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`The NEW ENGLAND
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`VOL. 366 NO. 26
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`PERSPECTIVE
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`Kk.Baicker
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`The Health Care Jobs Fallacy
`and A. Chandra
`Overcoming Barriers to Care for Hepatitis C
`PJ. Clark and A.J. Muir
`Pathological Complete Response and Accelerated
`Drug Approval in Early Breast Cancer
`T.M. Prowell and R. Pazdur
`
`ORIGINAL ARTICLES
`
`Safety, Activity, and ImmuneCorrelates
`ofAnti-PD-1 Antibody in Cancer
`S.L. Topalian and Others
`
`Safety and Activity ofAnti-PD-L1 Antibody
`in Patients with Advanced Cancer
`J.R. Brahmer and Others
`
`Early Surgery versus Conventional Treatment
`for Infective Endocarditis
`D.-H. Kang and Others
`
`The Natural Course ofUnruptured Cerebral
`Aneurysmsin a Japanese Cohort
`The UCASJapan Investigators
`
`Cumulative Birth Rates with Linked Assisted
`Reproductive Technology Cycles
`B. Luke and Others
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`IN
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`CLINICAL PRACTICE
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`Exanthematous Drug Eruptions
`R.S. Stern
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`IMAGES IN CLINICAL MEDICINE
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`Necrobiosis Lipoidica Diabeticorum
`J. Dissemond
`Porcelain Aorta
`M.-K. Kang and J.-W. Ha
`CASE RECORDS OF THE MASSACHUSETTS
`GENERAL HOSPITAL
`
`A Man with Leg Edema, Hematuria, and Acute
`RenalFailure
`H. Bazari, A.R. Guimaraes, and Y.B. Kushner
`EDITORIALS
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`Tumor Immunotherapy Directed at PD-1
`A. Ribas
`
`Native-Valve Infective Endocarditis — When Does
`It Require Surgery?
`S.M. Gordon and G.B. Pettersson
`
`CLINICAL IMPLICATIONS OF BASIC RESEARCH
`
`Replenishing Cartilage from Endogenous
`Stem Cells
`J.C. Marini and A. Forlino
`CORRESPONDENCE
`
`Oral Rivaroxaban for Pulmonary Embolism
`Oral Laquinimodfor Multiple Sclerosis
`More on Influenza Vaccine in Young Children
`A Boy with Epigastric Pain and a Mediastinal Mass
`Chronic Lymphocytic Leukemia with SF3B1
`Mutation
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`CONTINUING MEDICAL EDUCATION
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`The NEW ENGLAND
`
`JOURNAL of MEDICINE ESTABLISHED IN 1812
`
`JUNE 28, 2012
`
`VOL, 366 NO. 26
`
`Safety, Activity, and Immune Correlates
`of Anti-PD-1 Antibody in Cancer
`Suzanne L. Topalian, M.D., F. Stephen Hodi, M.D., Julie R. Brahmer, M.D., Scott N. Gettinger, M.D.,
`David C. Smith, M.D., David F. McDermott, M.D., John D. Powderly, M.D., Richard D. Carvajal, M.D.,
`Jeffrey A. Sosman, M.D., Michael B. Atkins, M.D., Philip D. Leming, M.D., David R. Spigel, M.D.,
`Scott J. Antonia, M.D., Ph.D., Leora Horn, M.D., Charles G. Drake, M.D., Ph.D., Drew M. Pardoll, M.D., Ph.D.,
`Lieping Chen, M.D., Ph.D., William H. Sharfman, M.D., Robert A. Anders, M.D., Ph.D., Janis M. Taube, M.D.,
`Tracee L. McMiller, M.S., Haiying Xu, B.A., Alan J. Korman, Ph.D., Maria Jure-Kunkel, Ph.D., Shruti Agrawal, Ph.D.,
`Daniel McDonald, M.B.A., Georgia D. Kollia, Ph.D., Ashok Gupta, M.D., Ph.D., Jon M. Wigginton, M.D.,
`and Mario Sznol, M.D.
`
`
`ABSTRACT
`
`BACKGROUND
`
`Blockade of programmeddeath 1 (PD-1), an inhibitory receptor expressed byT cells,
`can overcome immuneresistance. We assessed the antitumoractivity and safety of
`BMS-936558, an antibody that specifically blocks PD-1.
`METHODS
`
`Weenrolled patients with advanced melanoma, non-small-cell lung cancer, castration-
`resistant prostate cancer,or renal-cell or colorectal cancer to receive anti-PD-1 anti-
`bodyat a dose of0.1 to 10.0 mgper kilogram ofbody weightevery 2 weeks. Response
`was assessed after each 8-week treatment cycle. Patients received up to 12 cycles
`until disease progression or a complete response occurred.
`RESULTS
`
`A total of296 patients received treatment through February 24, 2012. Grade3 or 4 drug-
`related adverse events occurred in 14%ofpatients; there were three deaths from
`pulmonary toxicity. No maximum tolerated dose was defined. Adverse events con-
`sistent with immune-related causes were observed. Among 236patients in whom
`responsecould be evaluated, objective responses (complete or partial responses) were
`observed in those with non-small-cell lung cancer, melanoma,or renal-cell cancer.
`Cumulative responserates (all doses) were 18% amongpatients with non-small-cell
`lungcancer(14 of76 patients), 28% amongpatients with melanoma(26 of94 patients),
`and 27% amongpatients with renal-cell cancer (9 of 33 patients). Responses were
`durable; 20 of 31 responseslasted 1 year or morein patients with 1 year or more of
`follow-up. To assess therole of intratumoral PD-1 ligand (PD-L1) expression in the
`modulation ofthe PD-1-PD-L1 pathway, immunohistochemical analysis was performed
`on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with
`PD-Li-negative tumors, none hadan objective response; 9 of25 patients (36%) with
`PD-L1_positive tumors had an objective response (P=0.006).
`CONCLUSIONS
`
`Anti-PD-1 antibody produced objective responses in approximately onein four to one
`in five patients with non-small-cell lung cancer, melanoma,orrenal-cell cancer; the
`adverse-event profile does not appearto precludeits use. Preliminary data suggest a
`relationship between PD-L1 expression on tumorcells and objective response. (Fund-
`ed by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)
`N ENGL] MED 366,26 NEJM.ORG JUNE 28, 2012
`
`From the Johns Hopkins University
`School of Medicine and the Sidney Kimmel
`Comprehensive Cancer Center, Baltimore
`(S.LT., J.R.B., C.G.D., D.M.P., W.H.S.,
`R.A.A., J.M.T., T.L.M., H.X.); Dana-Farber
`CancerInstitute (F.S.H.) and Beth Israel
`Deaconess Medical Center
`(D.F.M.,
`M.B.A.) — both in Boston; Yale Universi-
`ty School of Medicine and Yale Cancer
`Center, New Haven, CT (S.N.G., L.C.,
`M.S.); University of Michigan, Ann Arbor
`(D.C.S.); Carolina BioOncology Institute,
`Huntersville, NC (J.D.P.); Memorial Sloan-
`Kettering Cancer Center, New York (R.D.C.);
`Vanderbilt University Medical Center
`(U.A.S., LH.) and Sarah Cannon Research
`Institute/Tennessee Oncology (D.R.S.) —
`both in Nashville; Cincinnati Hematology-
`Oncology, Cincinnati (P.D.L.); H. Lee Mof-
`fitt Cancer Center and Research Institute,
`Tampa, FL (SJ.A.); Bristol-Myers Squibb,
`Milpitas, CA (AJ.K.); and Bristol-Myers
`Squibb, Princeton, NJ (M,J.-K., S.A., D.M.,
`G.D.K., A.G., ].M.W.). Address reprint re-
`quests to Dr. Topalian at the Department
`of Surgery, Johns Hopkins University
`School of Medicine, 1550 Orleans St.,
`CRB 2, Rm. 508,Baltimore, MD 21287,or
`at stopalil@jhmi.edu.
`
`This article (10.1056/NEJMoai200690) was
`published on June 2, 2012, and updated on
`June 28, 2012, at NEJM.org.
`
`N Engl J Med 2012;366:2443-54,
`Copyright © 2012 Massachusetts Medical Society.
`
`2443
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`

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`The NEW ENGLAND JOURNAL of MEDICINE
`
`‘UMAN CANCERS HARBOR NUMEROUS
`genetic and epigenetic alterations, gen-
`erating neoantigens that are potentially
`recognizable by the immunesystem.* Although an
`endogenous immune response to cancer is ob-
`served in preclinical models and patients, this
`responseis ineffective, because tumors develop
`multiple resistance mechanisms,including local
`immunesuppression, induction of tolerance, and
`systemic dysfunctionin T-cell signaling.25 More-
`over, tumors mayexploit several distinct pathways
`to actively evade immunedestruction, including en-
`dogenous “immune checkpoints” that normally
`terminate immuneresponsesafter antigen activa-
`tion. These observationshaveresulted in intensive
`efforts to develop immunotherapeutic approaches
`for cancer, including immune-checkpoint-pathway
`inhibitors such as anti-CTLA-4 antibody (ipilimu-
`mab) for the treatment ofpatients with advanced
`melanoma.*®
`Programmed death 1 (PD-1) is a key immune-
`checkpoint receptor expressed by activated T cells,
`and it mediates immunosuppression. PD-1 func-
`tions primarily in peripheral tissues, where T cells
`may encounter the immunosuppressive PD-1 li-
`gands PD-L1 (B7-H1) and PD-L2 (B7-DC), which
`are expressed by tumorcells, stromal cells, or
`both.??? Inhibition ofthe interaction between PD-1
`and PD-L1 can enhance T-cell responses in vitro
`and mediate preclinical antitumoractivity.+43 In
`a dose-escalation study, the anti-PD-1 monoclonal
`antibody BMS-936558 (also known as MDX-1106
`and ONO-4538) was administered as a single dose
`in 39 patients with advanced solid tumors.1* A
`favorable safety profile and preliminary evidence
`ofclinical activity were shownin this pilot study,
`establishing the basis for the current multiple-
`dosetrial involving patients with diverse cancers.
`Wereport clinical results for 296 patients in this
`trial.
`
`
`METHODS
`
`STUDY DESIGN
`
`This study was sponsored by Bristol-Myers Squibb,
`whichprovided the study drug and workedjoint-
`ly with the senior academic authors to design,
`collect, analyze, and interpret the study results.
`All the authors signed a confidentiality agree-
`ment with the sponsor. The protocol,including a
`detailed statistical analysis plan, is available with
`the full text ofthis article at NEJM.org. All drafts
`
`of the manuscript were prepared by the authors
`with editorial assistance from a professional
`medical writer paid by the sponsor. All the au-
`thors vouch for the accuracy and completeness of
`the reported data and for the fidelity of this re-
`port to the trial protocol, and all the authors
`madethe decision to submit the manuscriptfor
`publication.
`This phase 1 study assessed the safety, anti-
`tumor activity, and pharmacokinetics of BMS-
`936558, a fully human IgG4-blocking monoclo-
`nal antibody directed against PD-1, in patients
`with selected advanced solid tumors.All patients
`(or their legal representatives) gave written in-
`formed consent before enrollment. The antibody
`was administered as an intravenous infusion
`every 2 weeks of each 8-week treatment cycle.
`Response was assessed after each treatment cy-
`cle. Patients received treatment for up to 2 years
`(12 cycles), unless they had a complete response,
`unacceptable adverse effects, or progressive dis-
`ease or they withdrew consent. In clinically sta-
`ble patients, study treatment could be continued
`beyond apparentinitial disease progression until
`progression was confirmed, as outlined by pro-
`posed immune-responsecriteria.45 Patients with
`stable disease or an ongoing objective response
`(complete or partial response) at
`the end of
`treatment were followed for up to 1 year and
`were offered retreatment for 1 additional yearin
`the event of disease progression.
`Safety evaluations (clinical examination and
`laboratory assessments) were conducted forall
`treated patients at baseline and regularintervals.
`The severity of adverse events was graded ac-
`cording to the National Cancer Institute Com-
`mon Terminology Criteria for Adverse Events,
`version 3.0.16
`
`DOSE ESCALATION
`
`Patients with advanced melanoma, non—small-
`cell lung cancer, renal-cell cancer, castration-
`resistant prostate cancer, or colorectal cancer were
`enrolled. Cohorts of three to six patients per
`dose level were enrolled sequentially at doses of
`1.0, 3.0, or 10.0 mg per kilogram ofbody weight.
`Dose escalation proceeded when a minimum of
`three patients had completed the safety-evalua-:
`tion period (56 days) at a given dose level, with
`dose-limiting toxicity in less than one third of
`patients. Intrapatient dose escalation was not
`permitted.
`
`2444
`
`N ENGL) MED 366;26 NEJM.ORG JUNE 28, 2012
`
`

`

`ANTI-PD-1 ANTIBODY IN CANCER
`
`COHORT EXPANSION
`
`A maximum tolerated dose was notreached. Ini-
`tially, five expansion cohorts ofapproximately 16
`patients each were enrolled at doses of 10.0 mg
`per kilogram for melanoma, non-small-cell lung
`cancer, renal-cell cancer, castration-resistant pros-
`tate cancer, and colorectal cancer. On the basis of
`initial signals of activity, additional expansion
`cohorts of approximately 16 patients each were
`enrolled for melanoma(at a dose of 1.0 or 3.0 mg
`per kilogram, followed by cohorts randomly as-
`signed to 0.1, 0.3; or 1.0 mg per kilogram), lung
`cancer(patients with the squamous or nonsqua-
`mous subtype, randomly assigned to a dose of
`1.0, 3.0, or 10.0 mg per kilogram), and renal-cell
`cancer(at a dose of 1.0 mg per kilogram).
`
`PATIENTS
`
`Eligible patients had documented advanced solid
`tumors; an age of 18 years or older; a life expec-
`tancy of 12 weeks or more; an Eastern Coopera-
`tive Oncology Group performancestatusof0, 1,
`or 2 (ona scale from 0 to 5, with 0 indicating that
`the patient is asymptomatic, 1 that the patientis
`restricted in strenuous activity, and 2 that the
`patient is ambulatory but unable to work)17; mea-
`surable disease according to Response Evaluation
`Criteria in Solid Tumors (RECIST), version 1.0,18
`with modification (see MethodsS1 in the Supple-
`mentary Appendix,available at NEJM.org; and the
`protocol); adequate hematologic, hepatic, andre-
`nal function; and a history of oneto five systemic
`treatment regimens. Patients with radiographically
`stable treated brain metastases were enrolled. Pa-
`tients with a history of chronic autoimmunedis-
`ease, prior therapy with antibodies that modulate
`T-cell function (e.g., anti-CTLA-4, anti-PD-1, and
`anti-PD-L1), conditions requiring immunosup-
`pressive medications, or chronicinfection (@.g., hu-
`man_immunodeficiencyvirus infection and hepa-
`titis B or C) were excluded.
`
`5% expression threshold’*2°, patients with mul-
`tiple specimens were considered PD-L1-positive
`if any specimen metthis criterion.
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`For pharmacokinetic analysis, serum concentra-
`tions of anti-PD-1 antibody were quantified with
`the use of an enzyme-linked immunosorbentas-
`say. For pharmacodynamic analysis, peripheral-
`blood mononuclear cells (PBMCs) were isolated
`from patientsat baseline andafter the first treat-
`mentcycle to estimate PD-1-receptor occupancy
`by the antibody on circulating CD3+ T cells by
`meansof flow cytometry.2*
`
`STATISTICAL ANALYSIS
`
`Data on all 296 patients treated as of the date of
`analysis for this report (February 24, 2012) were
`used for summaries of baseline characteristics
`and adverse events. Pharmacokinetic and molec-
`ular-marker analyses included treated patients
`with available data as of February 24, 2012. The
`efficacy analysis included the 236 patients who
`could be evaluated for a response and who began
`treatmentbyJuly 1, 2011. Adverse events were cod-
`ed with the use of the Medical Dictionary for Reg-
`ulatory Activities (MedDRA),version 14.1. Adverse
`events ofspecial interest, with a potential immune-
`related cause, were identified with the use of a
`predefined list of MedDRA terms. The bestre-
`sponsesin individual patients were derived from
`investigator-reported data per modified RECIST,
`version 1.0. Objective responses were confirmed
`by at least one sequential tumor assessment, and
`objective response rates were calculated as [(com-
`plete responses+ partial responses)+number of
`patients] x 100. Fisher’s exact test was used to as-
`sess the association between PD-L1 expression and
`objective response.
`
`RESULTS
`
`IMMUNOHISTOCHEMICAL ANALYSIS FOR PD-L1
`
`BASELINE PATIENT CHARACTERISTICS
`
`Immunohistochemical analysis for PD-L1 wasper-
`formed on archival or newly obtained pretreat-
`ment formalin-fixed, paraffin-embedded tumor
`specimenswith the use ofthe murine antihuman
`PD-L1 monoclonal antibody 5H1.1+19 The per-
`centage of tumor cells exhibiting cell-surface
`staining for PD-L1 was scored by two indepen-
`dent pathologists who were unaware ofoutcomes.
`PD-L1 positivity was defined per specimen by a
`
`A total of 296 patients with advanced solid tu-
`mors, including melanoma (104 patients), non—
`small-cell
`lung cancer (122), renal-cell cancer
`(34), castration-resistant prostate cancer (17), and
`colorectal cancer (19), began treatment with anti-
`PD-1 antibody between October 2008 and Febru-
`ary 24, 2012. The majority ofpatients were heav-
`ily pretreated; 47% had received at least three
`prior regimens (Table S1-A in the Supplementary
`
`N ENGL) MED 366;26
`
`NEJM.ORG JUNE 28, 2012
`
`2445
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`Appendix). Notable prior therapies included im-
`munotherapy and BRAF inhibitors in patients with
`melanoma (64%and 8%ofpatients, respectively);
`platinum-based chemotherapy andtyrosine kinase
`inhibitors in patients with lung cancer (94%and
`34%, respectively); and nephrectomy, immunother-
`apy, and antiangiogenic therapy in patients with
`renal-cell cancer (94%, 59%, and 74%, respective-
`ly) (Tables S1-B, S1-C, and S1-D in the Supplemen-
`tary Appendix). Baseline characteristics of the to-
`tal treated population (296 patients) were similar
`to thoseofthe efficacy population (236 patients).
`
`SAFETY
`
`two grade3 or 4 events) were reversible in all cases.
`Endocrine disorders were managedwith replace-
`ment therapy. At the discretion of the treating
`physician, treatment with anti-PD-1 antibody was
`reinitiated once the adverse event had been suc-
`cessfully managed. Drug-related pneumonitis oc-
`curred in 9 of the 296 patients (3%). Grade 3 or
`4 pneumonitis developed in 3 patients (1%). No
`clear relationship between the occurrence ofpneu-
`monitis and tumortype, dose level, or the number
`of doses received was noted. Early-grade pneumo-
`nitis in 6 patients was reversible with treatment
`discontinuation, glucocorticoid administration, or
`both. In 3 patients with pneumonitis, infliximab,
`A maximum tolerated dose was not defined at
`mycophenolate, or both were used for additional
`the dosestested in this study. A relative dose in-
`immunosuppression; however, given the small
`tensity (the proportion of administered doses
`number of patients and variable outcomes, the
`relative to planned doses) of 90% or more was
`effectiveness of such treatment was unclear. There
`achieved in 86% of patients (Table $2-A in the
`were three drug-related deaths (1%) due to pneu-
`Supplementary Appendix). Fifteen of 296 patients
`monitis (two in patients with non-small-cell lung
`(5%) discontinued treatment owingto treatment-
`cancer and one inapatient with colorectal cancer).
`related adverse events (Tables S2-B and S3-A in
`the Supplementary Appendix). As of the date of
`analysis, 62 patients (21%) had died; disease pro-
`Antitumoractivity was observed atall dosestest-
`gression was the most common cause of death
`ed. Objective responses were observed in a sub-
`(Table $2-C in the Supplementary Appendix).
`stantial proportion of patients with non—small-
`The most common adverseevents, regardless
`cell lung cancer, melanoma,or renal-cell cancer
`of causality, were fatigue, decreased appetite,
`(Table 2 and Fig. 1) andin varioussites of metas-
`diarrhea, nausea, cough, dyspnea, constipation,
`tasis, including theliver, lung, lymph nodes, and
`vomiting, rash, pyrexia, and headache (Table $3-A
`bone. At the time of data analysis, two patients
`in the Supplementary Appendix). Commontreat-
`with lung cancer whoreceived 10 mg perkilo-
`ment-related adverse events included fatigue,
`gram had unconfirmed responses, and eight ad-
`rash, diarrhea, pruritus, decreased appetite, and
`ditional patients (with melanoma, lung cancer,
`nausea (Tables $3-A and $3-B in the Supplemen-
`or renal-cell cancer) had a persistent reduction in
`tary Appendix). Grade 3 or 4 treatment-related
`baseline target lesions in the presence of new le-
`adverse events were observed in 41 of 296 pa-
`sions (a finding consistent with an immune-
`tients (14%). Drug-related serious adverse events
`related response pattern’). Noneofthese patients
`(as defined in Table S4 in the Supplementary
`wete categorized as having had a response for
`Appendix) occurred in 32 of 296 patients (11%).
`the purpose of calculating objective-response
`The spectrum,frequency, andseverity oftreatment-
`rates, Objective responses, prolonged disease
`related adverse events were generally similar
`stabilization, or both were observed in patients
`across the doselevels tested. Drug-related adverse
`whohadreceivedavariety of prior therapies. No
`events ofspecialinterest(e.g., those with potential
`objective responses were observed in patients
`immune-related causes) included pneumonitis,
`with colorectal or prostate cancer.
`vitiligo, colitis, hepatitis, hypophysitis, and thy-
`‘In patients with lung cancer, 14 objective re-
`roiditis (Table 1 and Fig. 1C).
`sponses were observed at doses of 1.0, 3.0, or
`Hepatic or gastrointestinal adverse events were
`10.0 mg per kilogram,with responserates of 6%,
`managed with treatmentinterruption and, as nec-
`32%, and 18%, respectively. Objective responses
`essary, with the administration of glucocorticoids.
`were observed across non-small-cell histologic
`Theseevents (e.g., diarrhea in 33 patients, includ-
`types: in 6 of 18 patients (33%) with squamous
`ing three grade 3 or 4 events and elevated alanine
`tumors, 7 of 56 (12%) with nonsquamous tu-
`aminotransferase levels in 11 patients, including
`mors, and 1 of 2 with tumors of unknowntype.
`
`CLINICAL ACTIVITY
`
`2446
`
`N ENGLJ MED 366;26 NEJM.ORG JUNE 28, 2012
`
`

`

`ANTI-PD-1 ANTIBODY IN CANCER
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`N ENGLJ MED 366
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`26 NEJM.ORG JUNE 28, 2012
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`2447
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`€
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`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`
`
`A Patients with Melanoma
`100
`
`A First occurrence of new lesion
`
`@ Patient off study
`
`
`
`
`
`of
`
`'
`
`80
`60
`
`40
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` ChangeinTargetLesionsfromBaseline(%)
`
`60
`
`70
`
`80
`
`90
`
`100
`
`Weeks since TreatmentInitiation
`
`B Patient with Renal-Cell Cancer
`Before Treatment
`
`D Patient with Non-Small-Cell Lung Cancer
`Before Treatment
`
`4
`
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`
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`2448
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`N ENGLJ MED 366;26 NEJM.ORG JUNE 28, 2012
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`

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`related pattern of response).
`
`In patients with melanoma, 26 objective re-
`sponses were observed at doses ranging from
`0.1 to 10.0 mg per kilogram, with responserates
`ranging from 19 to 41%per doselevel. At a dose
`of 3.0 mg per kilogram,objective responses were
`noted in 7 of 17 patients (41%). Of 26 patients
`with melanoma who had an objective response,
`18 started treatment 1 year or more before Feb-
`ruary 24, 2012, and of these, 13 had a response
`that lasted 1 year or more. The remaining 8 pa-
`tients with objective responses received study
`medication for less than 1 year, and 6 had re-
`sponses ranging from 1.9 to 5.6 months. Stable
`disease lasting 24 weeks or more was observed
`in 6 patients (6%).
`Amongpatients with renal-cell cancer, objec-
`tive responses occurred in 4 of 17 patients (24%)
`treated with a dose of 1.0 mg per kilogram and
`5 of 16 (31%) treated with 10.0 mg per kilogram.
`Of8 patients with objective responses whostart-
`ed treatment 1 year or morebefore data analysis,
`5 had a response that lasted 1 year or more.
`Stable disease lasting 24 weeks or more was
`observed in an additional 9 patients (27%).
`
`PHARMACOKINETICS AND PHARMACODYNAMICS
`
`The median timeto the peak concentration ofanti—
`PD-1 antibody was 1 to 4 hoursafter the start of
`infusion. The pharmacokinetics of the antibody
`were linear, with a dose-proportionalincrease in
`the peak concentration and area under the curve
`calculated from day 1 to day 14 in the dose range
`of 0.1 to 10.0 mg per kilogram (35 patients). The
`pharmacodynamics of anti-PD-1 antibody were
`assessed according to PD-1-receptor occupancy
`on circulating CD3+ T cells. In PBMCs from 65
`patients with melanoma who were treated with
`one cycle ofanti-PD-1 antibodyat a dose of0.1 to
`10.0 mg per kilogram every 2 weeks, the median
`PD-1-receptor occupancy by anti-PD-1 antibody
`was 64 to 70% according to doselevel (Fig. 2A).
`
`PD-L1 EXPRESSION IN TUMORS
`
`ANTI-—PD-1 ANTIBODY IN CANCER
`
`Figure 1 (facing page). Activity of Anti~Programmed
`Death 1 (PD-1) Antibody in Patients with Treatment-
`Refractory Melanoma, Non-Small-Cell Lung Cancer,
`or Renal-Cell Cancer.
`
`In Panel A, a representative plot shows changes from
`baseline in the tumor burden, measured as the sum of
`the longest diameters oftarget lesions, in 27 patients
`with melanoma who received anti-PD-1 antibody at
`a dose of 1.0 mg per kilogram of body weight every
`2 weeks. In the majority of patients who had an objec-
`tive response, responses were durable and evident by
`the end of cycle 2 (16 weeks) of treatment. The vertical
`dashed line marks the 24-week time point at which the
`progression-free survival rate was calculated, and the
`horizontal dashed line marks the threshold for objective
`response(partial tumor regression) according to modi-
`fied Response Evaluation Criteria in Solid Tumors. Tumor
`regression followed conventional as well as immune-
`related patterns of response, such as prolonged reduc-
`tion in tumor burdenin the presence of new lesions.?>:24
`Panel B showspartial regression of metastatic renal-
`cell cancerin a 57-year-old patient who received anti-
`PD-1 antibodyat a doseof 1.0 mg per kilogram. This
`patient had previously undergoneradical surgery, and
`progressive disease had developed after treatment with
`sunitinib, temsirolimus, sorafenib, and pazopanib. The
`arrowheads showregression of recurrent tumor in the
`operative field. Panel C shows a complete response in
`a 62-year-old patient with metastatic melanoma who
`received anti-PD-1 antibody at a doseof3.0 mg perkilo-
`gram. Pretreatment computed tomographic scanning(i)
`revealed inguinal-lymph-node metastasis (arrowhead),
`which regressed completely after 13 months oftreat-
`ment(ii). Numerous metastases in the subcutaneous
`tissue and retroperitoneum also regressed completely
`(not shown). Vitiligo, which developed after 6 months
`of treatment,is evident in photographs taken at 9 months
`under visible light (iii) and ultraviolet light (iv). Skin-
`biopsy specimens with immunohistochemical staining
`for micro-ophthalmia—associated transcription factor
`show that melanocytes (arrows) are abundantat the
`epidermal—dermal junction in normal skin (v), scarce
`in skin partially affected byvitiligo (vi), and absent in
`skin fully affected by vitiligo (vii). Panel D showsa par-
`tial responsein a patient with metastatic non—small-
`cell lung cancer (nonsquamous histologic type) who
`received anti-PD-1 antibody at a dose of 10.0 mg per
`kilogram. The arrowheads showinitial progression in
`pulmonarylesions, followed by regression (an immune-
`
`All 14 patients with objective responses started
`treatment 24 weeks or more before data analysis,
`and of these, 8 had a response that lasted 24
`weeks or more (Table 2). Five of 14 patients with
`objective responses started treatment 1 year or
`more before data analysis, and of these, 2 had
`a response that lasted 1 year or more. Stable
`disease lasting 24 weeks or more was observed
`in 5 patients (7%) with lung cancer, all ofwhom
`had nonsquamous tumors.
`
`Sixty-one pretreatment tumor specimens from
`42 patients (18 with melanoma, 10 with non—
`small-cell lung cancer, 7 with colorectal cancer,
`5 with renal-cell cancer, and 2 with prostate can-
`cer) (Table S5 in the Supplementary Appendix)
`were analyzed for PD-L1 expression on the sur-
`face of tumorcells (Fig. 2B). Biopsy specimens
`from 25 of the 42 patients were positive for PD-
`L1 expression by immunohistochemicalanalysis.
`Of these 25 patients, 9 (36%) had an objective
`
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`The NEW ENGLAND JOURNAL of MEDICINE
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`response. None of the 17 patients with PD-Li—
`negative tumors had an objective response. This
`analysis is based on optional biopsies in a non-
`random subset of the population,and testing of
`a statistical hypothesis was not prespecified.
`These preliminary results must therefore be in-
`terpreted with caution.
`
`DISCUSSION
`
`Our data show that approximately onein four to
`one in five patients treated with anti-PD-1 anti-
`body had objective responses with durability; these
`occurred in heavily pretreated patients with diverse
`
`tumor types. PD-1 blockade extends the spectrum
`of clinical activity by immunotherapy beyond im-
`munogenic tumor types, such as melanoma and
`renal-cell cancer, to treatment-refractory, meta-
`static non-small-cell lung cancer, a tumor type
`that is generally not considered to be responsive
`to immunotherapy. Thelevel ofactivity seen with
`anti-PD-1 antibody in patients with lung cancer
`who had received substantial amounts ofprior
`therapy (55%with at least three lines of previous
`therapy) (Table S1-B in the Supplementary Ap-
`pendix) andacrosshistologic typesis ofinterest,
`particularly in the patients with squamous tu-
`mors.?2:23 These unexpected findings underscore
`
`Table 2. Ctinical Activity ofAnti-PD-1 Antibodyin the Efficacy Population.*
`
`Objective-
`Response
`Rate:
`
`Duration of Response§
`
`Progression-free
`Survival Rate
`at 24 wk]
`
`Objective
`Response‘
`Stable Disease 224 wk
`no. ofpatients/
`no. ofpatients/
`total no. of
`total no. of
`patients
`% (95% Cl)
`patients—% (95% Cl)% (95% Cl)
`
`
`
`
`26 (16-36)
`
`Dose of Anti-PD-1
`Antibody
`
`
`Melanoma
`
`0.1 mg/kg
`0.3 mg/kg
`1.0 mg/kg
`
`3.0 mg/kg
`
`10.0 mg/kg
`All doses
`
`Non-small-cell lung cancer
`Squamous
`
`4/14
`3/16
`8/27
`
`7/17
`
`4/20
`26/94
`
`1.0 mg/kg
`3.0 mg/kg
`10.0 mg/kg
`All doses
`
`Nonsquamous
`1.0 mg/kg
`3.0 mg/kg
`10.0 mg/kg
`All doses
`
`Unknowntype
`1.0 mg/kg
`10.0 mg/kg
`All types
`1.0 mg/kg
`3.0 mg/kg
`
`10.0 mg/kg
`
`All doses
`
`29 (8-58)
`19 (4-46)
`30 (14-50)
`
`41 (18-67)|
`
`20 (6-44)
`28 (19-38)
`
`0
`
`50 (12-88)
`43 (10-82)
`33 (13-59)
`
`0
`
`23 (5-54)
`13 (4-30)
`12 (5-24)
`
`NA
`0
`
`6 (0.1-27)
`32 (13-57)
`
`18 (8-34)
`18 (11-29)
`
`7.5+, 5.6+, 5.6, 5.6
`3.84, 2.14, 1.9+
`
`24.94, 22.9, 20.34, 19.34, 18.44,
`“
`7.6+, 5.64, 5.3+
`22.44, 18.3+, 15.2+, 12.9,
`11.1, 9.3, 9.2+
`24.6+, 23.9+, 18.0+, 17.0
`
`1/14
`1/16
`3/27
`
`1/17
`
`0/20
`
`6/94
`
`7 (0.2-34)
`6 (0.2-30)
`11 (2-29)
`
`40 (13-66)
`31 (9-54)
`45 (26-65)
`
`6 (0.1-29)
`
`55 (30-80)
`
`0
`
`6 (2-13)
`
`30 (9-51)
`41 (30-51)
`
`0
`
`50 (10-90)
`43 (6-80)
`33 (12-55)
`
`14 (0-37)
`37 (10-64)
`21 (6-36)
`22 (11-34)
`
`NA
`0
`
`8 (0.2-39)
`15 (2-45)
`6 (0.8-21)
`9 (3-20)
`
`9.2+
`
`30.8+, 7.6+, 5.54, 3.74, 1.94,
`NA**
`14.84, 7.64, 7.3+, 6.7, 4.2,
`oe7+,
`3.
`
`6 (0.1-27)
`11 (1-33)
`
`16 (0-34)
`41 (18-64)
`
`5 (0.6-17)
`
`24 (11-38)
`
`7 (2-15)
`
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`

`ANTI-PD-1 ANTIBODY IN CANCER
`
`
`
`Duration of Response§,
`
`Stable Disease >24 wk
`
`Progression-free
`Survival Rate
`at 24 wk]
`
`Table 2. (Continued.)
`
`Dose of Anti-PD-1
`Antibody
`
`Renal-cell cancer
`
`1.0 mg/kg
`
`10.0 mg/kg
`All doses
`
`Objective
`Response7y
`
`no. ofpatients/
`total no. of
`patients
`
`4/17
`
`5/16
`
`9/33
`
`Objective-
`Response
`Rate
`
`% (95% Cl)
`
`24 (7-50)
`31 (11-59)|
`27 (13-46)
`
`56 (39-73)
`
`no. ofpatients/
`total no. of
`patients
`
`% (95% Cl)
`
`% (95% Cl)
`
`17.5+, 9.2+, 9.2, 5.6+
`
`22,34, 21.7+, 12.9, 12.0, 8.4
`
`4/17
`
`5/16
`
`9/33
`
`24 (7-50)
`
`31 (11-59)
`
`27 (13-46)
`
`47 (23-71)
`
`67 (43-91)
`
`*
`
`Theefficacy population consisted of patients in whom the response could be evaluated, whosetreatment wasinitiated by July 1, 2011, and
`who had measurable disease at baseline with one ofthe following: at least one scan obtained during treatment, clinical evidence ofdisease
`progression, or death. NA denotes not applicable, and ND not determined.
`{ Responses were adjudicated according to the Response Evaluati