five-year follow-up of nivolumab in previously treated

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

Five-Year Follow-Up of Nivolumab in Previously TreatedAdvanced Non–Small-Cell Lung Cancer: Results From theCA209-003 StudyScott Gettinger, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly,Rebecca Heist, Lecia V. Sequist, David C. Smith, Philip Leming, William J. Geese, Dennis Yoon, Ang Li, and JulieBrahmer

A B S T R A C T

PurposeIn two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improvedoverall survival (OS) versus docetaxel in pretreated advanced non–small-cell lung cancer (NSCLC).We report 5-year follow-up results from an early phase I study of nivolumab in this patient populationand describe characteristics of 5-year survivors.

Patients and MethodsPatients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in8-week cycles for up to 96weeks. OS from the time of first dosewas estimated by the Kaplan-Meiermethod.

ResultsThe estimated 5-year OS ratewas 16% for all treated patients (N = 129); 5-year OS rateswere similarfor squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) wereknown current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression,70% had $ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieveda partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, andtwo each (12%) had stable disease and progressive disease as best response. Nine 5-year survivors(56%) completed the maximum 96 weeks of nivolumab; four (25%) discontinued owing to adverseevents and three (19%) owing to disease progression. As of a November 2016 database lock, 125-year survivors (75%) received no subsequent therapy and were without evidence of progressivedisease at last follow-up.

ConclusionsNivolumab treatment resulted in long-term OS and durable responses in a proportion of patientswith pretreated advanced NSCLC. Long-term survivors had diverse baseline and on-treatmentcharacteristics.

J Clin Oncol 36. © 2018 by American Society of Clinical Oncology

INTRODUCTION

In two randomized, controlled phase III trials inpatients with previously treated advanced squa-mous (CheckMate 017; ClinicalTrials.gov identifier:NCT01642004)1 or nonsquamous (CheckMate 057;ClinicalTrials.gov identifier: NCT01673867)2

non2small-cell lung cancer (NSCLC), nivolumab,a programmed death-1 (PD-1) immune checkpointinhibitor antibody, significantly prolonged overallsurvival (OS), had a favorable safety profile, and wasassociated with lower symptom burden and betterquality of life compared with docetaxel.1-5 The

outcomes of these two trials resulted in the approvalof nivolumab for the treatment of patients withpreviously treated squamous or nonsquamous ad-vanced NSCLC.6,7 With similar results from phaseIII studies of other PD-1/PD-1 ligand 1 (PD-L1)inhibitors,8,9 immunotherapy has become the newstandard of care for this patient population.However, there is limited information about long-term efficacy and safety of such therapies in patientswith NSCLC, including a lack of published data onoutcomes at 5 years, a clinical landmark in oncology.

CA209-003 (ClinicalTrials.gov identifier:NCT00730639)was an early, phase I, dose-escalationcohort expansion study that evaluated nivolumab

Author affiliations and support information

(if applicable) appear at the end of this

article.

Published at jco.org on March 23, 2018.

Corresponding author: Scott Gettinger,

MD, Yale Cancer Center, Yale University

School of Medicine, 127 FMP, 333 Cedar

Street, New Haven, CT 06510; e-mail:

[email protected].

© 2018 by American Society of Clinical

Oncology

0732-183X/18/3699-1/$20.00

ASSOCIATED CONTENT

Appendix

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

2017.77.0412

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

77.0412

© 2018 by American Society of Clinical Oncology 1

Downloaded from ascopubs.org by Journals Press Access on April 30, 2018 from 162.234.150.177Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

http://ClinicalTrials.gov



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mailto:[email protected]

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treatment in 306 patients with a variety of solid tumors. Primary resultsof the study, as well as 3-year follow-up data from the cohort of patients(n = 129) with previously treated advanced NSCLC have beenpublished.10,11 In this cohort, nivolumab was associated with an ob-jective response rate of 17% (95% CI, 11% to 25%) with a medianresponse duration of 17months, and a 3-year survival rate of 18% (95%CI, 11% to 25%) across various doses.11 In addition, nivolumab wasgenerally well tolerated, with mostly low-grade treatment-relatedadverse events including those of potential immunologic cause.11

Here, we report updated results from CA209-003 based on a min-imum follow-up of 58.25 months, and describe the characteristicsand treatment outcomes of long-term survivors.

PATIENTS AND METHODS

PatientsPatient eligibility criteria have been previously described.11 Briefly,

eligible patients were adults with pathologically confirmed advancedNSCLC who had received one to five prior systemic anticancer regimens,with progression after at least one platinum- or taxane-based regimen, andhad at least one measurable lesion by Response Evaluation Criteria in SolidTumors (RECIST), version 1.0.12 Patients with EGFR or ALK mutationswere eligible. Patients with treated brain or meningeal metastases wereeligible if they were without magnetic resonance imaging evidence ofprogression for at least 8 weeks before first study-drug administration.Patients with autoimmune disease, a condition requiring immunosup-pressive medications, a history of HIV infection, or active hepatitis B or Cinfections were excluded.

Study Design and TreatmentCA209-003, a multicenter, phase I, dose-escalation cohort expansion

trial in the United States, evaluated the safety and clinical activity ofnivolumab in patients with advanced NSCLC, melanoma, or kidney,colorectal, or castration-resistant prostate cancer.10 Patients receiveda 1-hour intravenous infusion of nivolumab at a dose of 1, 3, or 10 mg/kgevery 2 weeks in 8-week treatment cycles. During cohort expansion,patients with NSCLC were stratified by tumor histology (squamous ornonsquamous) and assigned to each dose. Treatment continued up to96 weeks (12 cycles) or until unacceptable toxicity, confirmed completeresponse, confirmed progressive disease, or withdrawal of consent. Treatmentbeyond initial disease progression was permitted in the absence of clinical

deterioration, to allow for patterns of response consistent with immune-related response criteria.13 Per protocol, patients were followed for survivalapproximately every 3 months by office visits or telephone calls. Post-studydata other than OS were collected by the investigators independent of thesponsor, as allowed by each institution.

The study protocol was approved by local institutional review boards,and the study was conducted in accordance with international standards ofgood clinical practice. All patients or their legal representatives providedwritten informed consent before enrollment.

AssessmentsRadiographic tumor assessments were performed at screening and

after each 8-week treatment cycle. After the last dose, patients whocompleted the 96-week treatment period or discontinued without diseaseprogression continued to be assessed every 8 weeks for up to 1 year as longas they did not relapse or start a new therapy. Response was assessed perRECIST, version 1.0. OS from the time of the first dose of nivolumab wasestimated using the Kaplan-Meier method. These analyses were post hocand not powered for statistical comparison of OS rates across subgroups.Effect of PD-L1 expression on nivolumab activity was an exploratory endpoint. PD-L1 expression in archived pretreatment tumor samples wasassessed using the 28-8 antibody.1,2

In the subgroup of patients who survived $ 5 years, informationabout patients’ clinical status after the protocol-specified follow-up period,including response and progression status and subsequent treatment re-ceived, was provided by the investigator.

Safety data were collected for all treated patients every 2 weeks duringtherapy and for # 70 days after the last dose of nivolumab. The MedicalDictionary for Regulatory Activities (version 15.1; https://www.meddra.org/)was used to code adverse events, and the National Cancer Institute CommonTerminology Criteria for Adverse Events (version 3.0) was used to grade theseverity of adverse events.14 A sponsor-derived prespecified list of MedicalDictionary for Regulatory Activities terms in seven categories was used toidentify select adverse events, which were defined as adverse events of po-tential immunologic etiology that require frequent monitoring or in-tervention with immune suppression or hormone replacement therapy.15

RESULTS

Patients and TreatmentBaseline characteristics of the 129 patients with NSCLC

treated with nivolumab have been described previously.11 Median

Table 1. Overall Survival Rates in All Treated Patients with Non–Small-Cell Lung Cancer

Patients No.

1 Year 2 Years 3 Years 5 Years

% 95% CI No. at Risk % 95% CI No. at Risk % 95% CI No. at Risk % 95% CI No. at Risk

All treated 129 42 33 to 50 49 25 17 to 33 27 18 12 to 26 20 16 10 to 23 16By histologySquamous 54 41 27 to 54 20 24 14 to 37 12 20 10 to 32 10 16 8 to 28 8Nonsquamous 74 42 30 to 53 28 24 14 to 35 14 17 9 to 27 10 15 8 to 25 8

By dose, mg/kg1 33 33 17 to 49 10 16 6 to 31 5 16 6 to 31 5 13 4 to 27 33 37 56 38 to 71 17 42 24 to 58 11 26 12 to 43 7 26 12 to 43 710 59 38 26 to 50 22 20 11 to 32 11 15 7 to 25 8 11 4 to 21 6

By PD-L1 expression, %, 1 30 48 28 to 64 13 35 18 to 53 7 25 10 to 43 5 20 7 to 38 3$ 1 38 32 18 to 48 10 26 13 to 42 8 23 10 to 38 7 23 10 to 38 7$ 50 13 43 16 to 68 5 43 16 to 68 5 43 16 to 68 5 43 16 to 68 5NQ 61 44 31 to 56 26 20 11 to 32 12 14 6 to 24 8 10 4 to 20 6

Abbreviations: NQ, not quantifiable; PD-L1, programmed death-1 ligand 1.

2 © 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Gettinger et al


https://www.meddra.org/

age was 65 years, 61.2% of the patients were male, 19.4% hadreceived only a single line of prior systemic therapy, and 57.4% hadnonsquamous tumor histology. Of 69 patients (53.5%) withknown EGFR mutation status, 13 (18.8%) were EGFR-mutationpositive. Of 68 patients with quantifiable tumor PD-L1 expression,38 (55.9%) had $ 1% and 13 (19.1%) had $ 50% PD-L1expression.

The administered dose of nivolumab was 1 mg/kg, 3 mg/kg,and 10 mg/kg in 33 (25.6%), 37 (28.7%), and 59 (45.7%) patients,respectively. Ten patients (7.8%) completed the maximum96 weeks of treatment per protocol. Seventy-six patients (58.9%)discontinued owing to progressive disease, 27 (20.9%) owing toadverse events, and four (3.1%) for other reasons. In addition, ninepatients (7.0%) withdrew consent and three (2.3%) died duringtreatment.

Overall SurvivalThe minimum follow-up for this analysis was 58.25 months,

based on a database lock on November 15, 2016. Median OS was9.9 months (95% CI, 7.8 to 12.4), and the estimated 5-year OS ratewas 16% (Table 1; Fig 1A). OS was similar in patients with

squamous and nonsquamous histology (Fig 1B). In patients whoreceived nivolumab 1mg/kg, 3 mg/kg, and 10mg/kg, the 5-year OSrates were 13%, 26%, and 11%, respectively (Table 1; Fig 1C).Among patients with quantifiable PD-L1 tumor expression (n =68), the estimated 5-year OS rate was similar for patients with, 1% versus $ 1% PD-L1 expression (20% v 23%) and nu-merically higher (43%) for those with $ 50% PD-L1 expression(Table 1; Fig 1D).

A total of 16 patients had an OS duration $ 5 years (up to88.6 months) after starting nivolumab (Fig 2; Table 2). Of those,two died before database lock, one due to chronic obstructivepulmonary disease and one due to disease progression (Table 2).

5-Year SurvivorsBaseline characteristics. The baseline characteristics of the 16

patients who survived$ 5 years were largely similar to those of alltreated patients (Table 3). Fourteen of the 5-year survivors (87.5%)were known current or former smokers, and two of eight evaluablepatients (25.0%) had EGFR mutations, including an exon 20 in-sertion mutation (patient 14 in Table 2) and an exon 18 missensemutation (G719A; patient 5 in Table 2). Of 10 patients with

A

No. at risk:

OS (%

)

1 2 3 4 5 6 7

Years

20

40

60

80

100

5-year OS, 16%3-year OS, 18%2-year OS, 25%

1-year OS, 42%

129 49 27 20 17 16 3 1 0

8

Overall (N = 129) 9.9 (7.8 to 12.4)

Median OS(95% CI), mo

BSquamous* (n = 54)

No. at risk:

OS (%

)

1 2 3 4 5 6 7 8

Years

20

40

60

80

100

5-year OS, 16% 3-year OS, 20%


54 20 12 10 8 8 3 1 0

20

40

60

80

100

No. at risk:

OS (%

)

Nonsquamous (n = 74)

74 28 14 10 9 8 0 00

Years 1 2 3 4 5 6 7 8


2-year OS, 24%

1-year OS, 42%

0

0 0

Fig 1. OS of all treated patients (A) overall,(B) by tumor histology (*) one patient hadmixed squamous/nonsquamous tumor histol-ogy, (C) by dose, and (D) by PD-L1 expressionlevel. Blue dots indicate censored events. Atthe time of database lock, 16 patients werealive at 5 years; 12 patients were censoredbefore 5 years because of withdrawn consent(n = 7), loss to follow-up (n = 4), and follow-up, 5 years (n = 1; this patient survived pastdatabase lock). OS, overall survival.

jco.org © 2018 by American Society of Clinical Oncology 3

Long-Term Survival With Nivolumab in NSCLC


http://jco.org

quantifiable PD-L1 expression, seven (70.0%) had $ 1% PD-L1expression, including five patients (50.0%) with $ 50% PD-L1expression, and three (30.0%) had , 1% PD-L1 expression.

Prior therapy. Themedian time from diagnosis to initiation ofnivolumab was 1.2 years (range, 0.4 to 6.1 years), with three of the

16 5-year survivors (18.8%) being diagnosed . 24 months beforenivolumab initiation. Of the 16 patients, three (18.8%) had re-ceived one prior line of systemic therapy, three (18.8%) had re-ceived two prior lines, seven (43.8%) had received three prior lines,and three (18.8%) had received four prior lines (Fig 2). Of the two

C10 mg/kg (n = 59)

No. at risk:

OS (%

)

1 2 3 4 5 6 7 8

Years

20

40

60

80

100

0

5-year OS, 11%

3-year OS, 15%

2-year OS, 20%

1-year OS, 38%

59 22 11 8 6 6 2 0 0

1 mg/kg (n = 33)

No. at risk:

OS (%

)

1 2 3 4 5 6 7 8

Years

20

40

60

80

100

0

5-year OS, 13%

3-year OS, 16%

2-year OS, 16%

1-year OS, 33%

33 10 5 5 4 3 0 0 0

3 mg/kg (n = 37)

20

40

60

80

100

0

No. at risk:OS

(%)

37 17 11 7 7 7 1 01

Years 1 2 3 4 5 6 7 8


2-year OS, 42%

1-year OS, 56%

DPD-L1 < 1% (n = 30)

No. at risk:

OS (%

)

1 2 3 4 5 6 7 8

Years

20

40

60

80

100

0


2-year OS, 35%

1-year OS, 48%

30 13 7 5 4 3 0 0 0

PD-L1 ≥ ≥ 1% (n = 38)

20

40

60

80

100

0

No. at risk:

OS (%

)

38 10 8 7 7 7 2 01

Years 1 2 3 4 5 6 7 8

3-year OS, 23%2-year OS, 26%

1-year OS, 32%

PD-L1 ≥ ≥ 50% (n = 13)

1-, 2-, 3-, and 5-year OS, 43%

No. at risk:

OS (%

)

1 2 3 4 5 6 7 8

Years

20

40

60

80

100

0

13 5 5 5 5 5 2 1 0

PD-L1 not quantifiable (n = 61)

20

40

60

80

100

0

No. at risk:

OS (%

)

61 26 12 8 6 6 1 0 0

Years 1 2 3 4 5 6 7 8

3-year OS, 14%2-year OS, 20%

1-year OS, 44%

5-year OS, 10%

5-year OS, 23%

Fig 1. (Continued).


Gettinger et al


patients with EGFR mutations, one patient (patient 5) received noprior EGFR tyrosine kinase inhibitor therapy, and the other patient(patient 14) received erlotinib for approximately 3 months im-mediately before starting nivolumab (Table 2). Ten patients(62.5%) had received prior radiotherapy, either for palliation (n =5; 31.3%) or as curative treatment (n = 5; 31.3%).

Four patients (25.0%) had prior lung surgery with curativeintent for NSCLC (patients 1, 5, 7, and 14; Table 2). Of those, threepatients had pathologic stage IIB disease at surgery, with sub-sequent disease-free intervals of 12months (patient 14), 16 months(patient 7), and 24 months (patient 1). The remaining patient(patient 5) had pathologic stage IIIA disease at surgery and diseaserecurrence 6 months later.

Nivolumab doses and treatment duration. Of the 16 5-yearsurvivors, three (18.8%), seven (43.8%), and six (37.5%) receivednivolumab at a dose of 1 mg/kg, 3 mg/kg, and 10mg/kg, respectively(Table 2). Nine of the 16 5-year survivors (56.2%) completed themaximum number of nivolumab treatment cycles per protocol (inthe overall population, 10 of 129 patients [7.8%] completed themaximum number of treatment cycles; Fig 2). Three 5-year sur-vivors (18.8%) discontinued nivolumab because of disease pro-gression, and four (25.0%) because of adverse events (Fig 2; Table 2).

Best overall response and survival. Twelve 5-year survivors(75.0%) had a partial response, two (12.5%) had stable disease (SD),and two (12.5%) had progressive disease as best response duringtherapy (Fig 2; Table 2). Among patients who responded to nivolumab(n = 22), 12 had an OS duration$ 5 years. Baseline characteristics ofresponders who survived$ 5 years were generally similar to those ofresponders who survived, 5 years (Appendix Table A1, online only).

Safety outcomes. Rates of treatment-related select adverseevents of any grade were 68.8% in 5-year survivors and 43.4% in alltreated patients (Table 4). Of the four 5-year survivors who

discontinued nivolumab owing to adverse events, three dis-continued between 18 and 19 months after treatment initiation(owing to grade 2 arthritis, grade 2 hypersensitivity, and grade 3hypersensitivity), and one patient discontinued approximately8 months after starting nivolumab, because of grade 2 pneumonitis(Fig 2).

Subsequent therapy. Twelve of the 5-year survivors (75%)received no further therapy after nivolumab and were withoutevidence of progressive disease at last follow-up before the databaselock. Of the four patients who received subsequent therapy beforethe database lock, one had surgical resection of right lower-lobelung nodules (and remains with no evidence of disease), anotherhad a lung transplant followed by systemic therapies, and tworeceived systemic therapies (Table 2).

Special cases. Two of the 16 5-year survivors were treated withnivolumab beyond disease progression. One of the two patients(patient 2; Table 2) acquired new lesions after 1.8 months ofnivolumab treatment, with a 45% reduction in target lesion tumorburden , 4 months after treatment initiation. The patient com-pleted nivolumab treatment per protocol, at which point there wasa 63% reduction in tumor burden. The patient received no furthersystemic therapy and was without recurrence until her death,which was the result of chronic obstructive pulmonary disease. Thesecond patient (patient 14; Table 2) continued nivolumab afterearly disease progression, with subsequent tumor regression andstability lasting 8 months, when nivolumab was discontinuedbecause of further disease progression.

Two of the 5-year survivors were retreated with a PD-1 in-hibitor after disease progression. The first patient (patient 5) hadan early response to nivolumab and received the maximumnumber of treatment cycles. However, the patient experienceddisease progression 16 months after completing treatment.

–36 –24 –12 0 12 24 36 48 60 72 84 96

Time Since Treatment Initiation (mo)–73

Time Since Diagnosis (mo)

1

2

3

4

6

7

8

9

10

11

12

13

15

5

14

16 SD

SD

Alive as of database lock

Adverse event leading to discontinuation

Nonconventional response

Prior line of systemic therapy

Time from diagnosis

OS not receiving nivolumab

Time receiving nivolumab

PR

Progressive disease

Fig 2. Treatment and outcomes of 5-year survivors. Patients 10 through 13 discontinued treatment because of grade 2 arthritis, grade 3 hypersensitivity reaction, grade 2pneumonitis, and grade 2 hypersensitivity reaction, respectively. Dashed line indicates the protocol-defined duration of nivolumab treatment (96 weeks). OS, overallsurvival; PR, partial response; SD, stable disease.




http://jco.org

Table2.

Cha

racteristic

san

dDisea

seCou

rseof

5-Yea

rSurvivo

rs

Patient

No.

Age

(yea

rs)

Sex

Nivolum

abDos

e(m

g/kg

)Tu

mor

Histology

PD-L1

Exp

ress

ion(%

)Disea

seCou

rse*

Sub

sequ

ent

Therap

yOS†

(mon

ths)

Progres

sive

Disea

seat

Last

Follow-Up†

172

M3

Mixed

SQ/NSQ

50Smok

er;prev

ious

right

uppe

rlobe

ctom

y,rig

htad

rena

lectom

y,an

dtw

opriorlines

ofsy

stem

ictherap

y;PR

while

rece

iving

nivo

lumab

(TTR

,1.7mon

ths;

best

chan

gein

tumor

burden

,267

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;resp

onse

maintaine

d

No

$88

.6No‡

262

F10

SQ

100

Smok

er;p

riorrad

iotherap

yan

don

epriorlineof

system

ictherap

y;prog

ressivedise

ase(new

lesion

s)after1.8mon

thsof

nivo

lumab

trea

tmen

t;no

ncon

ventiona

lres

pons

e(45%

tumor

burden

decrea

sefrom

BL)

,2mon

thsafterinitia

lprogres

sive

dise

ase;

completed

trea

tmen

tpe

rprotoc

ol;died

ofCOPD

exacerba

tion

No

76.8

No

357

F10

SQ

Not

quan

tifiab

leSmok

er;fou

rpriorlines

ofsy

stem

ictherap

y;PRwhile

rece

iving

nivo

lumab

(TTR

,3.5mon

ths;

best

chan

gein

tumor

burden

,266

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;resp

onse

maintaine

d

No

$73

.7No

467

M1

NSQ

70Smok

er;three

priorlines

ofsy

stem

ictherap

y;PRwhile

rece

iving

nivo

lumab

(TTR

,1.9mon

ths;

best

chan

gein

tumor

burden

,293

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;resp

onse

maintaine

d

No

$65

.6No

575

F3

NSQ

,1

Form

ersm

oker;EGFR

mutation(G71

9A);priorRLL

,lung

radios

urge

ry,a

ndtw

opriorlines

ofsy

stem

ictherap

y(noprior

EGFR

inhibitor);

PRwhile

rece

ivingnivo

lumab

(TTR

,1.8

mon

ths;

best

chan

gein

tumor

burden

,271

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;prog

ress

ivedise

ase16

mon

thslater;

nivo

lumab

restartedan

dpa

tient

hadase

cond

PR;p

rogres

sive

dise

ase8mon

thslater;rece

ived

afatinib;d

iedof

thedise

ase

Nivolum

abrech

alleng

e,afatinib

65.0

Yes

(dea

thdu

eto

maligna

ntdise

ase)

655

M3

NSQ

Not

quan

tifiab

leSmok

er;three

priorlines

ofsy

stem

ictherap

y;PRwhile

rece

iving

nivo

lumab

(TTR

,3.6mon

ths;

best

chan

gein

tumor

burden

,262

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;resp

onse

maintaine

d

No

$64

.9No

761

M3

SQ

Not

quan

tifiab

leFo

rmer

smok

er;priorrig

htmiddlean

dlower

lobe

ctom

y,radiothe

rapy

andthreepriorlines

ofsy

stem

ictherap

y;PRwhile

rece

ivingnivo

lumab

(TTR

,1.7mon

ths;

best

chan

gein

tumor

burden

,293

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;res

pons

emaintaine

d

No

$64

.9No

852

F3

SQ

Not

quan

tifiab

leSmok

er;fou

rpriorlines

ofsy

stem

ictherap

y;PRwhile

rece

iving

nivo

lumab

(TTR

,1.1mon

ths;

best

chan

gein

tumor

burden

,271

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;resp

onse

maintaine

d

No

$64

.3No

944

M10

NSQ

15Smok

er;three

priorlines

ofsy

stem

ictherap

y;PRwhile

rece

iving

nivo

lumab

(TTR

,5.4mon

ths;

best

chan

gein

tumor

burden

,248

%);co

mpleted

trea

tmen

tpe

rprotoc

ol;resp

onse

maintaine

d

No

$61

.3No

1062

M10

NSQ

Not

quan

tifiab

leSmok

er;on

epriorlineof

system

ictherap

y;PR

while

rece

iving

nivo

lumab

(TTR

,7.2mon

ths;

best

chan

gein

tumor

burden

,257

%);disc

ontin

uedtrea

tmen

tafter18

.4mon

thsow

ingto

grad

e2arthritis;resp

onse

maintaine

d

No

$64

.9No

1180

F10

NSQ

53Smok

er;priorradiothe

rapy

andfour

priorlines

ofsy

stem

ictherap

y;PRwhile

rece

ivingnivo

lumab

(TTR

,3.5

mon

ths;

best

chan

gein

tumor

burden

,257

%);disc

ontin

uedtrea

tmen

tafter

18.7

mon

thsow

ingto

grad

e2hy

persen

sitiv

ity;resp

onse

maintaine

d

No

$63

.7No

(con

tinue

don

followingpa

ge)


Gettinger et al


Table2.

Cha

racteristic

san

dDisea

seCou

rseof

5-Yea

rSurvivo

rs(con

tinue

d)

Patient

No.

Age

(yea

rs)

Sex

Nivolum

abDos

e(m

g/kg

)Tu

mor

Histology

PD-L1

Exp

ress

ion(%

)Disea

seCou

rse*

Sub

sequ

ent

Therap

yOS†

(mon

ths)

Progres

sive

Disea

seat

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http://jco.org

Retreatment with nivolumab (2 years after completion of the initialtreatment) again resulted in a response within 3months; however, thepatient had a second progression 11 months after starting nivolumabretreatment and eventually died of the disease (Table 2). The secondpatient (patient 1) also had an early response to nivolumab, completedtreatment per protocol, and was without evidence of disease at theNovember 2016 database lock, . 5 years after stopping treatment(OS, 88.5 months; Table 2). However, 5 months later, the patient hadpathologically confirmed disease progression, including squamous cellcarcinoma metastatic to the colon wall and a small, solitary brainmetastasis. The patient joined a clinical trial with an experimental PD-1inhibitor and, at last follow-up (2 months after initiating therapy) hadachieved a response.

One 5-year survivor (patient 15) with SD as best responsediscontinued nivolumab after 14 months because of diseaseprogression. The patient had isolated tumor progression that wastreated with resection of right lower-lobe lung nodules. The patientreceived no further systemic anticancer therapy. The patient wasalive and without evidence of further disease progression at da-tabase lock (Table 2).

DISCUSSION

Nivolumab is an established standard-of-care therapy for patientswith previously treated advanced NSCLC. Here, we present thelongest follow-up of previously treated patients with advancedNSCLC after initiation of PD-1 axis inhibitor therapy. Prioranalysis of this cohort from CA209-003 demonstrated 3-year OSrates with nivolumab of 19% for squamous and 16% for non-squamous NSCLC,11 consistent with the recently reported 3-yearOS rates in the Checkmate 017 and 057 trials (16% and 18%,respectively),16 and similar to the 3-year OS rates observed withpembrolizumab (19%) and atezolizumab (19%) in patients withpreviously treated advanced NSCLC.17,18 With a minimum follow-up now of 58.25 months, we report an unprecedented 5-year OSrate of 16%. This number compares favorably with historic 5-yearOS rates for stage IV NSCLC of 1% to 8%, depending on the extentof metastasis.19,20

Characteristics of 5-year survivors generally resembled thoseof the overall population, including tumor histology, EasternCooperative Oncology Group performance status, smoking status,and diversity of prior systemic therapies. Although five of the 105-year survivors with evaluable tumor tissue had $ 50% PD-L1expression, three had no detectable PD-L1 expression. Overall,these findings are consistent with those from CheckMate 017 and057, which showed a survival benefit with nivolumab across alllevels of PD-L1 expression.1,2,21

As previously reported, 22 patients (17.1%) in the NSCLCcohort of CA209-003 had a response to nivolumab.11 Of those, 12patients (54.5%) were among the 16 5-year survivors. The otherfour 5-year survivors had progressive disease or SD as best re-sponse; two did not receive additional systemic therapy. No cleardifferences in baseline characteristics were observed between theresponders who did and did not achieve 5-year survival.

One of several remaining questions concerning treatmentapproaches involving immuno-oncology agents is the optimaltreatment duration. The 5-year follow-up data from CA209-003suggest patients may achieve long-term survival with nivolumabtreatment of 2 years (per protocol for this study) or less. However,current indications for nivolumab and other approved PD-1 in-hibitors require continuous dosing until unacceptable toxicity ordisease progression, based on corresponding registrational studies.Recently, exploratory survival data based on a minimum follow-upof 10 months were reported from CheckMate 153 (ClinicalTrials.gov identifier: NCT02066636), a randomized study of nivolumabin patients with previously treated advanced NSCLC that com-pared continuous treatment with treatment of a fixed 1-year period(with the option to reinitiate treatment at the time of progression).The hazard ratios for progression-free survival and OS were 0.42(95% CI, 0.25 to 0.71) and 0.63 (95% CI, 0.33, 1.20), respectively,in favor of continuous therapy.22 The findings from CA209-003indicate some patients can derive long-term benefit from nivo-lumab treatment that is limited to 2 years; however, the question ofoptimal treatment duration remains to be formally addressed ina prospective controlled trial.

Another uncertainty related to immune checkpoint inhibitortherapy is the optimal management of recurrence on and offtherapy. The present findings from CA209-003 suggest that

Table 3. Baseline Characteristics of All Treated Patients and 5-Year Survivors

CharacteristicAll Treated

Patients (N = 129)Survived

$ 5 Years (n = 16)

Age, median (range), years 65 (38-85) 62 (44-80)$ 65 66 (51.2) 6 (37.5)

SexMale 79 (61.2) 9 (56.2)Female 50 (38.8) 7 (43.8)

ECOG performance status score0 27 (20.9) 4 (25.0)1 100 (77.5) 12 (75.0)2 2 (1.6) 0

Prior lines of systemic therapy1 25 (19.4) 3 (18.8)2 34 (26.4) 3 (18.8)3 27 (20.9) 7 (43.8)$ 4 43 (33.3) 3 (18.8)

Smoking statusFormer 16 (12.4)* 3 (18.8)*Current 92 (71.3) 11 (68.8)Never 1 (0.8)* 1 (6.2)*Unknown 20 (15.5) 1 (6.2)

Tumor histologySquamous cell carcinoma 54 (41.9) 8 (50.0)Nonsquamous cell carcinoma 74 (57.4) 8 (50.0)Unknown 1(0.8) 0

EGFR mutation statusNot evaluable 60 (46.5) 8 (50.0)Evaluable 69 (53.5) 8 (50.0)Mutant 13 (18.8)†‡ 2 (25.0)†‡Wild type 56 (81.2)† 6 (75.0)†

PD-L1 expression levelNot quantifiable 61 (47.3) 6 (37.5)Quantifiable, % 68 (52.7) 10 (62.5), 1 30 (44.1)† 3 (30.0)†$ 1 38 (55.9)† 7 (70.0)†$ 50 13 (19.1)† 5 (50.0)†

NOTE. Data given as no. (%) unless otherwise indicated.Abbreviations: ECOG, Eastern Cooperative Oncology Group; PD-L1, pro-grammed death-1 ligand 1.*Smoking status in one patient was confirmed by the investigator.†Percent of evaluable patients.‡EGFR mutations in two patients were confirmed by the investigator.


Gettinger et al




rechallenge with nivolumab and/or local intervention (particularlyfor oligoprogressive disease) may have a positive effect on the long-term survival of patients with disease progression after initialresponse to nivolumab. Two 5-year survivors in our study wererechallenged with PD-1 inhibitor therapy after disease recurrenceoff therapy (one with nivolumab and the other with an experi-mental PD-1 inhibitor). Both patients achieved a second response.A 5-year survivor with RECIST progression due to the early de-velopment of new lung lesions in the setting of regressing targetlesions continued nivolumab without subsequent progression ofdisease. Two additional 5-year survivors without RECIST responseunderwent resection of progressing sites of disease 15 and 24monthsafter starting nivolumab treatment. One of the two patients had norecurrence at the time of database lock, without having received anysubsequent systemic therapy.

In conclusion, the results from this analysis of CA209-003demonstrate that nivolumab treatment can enable long-term sur-vival in a diverse population of patients with previously treated ad-vanced NSCLC. Considering the historically low 5-year survival ratefor patients with metastatic lung cancer, the estimated 5-year OS rateof 16% from the time of nivolumab treatment initiation observed in

this cohort of heavily pretreated patients with advanced NSCLCconstitutes a milestone in the advancement of lung cancer treatment.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

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

AUTHOR CONTRIBUTIONS

Conception and design: Scott Gettinger, Dennis Yoon, Julie BrahmerProvision of study materials or patients: Scott Gettinger, Leora Horn,David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, JohnPowderly, Rebecca Heist, Lecia V. Sequist, David C. Smith, Philip Leming,Julie BrahmerCollection and assembly of data: All authorsData analysis and interpretation: All authorsManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authors

REFERENCES

1. Brahmer J, Reckamp KL, Baas P, et al: Nivo-lumab versus docetaxel in advanced squamous-cellnon–small-cell lung cancer. N Engl J Med 373:123-135, 2015

2. Borghaei H, Paz-Ares L, Horn L, et al: Nivo-lumab versus docetaxel in advanced nonsquamousnon–small-cell lung cancer. N Engl J Med 373:1627-1639, 2015

3. Reck M, Taylor F, Penrod JR, et al: Impact ofnivolumab versus docetaxel on health-related quality oflife and symptoms in patients with advanced squamousnon-small cell lung cancer: Results from the CheckMate017 study. J Thorac Oncol 13:194-204, 2018

4. Gralla RJ, Spigel D, Bennett B, et al: Lungcancer symptom scale as a marker of treatment

benefit with nivolumab vs docetaxel in patients withadvanced non-squamous NSCLC from CheckMate057. Presented at the American Society of ClinicalOncology Annual Meeting, Chicago, IL, June 3-7,2016

5. Reck M, Brahmer J, Bennett B, et al: Overallhealth status in patients with advanced non-squamous NSCLC treated with nivolumab or doce-taxel in CheckMate 057. Presented at the EuropeanSociety for Medical Oncology 41st Congress,Copenhagen, Denmark, October 7-11, 2015

6. Bristol-Myers Squibb: OPDIVO [package in-sert]. 2018. https://packageinserts.bms.com/pi/pi_opdivo.pdf

7. Bristol-Myers Squibb: Annex I: Summary ofproduct characteristics [OPDIVO]. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003985/WC500189765.pdf

8. Herbst RS, Baas P, Kim DW, et al: Pem-brolizumab versus docetaxel for previously treated,PD-L1-positive, advanced non-small-cell lung cancer(KEYNOTE-010): A randomised controlled trial. Lan-cet 387:1540-1550, 2016

9. Rittmeyer A, Barlesi F, Waterkamp D, et al:Atezolizumab versus docetaxel in patients withpreviously treated non-small-cell lung cancer (OAK):A phase 3, open-label, multicentre randomisedcontrolled trial. Lancet 389:255-265, 2017

10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety,activity, and immune correlates of anti-PD-1 antibody incancer. N Engl J Med 366:2443-2454, 2012

11. Gettinger SN, Horn L, Gandhi L, et al: Overallsurvival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538)in patients with previously treated advanced non-small-celllung cancer. J Clin Oncol 33:2004-2012, 2015

Table 4. Summary of Treatment-Related Adverse Events in All Treated Patients and 5-Year Survivors

Treatment-Related Adverse Event

All Treated Patients (N = 129) 5-Year Survivors (n = 16)

Any Grade Grade $ 3* Any Grade Grade $ 3

Any 91 (70.5) 22 (17.1) 14 (87.5) 3 (18.8)Led to discontinuation 17 (13.2) 7 (5.4) 4 (25.0)† 1 (6.2)‡Select TRAEs§ 56 (43.4) 7 (5.4) 11 (68.8) 1 (6.2)‡Endocrine 9 (7.0) 0 4 (25.0) 0Gastrointestinal 17 (13.2) 1 (0.8) 5 (31.2) 0Hepatic 6 (4.7) 1 (0.8) 0 0Pulmonary 12 (9.3) 4 (3.1) 3 (18.8) 0Renal 4 (3.1) 0 1 (6.2) 0Skin 21 (16.3) 0 8 (50.0) 0Hypersensitivity/infusion reaction 7 (5.4) 1 (0.8) 2 (12.5) 1 (6.2)†

NOTE. Data given as no. (%). Where n = 0, no percentage is given.Abbreviation: TRAE, treatment-related adverse event.*A grade 5 TRAE (sepsis) occurred in one patient, resulting in treatment discontinuation.†Grade 2 arthritis and three selected TRAEs: grade 2 hypersensitivity, grade 3 hypersensitivity, and grade 2 pneumonitis.‡Grade 3 hypersensitivity in patient 11 (Fig 2).§Those with potential immunologic cause.




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https://packageinserts.bms.com/pi/pi_opdivo.pdf

https://packageinserts.bms.com/pi/pi_opdivo.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003985/WC500189765.pdf



http://jco.org

12. Therasse P, Arbuck SG, Eisenhauer EA, et al:New guidelines to evaluate the response to treat-ment in solid tumors. J Natl Cancer Inst 92:205-216,2000

13. Wolchok JD, Hoos A, O’Day S, et al: Guide-lines for the evaluation of immune therapy activity insolid tumors: immune-related response criteria. ClinCancer Res 15:7412-7420, 2009

14. National Cancer Institute Cancer TherapyEvaluation Program: Common Terminology Criteriafor Adverse Events (version 3.0). 2009. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf

15. Topalian SL, Sznol M, McDermott DF, et al:Survival, durable tumor remission, and long-termsafety in patients with advanced melanoma re-ceiving nivolumab. J Clin Oncol 32:1020-1030,2014

16. Vokes EE, Ready N, Felip E, et al: Nivolumabversus docetaxel in previously treated advanced non-small cell lung cancer (CheckMate 017 and Check-Mate 057): 3-year update and outcomes in patientswith liver metastases. Ann Oncol 10.1093/annonc/mdy041 [epub ahead of print on February 2, 2018]

17. Leighl NB, Hellmann MD, Hui R, et al:KEYNOTE-001: 3-year survival for patients withadvanced NSCLC treated with pembrolizumab.Presented at the American Society of Clinical On-cology Annual Meeting, Chicago, IL, USA, June 2-6,2017

18. Park K, Lewanski C, Gadgeel S, et al: 3-yearsurvival and duration of response in randomizedphase II study of atezolizumab vs docetaxel in 2L/3LNSCLC (POPLAR). Presented at the IASLC 18thWorld Conference on Lung Cancer, Yokohama, Ja-pan, October 15-18, 2017

19. William WN, Jr., Lin HY, Lee JJ, et al: Revis-iting stage IIIB and IV non-small cell lung cancer:Analysis of the surveillance, epidemiology, and endresults data. Chest 136:701-709, 2009

20. Siegel RL, Miller KD, Jemal A: Cancer statis-tics, 2016. CA Cancer J Clin 66:7-30, 2016

21. Horn L, Spigel DR, Vokes EE, et al: Nivolumabversus docetaxel in previously treated patients withadvanced non–small-cell lung cancer: Two-year out-comes from two randomized, open-label, phase IIItrials (CheckMate 017 and CheckMate 057). J ClinOncol 35:3924-3933, 2017

22. Spigel DR, McCleod M, Hussein MA, et al:Randomized results of continuous vs 1-year fixed-duration nivolumab in patients with advanced non-small cell lung cancer. Presented at the EuropeanSociety for Medical Oncology 2017 Congress,Madrid, Spain, September 8-12, 2017

AffiliationsScott Gettinger, Yale Cancer Center, New Haven, CT; Leora Horn, Vanderbilt University Medical Center; David Spigel, Sarah

Cannon Research Institute/Tennessee Oncology, Nashville, TN; David Jackman, Dana-Farber Cancer Institute; Rebecca Heist and LeciaV. Sequist, Massachusetts General Hospital, Boston, MA; Scott Antonia, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL;Matthew Hellmann, Memorial Sloan-Kettering Cancer Center, New York, NY; John Powderly, Carolina BioOncology Institute,Huntersville, NC; David C. Smith, University of Michigan, Ann Arbor, MI; Philip Leming, The Christ Hospital Cancer Center,Cincinnati, OH; William J. Geese, Dennis Yoon, and Ang Li, Bristol-Myers Squibb, Princeton, NJ; Julie Brahmer, The Sidney KimmelComprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

SupportSupported by Bristol-Myers Squibb and ONO Pharmaceutical.

Prior PresentationPresented at American Association for Cancer Research Annual Meeting 2017, Washington, DC, April 1-5, 2017.

n n n


Gettinger et al


http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf



AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non–Small-Cell Lung Cancer: Results From the CA209-003 Study

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.

Scott GettingerConsulting or Advisory Role: Bristol-Myers Squibb, ARIAD, AlexionPharmaceuticals, PfizerResearch Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), ARIAD(Inst), Incyte (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Merck

Leora HornConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Xcovery,Genentech, Boehringer Ingelheim, Eli Lilly, AbbVie, AstraZenecaTravel, Accommodations, Expenses: Boehringer Ingelheim, Bristol-Myers Squibb

David JackmanConsulting or Advisory Role: Genentech, Eli Lilly, Celgene, Bayer, CVSCaremark, AstraZeneca

David SpigelNo relationship to disclose

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

Matthew HellmannConsulting or Advisory Role: Bristol-Myers Squibb, Merck, Genentech,AstraZeneca/MedImmune, Novartis, Janssen, Mirati Therapeutics,Shattuck LabsResearch Funding: Bristol-Myers Squibb

John PowderlyEmployment: Carolina BioOncology Institute, BioCyticsLeadership: BioCytics, Carolina BioOncology InstituteStock or Other Ownership: BioCytics, Lion Biotechnologies, JunoTherapeutics, Bluebird Bio, Kite Pharma, ZIOPHARMOncology, CarolinaBioOncology InstituteConsulting or Advisory Role: Bristol-Myers Squibb, Roche, AstraZeneca/MedImmune, Curis, TopAlliance BioSciencesSpeakers’ Bureau: Roche, Dendreon, Merck, Bristol-Myers SquibbResearch Funding: Bristol-Myers Squibb, Roche, AstraZeneca/MedImmune, EMD Serono, Eli Lilly/ImClone, Macrogenics, Incyte, TopAlliance BioScience, Seattle Genetics, AbbVie, Corvus Pharmaceuticals,Curis

Patents, Royalties, Other Intellectual Property: BioCytics is developingintellectual property for cellular immunotherapy

Rebecca HeistConsulting or Advisory Role: Boehringer IngelheimResearch Funding: GlaxoSmithKline, Sanofi, AbbVie, Novartis, Roche,Incyte, Celgene, Mirati Therapeutics, Peregrine Pharmaceuticals, Exelixis,Millennium, Debiopharm Group

Lecia V. SequistHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca, Roche, Bristol-Myers Squibb,PfizerResearch Funding: Boehringer Ingelheim (Inst), Clovis Oncology (Inst),Genentech (Inst), Merrimack (Inst), Novartis (Inst), AstraZeneca (Inst),Johnson & Johnson (Inst), Merck (Inst), Pfizer (Inst)

David C. SmithConsulting or Advisory Role: MerckResearch Funding: Agensys (Inst), Atterocor (Inst), Bayer (Inst), BostonBiomedical (Inst), Exelixis (Inst), Incyte (Inst), Eli Lilly (Inst),MedImmune (Inst), Novartis (Inst), OncoMed (Inst), Seattle Genetics(Inst), Bristol-Myers Squibb/Medarex (Inst), ESSA (Inst), Genentech(Inst), Medivation/Astellas (Inst), Merck (Inst)

Philip LemingNo relationship to disclose

William J. GeeseEmployment: Bristol-Myers SquibbStock or Other Ownership: Bristol-Myers Squibb

Dennis YoonEmployment: Bristol-Myers SquibbStock or Other Ownership: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb (I)

Ang LiEmployment: Bristol-Myers Squibb

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

jco.org © 2018 by American Society of Clinical Oncology



http://www.asco.org/rwc

http://ascopubs.org/jco/site/ifc

http://jco.org

Acknowledgment

We thank the patients and their families. We thank Allyson Pollack for her contributions as protocol manager for this study and Dakofor collaborative development of the PD-L1 IHC 28-8 pharmDx assay. Medical-writing and editorial assistance was provided by RolandTacke of Evidence Scientific Solutions, with funding from Bristol-Myers Squibb.

Appendix

CA209-003 Investigators and Participating SitesJulie Brahmer, MD, Drew Pardoll, MD, PhD, and Suzanne Topalian, MD; The Sidney Kimmel Comprehensive Cancer Center

at Johns Hopkins, Baltimore, MDJohn D Powderly, MD; Carolina BioOncology Institute, Huntersville, NCMario Sznol, MD, and Scott Gettinger, MD; Yale Cancer Center, New Haven, CTDavid C Smith, MD; University of Michigan Health System Cancer Center, Ann Arbor, MIF Stephen Hodi, MD, Leena Gandhi, MD, and David M Jackman, MD; Dana Farber Cancer Institute, Boston, MARebecca S Heist, MD, MPH, and Lecia V Sequist, MD, MPH; Massachusetts General Hospital, Boston, MADavid McDermott, MD; Beth Israel Deaconess Medical Center, Boston, MARichardDCarvajal,MD,MathewHellmann,MD, andNaiyer Rizvi,MD;Memorial Sloan-Kettering Cancer Center, New York, NYDavid P Carbone, MD, PhD, Leora Horn, MD, and Jeffrey Sosman, MD; Vanderbilt University Medical Center, Nashville, TNPhilip Leming, MD; Christ Hospital Cancer Center, Cincinnati, OHDavid R Spigel, MD; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TNScott Antonia, MD, and Mary Pinder-Schenck, MD; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDavid S Mendelson, MD; Oncology Research Associates d/b/a Pinnacle Oncology Hematology, Scottsdale, AZ

© 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Gettinger et al


Table A1. Baseline Characteristics of Patients with an Objective Response to Nivolumab (per RECIST, version 1.0) by Survival at 5 Years

CharacteristicAll Treated

Patients (N = 129)All Responders

(n = 22)Responders with

OS $ 5 Years (n = 12)Responders with

OS , 5 Years (n = 10)

Age, years, 65 63 (48.8) 9 (40.9) 6 (50.0) 3 (30.0)$ 65 66 (51.2) 13 (59.1) 6 (50.0) 7 (70.0)

SexMale 79 (61.2) 13 (59.1) 7 (58.3) 6 (60.0)Female 50 (38.8) 9 (40.9) 5 (41.7) 4 (40.0)

ECOG PS score0 27 (20.9) 3 (13.6) 3 (25.0) 01 100 (77.5) 19 (86.4) 9 (75.0) 10 (100.0)2 2 (1.6) 0 0 0

Time from diagnosis to first dose, months, 18 71 (55.0) 12 (54.5) 8 (66.7) 4 (40.0)$ 18 58 (45.0) 10 (45.5) 4 (33.3) 6 (60.0)

Prior line of systemic therapy1 25 (19.4) 3 (13.6) 2 (16.7) 1 (10.0)2 34 (26.4) 5 (22.7) 2 (16.7) 3 (30.0)3 27 (20.9) 6 (27.3) 5 (41.7) 1 (10.0)4 43 (33.3) 8 (36.4) 3 (25.0) 5 (50.0)

Smoking statusFormer 16 (12.4)* 5 (22.7)* 3 (25.0)* 2 (20.0)Current 92 (71.3) 16 (72.7) 8 (66.7) 8 (80.0)Never 1 (0.8) 0 0 0Unknown 20 (15.5) 1 (4.5) 1 (8.3) 0

Tumor histologySQ 54 (41.9) 9 (40.9) 5 (41.7) 4 (40.0)NSQ 74 (57.4) 13 (59.1) 7 (58.3) 6 (60.0)Unknown 1 (0.8) 0 0 0

EGFR mutation statusWild type 56 (43.4) 11 (50.0) 6 (50.0) 5 (50.0)Mutant 13 (10.1)† 2 (9.1)† 1 (8.3)† 1 (10.0)Unknown 60 (46.5) 9 (40.9) 5 (41.7) 4 (40.0)

PD-L1 expression level, %, 1 30 (21.6) 5 (22.7) 2 (16.7) 3 (30.0)$ 1 38 (29.5) 5 (22.7) 4 (33.3) 1 (10.0)Not quantifiable 61 (47.3) 12 (54.5) 6 (50.0) 6 (60.0)

NOTE. Data given as no. (%). Where n = 0, no percentage is given.Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; NSQ, nonsquamous; PD-L1, programmeddeath-1 ligand 1; OS, overall survival; RECIST, Response Evaluation Criteria in Solid Tumors; SQ, squamous.*Smoking status in one patient was confirmed by the investigator.†EGFR mutations in two patients were confirmed by the investigator.

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