New England journal of medicine.
`v. 369. no. 2 (July 11 2013)
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`This material may be protected by Copyright law runs 17 us. Codei
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`
`
`'l'hr NIEW ENGLAND JOURNAL of MEDICINE
`
`
`
`if
`
`ORIGINALARTICLE
`
`l
`
`From the Ludwig Center. Memorial
`Sloan-Kettering Cancer Center. New York
`UDWHMKCHMAR.NARWAML
`NH5“C£A.RfifiqSAflHEURh
`Yale University School of Medicine and
`Smilow Cancer Center. Yale—New Haven
`Hespital. New Haven. CT [H.K.. K.R..
`M.M.B.. A.C.. MS}: Dako North Ameri-
`ca. Carpinteria [XL]. and Bristol-Myers
`Squibb. Redwood City (AJ.K.} — both in
`California.- and Bristol-Myers Squibb.
`Princeton. NJ
`[I.L.. H.D.l.. W.F,. C.E.H..
`Q.H.. J.M.W.. All}. Address reprint re-
`quests to Dr. Wolcholr at Memorial Sloanv
`Kettering Cancer Center. 12?5 York Ave,
`New York. NY 10065. or at wolchoki@
`rnskcccrg.
`
`This article was published onJune 2. 2013.
`at NEjM.org.
`
`N Englj Med EUI 3:369:122-33.
`DOI:10.1056fNEJMoaUflZ369
`Copyright it) 201'} Massachusetts Medical SDEII‘JY
`
`Nivolumab plus Ipilimumab
`in Advanced Melanoma
`
`Jerltl D. Wlerjlloli, Mil. Pl'1,l'J.. Harriet Kluger, M.D.. Margaret K. Callahan. M.D., PHD.
`Michael A. Postow. Mil. Naiycr' A. Rizvi, M.D.. Alexander M. Lesokhin. M.D..
`Neil H. Segnl. M.D.. Pl1.D.. Charlotte E. Ariyan. M.D.. Phil. Ruth-Ann Gordon, B.S.N..
`Kathleen Pet-cl, M.S.. Matthew M. Burke. M.B.A.. M.S.N.. Anne Caldwell. B.S.N..
`Sleplianic A,l'ifti)ll€.‘t1berg.B.A.. Blessing U. Agunwamba. BA. Xiaoling Zhang. Ph.D.,
`Israel Lowy. MD. Ph.D.. Hector David lnzunaa. M.D.. William Feely, M.S..
`Christine E. l-lorale. Phil. Quan Hang. Phil. Alan]. Korman. PhD,
`Jon M. Wigginton, MIL. Ashok Gupta. M.D.. Phil. and Mario Sznol. MD.
`
`ABSTRACT
`
`BACKGROUND
`
`In patients with melanoma, ipilimumab (an antibody against cytotoxic T—lymphocyte—
`associated antigen 4 [CTLA-4D prolongs overall survival. and nivolumab [an anti—
`body against the programmed death 1 [PD-1] receptor] produced durable tumor
`regression in a phase 1 trial. On the basis oftheir distinct immunologic mechanisms
`of action and supportive preclinical data, we conducted a phase 1 trial of' nivolu mab
`combined with ipilimumab in patients with advanced melanoma.
`METHODS
`
`We administered intravenous doses ofnivolumab and ipilimumab in patients every
`3 weeks for 4 doses. Followed by nivolumab alone every 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 with ipilim-
`umab received nivolumab every 2 weeks for up to 48 doses.
`R E su us
`
`A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33
`received sequenced treatment. The objective-response rate {according to modified World
`l-ieaith Organization criteria) for all patients in the concurrent-regimen group was 40%.
`Evidence of clinical activity (conventional. unconfirmed. or i m mane—related response or
`stable disease for 224 weeks] was observed in 65% of patients. At the maximum doses
`that were associated with an acceptable level of adverse events {nivolurnab at a dose of
`
`1 mg per kilogram of body weight and ipilimumab at a dose of‘3 mg per kilogram). 53%
`of patients had an objective response. all with tumor reduction 0F80% or more. Grade 3
`or 4 adverse events related to therapy occurred in 53% of patients in the concu rrenr—regi-
`men group but were 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%.
`coucrusious
`
`Concurrent therapy with nivoiumab and ipilimumab 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 tumor regression in a substantial pro-
`portion of patients. [Funded by Bristol-Myers Squibb and Ono Pharmaceutical;
`ClinicalTrials.gov number. NC‘1‘01024231J
`
`122
`
`n ENGLJ MED 369:2 mimosa jUL‘r II. 2013
`
`

`

`NIV()].UMAB PLUS Il'II.|MUMAI1 IN ADVANCED MELANOMA
`
`scams FROM IMMUNE SURVEILLANCE Is
`
`a recognized feature of cancer; therefore,
`the development oftherapies to enhance tu—
`mor immunity is a rational treatment strategy}-2
`lmmune checkpoint blockade is one approach that
`has induced regressions in several types ofcancer.
`Ipilimumab, a fully human. IgG1 monoclonal an-
`tibody blocking cytotoxic T—lymphocyte—associat-
`ed antigen 4 [CTLA—4), improved overall survival in
`patients with advanced melanoma)»4 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.“
`C’I‘LA—4 and PD-l appear to play complemen-
`tary roles in regulating adaptive immunity. Where-
`as PD-l contributes to T—cell exhaustion in periph-
`eral tissues, C‘I‘LA-4 inhibits at earlier points in
`'I'-cell activation. In preclinical models, combined
`blockade of I‘D—1 and CTLA-4 achieved more pro-
`
`nounced antitumor activity than blockade of either
`pathway alone."~’ On the basis of these observa—
`tions, we conducted a phase 1 study to investigate
`the safety and efficacy of combined CTLA-4 and
`I’D-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.
`
`M ETHODS
`
`PITIENTS
`
`Eligible patients were at least 18 years ofage; had
`received a diagnosis ofmeasurable, unresectable,
`stage III or IV melanoma; had an Eastern Coop-
`erative Oncology Group performance status oft)
`(asymptomatic) or I (ambulatory but restricted in
`strenuous activity)”; had adequate organ function;
`and had a life expectancy of at least 4 months.
`Exclusion criteria were active, untreated central
`
`nervous system metastasis, a history ofautoim-
`mune disease, previous therapy with T—cell mod-
`ulating antibodies {excluding ipilimumab for pa-
`tients in the sequenced-regimen cohorts), human
`immunodeficiency virus infection, and hepatitis
`1% 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 of clinical deterioration,
`
`or a history of high-grade adverse events related
`to ipilimumab were excluded.
`
`STUDY DESIGN
`
`In this phase 1 study we treated successive cohorts
`of patients with escalating doses of intravenous
`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. 81 in the Sup-
`plementary Appendix, available with the full text
`oftllis article at NEJM.org}. The combined treat-
`
`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 ofnivolumab
`and ipilimumab were kept constant.
`The protocol-specified dose levels in the co-
`
`horts were as follows. In the concurrent-regimen
`group, cohort I was designated to receive 0.3 mg
`ofnivolumab per kilogram of body weight and
`3 mg of ipilimumab per kilogram; cohort 2, 1 mg
`of nivolumab per kilogram and 3 mg of ipilim-
`umab per kilogram; cohort 2a, 3 mg of niv-
`olumab per kilogram and 1 mg of ipilimumab
`per kilogram; cohort 3, 3 mg of nivolumab per
`kilogram and 3 mg ofipilimurnab per kilogram;
`cohort 4, 10 mg ofnivolumab per kilogram and
`3 mg of ipilimumab; and cohort '3, 10 mg of
`nivolumab per kilogram and 10 mg of ipilim-
`umab per kilogram.
`In the sequenced-regimen
`group, patients in cohorts o and 7 were treated
`with nivolumab at doses of1 mg per kilogram
`and 3 mg per kilogram, respectively, every 2 weeks
`for up to 48 doses (Fig. 51 in the Supplementary
`Appendix].
`Patients could be followed for a total of 2.5
`
`years after the initiation oftherapy. Patients with
`a complete response, a partial response, or stable
`disease for at least 24 weeks and subsequent dis-
`ease progression could be retreated with the 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-
`dixJI.‘l
`In the concurrent-regimen group,
`tumor
`assessments were performed at weeks 12, 18, 24,
`30, and 36 and then every 12 weeks thereafter.
`In the sequenced-regimen group, tumor assess—
`
`N tum; Mto 369:2
`
`Musician
`
`JULY II. 2013
`
`123
`
`

`

`'l'hr Nl-LW'
`
`li.Nt_il.J\Nl') [OURNAL nl' MEDICINI‘.
`
`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 Natioml Camber histitute (harn-
`mon Terminology Criteria for Adverse Events,
`version 3.0.1"
`
`STUDY OVERSIGHT
`
`ing toxicity, patients who withdrew from the 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. 'l‘wo
`sequenced-regimen cohorts [6 to 16 patients each]
`were added later.
`
`The study protocol was approved by the institution—
`al review boards at 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 vouch for the accuracy and completeness
`of the data reported and the adherence of the
`study to the protocol, and all the authors made the
`decision to submit the manuscript for publication.
`The protocol,
`including the statistical analysis
`plan, is available at NE]M.org.
`
`IMMUNOHISTOCHEMICAL assessment roe ro-u
`
`Expression of one ofthe ligands of l’D-l, PD-Ll.
`before treatment was measured by means of im-
`munohistochemical testing in formalin-fixed, pat—
`affin-emhedded tumor specimens with the use of
`a rabbit monoclonal antihuman PD-Ll antibody
`[clone 28—8) and an automated assay developed
`by Dako. Antibody specificity was assessed by
`means of Western blotting against recombinant
`PD-Ll protein and lysates from I‘D-Ll—exprcss—
`ing and PD-IJ—nonexpressing cell 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-
`man tissues. Analytic sensitivity, specificity, re-
`peatability, reproducibility, and robustness ofthe
`immunohistochemical assay were tested and inc!
`all prespeciiied acceptance criteria. Two patholo-
`gists, who Were unaware ofthe clinical outcome.
`independently read and adjudicated scores for all
`clinical specimens. A sample was defined as PD-
`Llepositive if at least 5% of the tumor cells ex-
`hibited membrane PD—Ll staining of any inten-
`sity in a section containing at least 100 cells that
`could be evaluated?“
`
`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 10
`patients at the maximum doses that were associ-
`ated with an acceptable level 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 ofdosc—limiting toxicity was incorporated
`in the protocol. No dose escalation was allowed in
`an individual patient, and patients who had dose—
`limiting adverse events discontinued therapy.
`During the period for evaluating dose-limit-
`
`All so patients who had received treatment as of
`February 1'5, 2013, were included in the descrip-
`tion of baseline characteristics and the analyses
`of safety and absolute lymphocyte count. Analysis
`of I‘D-L1 staining included tumor specimens avail-
`able as of February 28, 2013. The efficacy popula-
`tion consisted of 82 patients who had a response
`that could be evaluated, defined as those patients
`who received at least one dose of study medica—
`tion, had measurable disease at baseline, and had
`one of the following: at least one tumor evalua-
`tion during treatment. clinical progression ot‘dis-
`ease, or death before the first tumor evaluation
`
`during treatment.
`
`124
`
`N ENoL] MED 369:2
`
`NEJMDRG jun 11,2013
`
`

`

`N1U{)l.llMAR PLUS ll'llJMUMAB IN ADVANCED MELANDMA
`
`Adverse events were coded with the use of'the
`
`Mrdiral Ditrioiiaryjor Regulatory Activities [MedDRAL
`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 or" a predefined list of
`McdDRA terms. These are similar to events previ-
`ously described as immune-related adverse events
`or adverse events of special interest.q
`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 response criteria.“ Complete and partial
`responses were confirmed by means of at least
`one subsequent tumor assessment. The magnitude
`of the reduction in target lesions was assessed
`radiographically. A response was characterized as
`“deep" il‘a reductiori 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.
`
`RESU LTS
`
`Supplementary Appendix). 'l‘reatment-related ad-
`verse events were observed in 03% of patients.
`with the most common events being rash (in 55%
`of patients), pruritus (in 47%), Fatigue (in 38%),
`and diarrhea (in 34%) ('l‘able 81—3 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 aminotransferasc [in 13%),
`and alanine aminotransfcrase (in 11%). A total of
`
`{J oF28 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% of patients in the concurrent—
`regimen group (Table Sl-C in the Supplementary
`Appendix). Common grade 3 or 4 selected adverse
`events that were related to the therapy included
`hepatic events (in 15% of' patients), gastrointesti-
`nal events (in 9%). and renal events (in 6%)
`
`BASELINE CHARACTERISTICS OF THE PATIENTS
`
`A total ot‘So 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
`ofthe two regimen groups are shown in 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
`Mlc 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 an elevated level of LDH. Most pa-
`tients {73%) enrolled in the sequenced-regimen
`cohorts had progression as assessed radiograph—
`ically during prior treatment with ipilimumab.
`
`SAFETY
`
`Aiming the 53 patients in the concurrent-regimen
`group. adverse events of any grade, regardless of"
`whether they were attributed to the therapy, were
`observed in 98% of patients (Table Sl—A in the
`
`Isolated cases of pneumonitis and
`(Table 2).
`uveitis were observed (Table 81-8 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 82
`in the Supplementary Appendix).
`The doses in cohort 3 (nivolumab at a dose of
`
`3 mg per kilogram and ipilimumab at a dose of
`3 mg per kilogram} exceeded the maximum doses
`that were associated with an acceptable level of
`adverse events (three of six patients had asymp-
`tomatic grade 3 or 4 elevated lipase levels that
`persisted for 23 weeks). The doses in cohort 2
`(nivolumab at 1 mg per kilogram and ipilimumab
`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 ofaspar-
`tate aminotransferasc and alanine aminotransfer-
`ase in one).
`
`Among the 33 patients in the sequenced-reg-
`imen group. adverse events ofany grade, regard—
`less of attribution, were observed in 2‘) patients
`(88%] (Table Sl-A in the Supplementary Appen-
`dix).
`'l‘reatment-related adverse events were ob—
`
`served in 24 patients (73%), with the most com-
`mon events including pruritus (in 18% ofpatients]
`and elevated lipase levels (in 12%) (Table 31-3 in
`the Supplementary Appendix). Grade 3 or 4 adverse
`events, rcga rdless ot‘whether they were attributed
`
`N ENGLJ MED 369:2
`
`NE]M.ORC.
`
`jULv 11.2013
`
`

`

`Til: NEW ENGLAND [OURNAL of MEDICINE
`
`
`
`Table 1. Baseline Characteristics of All Treated Patients}r
`
`Concurrent Treatment
`(N = 53]:
`
`Sequenced Treatment
`l” = 33}
`
`Characteristic
`Age— yr
`Median
`
`Range
`
`Sex — no. {‘36)
`
`Male
`
`Female
`ECOG performance status — no. [%)‘i
`
`o
`
`1
`
`Unknown
`
`Disease status — no. (%)$
`Mla
`
`Mlb
`
`Mlc
`Unknown
`
`Lactate dehydrogenase — no. [%}
`
`sUpper limit ofthe normal range
`
`bUpper limit ofthe normal range
`Prior therapy — no. [96)
`
`Surgery
`
`Radiotherapy
`
`Systemic therapy
`
`immunotherapy
`
`interleukinv2
`BRAF inhibitor
`
`No. ofprior systemic therapies — no. (96)
`
`Lesions — no. [96)
`
`Bone
`
`Central nervous system
`
`Liver
`Lung
`
`Lymph node
`
`
`
`58
`
`22—?9
`
`32 (60}
`
`21 {40}
`
`44 (83}
`
`3 (15}
`
`1 [2]
`
`8 (15]
`
`11 (21)
`
`30 [5?]
`4 (3)
`
`33 (62]
`
`20 (38]
`
`51 {96)
`
`ll {21)
`
`20 [38)
`
`9 (1?)
`
`8 (15)
`3 (a)
`
`33 [52)
`
`14 (26]
`
`5 (9)
`
`1 (2)
`
`5 (9)
`
`0
`
`16 {30)
`25 (4:)
`
`26 (49]
`
`54
`
`23—39
`
`13 (55}
`
`15 (4S)
`
`22 (6?)
`
`11 (33)
`
`0
`
`5 {15}
`
`5 [15)
`
`13 [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 (43]
`
`3 (24}
`
`Soft tissue or other organ
`
`34 (64]
`
`19 (53)
`
`* Treatment groups were not formallyr compared in this phase 1 trial.
`'i'fim Eastern Cooperative Oncology Group [ECOG] performance status oFO indicates that the patient is asymptomatic.
`and 1 indicates that the patient is ambulatory but restricted in strenuous activity.3
`it Mla indicates metastases to the skin. subcutaneous tissue. or distant lymph nodes: Mlb metastases to the lUng: and
`Mic metastases to all other visceral sites or distant metastases to any site combined with an elevated serum lactate
`dehydrogenase level.
`
`126
`
`N ENC-L] MED 369:2 mamono JULY ii. 2013
`
`

`

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`”amour.
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`
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`

`'i'lrr Nl-IW ENGLAND IOURNAI, DI MEDICLINE
`
`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 common event (in 6% of pa-
`tients). Serious adverse events related to therapy
`
`were reported in 7 patients (21%) (Table 81—0 in
`the Supplementary Appendix). Grade 3 or 4 endo-
`crine events were noted as treatment-related se-
`
`lected adverse events in 2 patients (Table Sl-D in
`the Supplementary Appendix). One patient had
`grade 2 pneumonitis. Three patients (9%} dis-
`continued therapy owing to treatment-related ad-
`verse events (1‘ab1e 82 in the Supplementary Ap—
`pendix).
`In both regimen groups, treatment-related ad—
`verse events were manageable and generally re-
`versible with the use ofimmunosuppressants (0r
`
`hormone-replacement therapy for endocrinopa-
`thies] according to previously established algo-
`rithms.12 Among the 86 patients treated during
`the study, 28 ofthe 73 patients (38%) with drug-
`related adverse events were treated with sys-
`
`temic glucocorticoids. A total of 3 patients re-
`quired additional
`immunosupprcssive therapy
`with inflixiniab (2 patients] or mycophenolate
`mofetil (1 patient]. No treatment-related deaths
`were reported.
`
`CLINICAL ACTIVITY
`
`Clinical activity was observed in both regimen
`groups (Table 3, and Table S4 in the Supplemen-
`tary Appendix).
`[n the concurrent-regimen co-
`horts, across all dose levels, confirmed objective
`
`responses according to modified WHO criteria
`were observed in 21 of 52 pat