New England journal of medicine
`Vv. 372, no. 4 (Jan. 22 2015)
`General Collection
`W1 NE388
`2015-01-28 10:38:32
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`PD-1 Blockade with Nivolumabin Relapsed
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`The NEW ENGLAND
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`JOURNAL of MEDICINE
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`ESTABLISHED IN 1812
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`JANUARY22, 2015
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`VOL. 372 NO. 4
`
`PD-1 Blockade with Nivolumabin Relapsed or Refractory
`Hodgkin’s Lymphoma
`Stephen M. Ansell, M.D., Ph.D., Alexander M. Lesokhin, M.D., Ivan Borrello, M.D., Ahmad Halwani, M.D.,
`Emma C. Scott, M.D., Martin Gutierrez, M.D., Stephen J, Schuster, M.D., Michael M. Millenson, M.D.,
`Deepika Cattry, M.S., Gordon J. Freeman, Ph.D., Scott J. Rodig, M.D., Ph.D., Bjoern Chapuy, M.D., Ph.D.,
`Azra H. Ligon, Ph.D., Lili Zhu, M.S., Joseph F. Grosso, Ph.D., Su Young Kim, M.D., Ph.D.,
`John M. Timmerman, M.D., Margaret A. Shipp, M.D., and Philippe Armand, M.D., Ph.D.
`
`
`ABSTRACT
`
`BACKGROUND
`Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1
`(PD-1) pathway to evade immunedetection.In classic Hodgkin’s lymphoma,altera-
`tions in chromosome 9p?24.1 increase the abundanceof the PD-1 ligands, PD-L1 and
`PD-L2, and promotetheir induction through Janus kinase (JAK)-signal transducer
`andactivator oftranscription (STAT) signaling. We hypothesizedthat nivolumab,a
`PD-1-blocking antibody, could inhibit tumor immuneevasion in patients with re-
`lapsed or refractory Hodgkin’s lymphoma.
`METHODS
`In this ongoing study, 23 patients with relapsed or refractory Hodgkin’s lymphoma
`that had already been heavily treated received nivolumab(at a dose of 3 mg perki-
`logram of body weight) every 2 weeks until they had a complete response, tumor
`progression, or excessive toxic effects. Study objectives were measurementof safety
`and efficacy and assessmentof the PDL1 and PDL2 (also called CD274 and PDCD1LG2,
`respectively) loci and PD-L1 and PD-L2protein expression.
`RESULTS
`Of the 23 study patients, 78% were enrolled in the study after a relapse following
`autologous stem-cell transplantation and 78% after a relapse following thereceipt
`of brentuximab vedotin. Drug-related adverse events of any grade and ofgrade 3
`occurred in 78% and 22% of patients, respectively. An objective response wasre-
`ported in 20 patients (87%), including 17% with a complete response and 70% with
`a partial response; the remaining 3 patients (13%) had stable disease. The rate of
`progression-free survival at 24 weeks was 86%; 11 patients were continuing to par-
`ticipate in the study. Reasons for discontinuation included stem-cell transplanta-
`tion (in 6 patients), disease progression (in 4 patients), and drugtoxicity (in 2 pa-
`tients). Analyses of pretreatment tumor specimens from 10 patients revealed
`copy-numbergains in PDL1 and PDL2 and increased expression of these ligands.
`Reed-Sternberg cells showed nuclearpositivity of phosphorylated STAT3, indica-
`tive of active JAK-STATsignaling.
`CONCLUSIONS
`
`Nivolumab had substantial therapeutic activity and an acceptable safety profile in
`patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma.
`(Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.)
`
`From the Mayo Clinic, Rochester, MN
`(S.M.A.); Memorial Sloan Kettering Can-
`cer Center (A.M.L., D.C.) and Weill Cor-
`nell Medical College (A.M.L.) — both in
`New York; Johns Hopkins University
`School of Medicine and the Sidney Kim-
`mel Comprehensive Cancer Center, Balti-
`more (I.B.); University of Utah Hunts-
`man Cancer
`Institute, Salt Lake City
`(A.H.); Oregon Health and Science Uni-
`versity and the Knight Cancer Institute,
`Portland (E.C.S.); John Theurer Cancer
`Center, Hackensack University Medical
`Center, Hackensack (M.G.), and Bristol-
`Myers Squibb, Lawrenceville (L.Z., J.F.G.,
`S.Y.K.) — both in New Jersey; Abramson
`Cancer Center, University of Pennsylva-
`nia (SJ.S.), and Fox Chase Cancer Center
`(M.M.M.) — both in Philadelphia; Dana—
`Farber Cancer
`Institute
`(GJ.F.,
`8.C.,
`M.A.S., P.A.) Brigham and Women's
`Hospital
`(SJ.R., A.H.L.), and Harvard
`Medical School (GJ.F., B.C., M.A.S., P.A.,
`S.J.R., A.H.L.) — all in Boston; and Jons-
`son Comprehensive Cancer Center, Uni-
`versity of California, Los Angeles, Los
`Angeles
`(J.M.T.). Address reprint
`re-
`quests to Dr. Ansell at the MayoClinic,
`200 First St. SW, Rochester, MN 55905,
`or at ansell.stephen@mayo.edu; or to
`Dr. Armand at the Dana-Farber Cancer
`Institute, 450 Brookline Ave., Boston,
`MA 02215, or at philippe_armand@
`dfci.harvard.edu.
`
`Drs. Ansell and Lesokhin and Drs. Shipp
`and Armand contributed equally to this
`article.
`
`This article was published on December6,
`2014, at NEJM.org.
`
`N Engl J Med 2015;372:311-9,
`DOI: 10,1056/NEJMoal411087
`Copyright © 2014 Massachusetts Medical Society.
`
`N ENGLJ MED 372;4 NEJM.ORG JANUARY 22, 2015
`
`311
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`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`poySHE PROGRAMMED DEATH 1 (PD-1) PATH-
`i way serves as a checkpoint to limit T-cell-
`I mediated immune responses. Both PD-1
`ligands, PD-L1 and PD-L2, engage the PD-1 recep-
`tor and induce PD-1 signaling and associated T-cell
`“exhaustion,” a reversible inhibition ofT-cell acti-
`vation and proliferation.’ By expressing PD-1 li-
`gands on the cell surface and engaging PD-1 re-
`ceptor—positive immuneeffectorcells, tumors can
`co-opt the PD-1 pathway to evade an immune
`~
`e?Ad-hiosldie antibodies have been used to
`enhance immunity in solid tumors and obtain
`durable clinical responses with an acceptable
`safety profile.** Preliminary data also support
`empirical PD-1 blockade as a therapeutic strate-
`gy in certain hematologic cancers.°** Adverse
`events that are commonly associated with PD-1-
`blocking antibodies include pruritus, rash, and
`diarrhea.* Immune-mediated pneumonitis, coli-
`tis, hepatitis, hypophysitis, and thyroiditis are
`less commontoxic effects of PD-1 blockade.*73
`Classic Hodgkin’s lymphomas include small
`numbers of malignant Reed-Sternberg cells
`within an extensive butineffective inflammatory
`and immune-cell
`infiltrate.\4° The genes en-
`coding the PD-1 ligands, PDLI and PDL2 (also
`called CD274 and PDCDILG2, respectively), are key
`targets of chromosome 9p24.1 amplification, a
`recurrent genetic abnormality in the nodular-
`sclerosis type of Hodgkin’s lymphoma.’* The
`9p24.1 amplicon also includes JAK2, and gene
`dose-dependentJAK-STATactivity further induces
`PD-1 ligandtranscription.* These copy-number—
`dependent mechanismsandless frequent chromo-
`somal rearrangements’ lead to overexpression
`of the PD-1 ligands on Reed-Sternbergcells in
`patients with Hodgkin’s lymphoma. Epstein—Barr
`virus (EBV) infection also increases the expres-
`sion of PD-1 ligands in EBV-positive Hodgkin’s
`lymphomas.*”
`The complementary mechanisms of PD-1 li-
`gand overexpression in Hodgkin's
`lymphoma
`suggest that this disease may have genetically
`determined vulnerability to PD-1 blockade. Coam-
`plification of PDLI and PDL2 on chromosome
`9p24.1 suggests receptor rather than selective
`ligand blockade as a treatmentstrategy. For these
`reasons, Hodgkin’s lymphomawasincluded as a
`cohort-expansion group in a phase 1 study of
`nivolumab (Bristol-Myers Squibb and Ono Phar-
`
`maceutical), a fully human monoclonal IgG4 an-
`tibody directed against PD-1,
`in patients with
`relapsed or refractory hematologic cancer.
`
`
`METHODS
`
`PATIENTS
`
`To beeligible for participation in this study, pa-
`tients had to be at least 18 years of age, have
`histologically confirmed evidence of relapsed or
`refractory Hodgkin’s lymphomawith at least one
`lesion measuring more than 1.5 cm (as defined
`by the Revised Response Criteria for Malignant
`Lymphomas?) (see the Supplementary Appendix,
`available with the full text of this article at NEJM
`.org), an Eastern Cooperative Oncology Group
`(ECOG)"* performance-status score of 0 or 1 (on a
`scale from 0 to 5, with 0 indicating no symptoms
`and higher scores indicating increasing disabili-
`ty), previous treatment with at least one chemo-
`therapy regimen, and no autologous stem-cell
`transplantation within the previous 100 days. Key
`exclusioncriteria were a history ofcancer involving
`the central nervous system, a history of or active
`autoimmunedisease, a concomitant second cancer,
`and previous organ allograft or allogeneic bone
`marrowtransplantation.
`
`STUDY DESIGN
`
`This phase 1 study consisted of dose-escalation
`and expansion cohorts.
`In the dose-escalation
`cohort, patients with relapsed or refractory he-
`matologic cancers were treated with nivolumab
`at a dose of 1 mg per kilogram of body weight,
`with escalation ofthe dose to 3 mgper kilogram.
`Since the maximumtolerated dose wasnot reached,
`a dose of 3 mg per kilogram was chosen for the
`expansion cohorts. Patients with relapsed or re-
`fractory Hodgkin’s lymphoma received nivolu-
`mabat a dose of 3 mg per kilogram at week 1,
`week 4, and then every 2 weeks until disease pro-
`gression or complete responseor for a maximum
`of 2 years.
`The primary objective wasto evaluate the safety
`and side-effect profile of nivolumab. Secondary
`objectives included characterizing the efficacy of
`nivolumab and assessing PD-1 ligandloci integrity
`and expression of the encodedligands.
`Adverse events were assessed throughout the
`study and for 100 days after the last dose was
`administered, according to the National Cancer
`
`312
`
`NENGLJ MED 372;4 NEJM.ORG JANUARY 22, 2015
`
`

`

`NIVOLUMAB IN RELAPSED OR REFRACTORY HODGKIN’S LYMPHOMA
`
`Institute Common Terminology Criteria for Ad-
`verse Events, version 4.2° Patients were evaluated
`for efficacy at weeks 4, 8, 16, and 24 and every
`16 weeks thereafter. All the patients underwent
`computed tomography (CT) and 'F-fluorodeoxy-
`glucose—positron-emission tomography (FDG-PET)
`at screening, subsequentCT(as described above),
`and FDG-PETscanningfor confirmation ofa com-
`plete response.
`
`STUDY OVERSIGHT
`
`The protocol was approved by the institutional
`review board at each center, and the study was
`conducted in accordancewith the Declaration of
`Helsinki and the International Conference on
`Harmonisation Guidelines for Good Clinical
`Practice. All
`the patients provided written in-
`formed consent before study entry. The principal
`investigators,
`in collaboration with the sponsor
`(Bristol-Myers Squibb), were responsible for the
`design and oversight of the study and develop-
`mentofthe protocol, available at NEJM.org. The
`sponsor wasresponsible for the collection and
`maintenance of the data. Initial drafts of the
`manuscript were prepared by the authors, with
`subsequent editorial assistance paid for by the
`sponsor. All
`the authors made the decision to
`submit the manuscript for publication and vouch
`for the accuracy and completeness of the data
`reported and adherencetothe protocol.
`
`BIOMARKER ASSESSMENT
`
`Fluorescence in situ hybridization (FISH) was
`performed on Hodgkin’s lymphomatissue sec-
`tions to assess copy number on chromosome
`9p24.1. The bacterial artificial chromosome
`probes (CHORI; www.chori.org) RP11-599H20,
`which maps to 9p24.1 and includes CD274 (en-
`coding PD-L1,
`labeled with Spectrum Orange),
`and RP11-635N21, which also maps to 9p24.1
`and includes PDCD1LG2 (encoding PD-L2,labeled
`with Spectrum Green), were cohybridized. A con-
`trol centromeric probe, Spectrum Aqua-labeled
`CEP9 (Abbott Molecular) that maps to 9p11-q11,
`was hybridized according to the manufacturer's
`recommendations. Malignant Reed—Sternberg cells
`wereidentified by means ofnuclear morphologic
`features, and all such cells were analyzed. Nuclei
`with a target:control probe ratio of at least 3:1
`were classified as amplified, those with a probe
`ratio of more than 1:1 but less than 3:1 were clas-
`
`sified as relative copy gain, and those with a
`probe ratio of 1:1 but with more than two copies
`of each probe were classified as polysomic for
`chromosome9p. Immunohistochemical staining
`was performed by meansofan automated stain-
`ing system (BOND-III, Leica Biosystems), with
`the use ofa double-staining technique for PD-L1
`(405.9A11) and PAXS (24/Pax-5, BD Biosciences),
`and for PD-L2 (366C.9E5) and phosphorylated
`STAT3 (pSTAT3; D3A7, Cell Signaling Technolo-
`gy). The methodsare detailed in the Supplemen-
`tary Appendix.
`
`STATISTICAL ANALYSIS
`
`All the patients who received at least one dose of
`nivolumab were included in the safety and effi-
`cacy analyses. The database was locked on June
`16, 2014. Adverse effects were coded with the use
`ofthe Medical Dictionaryfor Regulatory Activities, ver-
`sion 17.0, and tabulated.
`The principal investigator at each site evalu-
`ated efficacy assessments using the Revised Re-
`sponseCriteria for Malignant Lymphomas'® (see
`the Supplementary Appendix). The best overall
`response was defined as the best response be-
`tween the date ofthe first dose and thelast effi-
`cacy assessment before subsequent therapy. The
`objective response rate was defined as the pro-
`portion ofthe total numberof patients whose best
`overall response waseithera partial or a complete
`response. A complete response wasdefined as tu-
`mor regression to 1.5 cm orless in greatest di-
`ameter, if the tumor measured more than 1.5 cm
`before therapy, or a decrease in previously in-
`volved nodes measuring 1.1 to 1.5 cm in greatest
`diameter to 1 cm or less or a decrease of more
`than 75%, with negative results on PET scan-
`ning (see the Supplementary Appendix).
`Progression-free survival was defined as the
`time from the date ofthe first dose of study
`medication to the date offirst disease progres-
`sion or the date of death. Progression-free sur-
`vival was estimated with the use of Kaplan-
`Meier methods. The time to a
`response was
`defined as the time from the date of the first
`dose to the date of the first response. The dura-
`tion of a response was defined as the time be-
`tween the date ofthe first response and the date
`of first progression or the date of death. Plots of
`the percentage changes in tumor burden over
`time for each patient are presented graphically.
`
`N ENGLJ MED 372;4 NEJM.ORG JANUARY 22, 2015
`
`313
`
`

`

`The NEW ENGLAND JOURNAL of MEDICINE
`
`
`RESULTS
`
`PATIENTS
`
`Since enrollment started in August 2012,a total
`of 23 patients with relapsed orrefractory Hodg-
`kin’s lymphoma have been enrolled in the study.
`Results are reported through June 16, 2014. The
`baseline characteristics of the patients are pre-
`sented in Table 1. The median age was 35 years
`
`Table 1. Characteristics ofthe 23 Patients at Baseline.
`
`Characteristic
`Value
`
`
`Age—yr
`
`
`Median
`35
`Range
`20-54
`
`
`Male sex — no. (%)
`12 (52)
`
`
`
`
`
`
`
`Race — no. (%)*
`White
`
`Black
`
`20 (87)
`
`2 (9)
`
`
`
`
`
`
`
`
`
`
`
`Other
`ECOG performance-status score —no.(%)j
`0
`1
`
`Histologic findings — no.(%)
`Nodular sclerosis
`
`Mixed cellularity
`No.of previous systemic therapies — no.(7%)
`2or3
`
`4or5
`
`=6
`
`Previous treatment — no. (76)
`
`1 (4)
`
`6 (26)
`17 (74)
`
`22 (96)
`
`1 (4)
`
`8 (35)
`
`7 (30)
`
`8 (35)
`
`Brentuximab vedotin
`
`18 (78)
`
`
`
`
`
`
`
`
`
`
`
`(range, 20 to 54), and 17 patients (74%) had an
`ECOGperformance-status score of1. All the pa-
`tients had been extensively pretreated, with 87%
`having received three or more previous treatment
`regimens; 78%ofthe patients had received bren-
`tuximab vedotin (hereafter referred to as bren-
`tuximab) previously, and 78% had undergone
`autologous stem-cell transplantation. Extranodal
`disease involving bone,lung, pelvis, peritoneum,
`or pleura was found in 17%of the patients. With
`one exception, all the patients had the nodular-
`sclerosis type of Hodgkin’s lymphoma; the remain-
`ing patient had mixed cellularity. The most common
`first-line chemotherapy was ABVD (doxorubicin,
`bleomycin, vinblastine, and dacarbazine), which
`was administered in 20 patients (87%).
`
`SAFETY
`
`Among the 23 patients, adverse events of any
`grade were reported in 22 (96%). Grade 3 or 4
`adverse events occurred in 12 patients (52%).
`Grade 3, 4, or 5 adverse events, listed according
`to whether they were deemedbythe investigators
`to be related or unrelated to the study drug, are
`included in Table $1 in the Supplementary Ap-
`pendix. Drug-related adverse events
`that oc-
`curred in at least 5% of the patients are listed in
`Table 2. Overall, drug-related adverse events were
`reported in 18 patients (78%). The most common
`were rash (in 22%) anda decreasedplatelet count
`(in 17%). Drug-related grade 3 adverse events,
`which were reported in 5 patients (22%), includ-
`ed the myelodysplastic syndrome, pancreatitis,
`pneumonitis, stomatitis, colitis, gastrointestinal
`inflammation, thrombocytopenia, an increased
`lipase level, a decreased lymphocyte level, and
`leukopenia. There were no drug-related grade 4
`or 5 adverse events. Three patients had oneseri-
`ous drug-related adverse event each (grade 3 pan-
`creatitis, grade 3 myelodysplastic syndrome, and
`grade 2 lymph-node pain) (Table 2). The patient
`with the myelodysplastic syndrome had under-
`gone six previous systemic chemotherapies, ra-
`diation therapy, and autologous stem-cell trans-
`plantation but had not received bendamustine
`previously. There were no treatment-related
`deaths.
`Of the 12 patients (52%) who discontinued
`treatment, 2 patients (9%) had toxic effects (the
`myelodysplastic syndrome and thrombocytopenia
`
`
`
`
`
`18 (78)
`Autologous stem-cell transplantation
`19 (83)
`Radiotherapy
`
`4 (17)
`Extranodal involvement — no. (%)+
`* Race waseither self-reported or reported by investigators.
`+ Eastern Cooperative Oncology Group (ECOG)scores indi-
`cate the performancestatus ofpatients with respect to ac-
`tivities ofdaily living on a scale from 0 to 5, with higher num-
`bers indicating greater disability. A score of 0 indicates that
`the patientis fully active and able to carry outall predisease
`activities without restriction, and a scoreof 1 indicates that
`the patientis restricted in physically strenuousactivity but is
`ambulatory and able to carry out workofa light nature.
`+ Sites of extranodal disease were bone,lung,pelvis, peri-
`toneum, and pleura.
`
`
`314
`
`NENGLJ MED 372;4 NEJM.ORG JANUARY 22, 2015
`
`

`

`
`
`Table 2. Drug-Related Adverse Events in the 23 Patients.
`
`Any Grade
`
`Grade 3
`
`no. ofpatients (%)
`
`18 (78)
`
`5 (22)
`
`
`
`oroocoeodooeoceoeoes
`
`1 (4)
`
`1 (4)
`
`1 (4)
`
`1(4)
`
`NIVOLUMAB IN RELAPSED OR REFRACTORY HODGKIN'S LYMPHOMA
`
`in 1 patient and pancreatitis in 1 patient), 4 pa-
`tients
`(17%) had progressive disease during
`treatment, and 6 patients (26%) elected to un-
`dergo either allogeneic stem-cell transplantation
`(in 5 patients) or autologous stem-cell transplan-
`tation (in 1). Adverse events werereversible in all
`the patients except the 2 who discontinued treat-
`ment. As of June 16, 2014, a total of 11 patients
`(48%) were continuing to participate in the study.
`The median number of nivolumab doses that
`patients received was 16 (range, 6 to 37), admin-
`istered over a median treatment duration of 36
`weeks (range, 13 to 77), with 15 patients (65%)
`receiving 90% or more of the intended overall
`dose. Nine patients (39%) had at least one dose
`delay (five delays because of nonhematologic
`drug-related adverse events, five delays because
`of infections unrelated to treatment, and one
`delay because of inclement weather). All the pa-
`tients who had delayed doses were able to restart
`treatment. Two patients (9%) had infusion inter-
`ruptions that were due to grade 1 hypersensitiv-
`ity reactions,
`
`Event
`
`Any adverse event
`
`Drug-related adverse events reported in =5%
`of patients
`
`Rash
`
`Decreased platelet count
`
`Fatigue
`Pyrexia
`
`Diarrhea
`
`Nausea
`
`Pruritus
`
`Cough
`
`Hypothyroidism
`Decreased lymphocyte count
`
`Hypophosphatemia
`
`Hypercalcemia
`
`Increasedlipase level
`
`Stomatitis
`
`CLINICAL ACTIVITY
`
`Drug-related serious adverse events
`
`5 (22)
`
`4 (17)
`
`3 (13)
`3 (13)
`
`3 (13)
`
`3 (13)
`
`3 (13)
`
`2 (9)
`
`2 (9)
`2 (9)
`
`2 (9)
`
`2 (9)
`
`2 (9)
`
`2 (9)
`
`The response rate was 87% (95% confidence in-
`terval [CI], 66 to 97), with a complete response
`occurring in 4 patients (17%), a partial response
`in 16 patients (70%), and stable disease in 3 pa-
`tients (13%) (Table 3). Of the 4 patients with
`complete responses, 3 had not received previous
`treatment with brentuximab. Results are also
`summarized according to three subgroups: pa-
`tients in whom previous autologous stem-cell
`transplantation and brentuximab treatment
`failed,
`those in whom brentuximab treatment
`had failed but who did not undergo autologous
`stem-cell
`transplantation before brentuximab
`treatment, and those who did not receive bren-
`tuximab (Table 3). Among 15 patients who had
`disease recurrence after autologous stem-cell
`transplantation and brentuximab treatment, the
`response rate was 87% (95% CI, 60 to 98). Of
`these patients, 1 (7%) had a complete response,
`12 (80%) hada partial response, and 2 (13%) had
`stable disease. For the 3 patients who did not
`undergo autologous stem-cell
`transplantation
`before brentuximabtreatment, the response rate
`was 100% (95% CI, 29 to 100), with all 3 patients
`having a partial response. Amongthe 5 patients
`
`Myelodysplastic syndrome
`Lymph-node pain
`Pancreatitis
`
`1 (4)
`1 (4)
`1 (4)
`
`
`* No grade 4 or grade 5 drug-related adverse events were reported. Decisions
`about whetherthe adverse event was related to the study drug were made by
`the investigators. A moredetailed list of adverse events is provided in Table
`$1 in the Supplementary Appendix.
`
`
`whodid not receive brentuximab, the response
`rate was 80% (95% CI, 28 to 99), with 3 patients
`(60%) having a complete response, 1 (20%) a par-
`tial response, and 1 (20%) stable disease.
`Of the 20 patients who had a complete or
`partial response, 12 patients (60%) had thefirst
`response by 8 weeks (range, 3 to 39 weeks) (Fig.
`1A). The rate of progression-free survival at 24
`weeks was 86% (95% Cl, 62 to 95). As of this
`writing, 6 patients chose to undergo stem-cell
`transplantation at the time of the best overall
`response, and 11 patients continued to have a
`response (Fig. 1A). The median overall survival
`had not been reached. The median duration of
`follow-up was 40 weeks (range, 0 to 75).
`Figure 1B shows the maximum reduction in
`
`N ENGL) MED 372;4 NEJM.ORG
`
`JANUARY 22, 2015
`
`315
`
`

`

`
`
`The NEW ENGLAND JOURNAL of MEDICINE
`
`Table 3. Clinical Activity in Nivolumab-Treated Patients.*
`
`
`
`Failure of Both Stem-Cell
`No Stem-Cell Transplantation No Brentuximab
`
`All Patients=Transplantation and Brentuximab —_and Failure of Brentuximab Treatment
`
`Variable
`(N=23)
`(N=15)
`(N=3)
`(N=5)7
`
`Best overall response — no. (%)
`Complete response
`Partial response
`Stable disease
`
`Progressive disease
`
`Objective response
`No.of patients
`Percent of patients (95% Cl)
`Progression-free survival at 24 wk
`—% (95% Cl) t
`Overall survival — wk
`
`4 (17)
`16 (70)
`3 (13)
`
`0
`
`20
`87 (66-97)
`86 (62-95)
`
`1 (7)
`12 (80)
`2 (13)
`
`0
`
`13
`87 (60-98)
`85 (52-96)
`
`0
`3 (100)
`)
`
`0
`
`3
`100 (29-100)
`Ncf
`
`3 (60)
`1 (20)
`1 (20)
`
`0
`
`4
`80 (28-99)
`80 (20-97)
`
`Median
`
`
`NR
`NR
`NR
`NR
`
`
`
`21-75 21-75 32-55Rangeat data cutoff4 30-50
`* NC denotes not calculated, and NR not reached.
`{In this group, two patients had undergone autologous stem-cell transplantation and three hadnot.
`+ Point estimates were derived from Kaplan-Meier analyses; 95% confidenceintervals were derived from Greenwood’s formula.
`Iculated when the percentage of data censoring was above 25%.
`{ The estimate was not ca
`4 Responses were ongoing in 11 patients.
`
`
`tumor burden from baseline for each patient.
`Progression-free survival for the entire cohortis
`shown in Figure $1 in the Supplementary Ap-
`pendix.
`
`ANALYSIS OF PD-1 LIGAND LOCI AND EXPRESSION
`In the subgroup of 10 patients with available tu-
`mor samples, PDL1 and PDL2 copy numbers in
`Reed-Sternbergcells were assessed with the use
`of fixed tumor-biopsy specimens and a three-
`probeFISH assay (PDL1 (CD274], PDL2 [PDCD1LG2),
`and control centromeric probe) (Fig. 2A). In all
`tumors analyzed by means of FISH, tumorcells
`had 3 to 15 copies of PDLI and PDL2in patterns
`characterized by amplification,
`relative copy
`gain, or polysomy of chromosome 9p(Fig. 2D,
`and Table $2 and Fig. $2 in the Supplementary
`Appendix). In all the samples, Reed—Sternberg
`cells, which were identified by their characteris-
`tic morphologic features and staining for PAX5,
`expressed PD-L1 and PD-L2proteins (Fig. 2C and
`2D, and Table $3 and Fig. S2 in the Supplemen-
`tary Appendix). Tumorcells were also positive
`for nuclear pSTAT3,indicative ofactive JAK-STAT
`
`signaling (Fig. 2C and 2D, and Table $3 andFig.
`$2 in the Supplementary Appendix). Infiltrating
`Tcells in the available Hodgkin’s lymphomabi-
`opsy specimens largely expressed low levels of
`the PD-1 receptors (Table $4 and Fig. $3 in the
`Supplementary Appendix). Together, these data
`indicate thatall the patients with Hodgkin’s lym-
`phomain this study who could be evaluated had
`numericalterations of the PD-1 ligand loci and
`associated protein expression.
`
`DISCUSSION
`
`In this study, we found that nivolumab-mediated
`PD-1 blockade wasa highly effective therapy in
`patients with Hodgkin’s lymphoma, a disease
`with a genetic basis for PD-1 ligand overexpres-
`sion and a marked butineffective inflammatory
`and immune-cell infiltrate. In heavily pretreated
`patients with relapsed or refractory Hodgkin’s
`lymphoma, the majority of whom had had a re-
`lapse after autologous stem-cell transplantation
`and brentuximab treatment,
`the use of nivolu-
`mab wasassociated with an overall responserate
`
`316
`
`N ENGL) MED 372;4 NEJM.ORG JANUARY 22, 2015
`
`

`

`NIVOLUMAB IN RELAPSED OR REFRACTORY HODGEIN’S LYMPHOMA
`
`© ASCTfailure and
`brentuximab failure
`
`®@ No ASCT and
`brentuximab failure
`
`No brentuxirmab
`
`RhWwhinm~so9
`
`
`
`
`Change(%)
`
`of 87%and a rate of progression-free survival of
`86% at 24 weeks. Adverse events were mainly of
`grade 1 or 2. The rate of adverse events was sim-
`
`A Response Characteristics
`ilar to that in trials of nivolumabin patients with
`Patient No.
`solid tumors.* Given the limited therapeutic op-
`
`
`« First complete response
`ae
`2040
`tions for patients with Hodgkin’s lymphoma
`19+
`;
`‘
`« First partial response
`
`13 -d«> » Therapy duration
`whose disease progresses after autologous stem-
`7
`=
`>
`* Transplantation
`
`» Ongoing response
`cell transplantation?'?? and the relatively short-
`lived responses to brentuximab after relapse,**
`nivolumab-mediated PD-1 blockade may repre-
`sent a promising targeted treatment for these
`patients.
`The frequent chromosome 9p24.1 amplifica-
`tion and associated PD-1 ligand overexpression
`in Hodgkin’s lymphoma and the pronounced but
`ineffective inflammatory response seen in in-
`volved lymph nodes provided a compelling ratio-
`nale for evaluating the efficacy of PD-1 blockade
`in patients with relapsed or refractory disease.
`In this study, all the patients with available tu-
`mor specimens had concurrent gain of the PDL1
`and PDL2 loci, increased expre