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
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`JOURNAL of MEDICINE
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`VOL. 369 N0. 2
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`l-LS'I‘AIIIJSI-Ilil) IN 1812
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`JULY 11, 2013
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`NI-I]M.0ut;
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`110
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`101
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`103
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`THIS WEEK AT NE}M.DRG
`
`PERSPECTIVE
`
`Guantanamo Bay: A Medical Ethics—free Zone?
`OJ. Annas, 5.3. CH'JSIZJ)‘, and |
`.I-I. Gloritz
`Force—Feeding. Autonomy, and the Public
`Interest M.I..C3r'oss
`
`105
`
`Failure to Launch? The Independent Payment
`Advisory Board’s Uncertain Prospects
`J. Ober'larldei and M. Mm'iisori
`The Gross Domestic Product and Health Care
`Spending V.R. FIJCI'I'S.
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`10'?
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`111
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`122
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`134
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`145
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`ORIGINAL ARTICLES
`
`Retinoic Acid and Arsenic Trioxide
`for Acute Promyelocytic Leukemia
`F. Lo-Coco and Others.
`
`Nivolutnab plus [pilimumab in Advanced Melanoma
`JD. Woltii'iok an d Others
`Safety and Tumor Responses with Lambrolizumab
`[Anti—PD-I) in Melanoma
`O. Hamid and Others
`
`Cardiovascular Effects oflntensive Lifestyle
`Intervention in Type 2 Diabetes
`The Look AHLAD Research Group
`
`[55
`
`US. Hospitalizations for Pneumonia
`after a Decade of I’neumococcal Vaccination
`M.R.(jl'il'lir1and Others
`Gina.
`
`thunni K- piihlislmi Ivy IIII‘ MAssmaIUSI-z'rrs II-llv'.l‘)l(.'.l\l.SUCH-211'
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`Brief Report: Delayed Puberty and Estrogen Resistance
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`IMAGES IN CLINICAL MEDICINE
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`Simultaneous Gangrene ofBoth Left Extremities
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`A Receding Hairline
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`CASE RECORDS OF THE MASSACHUSETTS
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`Targeting Agents Alone to Cure Acute
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`CLINICAL IMPLICATIONS OF BASIC RESEARCH
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`[hr NliW ENGLAND IOURNAI. of MEDICINE
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`
`ORIGINALARTICLE
`
`l
`
`Safety and Tumor Responses
`with Lambrolizumab (Anti—PD-l) in Melanoma
`
`Orr-id Han-rid. MD. Caroline Robert.M.D..Pl1.D..AdilDaud,M_D..
`
`F, Stephen Hodi. M.D.. chvlen ku. MD, Ph.D.. Richard Kciiord. M.D.. Ph.D..
`Jc-dd D. Wdchok. M.D_. Phi). Peter Hersey. M.D.. Ph.D.. Richard W.Josepl:_ M.D..
`jel'i'r'ey S. Weber. M.D_. PhD. Roxana Dronca. M11. Tara C. Garigadhar, M.D..
`Amita Patnaik, Mil, Hassane Zarour. M.D., Anthony M.Joshua, MB. 35.. PhD,
`Kevin Gergich. M.A..lcroen Elassaiss-Schaap, Phil. Alain Algazi. M,D_.
`Christine Marcus. M.D_. Peter Boasberg. MD. Paul C, Tumeh. MD.
`Bartosz Chit-tielowski. M_D., Ph.D.. Scot W. Ebbinghaus. M.D_.
`Xiaoyun Nit ole Li. Pli_D.. 5. Peter Kong. Ml). and Antoni Rihas. M.D.. PhD.
`
`ABSTRACT
`
`nacxonouno
`
`From the Angeles Clinic and Research in-
`stitute (O.H.. RB.) and the University of
`California. Los Angeles (PCT. B.C_. AR.)
`— both in Los Angeles; Institute Gustave
`Roussy. Villejuii‘. France {C.R.. CMJ: Uni-
`versity of California. San Francisco. San
`Francisco {A.D..A.A.)‘. Dana—FarberCanv
`cer Institute. Boston {F.S.H.}: University
`of Texas MD. Anderson Cancer Center.
`
`Houston {W.-J.H.}; Westmead Hospital
`and Melanoma Institute Australia. Univ
`versityofSydney. Sydney {R.K.}. and Kolling
`Institute, Melanoma Institute of Austra-
`lia and Newcastle Melanoma Unit. New-
`castle, NSW (P_H.} — both in Australia:
`Memorial Sloan-Kettering Cancer Center.
`NewI York U.D.W.); Mayo Clinic.Jacl<son-
`ville [R.W.J.). and H, Lee Moffitt Cancer
`Center. Tampa U.S.W.) — both in Florida:
`Mayo Clinic. Rochester. MN {R.D.}.‘
`Abramson Cancer Center ofthe University
`of Pennsylvania. Philadelphia {T.C.G.}:
`South Texas Accelerated Research Thera-
`peutics. San Antonio {AR}; University of
`Pittsburgh. Pittsburgh {H2}; Princess
`MargaretCancer Centre. Toronto {A.MJ.}:
`and Merck Sharp and Dohme. White-
`house Station. NJ (KG. J.E.-S.. S.W.E..
`X.N_L_. S.P.K.}. Address reprint requests
`to Dr. Ribas at the Department of MediA
`cine. Division of HematologyAOncologv.
`Jonsson Comprehensive Cancer Center.
`University ofCalil'ornia. Los Angeles. 11-
`934 Factor Bldg. 10833 Le Conte Ave..
`Los Angeles.CA90095-l?82.orataribas@
`mednet.ucla.edu.
`Drs. Hamid. Robert. Daud. Kang. and Ri-
`bas contributed equally to this article.
`This article was published on June 2.
`2013. at NEJM.org.
`N Engl] Med 2013369111444.
`D01;10.105tinyEjMoal305133
`Copyright to 2013 Massachusetts Marika-l Smitty.
`
`The programmed death 1 (PD-1) receptor is a negative regulator OFT-cell effector
`meehanisms that limits immune responses against cancer. We tested the anti—PD-l
`
`antibody lambrolizumab [previously known as MK-3475} in patients with advanced
`melanoma.
`
`METHODS
`
`We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of
`body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with
`advanced melanoma, both those who had received prior treatment with the im—
`mune checkpoint inhibitor ipilimumab and those who had not. Tumor responses
`were assessed every 12 weeks.
`nesuns
`
`A total of 135 patients with advanced melanoma were treated. Common adverse
`events attributed to treatment were fatigue. rash. pruritus, and diarrhea; most of
`the adverse events were low grade. The confirmed response rate across all close
`cohorts, evaluated by central radiologic review according to the Response Evalua-
`tion Criteria in Solid Tumors tRECIST), version 1.1, was 38% [95% confidence in-
`
`terval [Cl]. 25 to 44], with the highest confirmed response rate observed in the
`cohort that received 10 mg per kilogram every 2 weeks [52%; 95% CI, 38 to 66). The
`response rate did not differ significantly between patients who had received prior
`ipilimumab treatment and those who had not (confirmed response rate. 38% [95%
`CI. 23 to 55] and 37% [95% CI. 26 to 49]. respectively]. Responses were durable in
`the majority or” patients [median follow-up. 11 months among patients who had a
`response): 81% of the patients who had a response [42 of 52) were still receiving
`treatment at the time of analysis in March 2013. The overall median progression—free
`survival among the 135 patients was longer than 7 months.
`CONCLUSIONS
`
`In patients with advanced melanoma, including those who had had disease pro-
`gression while they had been receiving ipilimumab. treatment with lambrolizu-
`mab resulted in a high rate of sustained tumor regression, with mainly grade 1
`or 2 toxic effects. (Funded by Merck Sharp and Dohme; Clinical’l‘rials.gov num-
`ber. NCT01295827.)
`
`134
`
`NENoLJMED369;2
`
`NEJMKJRC.
`
`JULYII.2013
`
`

`

`LAMBROLIKUMAB IN MELANOMA
`
`ANGER L-‘vOLves To uxntorr MULTIPLE
`
`mechanisms in order to avoid immune-
`
`cell recognition and antitumor effector
`functions, thereby limiting the clinical benefits
`of immunotherapy strategies. Antibodies that
`block the inhibitory receptor cytotoxic T—lympho-
`eyte—associated antigen 4 (CTLA—4], such as ipi-
`limumab, have been shown to release one of
`
`these negative immune regulatory pathways.
`leading to durable responses in a subgroup of
`patients with metastatic melanoma and an overall
`survival benefit in patients with metastatic mela-
`noma.“2 The programmed cell death 1 (PD-1]
`receptor is another inhibitory receptor expressed
`by T cells preferentially with long—term exposure
`to antigens.
`Its primary ligand,
`I’D-L1
`(also
`known as B7-H1 or C0274),
`is
`frequently ex-
`pressed within the tumor microenvironment. in-
`cluding cancer cells and tumor-infiltrating mac—
`rophages. The PD—I receptor has a second ligand,
`I’D-L2 {also known as B7-DC or CD273), that is
`
`preferentially expressed by antigen-presenting
`cells.“ In tumor models,
`I’D-1 negatively regu—
`lates the effector phase ofT-cell responses after
`ligation ofPD—Ll expressed within the tumor.‘I It
`has been postulated that antibodies that block
`the interaction between PD—l and PD—Ll
`in tu—
`
`mors may preferentially release the cytotoxic
`function oftuinor-specific T cells with fewer sys—
`temic toxic effects than those that are seen with
`
`other immune checkpoint inliibitors.‘-"‘"
`Two large, dose-escalation, phase 1 clinical
`trials evaluating the safety of the antimPD-l anti-
`body nivolumab [formerly known as BMS9365'38)
`and the anti—PD-Ll antibody BMS‘BGSS‘) showed
`significant antitumor activity in patients with
`advanced melanoma, lung carcinoma, and renal-
`cell carcinoma, among other cancers, thus vali-
`dating the l)D—1—-PD-L1 axis as a therapeutic tar-
`get?" Most tumor responses were durable beyond
`1 year.“ Toxic effects were generally of low grade.
`Lambrolizumab (previously known as MK—3475}
`is a highly selective. humanized monoclonal
`lgG4~kappa isotype antibody against PD-1 that
`is designed to block the negative immune regu-
`latory signaling of the PD-l receptor expressed
`by T cells. The variable region sequences of a
`very-high—affinity mouse antihuman I’D-1 anti-
`body (dissociation constanr, 28 pM) were graft-
`ed into a human IgG4 immunoglobulin with a
`stabilizing 5228p Fc alteration. The [gG4 immu—
`noglobulin subtype does not engage Fc receptors
`
`or activate complement. thus avoiding cytotoxic
`effects ofthe antibody when it binds to the '1‘ cells
`that it is intended to activate. In T-cell activation
`
`assays that used human donor blood cells, the
`50% effective concentration was in the range of
`0.1 to 0.3 nM [unpublished data). The first dose-
`escalation phase I study involving patients with
`solid tumors showed that lambrolizumab was
`
`safe at the dose levels tested (1 mg per kilogram
`of body weight, 3 mg per kilogram, and 10 mg
`per kilogram. administered every 2 weeks) with-
`out reaching a maximum tolerated dose. In ad—
`dition, clinical responses were observed at all
`the dose levels.In We report here the safety and
`antitumor activity of three dosing regimens of
`lambrolizumab that we evaluated in patients with
`advanced melanoma.
`
`
`
`
`METHODS
`
`
`51'qu OVERSIGHT
`
`This study was sponsored by Merck Sharp and
`Dohme, which provided the study drug and
`worked jointly with the senior academic authors
`to design the study. collect the data, and inter-
`pret the study results. The data were analyzed by
`a statistician employed by the sponsor and by the
`senior academic authors. All the authors made the
`
`decision to submit the manuscript for publication,
`vouch for the accuracy and completeness of the
`data, and attest that the study was conducted as
`specified in the protocol, which is available with
`the full text ofthis article at NEJM.org. The pro-
`tocol and its amendments were approved by the
`relevant institutional review boards or ethics com-
`
`mittees, and all participants provided written in—
`formed consent. All drafts ofthe manuscript were
`written by the corresponding author with input
`from the other authors. The sponsor provided as-
`sistance with the preparation ofthe manuscript.
`Aside from the authors and those listed in the
`
`acknowledgments, no others contributed to the
`preparation ofthe manuscript.
`
`sruov DESIGN
`
`The primary objective ofthis study was to evalu-
`ate the safety profile oflambrolizumab. The sec—
`ondary end point was a preliminary analysis of
`the antitumor activity oflambrolizumab, both in
`patients who had received prior treatment with
`ipilimumab and in those who had not. After
`dose escalation oflambrolizumab to a maximum
`
`N ENGL] into 369;: NEJMJJRG jIJLv n. 2013
`
`135
`
`

`

`'l'llt NEW ItNliLAND HIURNAI. of MEDICINE
`
`administered dose of 10 mg per kilogram every
`2 weeks,” an expansion cohort [Part B of the
`study) was initiated, with eligibility restricted to
`patients with advanced melanoma. In Part B of
`the study. which we report on here. the initial
`cohort of patients who were enrolled received
`lambrolizumab as a 30-minute intravenous infu—
`
`sion, every 2 weeks at a dose of 10 mg per kilov
`gram; patients enrolled in additional cohorts in
`Part B received lambrolizumab as a 30—minute
`
`intravenous infusion every 3 weeks at a close of
`2 mg per kilogram or 10 mg per kilogram in se-
`quential or concurrent cohorts without random-
`ization. The study therapy was continued until
`disease progression was confirmed. unacceptable
`toxic effects developed. or consent was with-
`drawn. Patients in whom a scheduled scan showed
`
`initial disease progression were allowed to con—
`tinuc receiving treatment until a confirmatory
`scan was obtained at least 1 month later. Patients
`
`underwent a mandatory baseline biopsy and op-
`tional biopsies during the course ofthc trial for
`biomarker studies. Safety evaluations [clinical
`and laboratory) were performed at baseline and
`before each dose of lambrolizumab was ad min-
`
`istered. No premedications were administered
`before lambrolizumab infusions. The first sched-
`
`not require patients who were asymptomatic to
`undergo screening brain imaging; however, pa—
`tients with previously treated brain metastases
`
`were required to undergo baseline imaging by
`means of computed tomographic scanning or
`magnetic resonance imaging and to have had no
`evidence of central nervous system progression
`for 8 weeks. Major exclusion criteria were a mcla-
`
`noma ofocular origin. prior therapy with a I’D-1
`or [TD—L1 blocking agent, current systemic immu—
`nosuppressive therapy. or active infections or auto—
`immune diseases.
`
`PHARMACOKINETIC ANALYSIS
`
`Peak—level and trough—level blood samples for
`pharmacokinetic analysis were obtained from
`patients at the initiation of treatment. Trough
`samples were also obtained approximately every
`12 weeks for the first 12 months ofthe study and
`every 6 months thereafter. The serum concentra-
`tion of lambrolizumab was quantified with the
`use ofa validated electrochemiluminescent assay
`with a lower limit ofquantifieation of 10 ng per
`milliliter.
`
`STATISTICAL ANALYSIS
`
`Data from 135 patients with melanoma who
`
`uled assessment oftutnor response was performed
`12 weeks after the first dose of [ambrolizumab
`
`were enrolled and treated according to protocol
`amendments 02, 03. and 04 were used for the
`
`and every 12 weeks thereafter. The evaluation of
`tumor response was made by investigators at the
`study site and by a central imaging vendor [Per—
`ceptive Informatics).
`
`PATIENTS
`
`Patients were eligible for participation in Part B
`ofthe study ifthey were 18 years ofage or older,
`had measurable metastatic or locally advanced
`unresectable melanoma, and had adequate per-
`formance status and organ function (according
`to criteria listed in the protocol]. The cohorts of
`patients who had not received prior treatment
`with ipilimumab were restricted to patients who
`had received no more than two prior regimens of
`systemic therapy. The cohorts of patients who
`had received prior therapy with ipilitnumab in-
`cluded only patients who had full resolution of
`ipilimumab-related adverse events and no history
`of severe immune-related adverse events associat-
`
`ed with ipilimumab therapy. Patients were allowed
`to enter the trial 6 weeks after the last dose of
`
`ipilimumab was administered. The protocol did
`
`analysis of adverse events. Ofthe 135 patients,
`117 had radiographically measurable disease as
`assessed by means of central radiologic review
`and were included in the efficacy analysis of re-
`sponses according to central review. All other
`efficacy analyses {an analysis of response on the
`basis ofasseSsment by the investigator, progres-
`sion—free survival. and overall survival] were
`based on data from all 135 patients. Patients
`were included in the analysis if they received a
`first dose of study medication by September (1,
`2012. Efficacy and safety data that were available
`as of February 1, 2013, were included in all the
`analyses. The efficacy analysis included two end
`points: overall responses derived from investigator—
`reported data. with assessment according to
`immune-related response criteria [135 patients)”;
`and overall responses derived from indepen-
`dent. central, blinded radiologic review, with
`assessment according to the Response Evalua-
`tion Criteria in Solid 'l‘umors (RECIS‘I‘), version 1.1
`
`[117 patients] [see Table 51 in the Supplemen—
`tary Appendix, available at NEWLorg.
`for re—
`
`136
`
`N ENGL] MED 369;: NEJMDRC.
`
`JULY 11, 2mg,
`
`

`

`LAM BRULIZUMA I! IN M ELANOMA
`
`
`
`
`Table 1. Baseline Characteristics of the Patients. According to Cohort.
`
`
`
`Characteristic
`
`Sex
`
`Male
`Female
`Age 1er
`Mean
`
`Range
`Racee
`
`Asian
`White
`ECOG performance statusj'
`Unknown
`0
`1
`BRAF mutation status
`
`Mutant
`Nonmutant
`Unknown
`Brain metastasis
`
`Yes
`No
`Lactate dehydrogenase
`Normal
`Elevatedi
`Unknown
`M staging ofextent of metastasis
`tux
`M0
`Mla
`Mlb
`MIC
`Unknown
`Previous treatmentfi
`
`No prior systemic treatment
`Immunotherapy. excluding
`ipilimumab
`
`10 mgfkg Every 2 Wk
`No Prior
`Prior
`Ipilimumab
`lpilimumab
`{61:41]
`(N=16]
`
`10 mgy'kg Every 3 Wk
`No Prior
`Prior
`lpilimumab
`lpilimurnab
`(N=24)
`(N=32)
`number {percent}
`
`2 mgy'kg Every 3 Wk
`No Prior
`Ipilimumab
`[14:22}
`
`Total [N = 135}
`
`23 [56)
`13 (44}
`
`60.4
`
`25—94
`
`9 (56)
`2 (44)
`
`59.4
`
`29—8?
`
`0
`41 (100}
`
`0
`16 (100]
`
`1 [2}
`32 (73)
`s [20}
`
`13 (32)
`23 [56)
`5 (12]
`
`3 {2}
`38 [93}
`
`23 [56}
`13 {32)
`5 [12)
`
`o
`7 (17]
`1 (21
`11 (22}
`20 {49}
`2 {5]
`
`16 (39}
`11 (27}
`
`0
`13 (81]
`3 (19)
`
`1 (6)
`14 {88}
`1 (6]
`
`3 (19)
`13 {31)
`
`11 (69]
`5 (31)
`0
`
`o
`2112)
`3 (19}
`3 (19)
`13 (50}
`0
`
`0
`4 (25)
`
`16 (62}
`s (33)
`
`6?
`
`3F-8?
`
`2 (3)
`22 (92)
`
`0
`13125)
`6 [25)
`
`1 [4)
`21 {as}
`2 (8)
`
`o
`24 (100)
`
`16 [6?)
`6 (25}
`2 [3}
`
`o
`2 (3]
`6 [25)
`7 (29)
`9 {38]
`0
`
`12 (50]
`S (21]
`
`12 (53}
`15 (42)
`
`5?.3
`
`32—???
`
`0
`32 (10(1)
`
`O
`21 (66)
`11 (34}
`
`5 (15]
`21 (66)
`6 {19}
`
`4 (12]
`23 (as)
`
`12 (53)
`7 (22)
`8 [25)
`
`1 t3)
`3 (9)
`3 (91
`s (16)
`18 [56)
`2 [6}
`
`0
`10 (31}
`
`14 [64)
`s (36]:
`
`53.6
`
`30—39
`
`0
`22 (100]
`
`0
`13 {59}
`9 (41}
`
`6 (27}
`14 (64)
`2 {9}
`
`2 (9)
`20 (91)
`
`13 {59)
`5 [23)
`4 [18}
`
`0
`1(5)
`1 {5)
`2 {9}
`18 (32)
`0
`
`14 {64]
`4 (18}
`
`29 [591
`56 {41}
`
`60.4
`
`25—94
`
`2 (1]
`133 {99)
`
`1 [1)
`97 (72}
`3? (2?)
`
`26 (19}
`93 (69)
`16 {12}
`
`12 (9)
`123 (91)
`
`130 {59)
`36 [22)
`19 {14}
`
`1 (11
`15 {11}
`14 [10}
`23 {21]
`23 (54}
`4 (3]
`
`42 (31)
`34 [25]
`
`47 (35}
`5 (23}
`14 (44}
`9 (33)
`s {so}
`11 [27)
`Chemotherapy
`10 {-1}
`1 (5)
`4 (12)
`1 [4}
`0
`4 {10)
`BRAF inhibitor
`
`* Race was self-reported.
`1 that the patient is restricted
`T An Eastern Cooperative Oncology Group (ECOG) performance status ofO indicates that the patient is fully active.
`in physically strenuous activity but ambulatory and able to carry out work ofa light or sedentary nature, and 2 that the patient is ambulatory
`and capable ofall self‘care but unable to carry out any work activities.
`:1; An elevated level was considered to be a level higher than the upper limit of the normal range.
`i This category included treatments for advanced disease. The numbers may add up to more than 100% since a patient may have received
`more than one type ofoncologic therapy.
`
`
`NENGLJMED369:2
`
`NEJM.ORG Jurrn.2013
`
`‘13?
`
`

`

`l'lliI NF.'W ENGLAND IUURNAL ui' MEI‘JlIIINE
`
`
`
`Table 2. Drug-Related Adverse Events."
`Grade 3 or 4
`All Grades
`[N=135]
`[N = 135)
`
`Drug-Related Event
`
`scriptive statistics were provided for the pharma-
`cokinetic analysis of trough and peak samples
`according to treatment cohort.
`
`
`RESULTS
`
`BASELINE CHARACTERISTICS OF THE PATIENTS
`
`Between December 1, 2011, and September 6,
`2012, a total of 135 patients with advanced mela-
`noma were enrolled in this mold—institutional,
`
`international, phase 1 expansion study. Initially,
`patients were enrolled in a cohort that received
`lambrolizumab at a dose of 10 mg per kilogram
`every 2 weeks. Subsequently, additional patients
`were enrolled in concurrent (not randomized) co-
`horts that received lambrolizumab at 10 mg per
`
`kilogram or 2 mg per kilogram every 3 weeks.
`A distinction was made between patients who
`had received prior treatment with ipilimumab (48
`patients) and those who had not {87 patients] to
`provide preliminary data on the safety and anti—
`tumor activity oflambrolizumab on the basis of
`prior or no prior treatment with ipilimumab. The
`median time between the last dose of ipilimu-
`mab and the initiation ot'larnbrolizumab was 23
`
`weeks (range, 6 to 83]. The majority of patients
`(38 of 48) were enrolled more than 12 weeks af-
`ter the last dose ofipilimumab, and 90% (43 of
`48] had received three or more infusions ofipili-
`mumab. The baseline characteristics of the pa—
`tients were similar across all
`the treatment
`
`groups (Table 1). Overall. more than 50% of the
`patients had visceral metastases [stage Mlc), ap-
`proximately 25% had an elevated lactate dehy—
`drogenase level, and close to 9% had a history of
`brain metastases — all of which are recognized
`as poor prognostic factors in patients with ad-
`vanced melanoma.
`
`SAFETY
`
`Table 2 shows the adverse events that were con—
`
`sidered to be related to lambrolizumab therapy.
`Table S2 in the Supplementary Appendix pro-
`vides further details ofdrug-related toxic effects
`according to the dosing cohort, and Table 83 in
`the Supplementary Appendix describes all
`ad—
`verse events regardless ofthe cause. according to
`the dosing cohort. Of the 135 patients who re-
`ceived at least one dose oflambrolizumab, 79%
`
`reported drug-related adverse events of any grade.
`and 13% reported grade 3 or 4 drug-related ad—
`
`Any
`
`Hypothyroidism
`Gastrointestinal disorder
`
`Diarrhea
`
`Nausea
`
`Abdominal pain
`
`Generalized symptom
`
`Fatigue
`
`Myalgia
`Headache
`
`Asthenia
`
`Pyrexia
`Chills
`
`Decreased appetite
`Increase in aminotransferase level
`AST
`
`ALT
`
`Renal Failure
`
`Respiratory disorder
`
`Cough
`
`Dyspnea
`Pneumonitis
`
`Skin disorder
`
`Rash
`
`Pruritus
`
`Vitiligo
`
`number {percent}
`
`102 (29)
`
`11 (3)
`
`12 (13)
`
`1(1)
`
`22 (20)
`
`13 (10)
`
`2(5)
`
`41 (30)
`
`16(12}
`
`14(10)
`
`13 (10)
`
`10 (2)
`
`9(2)
`
`6 (4)
`
`13 (10)
`
`11 (3)
`
`3 (2)
`
`11(8)
`
`a (4)
`
`a (4)
`
`2a (21)
`
`28 (21)
`
`1(1)
`
`0
`
`1(1)
`
`2 (1)
`
`0
`
`0
`
`o
`
`0
`
`0
`
`1(1)
`
`2 (1)
`
`o
`
`2 (1)
`
`0
`
`o
`
`0
`
`3(2)
`
`1(1)
`
`
`
`12 (9) o
`
`3* Included are drug-related adverse events that occurred in at least five patients
`or drug-related grade 3 or 4 adverse events that occurred in at least two patients.
`ALT denotes alanine aminotransierase, and AST aspartate aminotransferase.
`
`spouse criteria).12 The overall response rate was
`defined as the number of patients with a com-
`plete or partial response divided by the total
`number of patients who had measurable disease
`at baseline and received at least one treatment
`
`dose. The overall response rate and exact two—
`sided 95% confidence interval were calculated.
`
`Toxic effects were graded with the use of the
`National Cancer Institute Common Terminolo-
`
`gy Criteria for Adverse Events, version 4.0.” De-
`
`138
`
`N ENGL] MED 369:2 NEJM.ORG
`
`JULY 11.2013
`
`

`

`LAMRIUHJZUMAB IN MELANUMA
`
`
`
`
`
`
`
`0 Prior ipilimumab treatment I No prior ipilimumah treatment
`
`
`
`A Best Objective Response
`160
`HO
`IZD
`100
`80
`60
`40
`
`
`
`
`
`
`
`
`
`PercentChangefromBaselineinLongest
`
`including
`verse events. Generalized symptoms,
`fatigue and asthenia, fever and chills, myalgias,
`and headaches, were reported frequently but
`were oflow grade in more than 95% ofthe cases.
`In addition to the data shown in the tables, there
`was one case of grade 1 infusion reaction. Rash-
`es and pruritus were reported in 21% of the pa-
`tients; grade 3 or 4 pruritus was reported in 1%
`of the patients, and grade 3 or 4 rash in 2%.
`Vitiligo was attributed to lambrolizumab in 9%
`of the patients. The highest incidence of overall
`treatment-related adverse events was seen among
`the patients who received 10 mg oflambrolizu-
`mat) per kilogram every 2 weeks, as compared
`with the patients receiving 10 mg per kilogram
`every 3 weeks and those receiving 2 mg per kilo-
`gram every 3 weeks (23%, vs. 4% and 9%, re—
`spectively} (Table 52 in the Supplementary Ap-
`pendix).
`Adverse events of particular interest were of
`an inflammatory or autoimmune nature. Treat-
`ment—related pneumonitis was reported in 4% of
`the patients; none of the cases were grade 3 or
`4. One patient, a 96-year—old man, died during
`the course of the study.
`Initial asymptomatic
`pneumonitis was identified on a scan, and lam-
`brolizumab was discontinued. Subsequently, af-
`ter shortness of breath developed,
`the patient
`received glucocorticoids. The clinical course was
`complicated when acute bronchopneumonia and
`pneumothorax due to bronchoscopy and biop-
`sies were diagnosed. AlrhOugh the pulmonary
`infiltrates were reduced with glucocorticoids,
`the patient died from a myocardial
`infarction
`and bronchopneumonia. Grade 3 or 4 elevations
`of‘aminotransferase levels were reported in 1%
`of the patients. Two cases of grade 3 renal fail-
`ure were reported. Both cases were potentially
`immune-mediated, and the patients’ renal func-
`
`tion improved with glucocorticoid therapy along
`with the discontinuation of lambrolizumab. Al-
`
`though diarrhea was reported in 20% of the
`patients, a single case ofgrade 3 treatment—relat-
`ed diarrhea was reported. This case was managed
`with treatment of the symptoms, and the patient
`recovered promptly without glucocorticoid treat-
`ment. Hypothyroidism was reported in 8% of
`the patients and was effectively managed with
`thyroid-replacement therapy. in addition to the
`data shown in the tables, grade 3 hyperthyroid—
`ism and grade 2 adrenal insufficiency developed
`
`DiameterofTargetLesion
`
`minimalism I Ill Ill
`Individual Patients Treated with Lambrolizumab
`'5"088
`
`
`
`
`
`
`
`
`
`B Time to Response and Duration of Study Treatment
`
`
`
`
`
`
`
`IndividualPatientsTreated
`
`
`
`withLsmbrolizurnab
`
`D
`
`
`
`—-
`
`Prior ipilimumab
`treatment
`I No prior ipilimumab
`treatment
`
`- Complete response
`. Partial response
`.. Still receiving
`treatment
`
`.—-O
`
`ND
`
`u: D
`
`40
`
`50
`
`60
`
`to
`
`Weeks
`
`
`Figure 1. Antitumor Activity of Lambrolizumab.
`
`
`
`
`
`
`
`
`
`
`
`
`Data on the antitumor activity ofl