New England journal of medicine.
`V. 369, no. 2 (July 11 2013)
`General Collection
`W1 NE388
`2013-07-22 09:57:54
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`ENGLAND
`JOURNALof MEDICINE
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`VOL. 369 NO. 2
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`ORIGINAL ARTICLES
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`Retinoic Acid and Arsenic Trioxide
`for Acute Promyelocytic Leukemia
`F. Lo-Coco and Others
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`NivolumabplusIpilimumab in Advanced Melanoma
`J.D. Wolchok and Others
`Safety and Tumor Responses with Lambrolizumab
`(Anti-—PD-1) in Melanoma
`O. Hamid and Others
`
`Cardiovascular Effects of Intensive Lifestyle
`Intervention in Type 2 Diabetes
`The Look AHEAD Research Group
`U.S. Hospitalizations for Pneumonia
`after a Decade of Pneumococcal Vaccination
`M.R. Griffin and Others
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`BriefReport: Delayed Puberty and Estrogen Resistance
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`CASE RECORDS OF THE MASSACHUSETTS
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`A Man with Metastatic Melanoma
`R.J. Sullivan and O
`EDITORIALS
`NEJM Group — More Offerings, Mission Unchanged
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`Targeting Agents Alone to Cure Acute
`Promyelocytic Leukemia
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`Combination Checkpoint Blockade — Taking
`Melanoma Immunotherapyto the Next Level
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`j.L. Riley
`DoLifestyle Changes Reduce Serious Outcomes
`in Diabetes?
`H.C. Gerstein
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`CLINICAL IMPLICATIONS OF BASIC RESEARCH
`Influenza — Time to Target the Host?
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`This material may beprotected by Copyright law (Title 17 U.S. Code)
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`
`
`From the Ludwig Center, Memorial
`Sloan-Kettering Cancer Center, New York
`(J.D.W., M.K.C., M.A.P., N.A.R., A.M.L.
`N.H.S., C.E.A., R.-A.G., S.A.K., B.ULA,);
`Yale University School of Medicine and
`Smilow Cancer Center, Yale-New Haven
`Hospital, New Haven, CT (H.K., K.R.,
`M.M.B., A.C., M.S.); Dako North Ameri-
`ca, Carpinteria (X.Z.), and Bristol-Myers
`Squibb, RedwoodCity (A.J.K.) — both in
`California; and Bristol-Myers Squibb,
`Princeton, NJ
`(I.L., H.D.I., W.F., C-E-H.,
`Q.H., J.M.W., A.G.). Address reprint re-
`quests to Dr, Wolchok at Memorial Sloan-
`Kettering Cancer Center, 1275 York Ave.,
`New York, NY 10065, or at wolchokj@
`mskcc.org.
`
`This article was published on June 2, 2013,
`at NEJM.org.
`
`N Engl) Med 2013;369:122-33.
`DOK: 10.1056/NEJMoal302369
`Copyright © 2013 Massachusetts Medical Society.
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`[
`
`
`
`ORIGINAL ARTICLE
`
`|
`
`Nivolumabplus Ipilimumab
`in Advanced Melanoma
`
`Jedd D, Wolchok, M.D., Ph.D., Harriet Kluger, M.D., Margaret K. Callahan, M.D., Ph.D.,
`Michael A. Postow, M.D., Naiyer A. Rizvi, M.D., Alexander M. Lesokhin, M.D.,
`Neil H. Segal, M.D., Ph.D., Charlotte E. Ariyan, M.D., Ph.D., Ruth-Ann Gordon, B.S.N.,
`Kathleen Reed, M.S., Matthew M. Burke, M.B.A., M.S.N., Anne Caldwell, B.S.N.,
`Stephanie A, Kronenberg, B.A., Blessing U. Agunwamba, B.A., Xiaoling Zhang, Ph.D.,
`Israel Lowy, M.D., Ph.D., Hector David Inzunza, M.D., William Feely, M.S.,
`Christine E. Horak, Ph.D., Quan Hong, Ph.D., Alan J. Korman, Ph.D.,
`Jon M. Wigginton, M.D., Ashok Gupta, M.D., Ph.D., and Mario Sznol, M.D.
`
`ABSTRACT
`
`BACKGROUND
`
`In patients with melanoma, ipilimumab(an antibody against cytotoxic T-lymphocyte—
`associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab(an anti-
`body against the programmed death 1 [PD-1] receptor) produced durable tumor
`regression in a phase1 trial. On the basis of their distinct immunologic mechanisms
`of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab
`combined withipilimumabin patients with advanced melanoma.
`METHODS
`
`We administered intravenous doses of nivolumab andipilimumabin patients every
`3 weeksfor 4 doses, followed by nivolumabaloneevery 3 weeks for 4 doses (concur-
`rent regimen). The combined treatment was subsequently administered every 12 weeks
`for up to 8 doses. In a sequenced regimen, patients previously treated withipilim-
`umab received nivolumab every 2 weeks for up to 48 doses.
`RESULTS
`
`A total of53 patients received concurrent therapy with nivolumabandipilimumab,and 33
`received sequenced treatment. The objective-responserate (according to modified World
`Health Organizationcriteria) for all patients in the concurrent-regimen group was 40%.
`Evidence ofclinical activity (conventional, unconfirmed, or immune-related response or
`stable disease for >24 weeks) was observed in 65%ofpatients. At the maximum doses
`that were associated with an acceptable level ofadverse events (nivolumabat a dose of
`1 mg per kilogram ofbody weight andipilimumabat a dose of3 mg per kilogram), 53%
`of patients had an objective response, all with tumor reduction of80% or more, Grade 3
`or 4 adverseevents related to therapy occurred in 53%ofpatients in the concurrentregi-
`men group butwere qualitatively similar to previous experience with monotherapy and
`were generally reversible. Among patients in the sequenced-regimen group, 18% had
`grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.
`CONCLUSIONS
`
`Concurrent therapy with nivolumab andipilimumab had a manageable safety pro-
`file and provided clinical activity that appears to be distinct from that in published
`data on monotherapy, with rapid and deep tumorregression in a substantial pro-
`portion ofpatients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical;
`ClinicalTrials.gov number, NCT01024231,)
`
`122
`
`N ENGLJ MED 369;2 NEJM.ORG JULY 11, 2013
`
`

`

`NIVOLUMABPLUS IPILIMUMAB IN ADVANCED MELANOMA
`
`SCAPE FROM IMMUNE SURVEILLANCE IS
`
`a recognized feature of cancer; therefore,
`the developmentoftherapies to enhance tu-
`mor immunity is a rational treatmentstrategy.'
`Immunecheckpoint blockade is one approachthat
`has induced regressions in several types ofcancer.
`[pilimumab, a fully human, IgG1 monoclonal an-
`tibody blocking cytotoxic T-lymphocyte—associat-
`ed antigen 4 (CTLA-4), improvedoverall survival in
`patients with advanced melanoma.** Nivolumab,
`a fully human IgG4 antibody blocking the pro-
`grammed death 1 (PD-1) receptor, produced dura-
`ble objective responses in patients with melanoma,
`renal-cell cancer, and non-small-cell lung cancer.*
`CTLA-4 and PD-1 appear to play complemen-
`tary roles in regulating adaptive immunity. Where-
`as PD-1 contributes to T-cell exhaustion in periph-
`eral tissues, CTLA-4 inhibits at earlier points in
`T-cell activation. In preclinical models, combined
`blockade of PD-1 and CTLA-4 achieved more pro-
`nounced antitumoractivity than blockade of either
`pathwayalone.®? On the basis of these observa-
`tions, we conducted a phase 1 study to investigate
`the safety and efficacy of combined CTLA-4 and
`PD-1 blockade (with the use of ipilimumab and
`nivolumab, respectively) in patients with advanced
`melanoma. Data for 86 patients treated in this
`ongoing study are reported.
`
`METHODS
`
`PATIENTS
`
`Eligible patients wereatleast 18 years ofage; had
`received a diagnosis of measurable, unresectable,
`stage III or IV melanoma; had an Eastern Coop-
`erative Oncology Group performance status of 0
`(asymptomatic) or 1 (ambulatory butrestricted in
`strenuousactivity)®; had adequate organ function;
`and had a life expectancy ofat least 4 months.
`Exclusion criteria were active, untreated central
`nervous system metastasis, a history of autoim-
`munedisease, previous therapy with T-cell mod-
`ulating antibodies(excluding ipilimumabfor pa-
`tients in the sequenced-regimen cohorts), human
`immunodeficiency virus infection, and hepatitis
`B or C infection.
`In the sequenced-regimen cohorts, patients
`were required to have received at least three pre-
`vious doses of ipilimumab, with the last dose ad-
`ministered 4 to 12 weeks before the administration
`of nivolumab. Patients with a complete response,
`progression with evidence ofclinical deterioration,
`
`or a history of high-grade adverse events related
`to ipilimumab were excluded.
`
`STUDY DESIGN
`
`In this phase 1 study wetreated successive cohorts
`of patients with escalating doses ofintravenous
`nivolumab and ipilimumab administered concur-
`rently every 3 weeks for four doses, followed by
`nivolumab alone every 3 weeks for four doses (con-
`current-regimen group) (see Fig. $1 in the Sup-
`plementary Appendix, available with the full text
`of this article at NEJM.org). The combinedtreat-
`ment was subsequently continued every 12 weeks
`for up to eight doses. When the two drugs were
`administered together, nivolumab was adminis-
`tered first. Within a cohort, doses of nivolumab
`and ipilimumab were kept constant.
`The protocol-specified dose levels in the co-
`horts were as follows. In the concurrent-regimen
`group, cohort 1 was designated to receive 0.3 mg
`of nivolumab per kilogram of body weight and
`3 mg ofipilimumabper kilogram; cohort 2, 1 mg
`of nivolumab per kilogram and 3 mgofipilim-
`umab per kilogram; cohort 2a, 3 mg of niv-
`olumab per kilogram and 1 mgofipilimumab
`per kilogram; cohort 3, 3 mg of nivolumab per
`kilogram and 3 mg ofipilimumab per kilogram;
`cohort 4, 10 mg ofnivolumab per kilogram and
`3 mg of ipilimumab; and cohort 5, 10 mg of
`nivolumab per kilogram and 10 mg ofipilim-
`umab per kilogram.
`In the sequenced-regimen
`group, patients in cohorts 6 and 7 were treated
`with nivolumab at doses of 1 mg per kilogram
`and 3 mg per kilogram, respectively, every 2 weeks
`for up to 48 doses (Fig. $1 in the Supplementary
`Appendix).
`Patients could be followed for a total of 2.5
`yearsafter the initiation oftherapy. Patients with
`a complete response, a partial response, or stable
`disease for at least 24 weeks and subsequentdis-
`ease progression could be retreated withthe origi-
`nal regimen. Disease assessment was performed
`per protocol, with the use of computed tomog-
`raphy or magnetic resonance imaging, as appro-
`priate. For both regimen groups, tumor responses
`were adjudicated with the use of modified World
`Health Organization (WHO) criteria and immune-
`related criteria (see the Supplementary Appen-
`dix).° In the concurrent-regimen group,
`tumor
`assessments were performedat weeks 12, 18, 24,
`30, and 36 and then every 12 weeks thereafter.
`In the sequenced-regimen group, tumorassess-
`
`N ENGLJ MED 369;2
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`NEJM.ORG JULY 11, 20173
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`123
`
`

`

`ments were performed at week 8 and then every
`8 weeks thereafter.
`The safety evaluation was performed per pro-
`tocol. The severity of adverse events was graded
`according to the National Cancer Institute Com-
`mon Terminology Criteria for Adverse Events,
`version 3.0.1°
`
`STUDY OVERSIGHT
`
`ing toxicity, patients who withdrew fromthe study
`owing to reasons other than drug-related adverse
`events could be replaced. The protocol was amend-
`ed to permit the expansion of any concurrent
`regimen cohort during the dose-escalation phase
`to a maximum of 12 patients, with approval by
`the Early Development Advisory Committee. Two
`sequenced-regimen cohorts (6 to 16 patients each)
`were addedlater.
`
`The study protocol was approvedby the institution-
`al review boardsat the participating centers, and
`the study was conducted in accordance with the
`Declaration of Helsinki and International Con-
`ference on Harmonisation Guidelines for Good
`Clinical Practice. For additional safety oversight,
`an independent Early Development Advisory Com-
`mittee was responsible for reviewing and adjudi-
`cating individual high-grade adverse events as po-
`tentially dose-limiting and for guiding the study
`team on decisions regarding dose escalation and
`cohort expansion. All participating patients pro-
`vided written informed consent.
`The study was designed by the senior academic
`authors and the sponsor, Bristol-Myers Squibb.
`Study medications were provided by the sponsor.
`Data were collected by the sponsor and analyzed
`and interpreted in collaboration with the academic
`authors. Manuscript drafts were prepared by the
`authors with editorial assistance from a profes-
`sional medical writer paid by the sponsor. All the
`authors vouchfor the accuracy and completeness
`of the data reported and the adherence of the
`study to the protocol, andall the authors made the
`decision to submit the manuscriptfor publication.
`The protocol,
`including the statistical analysis
`plan, is available at NEJM.org.
`
`IMMUNOHISTOCHEMICAL ASSESSMENT FOR PD-L1
`
`Expression ofone ofthe ligands of PD-1, PD-L1,
`before treatment was measured by means of im-
`munohistochemical testing in formalin-fixed, par-
`affin-embedded tumorspecimenswiththe use of
`a rabbit monoclonal antihuman PD-L1 antibody
`(clone 28-8) and an automated assay developed
`by Dako. Antibody specificity was assessed by
`means of Western blotting against recombinant
`PD-L1 protein and lysates from PD-L1-express-
`ing and PD-L1-nonexpressingcell lines. An im-
`munohistochemical assay with and without the
`addition of antigen that competes with binding
`to the antibody was performed, with a comparative
`assessment of staining patterns in normal hu-
`mantissues. Analytic sensitivity, specificity, re-
`peatability, reproducibility, and robustness of the
`immunohistochemical assay were tested and met
`all prespecified acceptancecriteria. ‘Two patholo-
`gists, who were unaware ofthe clinical outcome,
`independently read and adjudicated scoresforall
`clinical specimens. A sample was defined as PD-
`L1—positive if at least 5% of the tumorcells ex-
`hibited membrane PD-L1 staining of any inten-
`sity in a section containingat least 100 cells that
`could be evaluated.5"!
`
`DOSE ESCALATION AND COHORT EXPANSION
`
`STATISTICAL ANALYSIS
`
`The study was initially planned to evaluate the
`concurrent regimen with the use of a standard
`3+3 design for the dose-escalation phase,
`fol-
`lowed by cohort expansion to a total of up to 16
`patients at the maximumdosesthat were associ-
`ated with an acceptablelevel of adverse events or
`the maximum administered dose. The period for
`evaluating dose-limiting toxicity for the purposes
`of dose escalation was 9 weeks. A modified defi-
`nition of dose-limiting toxicity was incorporated
`in the protocol. No doseescalation was allowed in
`an individual patient, and patients who had dose-
`limiting adverse events discontinued therapy.
`During the period for evaluating dose-limit-
`
`All 86 patients who had received treatment as of
`February 15, 2013, were included in the descrip-
`tion ofbaseline characteristics and the analyses
`of safety and absolute lymphocyte count. Analysis
`of PD-L1 staining included tumor specimensavail-
`able as of February 28, 2013. Theefficacy popula-
`tion consisted of 82 patients who had a response
`that could be evaluated, defined as those patients
`whoreceived at least one dose of study medica-
`tion, had measurable disease at baseline, and had
`one ofthe following: at least one tumor evalua-
`tion during treatment,clinical progressionofdis-
`ease, or death before the first tumor evaluation
`during treatment.
`
`124
`
`N ENGL) MED 369;2 NEJM.ORG JULY 11, 2013
`
`

`

`NIVOLUMAB PLUS IPILIMUMAB IN ADVANCED MELANOMA
`
`Adverse events were coded with the use ofthe
`Medical Dictionaryfor Regulatory Activities (MedDRA),
`version 15.1. Selected adverse events with poten-
`tial immunologic causes and those that require
`more frequent monitoring or intervention with im-
`mune suppression or hormone replacement were
`identified with the use of a predefined list of
`MedDRAterms. These are similar to events previ-
`ously described as immune-related adverse events
`or adverse events of special interest.°
`Best overall responses were derived program-
`matically from tumor measurements provided by
`the study-site radiologist and investigators accord-
`ing to the modified WHO criteria or immune-
`related responsecriteria.1' Complete and partial
`responses were confirmed by meansofat least
`one subsequent tumor assessment. The magnitude
`of the reduction in target lesions was assessed
`radiographically. A response was characterized as
`“deep” if a reduction of 80%or more from the
`baseline measurements was noted. Unconfirmed
`responses as ofthe date ofthis analysis were also
`included in an estimation of aggregate clinical
`activity.
`
`RESULTS
`
`BASELINE CHARACTERISTICS OF THE PATIENTS
`
`A total of 86 patients were treated from Decem-
`ber 2009 through February 2013; 53 patients re-
`ceived the concurrent regimen and 33 received
`the sequenced regimen. Baseline characteristics
`of the two regimengroups are shownin Table 1.
`A total of 38% of patients in the concurrent-
`regimen group and 100% of patients in the se-
`quenced-regimen group had received systemic
`therapy previously. The majority of patients had
`Mic disease(i.e., metastases to visceral sites other
`than skin, subcutaneous tissue, distant lymph
`nodes, or lung or distant metastases to any site
`combined with an elevated serum lactate dehy-
`drogenase [LDH] level), and more than 30% of
`patients had anelevated level of LDH. Most pa-
`tients (73%) enrolled in the sequenced-regimen
`cohorts had progression as assessed radiograph-
`ically during prior treatment with ipilimumab,
`
`Supplementary Appendix), Treatmentrelated ad-
`verse events were observed in 93% ofpatients,
`with the most commonevents being rash(in 55%
`of patients), pruritus (in 47%), fatigue (in 38%),
`and diarrhea (in 34%) (Table S1-B in the Supple-
`mentary Appendix). Grade 3 or 4 adverse events,
`regardless of attribution, were observed in 72%
`of patients, and grade 3 or 4 treatment-related
`events were noted in 53%, with the most common
`events being elevated levels oflipase (in 13% of
`patients), aspartate aminotransferase (in 13%),
`and alanine aminotransferase (in 11%). A total of
`6 of 28 patients (21%) had grade 3 or 4 treatment-
`related events that were dose-limiting.
`Serious adverse events related to the treatment
`were reported in 49% ofpatients in the concurrent
`regimen group (Table S1-C in the Supplementary
`Appendix), Commongrade 3 or 4 selected adverse
`events that were related to the therapy included
`hepatic events (in 15% ofpatients), gastrointesti-
`nal events (in 9%), and renal events (in 6%)
`(Table 2).
`Isolated cases of pneumonitis and
`uveitis were observed (Table S1-B in the Supple-
`mentary Appendix), a finding that is consistent
`with previous experience with monotherapy. A to-
`tal of 11 patients (21%) discontinued therapy ow-
`ing to treatment-related adverse events (Table $2
`in the Supplementary Appendix).
`The doses in cohort 3 (nivolumab at a dose of
`3 mg per kilogram and ipilimumabat a dose of
`3 mg per kilogram) exceeded the maximumdoses
`that were associated with an acceptable level of
`adverse events (three ofsix patients had asymp-
`tomatic grade 3 or 4 elevated lipase levels that
`persisted for >3 weeks). The doses in cohort 2
`(nivolumab at 1 mg per kilogram andipilimumab
`at 3 mg per kilogram) were identified as the
`maximum doses that were associated with an
`acceptable level of adverse events (grade 3 uveitis
`in one patient and grade 3 elevated levels of aspar-
`tate aminotransferase and alanine aminotransfer-
`ase in one).
`Amongthe 33 patients in the sequenced-reg-
`imen group, adverse events of any grade, regard-
`less of attribution, were observed in 29 patients
`(88%) (Table S1-A in the Supplementary Appen-
`dix). Treatment-related adverse events were ob-
`served in 24 patients (73%), with the most com-
`moneventsincluding pruritus (in 18%of patients)
`andelevated lipase levels (in 12%) (‘Table $1-B in
`the Supplementary Appendix). Grade 3 or 4 adverse
`events, regardless ofwhether they were attributed
`
`SAFETY
`
`Among the 53 patients in the concurrentregimen
`group, adverse events of any grade, regardless of
`whether they were attributed to the therapy, were
`observed in 98%of patients (Table $1-A in the
`
`N ENGL) MED 369;2 NEJM.ORG
`
`JULY 1), 2013
`
`

`

` The NEW ENGLAND JOURNALof MEDICINE
`
`Characteristic
`Age — yr
`Median
`
`Range
`
`Sex — no. (%)
`Male
`Female
`ECOG performance status — no. (%)7
`0
`1
`Unknown
`Disease status — no. (%)x
`Mla
`
`Mlb
`Mlc
`Unknown
`Lactate dehydrogenase — no. (%)
`<Upper limit of the normal range
`>Upper limit of the normal range
`Prior therapy — no. (%)
`
`Surgery
`Radiotherapy
`Systemic therapy
`Immunotherapy
`Interleukin-2
`BRAF inhibitor
`No. of prior systemic therapies — no. (%)
`
`Lesions — no. (%)
`
`Bone
`Central nervous system
`Liver
`Lung
`Lymph node
`Soft tissue or other organ
`
`
`
`Table 1. Baseline Characteristics of All Treated Patients.
`
`Concurrent Treatment
`(N=53)
`
`Sequenced Treatment
`(N=33)
`
`58
`
`22-79
`
`32 (60)
`21 (40)
`
`44 (83)
`8 (15)
`1 (2)
`
`8 (15)
`
`Ll (21)
`30 (57)
`4 (8)
`
`33 (62)
`20 (38)
`
`51 (96)
`11 (21)
`20 (38)
`9 (17)
`8 (15)
`3 (6)
`
`33 (62)
`
`14 (26)
`
`5 (9)
`
`1 (2)
`
`5 (9)
`0
`16 (30)
`25 (47)
`26 (49)
`34 (64)
`
`64
`
`23-89
`
`18 (55)
`15 (45)
`
`22 (67)
`11 (33)
`0
`
`5 (15)
`
`5 (15)
`18 (55)
`5 (15)
`
`21 (64)
`12 (36)
`
`31 (94)
`17 (52)
`33 (100)
`33 (100)
`1 (3)
`2 (6)
`
`0
`
`18 (55)
`
`10 (30)
`
`5 (15)
`
`1 (3)
`1 (3)
`13 (39)
`16 (48)
`8 (24)
`19 (58)
`
`* Treatment groups were not formally comparedin this phase1trial.
`{An Eastern Cooperative Oncology Group (ECOG) performance status of0 indicates that the patient is asymptomatic,
`and 1] indicates that the patient is ambulatory butrestricted in strenuous activity.®
`¢ Mlaindicates metastases to the skin, subcutaneoustissue, or distant lymph nodes; Mlb metastasesto the lung; and
`Mlc metastasestoall other visceral sites or distant metastases to any site combined with an elevated serum lactate
`dehydrogenase level.
`
`126
`
`N ENGL] MED 369:2 NEJM.ORG JULY 11, 2019
`
`

`

`
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`NIVOLUMAB PLUS IPILIMUMAB IN ADVANC
`
`ED MELANOMA
`
`
`
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`
`N ENGL) MED 369;2
`
`NEJM.ORG JULY 11, 2013
`
`127
`
`
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`to the therapy, were observed in 11 patients (33%),
`and grade 3 or 4 adverse events related to therapy
`were observed in 6 (18%), with an elevated lipase
`level as the most commonevent (in 6% ofpa-
`tients). Serious adverse events related to therapy
`were reported in 7 patients (21%) (Table S1-C in
`the Supplementary Appendix). Grade 3 or 4 endo-
`crine events were noted as treatment-related se-
`lected adverse events in 2 patients (Table $1-D in
`the Supplementary Appendix). One patient had
`grade 2 pneumonitis. Three patients (9%) dis-
`continued therapy owing to treatment-related ad-
`verse events (Table $2 in the Supplementary Ap-
`pendix).
`In both regimen groups, treatment-related ad-
`verse events were manageable and generally re-
`versible with the use of immunosuppressants (or
`hormone-replacement therapy for endocrinopa-
`thies) according to previously established algo-
`rithms.!2 Amongthe 86patients treated during
`the study, 28 of the 73 patients (38%) with drug-
`related adverse events were treated with sys-
`temic glucocorticoids. A total of 3 patients re-
`quired additional
`immunosuppressive therapy
`with infliximab (2 patients) or mycophenolate
`mofetil (1 patient). No treatment-related deaths
`were reported.
`
`CLINICAL ACTIVITY
`
`In the concurrent-regimen group, overall evi-
`dence ofclinical activity (conventional, uncon-
`firmed, or immune-related response or stable
`disease for 224 weeks) was observed in 65%of
`patients (95% CI, 51 to 78) (Table 3). The pro-
`found effect of the concurrent combination ther-
`apy is shown in the waterfall plot in Figure 1B.
`Responses were ongoing in 19 of 21 patients
`who had a response, with the duration ranging
`from 6.1 to 72.1 weeks at the time of data analy-
`sis (Table $3 in the Supplementary Appendix).
`Amongpatients who received the maximum
`doses associated with an acceptable level of ad-
`verse events (cohort 2, with nivolumab at a dose
`of 1 mg per kilogram and ipilimumab at a dose
`of 3 mg per kilogram), objective responses oc-
`curred in 9 of 17 patients (53%; 95% CI, 28 to
`77), including 3 with a complete response. All
`9 patients who had a response had tumor reduc-
`tion of 80% or more at their first scheduled as-
`sessment during treatment