Disorders
`Hidden Formaldehyde
`in E-Cigarette Aerosols
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`CORRECTION
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`NOTICES
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`CONTINUING
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`Tht NEW ENGLAND
`
`JOURNAL
`
`of MEDICINE
`
`II
`
`O_R_I_G_I_N_A_L_A_R_T_I_C_L_E
`Nivolumab in Previously Untreated
`Melanoma without BRAFMutation
`
`-JII
`
`Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D.,
`Caroline Dutriaux, M.D., Michele Maio, M.D., Laurent Mortier, M.D.,
`jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Catriona McNeil, M.D., Ph.D.,
`Ewa Kalinka-warzocha, M.D., Ph.D., Kerryj. Savage, M.D.,
`Micaela M. Hernberg, M.D., Ph.D., Celeste l.ebbe, M.D., Ph.D.,
`julie Charles, M.D., Ph.D., Catalin Mihalcioiu, M.D., Vanna Chiarion-Sileni, M.D.,
`Cornelia Mauch, M.D., Ph.D., Francesco Cognetti, M.D., Ana Arance, M.D., Ph.D.,
`Henrik Schmidt, M.D., D.M.Sc., Dirk Schadendorf, M.D., Helen Gogas, M.D.,
`Lotta Lundgren-Eriksson, M.D., Christine Horak, Ph.D., Brian Sharkey, Ph.D.,
`Ian M. Waxman, M.D., Victoria Atkinson, M.D., and Paolo A. Ascierto, M.D.
`
`ABSTRACT
`
`BACKGROUND
`The authors' affiliations are listed in the. Nivolumab was associated with higher rates of objective re$ponse than cherno-
`therapyin a phase 3 study involving patients with ipilimumab-refractory metastatic
`Appendix. Address reprint requests to Dr.
`Robert at Dermatology Service,
`INSERM
`Unite 981, Gustave Roussy, Villejuif-Paris melanoma. ·The use of nivolumab in previously untreated patients with advanced
`carolrne.roberngi melanoma has not been tested in a phase 3 controlled study.
`Sud, France, or at
`gustaveroussy.fr.
`
`Drs. Atkinson and Ascierto contributed
`equally to this article.
`
`This article was published on November 16,
`2014, at NEJM.org~
`-
`
`N EnglJ Med 2015;372:320-30.
`001: 10.1056jNEJMoa1412082
`Copyright © 2014 Massachusetts Medic;alSociety.
`
`METHODS
`We randomly assigned 418 previously untreated patients who had metastatic melanoma
`without a BRAF mutation to receive nivolumab (at a dose of3 mg per kilogram of body
`weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine
`(at a dose of1000 mg per square meter of body-surface area every 3 weeks and nivolu-
`mab-matched placebo every 2 weeks). The primary end point was overall survival.
`
`RESULTS
`At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 655 to
`78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the
`dacarbazine group (hazard ratio for death, 0.42; 99.79% Cl, 0.25 to 0.73; 1'<0.001).
`The median progression-free survivalwas 5.1 months in the nivolumab group versus
`2.2 inonths in the dacarbazine group (hazard ratio for death or progression of dis-
`ease, 0.43; 95% Cl, 0.34 to 056; 1'<0.001).The objective response rate was 40.0% (95%
`CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the
`dacarbazine group' (odds ratio, 4.06; 1'<0.001). The survival benefit with nivolumab
`versus dacarbazine was observed across prespecified subgroups,
`including subgroups
`defined by status regarding the programmed
`death ligand 1 (1'D-Ll). Common ad-
`verse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-
`,
`related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with
`nivolumab and 17.6% of those treated with dacarbazine.
`
`CONCLUSIONS
`improvements in overall survival and
`Nivolumab was associated with significant
`among previously un-
`progression-free survival, as compared with dacarbazine,
`treated patients who had metastatic melanoma without a BRAF mutation.
`(Funded
`by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.)
`
`320
`
`N ENGlJ MED 372;4
`
`NEJM.ORG JANUARY 22, 2015
`
`

`

`NIVOLUMAB
`
`IN UNTREATED
`
`MELANOMA WITHOUT
`
`BRAF MUTATION
`
`E
`
`GLOBAL INCIDENCE OF MELANOMA
`continues to rise, and the mortality associ-
`ated with unresectable or metastatic mela-
`~
`noma remains high.' Globally, 132,000 new cas-
`es of melanoma are diagnosed and an estimated
`48,000 persons die from advanced melanoma
`each year.2,3 Ipilimumab has been shown to im-
`. prove the rate of survival at 2 years, as compared
`with a vaccine control, among previously treated
`patients with metastatic melanoma as well as
`among previously untreated patients who also
`received dacarbazine.v" BRAFand MEK inhibi-
`tors are approved agents that, as monotherapy,
`have been associated with a survival advantage as
`compared with chemotherapy, with a median
`overall survival of 13 to 20 months." Although
`the objective response rate is high with these
`agents (45 to 53%), the median duration of re-
`sponse is less than L year.6-10
`Recently, a combination of anti-Bk.Af and
`anti-MEKagents
`has been associated with a
`higher response rate and longer duration of re-
`sponse, as compared with anti·BRAF mono-
`therapies.v-v However, the use of these targeted
`agents, as. monotherapy or in combination,
`is
`limited to the approximately 40% of patients
`who have melanoma with a BRAF V600 muta-
`tion. Dacarbazine is associated with a median
`overall survival of 5.6 to' 7.8 months and re-
`mained until recently a commonly used therapy
`in patients with previously untreated melanoma
`without a BRAF mutation.v'" Despite new treat-
`ment options, there remains a substantial unmet
`need for treatments
`that extend survival and
`provide a better quality oflife.
`Nivolumab is a fully human IgG4 pro-
`grammed death 1 (PD-l) immune-checkpoint-
`inhibitor antibody that selectively blocks the in-
`teraction of the PD-l
`receptor with its" two
`known programmed death ligands, PD-Ll and
`. PD-L2,disrupting the negative signal that regu-
`lates T-cell activation and proliferation."
`In a-
`phase 1 study, nivolumab was associated with
`promising antitumor activityand a favorablesafety
`profile in patients' with solid tumors, including
`advanced melanoma.v-"
`In an open-label, ran-
`domized, phase 3 study involving patients with
`ipilimumab-refractory melanoma, nivolumab was
`associated with a higher rate of objective re-
`sponse than chemotherapy (32% vs. 11%)? Re-
`cently, another anti-Plr-L antibody, pembroli-
`zumab, has shown robust clinical activity and
`
`.has been approved in the United States on the
`basis of an objectiveresponse rate of24% among
`patients with advancedmelanomathat progressed
`after ipilimumab, as well as treatment with a
`BRAEinhibitor if the patient had a BRAF V600
`mutation." Here, we report the resul~ of a phase
`3, randomized, double-blind study conducted to
`determine whether nivolumab, as compared with
`dacarbazine, improves overall survival among pre-
`viously untreated patients who have' advanced
`melanoma without a BRAF mutation.
`
`METHODS
`
`PATIENTS.
`Eligible patients had confirmed, unresectable,
`previously untreated stage III or N melanoma
`.without a'BRAF mutation. Other eligibility crite-
`ria included an age of 18 years or more, an East-
`ern CooperativeOncologyGroup (ECOG)perfor-
`mance-status score of 0 or.L (on a scale of 0 to 5,
`with 0 indicating no symptoms and Lindicating
`mild symptoms), and the availability of tumor
`tissue from a metastatic or unresectable site for
`PD-Ll biomarker analysis. Key exclusion criteria
`were active brain metastases, uveal melanoma,
`and a history of serious autoimmune disease. Pa-
`tients who had received adjuvant therapy previ-
`ously were not excluded.
`
`STUDY DESIGN AND TREATMENT
`Patients were randomly assigned in a 1:1 ratio to
`receive by means of intravenous infusion either
`3 mg of nivolumab per kilogram of body weight
`every 2 weeks, plus a dacarbazine-matched pla-
`cebo every 3 weeks, or 1000 mg of dacarbazine
`per square meter of body-surface area every
`3 weeks, plus a nivolumab-matched placebo ev-
`ery 2 weeks. Randomization' was stratified ac-
`cording to tumor PD-Ll status (positivevs. nega-
`tive.or indeterminate) and metastasis stage (MO,
`MIa, or Mlb vs. Mlc, defined according to the
`turnor-node-metastasis
`system of the American
`Joint Committee on Cancer and the International
`Union against Cancer). Treatment continued
`until there was disease progression, as assessed
`by the investigator, or an unacceptable level of
`toxic effects. Treatment after disease progres-
`sion was permitted for patients who had a clin-
`ical benefit and did not have substantial adverse
`effects with the study drug, as determined by
`the investigator (Fig. sf in the Supplementary
`
`N ENGLJ MED 372;4
`
`NEJM.ORG JANUARY 22, 2015
`
`321
`
`

`

`Thl NEW ENGLAND
`
`JOURNAL
`
`of MEDICINE
`
`Appendix, available with the full text of this ar-
`ticle at NEJM.org).
`The primary end point was overall survival.
`Secondary end points included investigator-as-
`sessed progression-free
`survival, objective re-
`sponse rate, and PD-Ll expression in the tumor
`as a predictive biomarker of overall survival.
`
`ASSESSMENT
`Tumor response was assessed according to the
`Response Evaluation Criteria in Solid Tumors
`(RECIST),version 1.1,'9at 9 weeks after random-
`ization, every 6 weeks thereafter for the first
`year, and then every 12 weeks until disease pro-
`gression or treatment discontinuation. Assess-
`ments
`for survival were performed every 3
`months. Safety evaluations were performed for
`patients who received at least one dose of the
`study treatment, and the severity of adverse
`events was graded according to the National
`Cancer Institute Common Terminology Criteria
`for Adverse Events, version 4.0.20
`
`mittee recommended that the study be unblind-
`ed and amended to-allowpatients enrolled in the
`dacarbazine group to receive nivolumab. Re~
`ported here are the results from the double-blind
`portion of the study before the amendment
`(clinical data cutoff on June 24, 2014).
`
`PD-Ll ASSESSMENT
`the expression of PD-Ll
`Before randomization,
`on the surface of the tumor cells was assessed
`in a central laboratory with the use of an auto-
`mated immunohistochemical assay (collabora-
`tively developed by Bristol-Myers Squibb and
`Dako), as described previously." PD-Ll positiv-
`ity was defined as at least 5% of tumor cells
`showing cell-surfacePD-Ll staining of any inten-
`sity in -a section containing at least 100 tumor
`cells that could be evaluated. Indeterminate sta-
`tus was attributed to samples for which tumor
`cell-surface expression could not be discerned
`because of melanin content or strong cytoplas-
`mic staining. PD-Ll status was prospectively
`determined, and the results were used to strat-
`lfy randomization, which was performed by
`means of a fully automated interactive voice-
`response system. Statistical analyses were pre-
`specified to assess the predictive value ofPD-Ll
`expression,
`
`STUDY OVERSIGHT
`The study protocol, available at NEJM.orgwith
`the most recent version of the statistical analysis
`plan, was approved by the institutional review
`board at each participating center. The study was
`conducted in accordance with the Declaration of
`Helsinki and the International Conference on STATISTICAL ANALYSIS
`Harmonisation Guidelines for Good Clinical A,sample of approximately'110patients, random-
`Practice. All the patients provided written in-
`ly assigned in a 1:1 ratio to the two treatment
`formed consent to participate in the study. Data groups, was planned. Overall survival and pro-
`were collected by the sponsor, Bristol-Myers gression-free survival were compared between
`Squibb, and analyzed in collaboration with the
`the two treatment groups with the use of a two-
`academic authors. All the authors vouch for the
`sided log-rank test stratified according to PD-L1
`accuracyand completeness of the data and analy-
`status (positive vs. negative or indeterminate)
`ses reported and for the fidelity of the study to and metastasis stage (MO,MIa, or M1b vs. M1c).
`the protocol. The first draft of the 'manuscript The hazard ratios for the nivolumab group, as
`was written by the first and last authors, with all
`compared with the dacarbazine group, and cor-
`the authors contributing to subsequent drafts.
`responding confidence intervals were estimated
`Medical-writing support, funded by the sponsor, with the use of a stratified Cox proportional-
`. was providedby StemScientific.
`hazards model. Survival curves for each treat-
`A data and safety monitoring committee was ment group were estimated with the use of
`established to provide oversight of safety and
`the Kaplan-Meier product-limit method. Rates
`efficacy considerations. On June 10, 2014, the
`at fixed time points were derived from the
`monitoring
`committee
`reviewed an expedited Kaplan-Meier estimate, along with their corre-
`report after noting a potential difference in over-
`sponding log-log-transformed 95% confidence
`all survival during an earlier safety review. Data
`interval.
`from the abbreviated report, which was based on '
`The objective response rate was compared
`an unplanned interim database lock, showed-a between the two treatment groups with the use
`significant difference in overall survival in favor of a two-sided Cochran-Mantel-Haenszel'
`test.
`of nivolumab, As a result, the monitoring com- The efficacy analyses were performed in the
`
`N ENGlJ MED 372;4
`
`NEJM.ORG JANUARY 22, 2015
`
`

`

`NIVOLUMAB
`
`IN UNTREATED MELANOMA WITHOUT BRAF MUTATION
`
`random-
`of patients who underwent
`population
`ization (the intention-to-treat
`population). The
`safety analyses were performed
`in the popula-
`tion of patients who received at least one dose of
`a study drug. At the time of data analysis, 146
`patients had died. The boundary
`for statistical
`significance, which was
`based
`on the Lan-
`DeMets alpha-spending
`function with O'Brien
`and Fleming-type
`boundaries,
`required the log-
`rank P value to be less than 0.0021, correspond-
`ing to a 99.79"10 confidence
`interval.
`
`RESULTS
`
`PATIENTS AND TREATMENT
`From January 2013 through February 2014, a to-
`tal of 518 patients were enrolled at 80 centers in
`Europe, Israel, Australia, Canada, and South
`America: A total of 418 patients underwent
`ran-
`domization:
`210" patients were assigned to the
`nivolumab
`group and 208 to the dacarbazine
`group (Fig. Sl
`in the Supplementary Appendix).
`One patient
`randomly assigned to the nivolumab
`group and 3 randomly assigned to the dacarba-
`zine group were inadvertently
`enrolled
`in the
`study, despite having an ECOG perforrnance-sta-
`russcore
`of 2; 1 additional patient
`in the nivolu-
`mab group did not report an ECOG performance-
`status
`score. Baseline
`characteristics were
`balanced
`between
`the two groups. A total of
`61.0"10 of patients had stage M1c disease, 36.6"10
`had an elevated lactate dehydrogenase
`level, and
`35.4"10 had a positive PD-Ll status (Table 1).
`At the time of the database lock, 95 of 206 pa-
`tients (46.1"10) treated with nivolumab and 13 of
`205 (6.3"10) treated with dacarbazine were continu-
`ing the study treatment.
`'The most frequent reason
`for discontinuation was disease progression, in 96
`(46.6"10)
`of 206 patients
`in the nivolumab group
`and 175 of 205 (85.4"10) in the dacarbazine group
`(Table Sl
`in the Supplementary Appendix). Afrer
`the discontinuation of study treatment, 63 of 210
`patients (30.0"10) in the nivolumab group and 114
`of 208 (54.8"10) in the dacarbazine group "received
`systemic therapy, most commonly ipilimumab (in
`45 of 63 patients and 79 of114, respectively) (Table
`S2 in the Supplementary Appendix). All the pa-
`tients who underwent
`randomization were
`fol-
`lowed for up to 16.7 months at the time of data-
`base lock on August 5, 2014, which was 5.2
`months after the first visit of the last patient who
`had undergone randomization.
`
`EFFICACY
`The median overall survival was not reached. in
`the nivolumab group and was 10.8 months
`(95%
`confidence interval
`[Cl], 9.3 to 12.1) in the dacar-
`bazine group. The overall survival rate at 1 year
`was 72.9"10 (95"10 Cl, 65.5 to 78.9) in the nivolu-
`mab group and 42.1"10 (95"10 Cl, 33.0 to 50.9) in
`the dacarbazine group. A significant benefit with
`respect
`to overall survival was observed in the
`nivolumab group, as compared with the dacarba-
`zine group (hazard ratio for death, 0.42; 99.79"10
`cr, 0.25 to 0.73; P<O.OOl)(Fig. lA).
`The median progression-free
`survival was 5.1
`months
`(95% Cl, 3.5 to 10.8) in the nivolumab
`(95"10 Cl, 2.1 to 2.4) in the
`group and 2.2 months
`dacarbazine
`group (Fig. 1B). A significant ben-
`efit with respect
`to progression-free
`survival was
`observed in the nivolumab group, as compared
`with
`the dacarbazine
`group (hazard ratio for
`of disease, 0.43; 95"10 Cl,
`death or progression
`0.34 to 0.56; P<O.OO1).
`The objective response rate in the nivolumab
`group was 40.0"10 (95"10 cr, 33.3 to 47.0), which
`was
`significantly
`higher
`than the rate in the
`group, which Was 13.9"10 (95% Cl,
`dacarbazine
`9.5 to 19.4) (odds ratio, 4.06; P<O.OOl).The per-
`centage of patients with a complete
`response
`was higher with nivolumab than with dacarba-
`zine (7.6"10 vs. 1.0"10) (Fig. 2 and Table 2). Among
`patients who had a response,
`the median dura-
`tion of response was not reached in the nivolu-
`mab group and was 6.0 months
`in the dacarba-
`zine group (95"10 Cl, 3.0 to not reached) (Fig. 2C).
`In the nivolumab group, a reduction of 30%
`or more in the tumor burden in the target lesion,
`representing an -unconventional response pat-
`tern sometimes
`seen with immunotherapies,
`was achieved or maintained
`in 17 of 54 patients
`who were treated beyond progression
`(8.1% of
`patients
`randomly assigned to nivolumab)
`(Fig,
`S4A in the Supplementary Appendix).
`In the da-
`carbazine group, this unconventional response
`was achieved or maintained
`in 8 of the 49 pa-
`tients who were
`treated
`beyond
`progression
`(3.8"10 of patients randomly assigned to dacarba-
`zine) (Fig. S4B in the Supplementary Appendix).
`
`SUBGROUP ANALYSES
`nivolumab-treated
`. Regardless
`of PD-Ll status,
`patients had improved overall survival, as com-
`pared with dacarbazine-treated
`patients
`(unad-
`justed
`hazard
`ratio for death among patients
`with positive PD-Ll status, 0.30 [95% Cl, 0.15 to
`
`N ENGLJ MED 372;4
`
`NEJM.ORG JANUARY 22, 2015
`
`323
`
`

`

`l'ht NEW ENGLAND
`
`JOURNAL
`
`of MEDICINE
`
`Table 1. Baseline Characteristics ofthe Patients,w
`
`(%)
`
`Characteristic
`Age-yr
`Median
`Range
`Sex-no.
`Male
`Female
`region -
`Geographic
`Europe or Canada
`Israel, Australia, or South America
`ECOG performance-status
`score-
`no. (%)t
`
`no. (%)
`
`Nivolumab
`(N=210)
`
`64
`18-86
`
`121 (57.6)
`89 (42.4)
`
`145 (69.0)
`65 (31.0)
`
`Dacarbazine
`(N = 208)
`
`66
`26-87
`
`125 (60.1)
`83 (39.9)
`
`145 (69.7)
`63 (30.3)
`
`Total
`(N=418)
`
`65
`18-87
`
`246 (58.9)
`172 (41.1)
`
`290 (69.4)
`128 (30.6)
`
`stage-
`
`no. (%):!:
`
`-
`
`no. (%)
`
`-
`
`no. (%)
`
`no. (%)§
`
`no. (%)
`
`148 (70.5)
`60 (28.6)
`1 (0.5)
`
`128 (61.0)
`82 (39.0)
`
`120 (57.1)
`79 (37.6)
`178 (84.8)
`21 (10.0)
`11 (5.2)
`
`7 (3.3)
`203 (96.7)
`
`74 (35.2)
`136 (64.8)
`
`0
`202 (96.2)
`8 (3.8)"
`
`32 (15.2)
`1 (0.5)
`
`121 (58.2)
`84 (40.4)
`3 (1.4)
`
`127 (61.1)
`81 (38.9)
`
`125 (60.1)
`74 (35.6)
`177 (85.1)
`22 (10.6)
`9 (4.3)
`
`8 (3.8)
`200 (96.2)
`
`74 (35.6)
`134 (64.4)
`
`0
`204 (98.1)
`4 (1.9)
`
`36 (17.3)
`1 (0.5)
`
`269 (64.4)
`144 (34.4)
`4 (1.0)
`
`255 (61.0)
`163 (39.0)
`
`245 (58.6)
`153 (36.6)
`355 (84.9)
`43 (10.3)
`20 (4.8)
`
`15 (3.6)
`403 (96.4)
`
`148 (35.4)
`270 (64.6)
`
`. 0
`406 (97.1)
`12 (2.9)
`
`68 (16.3)
`2 (0.5)
`
`upper
`
`limit of the
`
`0
`1
`2
`Metastasis
`Mlc
`MO, MIa, or Ml~
`lactate dehydrogenase
`sUlN
`>UlN
`:s:2x OlN
`>2x UlN
`Not reported
`History of brain metastases
`Yes
`No
`status -
`PO-l!
`Positive
`Negative or indeterminate
`(%)
`BRAF status -
`no.
`Mutation
`No mutation
`Not reported'
`Prior systemic therapy -
`Adjuvant
`therapy
`Neoadjuvant
`therapy
`* There were no significant
`between-group
`differences
`in the baseline characteristics. UlN denotes
`normal
`range.
`-
`t An Eastern Cooperative Oncology Group (ECOG) performance-status
`1 mild symp-
`score of 0 indicates no symptoms,
`toms, and 2 moderate
`symptoms, with the patient being ambulatory
`and capable of all self-care but unable to carry out
`any work activities. One patient
`randomly assigned to the nivolumab groL1Pand three randomly assigned to the dacar-
`bazine group were inadvertently
`enrolled in the study, despite having an_ECOG performance-status
`score of 2. One ad-
`ditional patient
`in the nivolumab group underwent
`randomization
`in error without having an ECOG performance-status
`report.
`stage was defined according to the tumor-node-metastasis
`:i:The metastasis
`on Cancer and the International Union against Cancer.
`$ A positive status
`for programmed
`death ligand!
`(PO-L!) was defined as at least 5% of the tumor cells having cell-sur-
`face PO·L! staining of any intensity in a section containing
`at least 100 tumor cells that could be evaluated.
`lndeterml-
`nate status was attributed
`to samples
`for which tumor cell-surface
`expression
`could not be discerned
`because of mela-
`nin content
`or strong cytoplasmic
`staining.·
`
`system of the American Joint Committee
`
`324
`
`N ENGLJ MEO 372;4
`
`NEJM.ORG JANUARY 22, 2015
`
`

`

`NIVOLUMAB
`
`IN UNTREATED MELANOMA WITHOUT
`
`BRAF MUTATION
`
`A Overall Survival
`100
`
`..
`[
`'"..
`c
`50,
`ci 30
`
`'0
`'80
`
`70
`
`60
`
`40
`
`ZO
`
`10
`
`0
`
`0
`
`" '
`
`~
`
`No. at Risk
`Nivolumab
`Dacarbazine
`
`ZW
`Z08
`
`185
`177
`
`B Progression-free
`
`Survival
`
`100
`
`'0
`
`Hazard ratio for death, 0.42 (99.79% cr, 0.25-0.73)
`P<O.OOl
`
`Nivolumab
`
`---------------
`
`Patients Who Died Median Survival
`no./rota! no.
`mo (95% CI)
`50/210
`Not reached
`96/208
`10.8 (9.3-12.1)
`
`Nivolumab
`Dacarbazine
`
`,
`
`Months
`
`105
`8Z
`
`6
`
`150
`IZ3
`
`12
`
`45
`ZZ
`
`15
`
`18
`
`8
`3
`
`0
`0
`
`Patients Who Died
`or Had Disease
`Progression
`no./total no.
`108/210
`. 163/208
`
`Nivolumab
`Dacarbazine
`
`.
`Median
`Progression-free
`Survival
`mo (95% Cf)
`5.1 (3.5-10.8)
`2.2 (2.1-2.4)
`
`Hazard ratio for death or disease
`progression,0.43
`(95% CI, 0.34-0.56);
`
`P<O.OOl
`
`Dacarbazine
`
`[
`c,2
`
`0.
`
`00
`
`0.
`
`••r 60
`..
`•
`::E
`c
`~
`
`80
`
`70
`
`50
`
`40
`
`30
`
`ZO
`
`10
`
`0
`
`0
`
`No. at Risk
`Nivolumab
`Dacarbazine
`
`ZIO
`Z08
`
`,
`
`Months
`
`57
`12
`
`3
`
`116
`74
`
`6
`
`82
`28
`
`IZ
`
`IZ
`0
`
`15
`
`I
`0
`
`18
`
`0
`0
`
`Figure 1. Survival
`End Points.
`curves for overall survival. The median
`Panel A shows the Kaplan-Meier
`8.9 months in the-nivolurrieb
`follow-up for overall survivalwas
`group and
`6.8 months in the dacarbaztne group. Panel B shows the Kaplan-Meier
`curves for progression-free
`survival.
`
`ing to adverse events was 6.8'\'0 in the nivolumab
`group and 11.7"10 in the dacarbazine group. No
`deaths were attributed to study-drug toxicity in
`either group.
`defined as those
`Selected adverse events -
`cause - were
`with a potential
`immunologic
`analyzed according to organ category. Grade 3
`
`0.60]; unadjusted hazard ratio for death among
`those with PD-11 negative or indeterminate PD-
`11 status, 0,48 [95"10 CI, 0.32 to 0.71]) (Fig. S2 in
`the Supplementary Appendix). In the nivolumab
`group,
`the median overall survival was not
`reached in either PD-11 subgroup. In the dacar-
`bazine group, .the median overall survival was
`slightly longer in the subgroup with positive PD-
`11 status than in the subgroup with negative or
`indeterminate PD-Ll status (12.4vs. 10.2months)
`(Fig. S3 in the Supplementary Appendix).
`In the two' PD-11 subgroups, nivolumab-
`treated patients had improved rates of objective
`response, as compared with dacarbazine-treated
`patients. In. the subgroup with positive PD-Ll
`status, the objective response rate was 52.7"10
`(95"10 CI, 40.8 to 64.3) in the nivolumabgroup
`versus 10.8"10 (95"10 CI, 4.8 to 20.2) in the dacar-
`bazine group. In the subgroup with negative or
`status,
`the objective re-
`indeterminate PD-Ll
`sponse rate was 33.1"10 (95"10 CI, 25.2 to 41.7) in
`the nivolumab group versus 15.7"10 (95"10 CI, 10.0
`to 23.0) in the dacarbazine group. The survival
`benefit with nivolumab versus dacarbazine was
`also observed across prespecified subgroups
`based on age, sex, metastasis stage, BCOG per-
`formance-status
`score, status with respect to a
`history of brain metastases, baseline lactate de-
`hydrogenase level, and geographic region (Fig.
`S2 in the Supplementary Appendix).
`
`ADVERSE EVENTS
`The incidence of treatment-related adverse events
`of any grade was similar in the nivolumab group
`and the dacarbazine group (74.3"10 and 75.6"10,
`respectively). However, treatment-related
`adverse
`events of grade 3 or 4 were reported less fre-
`quently in the nivolumab group than in the da-
`carbazine group (11.7"10 vs, 17.6"10) (Table 3, and
`Table S3 in the Supplementary Apperidix). The
`most common adverse events related, to nivolu-
`mab treatment were fatigue (in 19.9% of pa-
`tients), pruritus
`(in 17.0"10),. and nausea (in
`16.5"10). In the dacarbazine group, common treat-
`ment-related adverse events were consistent with-
`those in previous reports and included gastroin-
`testinal and hematologic toxic events. The fre-
`quency of
`treatment-related
`serious adverse
`events of grade 3 or 4 was similar in the two
`groups (5.8"10 in the riivolumab group and 5.9"10
`in the dacarbazine group). The percentage of pa-
`tients who discontinued the study treatment ow- .
`
`N ENGLJ MEO 372;4
`
`NEJM.ORG JANUARY 22, 2015
`
`325
`
`

`

`Th~ NEW ENGLAND
`
`JOURNAL
`
`of MEDICINE
`
`Figure 2. Characteristics of Response.
`The waterfall plots show the maximum change from
`reference diameters of the
`baseline in the sum ofthe
`lesion in patients receiving nivolumab
`target
`(Panel A)
`and those receiving dacarbaztne (Pan~ B). Data are
`shown for all the patients who had a response that
`could be evaluated in the target
`lesion at baseline and
`at least one tumor assessment during
`who underwent
`treatment.
`The percentage
`increase was truncated
`at
`100% (red squares). Red dots indicate patients who
`had a response to treatment
`according to the Response
`Evaluation Criteria in Solid Tumors, version Ll , The
`da;'hed lines in Panels A and B indicate a 30% reduc-
`tion in the tumor burden in the target
`lesion. Kaplan-
`(Panel C)
`Meier curves for the duration of response
`show that
`the median duration of response in the 84
`patients in the nivolumab
`group who had a response
`was not reached; 12 of these patients did not have a
`durable response. Of
`the 29 patients in the dacarba-
`zine group' who had a response, 14 did not have a du-
`rable response. The dashed line in Panel C indicates
`the median duration of response.
`
`,;.c..'
`
`or 4 selected adverse events that were considered
`to be related to nivolumab treatment were infre-
`quent and included diarrhea and an elevated ala-
`nine aminotransferase level (each in 1.0% of
`patients) (Table S4 in the Supplementary Appen-
`dix). The majority of selected adverse events o