V O L U M E 3 2 䡠 N U M B E R 1 0 䡠 A P R I L 1 2 0 1 4
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Author affiliations appear at the end of
`this article.
`
`Published online ahead of print at
`www.jco.org on March 3, 2014.
`
`Supported by Bristol-Myers Squibb and
`Ono Pharmaceutical Company.
`
`S.L.T. and M.S. contributed equally to
`this work.
`
`Terms in blue are defined in the glos-
`sary, found at the end of this article
`and online at www.jco.org.
`
`Presented in part at the 49th Annual
`Meeting of the American Society of
`Clinical Oncology, Chicago, IL, May
`31-June 4, 2013.
`
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical trial information: NCT00730639.
`
`Corresponding author: Suzanne L.
`Topalian, MD, Department of Surgery,
`Johns Hopkins University School of
`Medicine, 1550 Orleans St, CRB 2,
`Room 508, Baltimore, MD 21287;
`e-mail: stopali1@jhmi.edu.
`
`© 2014 by American Society of Clinical
`Oncology
`
`0732-183X/14/3210w-1020w/$20.00
`
`DOI: 10.1200/JCO.2013.53.0105
`
`Survival, Durable Tumor Remission, and Long-Term Safety
`in Patients With Advanced Melanoma Receiving Nivolumab
`Suzanne L. Topalian, Mario Sznol, David F. McDermott, Harriet M. Kluger, Richard D. Carvajal,
`William H. Sharfman, Julie R. Brahmer, Donald P. Lawrence, Michael B. Atkins, John D. Powderly,
`Philip D. Leming, Evan J. Lipson, Igor Puzanov, David C. Smith, Janis M. Taube, Jon M. Wigginton,
`Georgia D. Kollia, Ashok Gupta, Drew M. Pardoll, Jeffrey A. Sosman, and F. Stephen Hodi
`See accompanying editorial on page 986; listen to the podcast by Dr Gulley at
`www.jco.org.podcasts
`
`A
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`B
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`Purpose
`Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that
`downmodulates effector functions and limits the generation of immune memory. PD-1 blockade
`can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not
`known whether this is associated with extended survival or maintenance of response after
`treatment is discontinued.
`Patients and Methods
`Patients with advanced melanoma (N ⫽ 107) enrolled between 2008 and 2012 received intravenous
`nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall
`survival, long-term safety, and response duration after treatment discontinuation.
`Results
`in nivolumab-treated patients (62% with two to five prior systemic
`Median overall survival
`therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively.
`Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median
`response duration was 2 years. Seventeen patients discontinued therapy for reasons other than
`disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks
`(range, 16 to 56⫹ weeks). Objective response and toxicity rates were similar to those reported
`previously; in an extended analysis of all 306 patients treated on this trial (including those with
`other cancer types), exposure-adjusted toxicity rates were not cumulative.
`Conclusion
`Overall survival following nivolumab treatment in patients with advanced treatment–refractory
`melanoma compares favorably with that in literature studies of similar patient populations.
`Responses were durable and persisted after drug discontinuation. Long-term safety was accept-
`able. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on
`overall survival in patients with metastatic melanoma.
`
`J Clin Oncol 32:1020-1030. © 2014 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`Melanoma harbors one of the highest somatic
`mutation frequencies among human cancers.1 Al-
`though the diversity of genetic alterations in mela-
`noma creates challenges for targeted therapies, it
`provides a common denominator for immunother-
`apy, namely, the creation of tumor-specific antigens
`recognizable by the immune system. The adaptive
`immune system has powerful anticancer potential,
`with a broad capacity and exquisite specificity to
`respond to diverse tumor antigens. It also demon-
`strates considerable plasticity and a memory com-
`
`ponent, making immunotherapy unique among all
`cancer treatment modalities. Evidence suggests that
`a properly educated immune system can provide a
`self-perpetuating mechanism to eliminate or dura-
`bly control melanoma and other cancers.2 The clin-
`ical
`translation of cancer immunotherapy has
`recently accelerated as advances in molecular im-
`munology have elucidated mechanistic pathways
`that subvert antitumor immunity. These include
`dysfunctional T-cell signaling,3 suppressive regula-
`tory cells,4 and key “immune checkpoints” that reg-
`ulate the outcome of lymphocyte engagement with
`antigen-presenting cells and tumor cells.5,6 In
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`Nivolumab in Advanced Melanoma: Survival and Long-Term Safety
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`particular, immune checkpoints, which serve to downmodulate
`the intensity of adaptive immune responses and protect normal
`tissues from collateral damage, can be co-opted by cancer cells to
`evade immune attack, which provides a spectrum of potential new
`targets for cancer immunotherapy.
`The recent clinical success of anti-CTLA-4 (CD152) (ipili-
`mumab) in improving survival in patients with advanced mela-
`noma was achieved by blocking a prototypical T-cell checkpoint.
`This innovation established a therapeutic role for targeting im-
`mune inhibitory receptors and ligands and fueled efforts to explore
`the clinical effects of inhibiting other molecules in the CD28 and B7
`families.7,8 Programmed cell death 1 (PD-1) is a key inhibitory
`receptor expressed by activated T and B cells. Its binding with
`programmed cell death ligand 1 (PD-L1 [B7-H1]) and PD-L2 (B7-
`DC), expressed on antigen-presenting cells and human cancers, deliv-
`ers a negative signal to lymphocytes.9-12 In the first-in-human study of
`the PD-1 immune checkpoint inhibitor nivolumab (BMS-936558,
`MDX-1106, ONO-4538), an acceptable safety profile and durable
`objective tumor regressions were observed in patients with ad-
`vanced solid tumors, including melanoma.13,14 On the basis of
`these findings, this study of a multidose nivolumab regimen was
`undertaken. We have reported preliminary findings showing that
`approximately 20% to 30% of patients with advanced treatment–
`refractory melanoma, non–small-cell lung cancer, or kidney can-
`cer experienced objective tumor regressions.15 We now report
`overall survival outcomes in patients with melanoma who received
`nivolumab. Response characteristics, including durability and per-
`sistence after treatment discontinuation, and the long-term safety
`profile are presented in patients with a minimum of 14 months and
`up to 4.3 years since treatment initiation.
`
`PATIENTS AND METHODS
`
`Study Design
`This dose-escalation, cohort expansion study evaluated the antitumor
`activity and safety of nivolumab, a fully human immunoglobulin G4 mono-
`clonal antibody blocking PD-1 in patients with advanced cancers, including
`melanoma and non–small-cell
`lung, kidney, colorectal, and castration-
`resistant prostate cancer. Study design and methods, including the protocol,
`amendments, and detailed statistical analysis plan, were previously pub-
`lished.15 The study was approved by local institutional review boards, and all
`patients or their legal representatives gave written informed consent before
`enrollment. Nivolumab was administered intravenously once every 2 weeks in
`an outpatient setting in 8-week treatment cycles at 1, 3, or 10 mg/kg during
`dose escalation. After completion of dose escalation, each dose cohort was
`expanded to accrue approximately 16 patients with advanced melanoma.
`Following a 6.5-month hiatus for protocol amendment, additional mela-
`noma cohorts randomly assigned to 0.1, 0.3, and 1.0 mg/kg were enrolled.
`In patients with melanoma receiving 0.1 or 0.3 mg/kg who had progressive
`disease, intrapatient dose escalation to 1.0 mg/kg was permitted. On the
`basis of observed objective responses, the protocol was further amended to
`evaluate overall survival.
`Tumors were reassessed radiographically following each treatment
`cycle. Treatment continued up to 96 weeks (12 cycles), until patients
`experienced confirmed complete response, unacceptable toxicity, or pro-
`gressive disease or until they withdrew consent. In clinically stable patients,
`treatment could be continued beyond initial disease progression pending
`subsequent confirmation of progression, consistent with proposed im-
`mune response criteria.16 Patients with stable disease or an ongoing objec-
`tive response (complete or partial) at the end of treatment were observed
`
`for up to 1 year and were offered re-treatment for 1 additional year if
`disease progressed.
`Clinical and laboratory safety assessments were conducted on all treated
`patients at regular intervals during therapy and were reported up to 70 days
`following the last drug administration. Adverse event severity was graded on
`the basis of the National Cancer Institute’s Common Terminology Criteria for
`Adverse Events, v3.0.17
`
`Patients
`Eligibility criteria have been previously described.15 Patients with
`melanoma arising from any primary site, including ocular, were required
`to have measurable disease by RECIST (Response Evaluation Criteria in
`Solid Tumors) v1.018 with modification. Those with brain metastases were
`eligible if lesions had been treated and were clinically stable for at least 8
`weeks. Patients must have received at least one but not more than five prior
`systemic cancer therapies. Those with a history of autoimmune disease,
`prior therapy with T-cell modulating antibodies (eg, anti–PD-1, anti–PD-
`L1, anti–CTLA-4), conditions requiring immunosuppression, chronic in-
`fections, or history of other invasive cancers within the previous 2 years
`were excluded.
`
`Statistical Analysis
`Baseline characteristics, response rates, adverse events, and survival
`results for all patients with melanoma (N ⫽ 107) are reported here as of
`March 5, 2013. Interim response rates for 94 patients and adverse events for
`104 patients were previously reported as of February 2012.15 Tumor mea-
`surements were collected by investigators, and individual best responses
`were centrally assessed by the sponsor per modified RECIST v1.0. Objec-
`tive response and stable disease rates with CIs were estimated by using the
`Clopper-Pearson method. Time-to-event end points, including progression-
`free survival, overall survival, survival rates, and response duration, were
`estimated by using the Kaplan-Meier method, with CIs based on Green-
`wood’s formula. Survival data were collected retrospectively. Progression-
`free survival estimates take into account all deaths, including four that
`occurred during the follow-up for survival. Adverse events were coded by
`using the Medical Dictionary for Regulatory Activities (MedDRA), version
`15.1. Categories of select adverse events with potential immunologic etiol-
`ogies, defined as adverse events that require more frequent monitoring or
`intervention with immune suppression or hormone replacement, were
`based on a prespecified list of MedDRA Terms (Data Supplement). An
`exposure-adjusted analysis of select adverse events that was based on the
`event rate per 100 person-years of nivolumab exposure was conducted for
`all 306 treated patients, including those with melanoma and non–small-
`cell lung, kidney, colorectal, and castration-resistant prostate cancer.15
`
`RESULTS
`
`Patient Characteristics
`In all, 107 patients with melanoma initiated treatment with niv-
`olumab from November 2008 through January 2012. Baseline char-
`acteristics are presented in the Data Supplement. Of note, 62% had
`received at least two prior systemic treatments for melanoma, 78%
`had a visceral metastatic lesion, and 36% had an increased lactate
`dehydrogenase level in the blood, a factor associated with adverse
`prognosis in patients with advanced melanoma.
`
`Overall and Progression-Free Survival
`We undertook a retrospective analysis of overall survival in pa-
`tients with advanced melanoma receiving nivolumab that was based
`on preliminary findings of durable tumor regression in these pa-
`tients.15 All patients initiated treatment at least 14 months before this
`analysis. The estimated median overall survival was 16.8 months (95%
`CI, 12.5 to 31.6 months; Table 1 and Fig 1A). One- and 2-year survival
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`www.jco.org
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`© 2014 by American Society of Clinical Oncology
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`§Thetimepointatwhichtheprobabilitythatresponder’sprogressdropsbelow50%hasnotbeenreachedbecauseofinsufficientnumberofeventsand/orfollow-up.
`‡Fivepatientswithtumorprogressionreceiveddose-escalationfrom0.1to1.0mg/kg,andsixpatientsreceiveddose-escalationfrom0.3to1.0mg/kg.Noneofthesepatientsrespondedtotherapy.
`†Kaplan-Meierestimate,timefromfirstresponsetotimeofdocumentedprogression,death,orforcensoreddata(denotedby“⫹”),timetolasttumorassessment.
`adjudicatedperResponseEvaluationCriteriainSolidTumors(RECIST)v1.0withmodification.Onecompleteresponsewasnoted.
`ⴱObjectiveresponserates{关(CR⫹PR)⫼N兴⫻100}havebeencalculatedonthebasisofconfirmedresponseswithCIscalculatedbyusingtheClopper-Pearsonmethod.Individualpatientresponseswere
`Abbreviations:NE,notestimable;n/N,No.ofpatients/totalNo.ofpatients;NR,notreached;ORR,objectiveresponserate;OS,overallsurvival;PFS,progression-freesurvival.
`
`Topalian et al
`
`7.2to37.8
`8.2toNE
`
`14.6toNE
`7.7toNE
`8.6toNE
`12.5to31.6
`
`11.7
`20.3
`
`25.3
`12.5
`16.2
`16.8
`
`1.7to20.5
`1.9to16.4
`
`1.8to24.7
`1.8to9.3
`1.7to9.1
`1.9to9.1
`
`3.7
`9.7
`
`9.1
`1.9
`3.6
`3.7
`
`0
`
`0.1to28.7
`
`4.8to30.3
`0.1to27.3
`
`0
`
`2.7to13.0
`
`95%CI
`
`Median
`
`95%CI
`
`Median
`
`95%CI
`
`0
`
`5.9
`
`14.3
`5.6
`
`0
`
`6.5
`
`%
`
`0
`
`1/17
`
`5/35
`1/18
`
`0
`
`7/107
`
`n/N
`
`73.9,78.3⫹,111.7,117.0⫹
`40.1⫹,40.4,48.1,56.1,95.7,106.7⫹,115.4⫹
`
`32.4,32.4,43.0⫹,64.1⫹,74.1⫹,80.1⫹,82.1⫹,
`18.4,44.4⫹,64.6⫹,65.1⫹,66.3⫹
`24.1,24.1,34.3,44.1⫹,48.1⫹,48.7⫹
`
`99.4,100.9⫹,104.1,108.1⫹
`
`—
`
`112
`75.9
`
`104
`NR§
`NR§
`104
`
`5.7to43.7
`18.4to67.1
`
`16.9to49.3
`9.7to53.5
`14.2to61.7
`22.3to40.5
`
`IndividualResponses
`
`Median
`
`95%CI
`
`20.0
`41.2
`
`31.4
`27.8
`35.3
`30.8
`
`%
`
`4/20
`7/17
`
`11/35
`5/18
`6/17
`33/107
`
`10
`
`1
`
`3
`
`0.3‡
`0.1‡
`Alldoses
`
`n/N
`
`Dose(mg/kg)
`
`OS(months)
`
`PFS(months)
`
`StableDiseaseⱖ24Weeks
`
`DurationofResponse(weeks)†
`
`ORRⴱ
`
`Table1.ClinicalActivityofNivolumabinMelanomabyDoseLevel
`
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`Nivolumab in Advanced Melanoma: Survival and Long-Term Safety
`
`rates were 62% (95% CI, 53% to 72%) and 43% (95% CI, 32% to
`53%), respectively (Fig 1A). Median progression-free survival was 3.7
`months (95% CI, 1.9 to 9.1 months), with 1- and 2-year progression-
`free survival rates of 36% (95% CI, 27% to 46%) and 27% (95% CI,
`17% to 36%), respectively (Table 1 and Fig 1B). Both the overall and
`progression-free survival curves appeared to flatten beyond the
`median, although verification of this observation will require lon-
`ger follow-up.
`
`Response Rate and Duration
`Objective responses were observed in 31% of patients (33 of
`107) with melanoma, and an additional 7% of patients (seven of
`107) experienced stable disease lasting for 24 weeks or more (Table
`1). Durable responses were observed across all nivolumab doses
`tested within a 2-log range (0.1 to 10 mg/kg). Changes in the sum of
`target lesion dimensions compared with baseline are shown in
`Figure 2A. Unconventional response patterns that did not meet
`RECIST criteria (eg, persistent reduction in target lesions in the
`presence of new lesions or regression following initial progres-
`sion)16 were observed in four patients (4%); three of them received
`nivolumab at 1 mg/kg (Fig 2B), and a fourth received 10 mg/kg.
`Among 11 patients who experienced disease progression following
`treatment with nivolumab at 0.1 or 0.3 mg/kg, none responded
`following dose escalation to 1.0 mg/kg.
`In 33 patients with objective responses, the Kaplan-Meier
`estimated median duration of response was 2 years (Fig 1C). Nine-
`teen of 33 responses (58%) were ongoing at the time of data
`analysis (Table 1 and Fig 2C). Fifteen responses (45%) occurred
`rapidly and were documented at the first tumor assessment 8 weeks
`after starting treatment (Fig 2B-C). Tumor regression was ob-
`served at various anatomic sites and in primary and metastatic
`lesions, as exemplified in Figures 3 and 4. Seventeen of 33 patients
`stopped therapy for reasons other than disease progression during
`response and were observed; 12 (71%) of 17 maintained their
`responses for at least 16 weeks off-drug (16 to 56⫹ weeks), and
`eight of the 12 had responses ongoing at the time of analysis. Figure
`4 shows an example of continued regression in multiple metastatic
`lesions after nivolumab discontinuation.
`
`Safety
`The maximum-tolerated dose of nivolumab was not reached
`within the tested dose range. With extended observation since our
`initial report (median time on treatment, 22 weeks; range, 2 to 122
`weeks), the spectrum and severity of treatment-related adverse
`events remained stable (Table 2 and Data Supplement).15 The most
`common events of any grade that occurred in patients with mela-
`noma were fatigue (32%), rash (23%), and diarrhea (18%).
`Twenty-four (22%) of 107 patients with melanoma experienced
`grade 3 to 4 treatment-related adverse events. Select adverse events
`with potential
`immune-related causality, previously termed
`“immune-related adverse events” or “adverse events of special
`interest,”15 were also analyzed (categorized in the Data Supple-
`ment). Treatment-related select adverse events of any grade were
`observed in 58 (54%) of 107 patients with melanoma, the most
`common of which included skin disorders (36%), GI events
`(18%), and endocrinopathies (13%; Data Supplement). Grade 3 to
`4 treatment-related select events were seen in five patients (5%).
`There were no drug-related deaths in the population of patients
`
`
`
` Died/Treated
`
`60/107
`
`Median, months
` (95% CI)
`16.8 (12.5 to 31.6)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Overall Survival (%)
`
`A
`
`0
`
`963
`12
`15
`18
`21
`24
`27
`30
`33
`36
`39
`42
`45
`48
`Time Since Treatment Initiation (months)
`No. at risk 107 97 86 70 57 40 31 28 26 25 22 20 17 6 2 2 1 0
`B
`
`51
`
`
`
`Events/Treated
`
`77/107
`
`Median, months
` (95% CI)
`3.7 (1.9 to 9.1)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Progression-Free
`
`Survival (%)
`
`3
`
`0
`
`6
`9
`12
`15
`18
`21
`24
`27
`30
`33
`Time Since Treatment Initiation (months)
`No. at risk 107 55
`40
`39
`29
`23 20
`11
`11
`8
`5
`1
`C
`
`36
`
`0
`
`
`
`Events/Responded
`
`14/33
`
`Median, months
` (95% CI)
`24.0 (17.0 to NE)
`
`3
`6
`9
`12
`15
`18
`21
`24
`27
`30
`Time Since Initiation of Response (months)
`33
`30
`27
`19
`15
`12
`9
`5
`0
`0
`
`33
`
`0
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Responders (%)
`Progression-Free
`
`No. at risk 33
`
`Fig 1. Kaplan-Meier curves of (A) overall survival and (B) progression-free
`survival
`in 107 nivolumab-treated patients with melanoma and (C) response
`duration in 33 objective responders. Analysis includes patients from all dose
`cohorts. (A) Patients with melanoma had 1- and 2-year overall survival rates of
`62% and 43% and a median overall survival of 16.8 months. (B) Progression-free
`survival rates were 36% and 27% at 1 and 2 years, and the median was 3.7
`months. (C) The median duration of response in 33 responding patients was 24
`months. Open circles indicate censored events defined for progression-free
`survival as the time to the last tumor assessment before the date of data analysis
`for patients without disease progression or death, and for overall survival as the
`time to the last known alive date before the date of data analysis for patients
`without a death. NE, not estimable.
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`Topalian et al
`
`Dose, mg/kg
`0.1
`0.3
`1.0
`3.0
`10.0
`
`Patients
`
`Nivolumab 1 mg/kg
`
`0
`
`10
`
`20
`
`30
`
`40
`50
`60
`70
`80
`90
`100 110 120 130 140 150
`Time Since Treatment Initiation (weeks)
`
`Nivolumab 3 mg/kg
`
`200
`
`150
`
`100
`
`50
`
`0
`
`−50
`
`−100
`
`100
`80
`60
`40
`20
`0
`−20
`−40
`−60
`−80
`−100
`
`100
`80
`60
`40
`20
`0
`−20
`−40
`−60
`−80
`−100
`
`Change in Target Lesions
`
`From Baseline (%)
`
`Change in Target Lesions
`
`From Baseline (%)
`
`Change in Target Lesions
`
`From Baseline (%)
`
`A
`
`B
`
`0
`
`10
`
`20
`
`30
`
`40
`50
`60
`70
`80
`90
`100 110 120 130 140 150
`Time Since Treatment Initiation (weeks)
`
`Fig 2. Characteristics of tumor regression in patients with melanoma receiving nivolumab therapy. (A) Maximum reduction or minimum increase in the sum of target
`lesion measurements compared with baseline in all treated patients with tumor measurements during treatment (n ⫽ 97). Responses were observed at all dose levels.
`Horizontal line at ⫹20% indicates the threshold for defining progressive disease according to RECIST. Horizontal line at ⫺30% indicates threshold for defining objective
`response (partial tumor regression) in the absence of new lesions or nontarget disease progression according to RECIST. (B) Response kinetics in patients receiving
`nivolumab at 1 mg/kg (n ⫽ 31) or 3 mg/kg (n ⫽ 17). Baseline tumor measurements are standardized to zero. Tumor burden is measured as the sum of the longest
`diameters of target lesions. Triangles indicate first occurrence of a new lesion. Vertical line at 96 weeks indicates the protocol-defined maximum duration of continuous
`nivolumab therapy. Horizontal line at ⫺30% marks the threshold for defining objective response (partial tumor regression) according to RECIST. Blue curves indicate
`three unconventional immune-related response patterns in the 1 mg/kg dose cohort that did not meet RECIST criteria (eg, persistent reduction in target lesions in the
`presence of new lesions or regression following initial progression). Objective responses, unconventional responses, and stable disease persisted following treatment
`discontinuation in some patients. (Continued on next page.)
`
`with melanoma, although there were three mortalities following
`treatment-related adverse events in the overall patient population
`(1%; two patients with non–small-cell lung cancer and one with
`colorectal cancer) associated with pneumonitis. Taking into ac-
`count multiple adverse events occurring in individual patients, we
`analyzed the select adverse event rate as adjusted for person-years
`
`of nivolumab treatment in the total patient population, including
`those with melanoma and those with other solid tumors (N ⫽ 306;
`Data Supplement). Notably, with up to 2 years of safety monitoring
`for some patients, most adverse events occurred within the first 6
`months of therapy, and cumulative toxicities were not observed
`with prolonged drug exposure.
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`Nivolumab in Advanced Melanoma: Survival and Long-Term Safety
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`Time to response
`Ongoing response
`Response following
`discontinuation of
`therapy
`
`Patients
`
`C
`
`0
`
`24
`
`144
`120
`96
`72
`48
`Time Since Treatment Initiation (weeks)
`
`168
`
`Fig 2. Continued. (C) Durability of tumor regressions in patients with melanoma who had objective responses to nivolumab therapy according to conventional RECIST
`criteria. Among 107 patients, 33 (31%) responded, including six (35%) of 17 who received nivolumab at 0.1 mg/kg, five (28%) of 18 at 0.3 mg/kg, 11 (31%) of 35 at
`1 mg/kg, seven (41%) of 17 at 3 mg/kg, and four (20%) of 20 at 10 mg/kg. Blue bars indicate the time to and duration of response while on treatment; gold bars indicate
`response duration after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis.
`Vertical line at 96 weeks indicates maximum planned duration of continuous nivolumab therapy. Reasons for treatment discontinuation with ongoing response included
`investigator-assessed complete response (n ⫽ 2), attainment of maximum treatment duration (n ⫽ 5), adverse events (n ⫽ 6), and other (eg, withdrew consent or
`investigator decision [n ⫽ 4]).
`
`A
`
`C
`
`Pretreatment
`
`4 months
`
`B
`
`D
`
`1 month
`
`Fig 3. Partial response of locally advanced unresectable primary melanoma to nivolumab therapy in a 34-year-old man with xeroderma pigmentosum. Tumor had
`progressed through prior treatment with high-dose interleukin-2. (A) Pretreatment magnetic resonance imaging scans show right facial tumor eroding the zygomatic
`bone and extending into the orbit (gold arrows). (B) Immediate pretreatment core-needle tumor biopsy of the facial mass shows melanoma cells (single arrow) adjacent
`to infiltrating lymphocytes (double arrows). (C) A partial response was observed after 4 months (two cycles) of nivolumab therapy at 0.3 mg/kg every 2 weeks. This
`patient remains in partial response 2 years after treatment initiation. (D) Post-treatment core-needle biopsy shows fibrosis and infiltrating lymphocytes (double arrows);
`no tumor was present in this specimen. Hematoxylin and eosin stain; original magnification, ⫻200.
`
`www.jco.org
`
`© 2014 by American Society of Clinical Oncology
`
`1025
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`Genome Ex. 1006
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`

`

`Topalian et al
`
`Pretreatment
`
`8 months (end of treatment)
`
`17 months (follow-up)
`
`A
`
`B
`
`C
`
`Fig 4. Partial response of metastatic mel-
`anoma to nivolumab, with continued tu-
`mor regression after drug discontinuation.
`This 59-year-old woman previously had
`experienced disease progression follow-
`ing high-dose interleukin-2,
`temozolo-
`mide,
`and sorafenib therapies. She
`received nivolumab 10 mg/kg every 2
`weeks and achieved a partial tumor re-
`gression at 2 months. Treatment was dis-
`continued at 8 months (four treatment
`cycles) as a result of exacerbation of an
`upper extremity neuropathy. Tumor re-
`gression continued after drug discontinu-
`ation. Computed tomographic scanning was
`performed with oral contrast but without intra-
`venous contrast dye. Gold arrows indicate
`melanoma metastases involving (A) the right
`adrenal gland, (B) small bowel, and (C) mes-
`enteric lymph nodes.
`
`DISCUSSION
`
`The critical role of the PD-1pathway in suppressing antitumorimmu-
`nity, first revealed in laboratory models, has now been validated in
`clinical studies. Monotherapy with drugs blocking PD-1 (nivolumab,
`MK-3475 [lambrolizumab])15,19 or its major ligand PD-L1 (BMS-
`936559, MPDL3280A)20,21 can mediate rapid and durable regressions
`in patients with advanced treatment–refractory solid tumors, includ-
`ing epithelial cancers not traditionally viewed as immune responsive.
`These findings have established the PD-1 pathway as a new therapeu-
`tic focus in oncology.22 This study presents the longest follow-up to
`date in patients with melanoma treated with a PD-1 pathway inhibi-
`tor, nivolumab, and allows us to assess for the first time survival
`outcomes and the durability of clinical activity mediated by this ther-
`apeutic approach. In addition to persistence of conventional re-
`sponses and unconventional (immune-related) responses in patients
`receiving this therapy, the follow-up presented here assesses response
`maintenance after treatment discontinuation and treatment-associated
`toxicity as a function of time on therapy.
`In the context of published clinical experience with similar pa-
`tient populations, the survival outcomes associated with nivolumab
`therapy in melanoma in this early-phase study are particularly impor-
`tant. Overall survival rates of 62% at 1 year and 43% at 2 years were
`achieved, with a median overall survival of 16.8 months. In a recent
`phase III trial enrolling patients with melanoma who had at least one
`prior treatment for metastatic disease, ipilimumab increased median
`overall survival from 6.4 to 10.1 months compared with a gp100
`peptide vaccine.8 In phase II trials of ipilimumab in previously treated
`patients, median overall survivals of 8.7 to 11.4 months were observed
`in patients receiving 3 or 10 mg/kg, with 1-year and 2-year survival
`rates of 39% to 49% and 24% to 33%, respectively.23 Treatment with
`selective BRAF and MEK inhibitors is restricted to patients with
`mutation-positive melanomas, which are found almost exclusively in
`
`tumors of cutaneous origin. In contrast, the trial of nivolumab
`described here enrolled patients regardless of anatomic site of mela-
`noma origin or oncogene mutational status. The median overall sur-
`vival in previously treated patients with BRAF-mutant melanoma
`enrolled onto a large phase II trial of vemurafenib was 15.9 months,
`and the 1-year survival rate was 58%; among 53% of patients with
`objective tumor regressions, the median response duration was 6.7
`months.24 Treatment of a similar patient population with the MEK
`inhibitor trametinib in those who had not previously received a BRAF
`inhibitor resulted in a median overall survival of 14.2 months and
`estimated 1-year survival of 59%; among the 25% of patients with
`objective tumor regressions, the median response duration was 5.7
`months.25 Of interest, PD-1 blockade has been reported to be effective
`in melanoma regardless of BRAF mutational status.19,26 Despite the
`limitations of cross-study comparisons, this information suggests that
`nivolumab therapy may have a favorable impact on the survival of
`patients with advanced melanoma.
`Notably, overall survival in patients with melanoma who received
`nivolumab was considerably longer than progression-free survival. Both
`survival curves appear to flatten after 1 year of follow-up. This mirrors
`observations reported for ipilimumab,8 suggesting that early disease pro-
`gression in some patients receiving immune checkpoint blockade can
`evolve to durable disease stabilization or regression. These findings sug-
`gest that progression-free survival may underestimate the efficacy of im-
`munomodulatory agents such as nivolumab.27
`We report here that 31% of patients with melanoma experienced
`confirmed objective tumor regressions when they were given niv-
`olumab therapy, and 7% had disease stabilization lasting at least 6
`months. In addition, 4% of patients manifested unconventional
`immune-related response patterns.28 The apparent durability of
`clinical activity in nivolumab-treated patients is remarkable,
`because this has generally not been observed with chemotherapy or
`small molecule kinase inhibitors to date but has been seen to a
`
`1026
`
`© 2014 by American Society of Clinical Oncology
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Genome Ex. 1006
`Page 7 of 12
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`

`

`Nivolumab in Advanced Melanoma: Survival and Long-Term Safety
`
`Table 2. Treatment-Related Adverse Events That Occurred in at Least 3% of the Total Population of Patients With Melanoma
`
`Patients
`(N ⫽ 107)
`
`All Grades
`
`Grades 3 to 4
`
`Treatment-Related Adverse Event
`
`Any adverse eventⴱ†
`General disorders
`Fatigue
`Pyrexia
`Pain
`Skin and subcutaneous tissue disorders
`Rash
`Pruritus
`Vitiligo
`Dermatitis acneiform
`Photosensitivity reaction
`GI disorders
`Diarrhea
`Nausea
`Abdominal pain
`Dry mouth
`Vomiting
`Musculoskeletal disorders
`Arthralgia
`Myalgia
`Metabolism and nutrition disorders
`Decreased appetite
`Hyperuricemia
`Hypophosphatemia
`Blood and lymphatic system disorders
`Lymphopenia
`Investigations
`Blood thyroid-stimulating hormone increased
`Weight decreased
`Alanine aminotransferase increased
`Hemoglobin decreased
`Platelet count decreased
`Aspartate aminotransferase increased
`WBC count decreased
`Endocrine disorders
`Hypothyroidism
`Procedural complications
`Infusion-related reaction
`Respiratory disorders
`Cough
`Vascular disorders
`Flushing
`Hypotension
`
`No.
`
`90
`
`34
`5
`4
`
`25
`14
`10
`6
`4
`
`19
`9
`8
`7
`5
`
`7
`4
`
`7
`4
`4
`
`7
`
`6
`6
`5
`5
`5
`4
`4
`
`6
`
`6
`
`4
`
`4
`4
`
`%
`
`84.1
`
`31.8
`4.7
`3.7
`
`23.4
`13.1
`9.3
`5.6
`3.7
`
`17.8
`8.4
`7.5
`6.5
`4.7
`
`6.5
`3.7
`
`6.5
`3.7
`3.7
`
`6.5
`
`5.6
`5.6
`4.7
`4.7
`4.7
`3.7
`3.7
`
`5.6
`
`5.6
`
`3.7
`
`3.7
`3.7
`
`No.
`
`24
`
`2
`0
`0
`
`0
`0
`0
`0
`0
`
`2
`1
`2
`1
`1
`
`0
`0
`
`0
`1
`1
`
`3
`
`1
`0
`0
`1
`1
`0
`0
`
`1
`
`0
`
`0
`
`0
`0
`
`%
`
`22.4
`
`1.9
`0
`0
`
`0
`0
`0
`0
`0
`
`1.9
`0.9
`1.9
`0.9
`0.9
`
`0
`0
`
`0
`0.9
`0.9
`
`2.8
`
`0.9
`0
`0
`0.9
`0.9
`0
`0
`
`0.9
`
`0
`
`0
`
`0
`0
`
`NOTE. Treatment-related adverse events are reported according to the nivolumab dose cohort in the Data Supplement.
`ⴱTreatment-related adverse events that were reported in less than 3% of the total melanoma population included pneumonitis, colitis, and renal failure (two each;
`2%) and hepatitis, hypophysitis, thyroiditis, uveitis, and tubulointerstitial nephritis (one each; 1%).
`†The numbers reported within a column may not add up to the total number reported under any adverse event, because patients who had more than one adverse
`event were counted for each event but were counted only once for any adverse event. Data for only those events that were reported in at least 3% of the treated
`patient population are presented.
`
`lesser degree in some patients with advanced melanoma receiving
`immunotherapies including ipilimumab and high-dose interleu-
`kin 2.5,8 Among 33 patients with objective responses to nivolumab,
`the median response duration was 2 years. Unconventional re-
`sponses also appeared to be long-las