Nivolumab Versus Docetaxel in Previously Treated Patients ......phase III studies in patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identiﬁer: NCT01642004)5 or

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Nivolumab Versus Docetaxel in Previously Treated PatientsWith Advanced Non–Small-Cell Lung Cancer: Two-YearOutcomes From Two Randomized, Open-Label, Phase IIITrials (CheckMate 017 and CheckMate 057)Leora Horn, David R. Spigel, Everett E. Vokes, Esther Holgado, Neal Ready, Martin Steins, Elena Poddubskaya,Hossein Borghaei, Enriqueta Felip, Luis Paz-Ares, Adam Pluzanski, Karen L. Reckamp, Marco A. Burgio, MartinKohlhaeufl, David Waterhouse, Fabrice Barlesi, Scott Antonia, Oscar Arrieta, Jerome Fayette, Lucio Crino, NaiyerRizvi, Martin Reck, Matthew D. Hellmann, William J. Geese, Ang Li, Anne Blackwood-Chirchir, Diane Healey,Julie Brahmer, and Wilfried E.E. Eberhardt

A B S T R A C T

PurposeNivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel intwo independent phase III studies in previously treated patients with advanced squamous(CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057;ClinicalTrials.gov identifier: NCT01673867) non–small-cell lung cancer (NSCLC). We report updatedresults, including a pooled analysis of the two studies.

MethodsPatients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and diseaseprogression during or after prior platinum-based chemotherapy were randomly assigned 1:1 tonivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up forsurvival was 24.2 months.

ResultsTwo-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%)versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16%(95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death withnivolumab versus docetaxel remained similar to those reported in the primary analyses. Durableresponses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamousNSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years’minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooledanalysis, the relative reduction in the risk of deathwith nivolumab versus docetaxel was 28% (hazardratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower withnivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%).

ConclusionNivolumab provides long-term clinical benefit and a favorable tolerability profile compared withdocetaxel in previously treated patients with advanced NSCLC.

J Clin Oncol 35. © 2017 by American Society of Clinical Oncology

INTRODUCTION

Lung cancer is the most common cancer and theleading cause of cancer-related deaths globally.1

Non–small-cell lung cancer (NSCLC) accountsfor 85% to 90% of lung cancers.2 Historically,effective treatment options were lacking for pa-tients with NSCLC without actionable drivermutations who experienced disease progression

after first-line platinum-based chemotherapy.Recognition of the key role of immune systemevasion by tumors in cancer pathogenesis, how-ever, has spurred development of immune check-point inhibitors for the treatment of variousmalignancies, including NSCLC.3,4

Nivolumab is an anti–programmed death-1(PD-1) inhibitor antibody with robust efficacyand a manageable safety profile across multipletumor types.5-11 In two randomized, open-label,

Author affiliations and support information

(if applicable) appear at the end of this

article.

Published at jco.org on October 12, 2017.

Clinical trial information: NCT01642004

and NCT01673867.

Corresponding author: Leora Horn, MD,

Vanderbilt-Ingram Cancer Center, 1301

Medical Center Dr, Ste 1710, Nashville,

TN 37232-7415; e-mail: leora.horn@

vanderbilt.edu.

© 2017 by American Society of Clinical

Oncology

0732-183X/17/3599-1/$20.00

ASSOCIATED CONTENT

Data Supplements

DOI: https://doi.org/10.1200/JCO.

2017.74.3062

DOI: https://doi.org/10.1200/JCO.2017.

74.3062

© 2017 by American Society of Clinical Oncology 1

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phase III studies in patients with advanced squamous (CheckMate017; ClinicalTrials.gov identifier: NCT01642004)5 or nonsquamous(CheckMate 057; ClinicalTrials.gov identifier: NCT01673867)6

NSCLC and disease progression during or after platinum-basedchemotherapy, nivolumab significantly prolonged overall survival(OS) and had a favorable safety profile compared with docetaxel. Onthe basis of the results from CheckMate 017 and CheckMate 057,nivolumabwas approved in the United States,12 the EuropeanUnion,13

and other countries for use in previously treated advanced NSCLC.Long-term efficacy and safety data for immune checkpoint

inhibitors are limited in patients with NSCLC, especially in ran-domized studies, compared with chemotherapy. Five-year follow-up from a phase I single-arm nivolumab study in 129 heavilypretreated patients with advanced NSCLC showed durable sur-vival, with a 5-year OS rate of 16%.14 We report updated efficacyand safety data for nivolumab in patients with advanced NSCLCfrom the CheckMate 017 and CheckMate 057 trials with a mini-mum follow-up of 2 years in all patients.

METHODS

PatientsEligibility criteria for CheckMate 017 and CheckMate 057 have been

previously described.5,6 Briefly, patients had stage IIIB/IV NSCLC withsquamous (CheckMate 017) or nonsquamous (CheckMate 057) histology.In both studies, patients were required to be $18 years of age; to have anEastern Cooperative Oncology Group performance status of 0 or 1,measurable disease per Response Evaluation Criteria in Solid Tumorsversion 1.1 (RECIST v1.1)15; disease recurrence or progression during orafter one prior platinum-based chemotherapy regimen; and to submita recent or archival tumor sample for biomarker analyses. In CheckMate057, an additional line of prior targeted tyrosine kinase inhibitor therapywas permitted in patients with known EGFR mutations or ALK trans-locations. Key exclusion criteria for both studies were autoimmune disease,active interstitial lung disease, systemic immunosuppression (eg, 10 mgdaily prednisone) within 14 days, and prior treatment with T-cell cos-timulation or immune checkpoint–targeted agents or docetaxel.

Study DesignCheckMate 017 and CheckMate 057 were international, randomized,

open-label, phase III studies.5,6 In each trial, patients were randomlyassigned 1:1 to receive nivolumab (3 mg/kg every 2 weeks) or docetaxel(75 mg/m2 every 3 weeks). Random assignment was stratified by priorpaclitaxel use (yes v no) and geographic region (United States or Canada vEurope v rest of the world [Argentina, Australia, Chile, Mexico, and Peru])in CheckMate 017 and by prior maintenance treatment (yes v no) and lineof therapy (second v third) in CheckMate 057.

Patients continued study treatment until disease progression, un-acceptable toxicity, or other protocol-specified reasons. Patients in thenivolumab groups were permitted to continue study treatment after initialdisease progression if the investigator determined a clinical benefit and thestudy drug was tolerated. In the crossover/extension phases of thesestudies, opened after completion of the primary analyses, patients in thedocetaxel groups who were no longer deriving benefit per the treatinginvestigator were eligible to receive nivolumab after a 3-week washoutperiod of prior systemic anticancer therapy.

The studies were conducted in accordance with the Declaration ofHelsinki and the International Conference on Harmonization GoodClinical Practice Guidelines. The study protocols were approved by aninstitutional review board or independent ethics committee at each site. Allpatients provided written informed consent.

AssessmentsTumors were assessed by investigators per RECIST v1.1 at baseline, at

9 weeks, and every 6 weeks thereafter. Patients were followed continuouslyfor survival while receiving study treatment and every 3 months aftertreatment discontinuation.

Safety was based on reports of adverse events (AEs) and laboratoryassessments and monitored throughout the treatment period and at twofollow-up visits within 100 days since the last dose of study treatment orbefore the start of crossover treatment. The severity of AEs was gradedaccording to the National Cancer Institute Common Terminology Criteriafor Adverse Events (version 4.0). Select AEs (ie, those with a potentialimmunologic cause that may require management through immune-modulating medications such as corticosteroids) were grouped accord-ing to prespecified categories (endocrine, GI, hepatic, pulmonary, renal,skin, and hypersensitivity/infusion reaction).

Expression of PD-1 ligand 1 (PD-L1) protein was assessed in archivalor recent pretreatment tumor biopsy specimens at a central laboratory byusing a validated automated immunohistochemical assay (PD-L1 IHC28-8 pharmDx; Dako, Carpinteria, CA) as previously described.5,6 PD-L1expression was classified according to prespecified levels ($ 1%, $ 5%,and $ 10%) and a post hoc level of $ 50%.

Statistical AnalysisEfficacy was assessed in all randomly assigned patients, and safety was

assessed in all patients who received one or more doses of study drug. Theprimary end point of each study, OS, and secondary end points, includingobjective response rate, progression-free survival (PFS), and efficacyaccording to PD-L1 protein expression, have been reported.5,6 This update(February 18, 2016, database locks) represents a 24-month follow-upanalysis corresponding to an additional 13.6 and 11.0 months of mini-mum follow-up (defined as the time since random assignment of the lastpatient to the database lock) in CheckMate 017 and CheckMate 057,respectively, since the primary analyses.

Time-to-event end points were compared between treatment groupsby using a two-sided log-rank test adjusted for stratification factors for eachstudy; hazard ratios (HRs) and CIs were estimated by using a stratified Coxproportional hazards regression model. Survival curves and rates wereestimated by using the Kaplan-Meier method. Post hoc analyses of thetreatment effect of PD-L1 expression on OS in the pooled squamous/nonsquamous NSCLC population and of best overall response on OS ineach trial were performed, including unstratified HRs and 95% CIs. Safetywas analyzed in the pooled squamous/nonsquamous NSCLC population.

RESULTS

Patients and TreatmentAs previously reported,5,6 baseline characteristics were gen-

erally well balanced between patients randomly assigned to receivenivolumab (CheckMate 017, n = 135; CheckMate 057, n = 292)and those randomly assigned to receive docetaxel (CheckMate 017,n = 137; CheckMate 057, n = 290; Data Supplement). Patientdisposition in each study (as of the February 18, 2016, databaselocks; minimum follow-up, 24.2 months among patients alive andin the study) is shown in Figure 1. At 2 years, 15 (11%) of 131patients with squamous NSCLC treated with nivolumab and 34(12%) of 287 patients with nonsquamous NSCLC treated withnivolumab remained on treatment; no docetaxel-treated patientsremained on treatment.

In the nivolumab and docetaxel groups, respectively, 55 pa-tients (41%) and 44 patients (32%) with squamous NSCLC and133 patients (46%) and 150 patients (52%) with nonsquamous

2 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Horn et al




NSCLC received other systemic therapy subsequent to studytreatment, most commonly chemotherapy (Data Supplement). Inthe docetaxel groups, 11 patients (8%) with squamous NSCLC and28 (10%) with nonsquamous NSCLC received anti–PD-(L)1 oranti–cytotoxic T-lymphocyte–associated antigen 4 immunother-apy either during crossover or as subsequent therapy poststudy.

EfficacyAs reported in the primary analyses,5,6 OS remained longer

with nivolumab than with docetaxel regardless of histology, withmedian OS in each study largely unchanged with longer follow-up(Figs 2A and 2B). Differences in OS rates between the nivolumaband docetaxel groups were consistent at 1 and 2 years. Kaplan-Meier–estimated 2-year OS rates were 23% (95% CI, 16% to 30%)with nivolumab versus 8% (95% CI, 4% to 13%) with docetaxel inpatients with squamous NSCLC and 29% (95% CI, 24% to 34%)with nivolumab versus 16% (95% CI, 12% to 20%) with docetaxelin patients with nonsquamous NSCLC. Differences in PFS rates,which favored nivolumab over docetaxel, were also consistent at

1 and 2 years (Figs 2C and 2D). Kaplan-Meier–estimated 2-year PFSrates with nivolumab were 16% (95% CI, 10% to 23%) in patientswith squamous NSCLC and 12% (95% CI, 8% to 16%) in patientswith nonsquamous NSCLC. Given the level of censoring in thisanalysis after the 2-year time point, OS and PFS estimates after 2 yearsshould be interpreted with caution. In CheckMate 057, patients whodid not have an EGFR mutation derived increased OS and PFSbenefits with nivolumab versus docetaxel (Data Supplement), whereaspatients with EGFR-positive disease had comparable outcomes withnivolumab and docetaxel. Results are consistent with those previouslyreported in the primary analysis; small numbers of patients withEGFR-positive disease may affect interpretation of these results.6

The objective response rates did not change from those re-ported in the primary analyses5,6 and were higher with nivolumabthan with docetaxel (Data Supplement). Of confirmed respondersin the nivolumab groups, 10 (37%) of 27 patients with squamousNSCLC and 19 (34%) of 56 patients with nonsquamous NSCLChad ongoing responses after 2 years’ minimum follow-up; nopatients in the docetaxel groups had ongoing responses (Fig 3).Eight (80%) of 10 patients with squamous NSCLC and 16 (84%) of

Patients With Squamous NSCLC (CheckMate 017)

Ineligible (n = 80) No longer met study criteria (n = 67)Adverse events (n = 6)

Withdrew consent (n = 3)Died (n = 3)

Other (n = 1)

Received nivolumab(n = 131)

Received docetaxel(n = 129)

Discontinued treatment (n = 129) Disease progression (n = 80) Study drug toxicity (n = 13) Adverse events unrelated to study drug (n = 13) Maximum clinical benefit (n = 9) Requested to discontinue treatment (n = 5) Withdrew consent (n = 5) No longer met study criteria (n = 2) Not reported (n = 2)

Discontinued treatment (n = 121) Disease progression (n = 94) Study drug toxicity (n = 9) Adverse events unrelated to study drug (n = 7) Requested to discontinue treatment (n = 5) Withdrew consent (n = 3) Maximum clinical benefit (n = 1) Poor or no compliance (n = 1) No longer met study criteria (n = 1)

Ongoing(n = 10)

Ongoing(n = 0)

Randomly assigned to nivolumab (n = 135)Did not receive study treatment (n = 4)

Randomly assigned to docetaxel (n = 137)Did not receive study treatment (n = 8)

Included in efficacy analyses (n = 135)Included in safety analyses (n = 131)


Enrolled(n = 272)

Patients With Nonsquamous NSCLC (CheckMate 057)

Assessed for eligibility(n = 792)

Ineligible (n = 210) No longer met study criteria (n = 163) Withdrew consent (n = 24) Died (n = 5) Adverse events (n = 4) Lost to follow-up (n = 1) Administrative reason by sponsor (n = 1) Other (n = 12)

Received nivolumab(n = 287)

Received docetaxel(n = 268)

Discontinued treatment (n = 268) Disease progression (n = 179) Study drug toxicity (n = 43) Requested to discontinue

treatment (n = 17) Adverse events

unrelated to study drug Maximum clinical benefit (n = 10) Withdrew consent (n = 5) Died (n = 1) Other (n = 2)

Discontinued treatment (n = 260) Disease progression (n = 202)

(n = 11)

(n = 21)

Adverse events unrelated to study drug (n = 22) Study drug toxicity Requested to discontinue treatment (n = 6) Withdrew consent (n = 4) No longer met study criteria (n = 2) Died (n =1) Other (n = 2)

Ongoing(n = 27)

Ongoing(n = 0)

Randomly assigned to docetaxel (n = 290)Did not receive study treatment (n = 22)



Enrolled(n = 582)

Assessed for eligibility(n = 352)

A B

Randomly assigned to nivolumab (n = 292)Did not receive study treatment (n = 5)

Fig 1. CONSORT diagram of disposition of patients with (A) squamous non–small-cell lung cancer (NSCLC) or (B) nonsquamous NSCLC.

jco.org © 2017 by American Society of Clinical Oncology 3

Nivolumab Versus Docetaxel in Advanced NSCLC: Two-Year Outcomes


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19 patients with nonsquamous NSCLCwho had ongoing responsesremained on nivolumab treatment; the remaining five respondersdiscontinued treatment as a result of AEs and as of the data cutoff,hadmaintained ongoing responses without treatment, which rangedfrom 3.8 to 20.7months since last dose.Median duration of responsewas longer with nivolumab than with docetaxel (squamous NSCLC,25.2 months [95% CI, 9.8 to 30.4 months] v 8.4 months [95% CI,3.6 months to not estimable]; nonsquamous NSCLC, 17.2 months[95%CI, 8.4 months to not estimable] v 5.6 months [95%CI, 4.4 to6.9 months]). Patients with disease control (ie, objective response orstable disease as best overall response) demonstrated improvedsurvival with nivolumab versus docetaxel (Fig 4).

Efficacy by PD-L1 expression in CheckMate 017 and Check-Mate 057 studies. Consistent with the primary analyses (DataSupplement),5,6 a 2-year OS benefit with nivolumab versusdocetaxel was observed in patients with squamous NSCLC re-gardless of PD-L1 expression level (Fig 5A). In patients withnonsquamous NSCLC, higher levels of PD-L1 were associatedwith a greater magnitude of OS benefit with nivolumab (Fig 5B),but treatment benefit also was seen in patients with, 1% PD-L1expression. In patients with$ 50% PD-L1 expression, the HR forOS on the basis of 2 years’minimum follow-up was 0.63 (95% CI,0.25 to 1.57) for patients with squamousNSCLC (nivolumab, n = 17;docetaxel, n = 10) and 0.38 (95% CI, 0.24 to 0.60) for patients with

BA

Nivolumab 135 86 57 38 29 14113 69 51 34 19 7 01

Docetaxel 137 69 33 17 11 6104 46 22 14 9 4 01

No. at risk:

Nivolumab

Docetaxel

No. at risk:

OS (%

)

Time (months)

20

40

60

80

100

1-y OS rate = 42%

2-y OS rate = 23%

1-y OS rate = 24%

2-y OS rate = 8%

15%

18%

Nivolumab

Docetaxel

0 6 12 18 24 30 393 9 15 21 27 33 36

9.2(7.3 to 12.6)

6.0(5.1 to 7.3)

Nivolumab(n = 135)

Docetaxel(n = 137)

Events, No. (%)

Median OS,months (95% CI)

110 (81) 128 (93)

292

290

Nivolumab

Docetaxel

No. at risk:

194

194

148

111

112

66

81

45

18

6

233

243

171

150

128

89

97

53

46

25

6

3

0

0

0

1

OS (%

)

Time (months)

20

40

60

80

100

Nivolumab

Docetaxel1-y OS rate = 51%

2-y OS rate = 29%1-y OS rate = 39%

2-y OS rate = 16%

13%

12%

0 6 12 18 24 30 393 9 15 21 27 33 36

12.2(9.7 to 15.1)

9.5(8.1 to 10.7)

Nivolumab(n = 292)

Docetaxel(n = 290)

Events, No. (%)

Median OS,months (95% CI)

228 (78) 247 (85)

DC

Nivolumab

Docetaxel

No. at risk:

Nivolumab

Docetaxel

14%

PFS

(%)

Time (months)

20

40

60

80

100

0 6 12 18 24 303 9 15 21 27 33 3936

135

137

48

27

24

8

16

1

15

0

7

0

68

62

33

10

21

3

16

1

10

0

0

0

–

–

–

–

1-y PFS = 21%

1-y PFS = 7%

2-y PFS = 16%

2-y PFS = NC*

Nivolumab(n = 135)

Docetaxel(n = 137)

Events, No. (%)

Median PFS,months (95% CI)

3.5(2.1 to 5.1)

2.8(2.1 to 3.5)

109 (81) 123 (90)

Nivolumab

DocetaxelPFS

(%)

Time (months)

20

40

60

80

100

36

10%

11%

0 6 12 18 24 303 9 15 21 27 33 39

292

290

82

87

47

19

38

4

27

2

4

1

128

155

59

39

40

7

30

2

13

1

2

1

0

0

–

–

1-y PFS = 19%

1-y PFS = 9%2-y PFS = 1%

2-y PFS = 12%

Nivolumab(n = 292)

Docetaxel(n = 290)

Events, No. (%)

Median PFS,months (95% CI)

240 (82) 249 (86)

2.3(2.2 to 3.4)

4.3(3.4 to 4.9)

Fig 2. Kaplan-Meier curves of (A and B) overall survival (OS) and (C and D) progression-free survival (PFS; investigator assessed) in patients with (A and C) squamousnon–small-cell lung cancer (NSCLC) or (B and D) nonsquamous NSCLC. (*) Not calculable (NC) because no patients continued with follow-up for progression at this timepoint; the PFS rate at the time of the last event was 3%, and the last observation at 2 years was not an event.


Horn et al


nonsquamous NSCLC (nivolumab, n = 66; docetaxel, n = 46).Durable responses were observed with nivolumab across his-tologies and PD-L1 expression levels (Data Supplement). Of fivecomplete responders (one with squamous NSCLC, four withnonsquamous NSCLC), three had $ 1% PD-L1 expression, onehad, 1% PD-L1 expression, and one had nonquantifiable PD-L1expression.

Pooled analysis of CheckMate 017 and CheckMate 057studies. In the pooled analysis of OS in the intention-to-treatpopulation (N = 854) with squamous (n = 272 [31.9%]) andnonsquamous (n = 582 [68.1%]) NSCLC, median OS was11.1 months (95% CI, 9.2 to 13.1 months) with nivolumab versus8.1 months (95% CI, 7.2 to 9.2 months) with docetaxel (HR, 0.72;95% CI, 0.62 to 0.84; Fig 5C). Higher PD-L1 expression levels wereassociated with greater OS benefit with nivolumab (HR, 0.42; 95%CI, 0.28 to 0.63) in patients with $ 50% PD-L1 expression, buta benefit was still observed in patients with , 1% PD-L1 ex-pression (HR, 0.78; 95% CI, 0.61 to 0.99).

SafetyAfter 2 years’ minimum follow-up, the mean treatment du-

ration in CheckMate 017 was 7.5 months (standard deviation [SD],9.4 months) with nivolumab and 2.5 months (SD, 3.0 months)with docetaxel; median treatment duration was 3.2 months (range,0 to 33.8 months) and 1.4 months (range, 0 to 20.0 months),respectively. In CheckMate 057, the mean treatment duration was7.0 months (SD, 9.3 months) with nivolumab and 3.3 months (SD,3.0 months) with docetaxel; median treatment duration was2.6 months (range, 0 to 35.7+months) and 2.3 months (range, 0 to15.9 months), respectively. Rates of the most frequently reportedtreatment-related AEs in each study remained similar to thosereported in the primary analyses (1 year of minimum follow-up;Data Supplement).5,6

In the pooled safety analysis, treatment-related AEs werereported in fewer patients treated with nivolumab than in patientstreated with docetaxel after 2 years’ minimum follow-up (anygrade, 68% v 88%; grade 3 to 4, 10% v 55%, respectively) and less

Time (weeks)12864 11296804832 160144160

CheckMate 017 (Docetaxel)

BA

Time (weeks)1281129680644832 160144160

CheckMate 017 (Nivolumab)

Resp

onde

rs W

ith S

quam

ous

NSC

LC (C

heck

Mat

e 01

7)

Resp

onde

rs W

ith S

quam

ous

NSC

LC (C

heck

Mat

e 01

7)

First response On treatment (nivolumab) On treatment (docetaxel) Off treatment Ongoing response

12864 11296804832 160144160

Time (weeks)

CheckMate 057 (Docetaxel)

DC

1281129680644832 160144160

Time (weeks)

CheckMate 057 (Nivolumab)

Resp

onde

rs W

ith N

onsq

uam

ous

NSC

LC(C

heck

Mat

e 05

7)

Resp

onde

rs W

ith N

onsq

uam

ous

NSC

LC(C

heck

Mat

e 05

7)

Fig 3. Swimmer plots that show time to first response and duration of response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) for responderswith (A) squamous non–small-cell lung cancer (NSCLC) treated with nivolumab, (B) squamous NSCLC treated with docetaxel, (C) nonsquamous NSCLC treated withnivolumab, and (D) nonsquamous NSCLC treated with docetaxel.




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frequently led to treatment discontinuation (any grade, 6% v 13%;grade 3 to 4, 4% v 7%, respectively). The most common treatment-related AEs (any grade and grade 3 to 4) were reported in lowerproportions of patients treated with nivolumab than in patientstreated with docetaxel (Fig 6A). No new treatment-related deathswere reported since the primary analyses.5,6

Treatment-related select AEs of any grade were observed in153 patients (37%) treated with nivolumab; 19 (5%) had grade 3 to4 treatment-related select AEs. The most common treatment-related select AEs were of the skin (Table 1). The majority oftreatment-related select AEs occurred within the first 3 months ofnivolumab treatment (Fig 6B). Eleven nivolumab-treated patients hadfirst onset of treatment-related select AEs (in skin, GI, endocrine,hepatic, and pulmonary categories). 1 year after initiating treatment;all were grade 1 or 2.Median times to onset of treatment-related selectAEs by category were , 3 months after initiating nivolumab treat-ment (Fig 6B), except for pulmonary events (6.97 months).

Treatment-related select AEs in most of the prespecifiedcategories resolved regardless of immune-modulating medicationuse (Table 1). Of 36 treatment-related endocrine select AEs, 19(53%) were considered unresolved because of the need to continuehormone replacement therapy. In patients in whom immune-modulating medications were administered to manage treatment-related select AEs, nearly all AEs resolved. Few patients dis-continued nivolumab because of treatment-related select AEs (anygrade, 17 [4%]; grade 3 to 4, 9 [2%]; Data Supplement).

DISCUSSION

Given significant improvements in OS and improved tolerabilitycompared with docetaxel, PD-(L)1 agents have become thestandard of care for patients with NSCLC with progression while

receiving or after platinum-based chemotherapy.16 On the basis ofclinically relevant and statistically significant improvements in OSfrom CheckMate 017 and CheckMate 057,5,6 nivolumab was ap-proved by multiple regulatory authorities12,13 and incorporated intoclinical practice guidelines for NSCLC treatment.16,17 Additionalfollow-up from these clinical trials is important to determine whetherthe survival benefit with nivolumab is sustained and whether new orunexpected safety signals arise with prolonged treatment.

This update shows that after 2 years’ minimum follow-up,nivolumab continues to demonstrate survival benefit compared withdocetaxel in previously treated patients with advanced squamous ornonsquamous NSCLC; long-term efficacy is supported by the 2-yearOS and PFS rates, which favor nivolumab over docetaxel. The 2-yearOS rates are consistent with those previously reported with nivolu-mab in a phase I study of pretreated patients with advanced NSCLC.14

Of note, durable responses were seen with nivolumab. Of 83patients across the two studies who achieved an objective response,approximately one third had ongoing responses at the 2-yeardatabase lock. In contrast, no patients treated with docetaxel hadan ongoing response. The post hoc analysis of the treatment effectof best overall response on OS showed that nivolumab prolongedOS not only in responders but also in patients with stable disease,indicating that a response is not a prerequisite for OS benefit.

As reported in the CheckMate 057 primary subgroup anal-ysis,6 higher levels of tumor PD-L1 expression continued to beassociated with a greater magnitude of OS benefit with nivolumabin patients with nonsquamous NSCLC after longer follow-up(2-year OS rate of 48% [95% CI, 36% to 59%] in patientswith $ 50% PD-L1 expression). Higher 2-year OS rates wereobserved with nivolumab versus docetaxel in patients with non-squamous NSCLC across PD-L1 thresholds, including those withno (, 1%) PD-L1 expression. Deep, durable responses withnivolumab were noted across PD-L1 expression levels.

Patients with squamous NSCLC (CheckMate 017)

Patients with nonsquamous NSCLC (CheckMate 057)

Nivolumab Docetaxel

Overall

Complete/partial response*

Stable disease

Progressive disease

Response not available†

0.125 0.25 0.5 1 2 4

Overall

Complete/partial response*

Stable disease

Progressive disease

Response not available†

0.62 (0.47 to 0.80)

(0.19 to 1.49)

(0.40 to 0.97)

(0.65 to 1.43)

(0.35 to 1.44)

(0.63 to 0.91)

(0.24 to 0.77)

(0.41 to 0.80)

(0.74 to 1.32)

(0.96 to 2.43)

0.53

0.62

0.96

0.71

0.75

0.43

0.57

0.99

1.52

Best overall response

135

27

39

56

13

292

56

74

129

33

Nivolumab,

No.

9.2

NR

11.9

4.9

2.7

12.2

NR

19.9

6.9

1.5

Median OS,

months (95% CI)

(7.3 to 12.6)

(30.5 to NR)

(9.2 to 17.1)

(4.2 to 5.7)

(0.5 to 5.8)

(9.7 to 15.1)

(25.5 to NR)

(14.7 to 24.4)

(5.3 to 9.2)

(1.0 to 1.9)

(5.1 to 7.3)

(5.4 to NR)

(6.0 to 11.1)

(4.4 to 7.3)

(1.0 to 2.6)

(8.1 to 10.7)

(14.5 to 23.3)

(10.6 to 13.9)

(5.0 to 7.5)

(1.8 to 4.8)

6.0

NR

8.4

5.3

1.5

9.5

19.2

11.9

6.0

2.1

Median OS,

months(95% CI) (95% CI)

137

12

47

48

30

290

36

122

85

47

Docetaxel,

No.

Unstratified

HR

Fig 4. Treatment effect on overall survival (OS) by best overall response. (*) Confirmed complete and partial response per Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1 as assessed by the investigator. (†) Includes death before disease assessment, never treated, early discontinuation because of toxicity, and other. HR,hazard ratio; NR, not reached; NSCLC, non–small-cell lung cancer.


Horn et al


A

0

10

20

30

40

50

60

70 CheckMate 017

CheckMate 057

Two-

Year

OS

(% [9

5% C

I])Tw

o-Ye

ar O

S (%

[95%

CI])

Nivolumab

Docetaxel

No. 135 137 54 52 63 56 42 39 36 33 17 10

PD-L1 expression All* < 1% 1% 5% 10% 50%

0.62(0.47 to 0.80)

0.57(0.38 to 0.86)

0.75(0.50 to 1.10)

0.57(0.36 to 0.92)

0.56(0.33 to 0.94)

0.63(0.25 to 1.57)

23 22 20 26 28 358 6 11 8 9 20

Nivolumab

Docetaxel

PD-L1 expression

29 25 37 44 45 4816 18 17 14 13 130

10

20

30

40

50

60

70

No.

All* < 1% 1% 5% 10% 50%

292 290 108 101 123 123 95 86 86 79 66 46

HR(95% CI)†

0.75(0.63 to 0.91)

0.91(0.67 to 1.22)

0.62(0.47 to 0.83)

0.48(0.34 to 0.68)

0.43(0.30 to 0.62)

0.38(0.24 to 0.60)

B

C PD-L1expression

Overall†

< 1%

1%

5%

10%

50%

0.25 0.5 2

Nivolumab Docetaxel

0.72 (0.62 to 0.84)

0.78 (0.61 to 0.99)

0.67 (0.53 to 0.85)

0.51 (0.38 to 0.67)

0.47 (0.35 to 0.63)

0.42 (0.28 to 0.63)

1

427

162

186

137

122

83

Nivolumab,No.

11.1 (9.2 to 13.1)

9.6 (7.6 to 13.3)

13.4 (10.3 to 17.5)

17.2 (12.9 to 22.1)

17.5 (13.0 to 23.3)

20.6 (15.1 to 29.7)

Median OS,months

8.1 (7.2 to 9.2)

7.8 (6.7 to 10.5)

8.5 (7.0 to 9.3)

7.7 (6.3 to 9.1)

7.7 (6.3 to 9.1)

8.0 (5.6 to 9.2)

Median OS,months

427

153

179

125

112

56

Docetaxel,No.

UnstratifiedHR

(95% CI)(95% CI)(95% CI)

HR(95% CI)†

Fig 5. Efficacy according to programmed death ligand-1 (PD-L1) expression. Two-year overall survival (OS) rates by PD-L1 expression level in patients with (A) squamousnon–small-cell lung cancer (NSCLC) and (B) nonsquamous NSCLC and (C) treatment effect on OS by PD-L1 expression (pooled analysis of patients with squamous andnonsquamous NSCLC). (*) All patients include those with no quantifiable PD-L1 expression (CheckMate 017, nivolumab [n = 18; docetaxel, n = 29]; CheckMate 057,nivolumab [n = 61; docetaxel, n = 66]). (†) Hazard ratios (HRs) shown are for overall OS on the basis of 2 years’ minimum follow-up.




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In the pooled safety analysis from CheckMate 017 andCheckMate 057, no new safety signals were identified for nivo-lumab after 2 years’ minimum follow-up. Nivolumab maintaineda favorable safety profile compared with docetaxel, with lower ratesof commonly reported treatment-related AEs. Most treatment-related select AEs occurred within the first year of nivolumabtreatment, although some patients experienced new events after. 1 year. Treatment-related select AEs were well managed withprotocol-defined toxicity management algorithms and resolved inthe majority of patients.18

The PD-1 inhibitor pembrolizumab and the PD-L1 inhibitoratezolizumab also are approved for treating patients with advancedNSCLC after prior platinum-based chemotherapy, althoughpembrolizumab is only approved for use in patients with $ 1%PD-L1 expression.19,20 Approvals of pembrolizumab and atezoli-zumab were based on results of the randomized phase III trialsKEYNOTE-010 (Pembrolizumab Versus Docetaxel for PreviouslyTreated, PD-L1-Positive, Advanced Non–Small-Cell Lung Cancer)21 and OAK (Atezolizumab Versus Docetaxel in Patients WithPreviously Treated Non–Small-Cell Lung Cancer),22 respectively.

A

0

5

10

15

20

25

30

35

Patie

nts

(%)

< 1

24

2

21

11

16

11

17 17

8

22

30

0

10

2

11 11

25

< 1

32

1

10

Nivolumab (n = 418)

Docetaxel (n = 397)

3/41/2

Grade

Alopecia Anemia Asthenia Decreasedappetite

Diarrhea Myalgia Nausea Neutropenia Peripheralneuropathy

Fatigue Febrileneutropenia

B

0

5

10

15

20

25

30

35

40

45

50

No.

of P

atie

nts

with

Firs

t AE

in C

ateg

ory

Time to Onset of First Treatment-Related Select AE (months)

Median (range) Time to OnsetFrom First Dose, months

Skin

GI

Endocrine

Hepatic

Pulmonary

Renal

Hypersensitivity/infusion reaction

1.43 (0.03-23.75)

1.12 (0.03-20.93)

2.81 (0.43-20.27)

2.00 (0.03-30.16)

6.97 (0.59-24.87)

2.04 (0.16-4.76)

0.05 (0.03-4.60)

0–3 > 3–6 > 6–12 > 12–24 > 24

No. in study 418 342 279 204 113

No. receiving treatment 418 224 146 82 50

No. with a first AE* 106 24 12 8† 3†

Fig 6. (A) Treatment-related adverse events (AEs) reported in $ 10% of patients and (B) time to onset of first treatment-related select AE in patients treated withnivolumab (pooled patients with squamous and nonsquamous non–small-cell lung cancer [NSCLC]). (*) Patients with one or more select AEs from first dose until 30 dayspost-treatment in a given category were counted only once in the time interval corresponding to the first event; patients with multiple events from different categorieswithin the same time interval were counted once in each category. (†) Of the 11 patients with a first AE. 12 months after initiating treatment, one was skin related (grade2), three were GI related (grade 1 [n = 1] and grade 2 [n = 2]), one was endocrine related (grade 1), three were hepatic related (grade 1 [n = 2] and grade 2 [n = 1]), and threewere pulmonary related (grade 1 [n = 1] and grade 2 [n = 2]).


Horn et al


Key differences were found among CheckMate 017, CheckMate057, KEYNOTE-010, and OAK. Instead of two independenthistology-based studies, the primary efficacy analysis populationsin KEYNOTE-010 and OAK were mixed, including patients withsquamous and nonsquamous NSCLC. Moreover, different assaysto determine PD-L1 expression as well as different PD-L1thresholds for enrollment and efficacy assessments were used.Consistent with KEYNOTE-01021 and OAK,22 the pooled OSanalysis of CheckMate 017 and CheckMate 057 (which bettermirrors the patient populations of KEYNOTE-010 and OAK)showed that higher PD-L1 expression levels were associated withgreater OS benefit with anti–PD-(L)1 therapy; this finding wasanticipated given the high proportions of patients with non-squamous histology in these studies (68% in pooled CheckMate017 and CheckMate 057, 70% in KEYNOTE-010, and 74% inOAK). However, a treatment benefit with nivolumab comparedwith docetaxel also was observed in patients with , 1% PD-L1expression in this analysis (HR, 0.78; 95% CI, 0.61 to 0.99).

These updated analyses from CheckMate 017 and CheckMate057 demonstrate long-term clinical benefit with nivolumab inpreviously treated patients with advanced squamous and non-squamous NSCLC, including those with high PD-L1 expression aswell as those with no or low PD-L1 expression. Nivolumab showedsustained tolerability, with a favorable safety profile compared withdocetaxel. These data support nivolumab as a standard-of-caretreatment option in this broad patient population.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atjco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Leora Horn, David R. Spigel, Everett E. Vokes,Esther Holgado, Neal Ready, Martin Steins, Elena Poddubskaya, HosseinBorghaei, Enriqueta Felip, Luis Paz-Ares, Adam Pluzanski, Karen L.Reckamp, Marco A. Burgio, Martin Kohlhaeufl, David Waterhouse,Fabrice Barlesi, Scott Antonia, Oscar Arrieta, Jerome Fayette, Lucio Crino,Naiyer Rizvi, Martin Reck, Matthew D. Hellmann, William J. Geese, AngLi, Anne Blackwood-Chirchir, Diane Healey, Julie Brahmer, Wilfried E.E.EberhardtProvision of study materials or patients: Leora Horn, David R. Spigel,Everett E. Vokes, Esther Holgado, Neal Ready, Martin Steins, ElenaPoddubskaya, Hossein Borghaei, Enriqueta Felip, Luis Paz-Ares, AdamPluzanski, Karen L. Reckamp, Marco A. Burgio, Martin Kohlhaeufl, DavidWaterhouse, Fabrice Barlesi, Scott Antonia, Oscar Arrieta, Jerome Fayette,Lucio Crino, Naiyer Rizvi, Martin Reck, Matthew D. Hellmann, JulieBrahmer, Wilfried E.E. EberhardtCollection and assembly of data: Leora Horn, David R. Spigel, Everett E.Vokes, Esther Holgado, Neal Ready, Martin Steins, Elena Poddubskaya,Hossein Borghaei, Enriqueta Felip, Luis Paz-Ares, Adam Pluzanski, KarenL. Reckamp, Marco A. Burgio, Martin Kohlhaeufl, David Waterhouse,Fabrice Barlesi, Scott Antonia, Oscar Arrieta, Jerome Fayette, Lucio Crino,Naiyer Rizvi, Martin Reck, Matthew D. Hellmann, William J. Geese, AngLi, Anne Blackwood-Chirchir, Diane Healey, Julie Brahmer, Wilfried E.E.EberhardtData analysis and interpretation: Leora Horn, David R. Spigel, Everett E.Vokes, Esther Holgado, Neal Ready, Martin Steins, Elena Poddubskaya,Hossein Borghaei, Enriqueta Felip, Luis Paz-Ares, AdamPluzanski, Karen L.Reckamp, Marco A. Burgio, Martin Kohlhaeufl, David Waterhouse,Fabrice Barlesi, Scott Antonia, Oscar Arrieta, Jerome Fayette, Lucio Crino,Naiyer Rizvi, Martin Reck, Matthew D. Hellmann,William J. Geese, Ang Li,Anne Blackwood-Chirchir, Diane Healey, Julie Brahmer, Wilfried E.E.EberhardtManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authors

Table 1. Pooled Analysis of the Frequency and Time to Resolution of Treatment-Related Select AEs in Nivolumab-Treated Patients (Pooled Patients With Squamousand Nonsquamous NSCLC, n = 418)

Category

Select AE, No.(%) All Patients With Select AEs

Patients With Select AEs Who Received Immune-ModulatingMedications*

AnyGrade

Grade 3to 4†

CasesResolved, No.

(%)Median (Range) Time to

Resolution, weeksPatients‡,No. (%)

Median (Range) Duration of Immune-Modulating Medications, weeks

CasesResolved,No. (%)

Skin 66 (16) 4 (1) 58 (88) 10.1 (0.1-32.3+) 23 (35) 9.1 (0.1-106.1) 20 (87)GI 36 (9) 5 (1) 34 (94) 2.3 (0.1-84.3+) 7 (19)§ 6.8 (2.3-41.6) 7 (100)Endocrine 36 (9) 0 17 (47)k NE (1.3+-130.9+)¶ 3 (8) 6.1 (0.6-10.9) 3 (100)Hepatic 23 (6) 4 (1) 17 (74) 4.0 (0.1-68.6+) 3 (13) 9.6 (1.0-13.0) 3 (100)Pulmonary 19 (5) 5 (1) 16 (84) 5.9 (0.6-58.1+) 14 (74) 6.1 (0.1-37.0) 13 (93)Renal 11 (3) 1 (, 1) 6 (55)# 10.5 (0.3+-104.1+) 2 (18) 11.8 (0.9-22.7) 2 (100)Hypersensitivity/infusion reaction

10 (2) 0 10 (100) 0.1 (0.1-2.1) 3 (30) 0.9 (0.1-1.9) 3 (100)

Abbreviations: AE, adverse event; NE, not estimable; NSCLC, non–small-cell lung cancer.*Immune-modulatingmedicationswere administered intravenously, orally, topically, or transdermally for skin select AEs; intravenously or orally for GI, hepatic, and renalselect AEs; orally for endocrine select AEs; intravenously, orally, or subcutaneously for pulmonary select AEs; and intramuscularly, intravenously, or orally forhypersensitivity/infusion reaction select AEs.+Represents a censored value.†No grade 5 treatment-related select AEs were observed in patients treated with nivolumab.‡Patients who received immune-modulating medication for the longest duration select AE.§One additional patient received immune-modulating medication for a GI event that was not the longest duration event.kCertain endocrine select AEs were not considered resolved because of the need for continued hormone replacement therapy.¶NE because , 50% of cases resolved.#Unresolved renal select AEs were of low grade; four patients died as a result of disease before resolution.




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AffiliationsLeora Horn, Vanderbilt-Ingram Cancer Center; David R. Spigel, Sarah Cannon Research Institute/Tennessee Oncology, Nashville,

TN; Everett E. Vokes, University of Chicago, Chicago, IL; Esther Holgado, Hospital De Madrid, Norte Sanchinarro, Madrid; EnriquetaFelip, Hospital Universitari Vall d’Hebron, Barcelona; Luis Paz-Ares, Hospital Universitario Virgen Del Rocio, Seville, Spain; Neal Ready,Duke University Medical Center, Durham, NC; Martin Steins, Thoraxklinik-Heidelberg gGmbH, Heidelberg; Martin Kohlhaeufl,Robert-Bosch-Krankenhaus, Stuttgart; Martin Reck, LungenClinic Grosshansdorf, Airway Research Center North, German Center forLung Research, Grosshansdorf; Wilfried E.E. Eberhardt, University Hospital and Ruhrlandclinic, University of Duisburg-Essen, Essen,Germany; Elena Poddubskaya, N.N. Blokhin Russian Cancer Research Center, Moscow, Russia; Hossein Borghaei, Fox Chase CancerCenter, Philadelphia, PA; Adam Pluzanski, Centrum Onkologii–Instytut Im. Marii Sklodowskiej-Curie, Warsaw, Poland; Karen L.Reckamp, City of Hope, Duarte, CA; Marco A. Burgio and Lucio Crino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS),Istituto Scientifico Romagnolo Per lo Studio e la Cura dei Tumori, Meldola, Italy;DavidWaterhouse, Oncology Hematology Care (OHC)/US Oncology, Cincinnati, OH; Fabrice Barlesi, Aix-Marseille Universite, Assistance Publique Hopitaux de Marseille, Marseille; JeromeFayette, Leon Berard, Lyon, France; Scott Antonia, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL;Oscar Arrieta, InstitutoNacional De Cancerologia, Mexico City, Mexico;Naiyer Rizvi andMatthew D. Hellmann, Memorial Sloan Kettering Cancer Center, NewYork, NY; William J. Geese, Ang Li, Anne Blackwood-Chirchir, and Diane Healey, Bristol-Myers Squibb, Princeton, NJ; and JulieBrahmer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

SupportSupported by Bristol-Myers Squibb.

Prior PresentationPresented in part at the 52nd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2016, and the

European Society for Medical Oncology 2016 Congress, Copenhagen, Denmark, October 7-11, 2016.

n n n


Horn et al


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https://www.cancer.org/cancer/non-small-cell-lung-cancer.htm

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer: Two-Year Outcomes From TwoRandomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057)

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Leora HornHonoraria: BiodesixConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Bayer AG,Xcovery, Genentech, Eli Lilly, AbbVie, AstraZenecaTravel, Accommodations, Expenses: Bristol-Myers Squibb

David R. SpigelConsulting or Advisory Role: Genentech (Inst), Roche (Inst),AstraZeneca (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst), Clovis Oncology (Inst), Eli Lilly (Inst),Novartis (Inst), Pfizer (Inst)Research Funding: Genentech (Inst), Roche (Inst), Amgen (Inst), AstexPharmaceuticals (Inst), AstraZeneca (Inst), BIND Biosciences (Inst),Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), Celgene (Inst),Clovis Oncology (Inst), CytRx (Inst), Daiichi Sankyo (Inst), EMD Serono(Inst), ImClone Systems (Inst), ImmunoGen (Inst), Eli Lilly (Inst),Novartis (Inst), OncoGenex Pharmaceuticals (Inst), OncoMed (Inst),Peregrine Pharmaceuticals (Inst), Pfizer (Inst), Verastem (Inst)

Everett E. VokesStock or Other Ownership: McKessonConsulting or Advisory Role: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Leidos Biomedical Research,Merck, Regeneron Pharmaceuticals, Merck Serono, TakedaPharmaceuticals, VentiRx Pharmaceuticals

Esther HolgadoConsulting or Advisory Role: Celgene, Roche, NovartisSpeakers’ Bureau: Celgene, RocheTravel, Accommodations, Expenses: Celgene, Roche

Neal ReadyHonoraria: Bristol-Myers Squibb, Celgene, Heat Biologics, Merck, ARIADPharmaceuticalsTravel, Accommodations, Expenses: AstraZeneca

Martin SteinsHonoraria: Bristol-Myers SquibbConsulting or Advisory Role: Bristol-Myers Squibb

Elena PoddubskayaNo relationship to disclose

Hossein BorghaeiHonoraria: Bristol-Myers Squibb, CelgeneConsulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, Celgene,Genentech, Pfizer, Boehringer Ingelheim, EMD Serono, Trovagene, Merck,AstraZeneca, Novartis, GenmabResearch Funding: Millennium Pharmaceuticals (Inst), Merck (Inst),Celgene (Inst)Travel, Accommodations, Expenses: Bristol-Myers Squibb, Eli Lilly,Celgene, Genentech, AstraZeneca, Novartis, MerckOther Relationship: University of Pennsylvania Data Safety MonitoringBoard

Enriqueta FelipHonoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, EliLilly, MSD, Novartis, Pfizer, RocheConsulting or Advisory Role: Boehringer Ingelheim, Bristol-MyersSquibb, Celgene, Eli Lilly, MSD, Novartis, Pfizer, RocheSpeakers’ Bureau: Bristol-Myers Squibb, Novartis, Roche, Pfizer

Luis Paz-AresHonoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD,Pfizer, Roche, Genentech, AstraZeneca, Novartis, AbbVie

Adam PluzanskiConsulting or Advisory Role: Boehringer Ingelheim, Bristol-MyersSquibb, AstraZeneca, Roche, GenentechSpeakers’ Bureau: Boehringer Ingelheim, Bristol-Myers Squibb,AstraZeneca, MSD, Roche, Genentech, Pierre FabreResearch Funding: Bristol-Myers Squibb, PfizerTravel, Accommodations, Expenses: Bristol-Myers Squibb, Roche,Genentech

Karen L. ReckampConsulting or Advisory Role: Amgen, Boehringer Ingelheim, ARIADPharmaceuticals, Astellas Pharma, Nektar, Euclises PharmaceuticalsResearch Funding: GlaxoSmithKline (Inst), Bristol-Myers Squibb (Inst),Pfizer (Inst), Novartis (Inst), ARIAD Pharmaceuticals (Inst), Eisai (Inst),Clovis Oncology (Inst), Xcovery (Inst), Gilead Sciences (Inst), Pfizer (Inst),Adaptimmune (Inst), Genentech (Inst), Roche (Inst)

Marco A. BurgioNo relationship to disclose

Martin KohlhaeuflHonoraria: Bristol-Myers-SquibbResearch Funding: Eli Lilly, Bristol-Myers Squibb, Chiesi Farmaceutici,Roche

David WaterhouseConsulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, AbbVieSpeakers’ Bureau: Bristol-Myers Squibb, Celgene, Eli Lilly, Roche,Genentech

Fabrice BarlesiHonoraria: Bristol-Myers SquibbConsulting or Advisory Role: Bristol-Myers SquibbResearch Funding: Bristol-Myers Squibb

Scott AntoniaStock or Other Ownership: Cellular Biomedicine GroupHonoraria: AstraZeneca, Bristol-Myers Squibb, Merck, BoehringerIngelheimConsulting or Advisory Role: Bristol-Myers Squibb, AstraZeneca, Merck,Boehringer IngelheimTravel, Accommodations, Expenses: Bristol-Myers Squibb, AstraZeneca,Merck, Boehringer Ingelheim

Oscar ArrietaSpeakers’ Bureau: AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD,Novartis, PfizerResearch Funding: AstraZeneca, Bristol-Myers Squibb, MSD, Novartis,Pfizer

Jerome FayetteLeadership: GlycotopeHonoraria: AstraZeneca, Bristol-Myers Squibb

Lucio CrinoSpeakers’ Bureau: AstraZeneca, Bristol-Myers Squibb, Novartis

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Naiyer RizviLeadership: ARMO BiosciencesStock or Other Ownership: Gritstone Oncology, ARMO BiosciencesConsulting or Advisory Role: AstraZeneca, MedImmune, Genentech,Roche, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Pfizer, EliLilly

Martin ReckConsulting or Advisory Role: Proacta, Eli Lilly, MSD Oncology, MerckSerono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim,Celgene, Pfizer, NovartisSpeakers’ Bureau: Roche, Genentech, Eli Lilly, MSD Oncology, MerckSerono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim,Celgene, Pfizer, Novartis

Matthew D. HellmannConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Genentech,AstraZeneca, MedImmune, Novartis, Janssen Pharmaceuticals, MiratiTherapeuticsResearch Funding: Bristol-Myers Squibb

William J. GeeseEmployment: Bristol-Myers SquibbStock or Other Ownership: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb

Ang LiEmployment: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb

Anne Blackwood-ChirchirEmployment: Bristol-Myers SquibbStock or Other Ownership: Bristol-Myers Squibb, Celgene, Sanofi, GileadSciencesConsulting or Advisory Role: Bristol-Myers SquibbPatents, Royalties, Other Intellectual Property: GenentechTravel, Accommodations, Expenses: Bristol-Myers Squibb

Diane HealeyEmployment: Bristol-Myers SquibbStock or Other Ownership: Bristol-Myers Squibb, Pfizer

Julie BrahmerConsulting or Advisory Role: Bristol-Myers Squibb, Eli Lilly, Celgene,Syndax, Janssen Pharmaceuticals, Merck, AstraZeneca, MedImmuneResearch Funding: Bristol-Myers Squibb (Inst), Merck (Inst),AstraZeneca (Inst), Incyte (Inst), Five Prime Therapeutics (Inst), JanssenPharmaceuticals (Inst)Travel, Accommodations, Expenses: Bristol-Myers Squibb, MerckOther Relationship: Bristol-Myers Squibb, Merck

Wilfried E.E. EberhardtHonoraria: Bristol-Myers Squibb, Merck, AstraZeneca, Roche, BoehringerIngelheim, Novartis, Eli Lilly, Pfizer, Guardant Health, Hexal, Amgen,Celgene, Daichi Sankyo, Abbott, AbbVieConsulting or Advisory Role: Bristol-Myers Squibb, Merck, AstraZeneca,Roche, Novartis, Pfizer, Bayer AG, Eli Lilly, Abbott, AbbVie, BoehringerIngelheim, CelgeneResearch Funding: Eli Lilly (Inst), Bristol-Myers Squibb (Inst)Travel, Accommodations, Expenses: Boehringer Ingelheim

© 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Horn et al


Acknowledgment

We thank the patients and their families as well as the clinical study teams for making these studies possible (complete lists ofCheckMate 017 and CheckMate 057 investigators are shown in the Data Supplement). We also thank Jessica Proszynski for contributions asprotocol manager for these studies and Dako for collaborative development of the automated PD-L1 immunohistochemistry assay.Professional medical writing assistance was provided by Kerry Brinkman and Joanna Bloom of Evidence Scientific Solutions.

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Nivolumab Versus Docetaxel in Previously Treated Patients ......phase III studies in patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identiﬁer: NCT01642004)5 or