The new engl and jour nal of medicine
n engl j med 373;2 nejm.org  july 9, 2015 123
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Brahmer at the Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins,
Bunting-Blaustein Cancer Research
Bldg., 1650 Orleans St., Rm. G94, Baltimore,
MD 21287, or at ­brahmju@​­jhmi​.­edu.
This article was published on May 31, 2015,
and last updated on July 9, 2015, at
NEJM.org.
N Engl J Med 2015;373:123-35.
DOI: 10.1056/NEJMoa1504627
Copyright © 2015 Massachusetts Medical Society.
BACKGROUND
Patients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who
have disease progression during or after first-line chemotherapy have limited treatment
options. This randomized, open-label, international, phase 3 study evaluated
the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1)
immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient
population.
METHODS
We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram
of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter
of body-surface area every 3 weeks. The primary end point was overall survival.
RESULTS
The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to
13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The
risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio,
0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42%
(95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel.
The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008).
The median progression-free survival was 3.5 months with nivolumab versus 2.8
months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI,
0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither
prognostic nor predictive of benefit. Treatment-related adverse events of grade 3
or 4 were reported in 7% of the patients in the nivolumab group as compared with
55% of those in the docetaxel group.
CONCLUSIONS
Among patients with advanced, previously treated squamous-cell NSCLC, overall
survival, response rate, and progression-free survival were significantly better with
nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by
Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.)
ABSTR ACT
Nivolumab versus Docetaxel in Advanced
Squamous-Cell Non–Small-Cell Lung Cancer
Julie Brahmer, M.D., Karen L. Reckamp, M.D., Paul Baas, M.D.,
Lucio Crinò, M.D., Wilfried E.E. Eberhardt, M.D., Elena Poddubskaya, M.D.,
Scott Antonia, M.D., Ph.D., Adam Pluzanski, M.D., Ph.D., Everett E. Vokes, M.D.,
Esther Holgado, M.D., Ph.D., David Waterhouse, M.D., Neal Ready, M.D.,
Justin Gainor, M.D., Osvaldo Arén Frontera, M.D., Libor Havel, M.D.,
Martin Steins, M.D., Marina C. Garassino, M.D., Joachim G. Aerts, M.D.,
Manuel Domine, M.D., Luis Paz‑Ares, M.D., Martin Reck, M.D.,
Christine Baudelet, Ph.D., Christopher T. Harbison, Ph.D.,
Brian Lestini, M.D., Ph.D., and David R. Spigel, M.D.​
Original Article
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n engl j med 373;2 nejm.org  july 9, 2015124
The new engl and jour nal of medicine
S
quamous-cell carcinoma represents
approximately 30% of all cases of non–
small-cell lung cancer (NSCLC).1
Treatment
for advanced squamous-cell NSCLC remains an
unmet need; little therapeutic progress has been
made since the approval of docetaxel for secondline
treatment in 1999.2-4
Most new agents for the
treatment of NSCLC are not indicated for this
subtype because of their toxicity or lack of efficacy
or because their activity is limited to tumors
with specific genetic alterations that are rarely
found in squamous-cell NSCLC.5-7
Furthermore,
no single-agent therapy has resulted in better
survival than that seen with docetaxel.
The programmed death 1 (PD-1) receptor,
which is expressed on activated T cells, is engaged
by ligands PD-L1 and PD-L2, which are expressed
by tumor cells and infiltrating immune cells.8
Tumor PD-L1 expression is prevalent in NSCLC,
and the interaction of PD-1 with the PD-L1 and
PD-L2 ligands inhibits T-cell activation and promotes
tumor immune escape (i.e., the mechanism
by which tumor cells escape recognition and
elimination by the immune system).8-10
Nivolumab
is a fully human IgG4 PD-1 immune-checkpoint–
inhibitor antibody that disrupts PD-1–mediated
signaling and restores antitumor immunity.11-13
Nivolumab has activity across NSCLCs with
various histologic features.11,13-15
In phase 1 and 2 trials, nivolumab was associated
with response rates of 15% and approximately
17%, with a median overall survival of 8.2
to 9.2 months and survival rates of 41% at 1 year
and 19% at 3 years, among previously treated
patients with advanced squamous-cell NSCLC.14,15
We report the results of a randomized, openlabel,
international, phase 3 study that compared
nivolumab monotherapy with docetaxel monotherapy
in patients with advanced squamous-cell
NSCLC in whom the disease progressed during
or after one prior platinum-containing chemotherapy
regimen.
Methods
Patients
Patients with stage IIIB or IV squamous-cell
NSCLC who had disease recurrence after one prior
platinum-containing regimen were eligible for participation
in the study. Eligible patients were 18
years of age or older, had an Eastern Cooperative
Oncology Group (ECOG) performance-status score
of 0 or 1 (on a scale from 0 to 5, with higher scores
indicating greater disability; a score of 0 indicates
no symptoms, and 1 mild symptoms), and
had submitted a pretreatment tumor-tissue specimen
for biomarker analyses. Patients with treated,
stable brain metastases were eligible. Key
exclusion criteria were autoimmune disease,
symptomatic interstitial lung disease, systemic
immunosuppression, prior therapy with T-cell
costimulation or checkpoint-targeted agents, or
prior docetaxel therapy. Patients who had received
more than one prior systemic therapy for metastatic
disease were excluded. Prior maintenance
therapy, including an epidermal growth factor
receptor tyrosine kinase inhibitor, was allowed.
The complete eligibility criteria are provided in
the study protocol, available with the full text of
this article at NEJM.org.
Study Design and Treatments
From October 2012 through December 2013, we
enrolled 352 patients, of whom 272 underwent
randomization; 135 patients were randomly assigned
to receive nivolumab, at a dose of 3 mg per
kilogram of body weight every 2 weeks, and 137
were randomly assigned to received docetaxel, at
a dose of 75 mg per square meter of body-surface
area every 3 weeks (Fig. S1A in the Supplementary
Appendix, available at NEJM.org). Both
drugs were administered intravenously. Patients
were treated until disease progression or discontinuation
of treatment owing to toxic effects or
for other reasons (Fig. S1B in the Supplementary
Appendix).
Randomization was stratified according to
prior use of paclitaxel therapy (yes vs. no) and
geographic region (United States or Canada vs.
Europe vs. rest of the world [Argentina, Australia,
Chile, Mexico, and Peru]). For patients in the
nivolumab group, treatment after initial disease
progression was permitted at the investigator’s
discretion according to criteria specified in the
protocol. Requirements for treatment delay or
discontinuation because of treatment-related adverse
events were specified in the protocol, as
were requirements regarding reductions in the
docetaxel dose owing to toxic effects, which
conformed with the prescribing information on
the product label. Reductions in the nivolumab
dose were not permitted.
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n engl j med 373;2 nejm.org  july 9, 2015 125
Nivolumab vs. Docetaxel in Advanced Squamous-Cell NSCLC
End Points and Assessments
The primary end point was overall survival. Patients
were followed for survival continuously
while they were receiving the study drugs and
then every 3 months after discontinuation of treatment.
Initially, confirmed objective response rate
was also a primary end point, but on the basis
of mature data regarding the objective response
rate in an expanded cohort of patients with
NSCLC who had been treated in the phase 1b
study MDX-1106-03 (ClinicalTrials.gov number,
NCT00730639),13
the current trial was amended
before the planned interim analysis to make
overall survival the sole primary end point. The
rate of investigator-assessed confirmed objective
response was modified to be the first secondary
end point. Additional end points included progression-free
survival, patient-reported outcomes, efficacy
according to tumor PD-L1 expression, and
safety.
Tumor response was assessed with the use of
the Response Evaluation Criteria in Solid Tumors
(RECIST), version 1.1,16
at week 9 and every
6 weeks thereafter. Patient-reported outcomes
regarding disease-related symptoms and health
status were assessed with the use of the Lung
Cancer Symptom Scale and the European Quality
of Life–5 Dimensions questionnaire. Outcome
measures included the proportion of patients who
had clinically meaningful improvement in the
average Lung Cancer Symptom Scale score by
week 12. Analyses of patient-reported outcomes
are ongoing.
Safety was assessed by means of evaluations
of the incidence of adverse events, which were
graded with the use of the National Cancer Institute
Common Terminology Criteria for Adverse
Events, version 4.0. Select adverse events (those
with potential immunologic causes) were grouped
according to prespecified categories.
PD-L1 Biomarker Analysis
PD-L1 protein expression was evaluated retrospectively
in pretreatment (archival or recent) tumor-biopsy
specimens with the use of a validated
automated immunohistochemical assay (Dako
North America) that used a rabbit monoclonal
antihuman PD-L1 antibody (clone 28–8, Epitomics).
Samples were categorized as positive when
staining of the tumor-cell membrane (at any intensity)
was observed at prespecified expression
levels of 1%, 5%, or 10% of cells in a section that
included at least 100 tumor cells that could be
evaluated.
Study Oversight
The study was designed by the academic authors
in collaboration with the sponsor (Bristol-Myers
Squibb); the sponsor also worked jointly with
investigators to collect and analyze the data. The
study protocol was approved by an institutional
review board at each participating institution.
The study was conducted in accordance with the
provisions of the Declaration of Helsinki and
Good Clinical Practice guidelines as defined by
the International Conference on Harmonisation.
Written informed consent was obtained from all
the patients before enrollment.
An independent data and safety monitoring
committee provided oversight of safety and efficacy.
On January 10, 2015, the committee recommended
early termination of the study on the
basis of a prespecified interim analysis that
showed that overall survival among patients receiving
nivolumab was superior to that among
those receiving docetaxel. Planned enrollment
was complete before the study was stopped. We
report the results of the interim analysis here,
which are based on a December 15, 2014, database
lock.
All the authors attest that the study was conducted
in accordance with the protocol and
vouch for the accuracy and completeness of the
data and analyses. The first draft of this manuscript
was written by the first and last authors;
all the authors contributed to subsequent drafts
and made the decision to submit the manuscript
for publication. All the authors signed a confidentiality
agreement with the sponsor. Medicalwriting
support, funded by the sponsor, was
provided by StemScientific.
Statistical Analysis
Overall survival and progression-free survival
were analyzed with the use of a two-sided logrank
test stratified according to prior or no prior
paclitaxel use and geographic region. Hazard
ratios and corresponding confidence intervals
were estimated with the use of a stratified Cox
proportional-hazards model, with randomized
group as a single covariate. Survival curves for
each treatment group were estimated with the
use of the Kaplan–Meier method. Survival rates
were derived from the Kaplan–Meier estimates.
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The new engl and jour nal of medicine
Characteristic
Nivolumab
(N = 135)
Docetaxel
(N = 137)
Total
(N = 272)
Age — yr
Median 62 64 63
Range 39–85 42–84 39–85
Age category — no. (%)
<65 yr 79 (59) 73 (53) 152 (56)
≥65 to <75 yr 45 (33) 46 (34) 91 (33)
≥75 yr 11 (8) 18 (13) 29 (11)
Sex — no. (%)
Male 111 (82) 97 (71) 208 (76)
Female 24 (18) 40 (29) 64 (24)
Race — no. (%)†
White 122 (90) 130 (95) 252 (93)
Black 6 (4) 2 (1) 8 (3)
Asian 4 (3) 2 (1) 6 (2)
Other 1 (1) 2 (1) 3 (1)
Not reported 2 (1) 1 (1) 3 (1)
Disease stage — no. (%)
IIIB 29 (21) 24 (18) 53 (19)
IV 105 (78) 112 (82) 217 (80)
Not reported 1 (1) 1 (1) 2 (1)
ECOG performance-status score — no. (%)‡
0 27 (20) 37 (27) 64 (24)
1 106 (79) 100 (73) 206 (76)
Not reported 2 (1) 0 2 (1)
Central nervous system metastasis — no. (%)
Yes 9 (7) 8 (6) 17 (6)
No 126 (93) 129 (94) 255 (94)
Smoking status — no. (%)
Current or former smoker 121 (90) 129 (94) 250 (92)
Never smoked 10 (7) 7 (5) 17 (6)
Unknown 4 (3) 1 (1) 5 (2)
Geographic region — no. (%)
United States or Canada 43 (32) 43 (31) 86 (32)
Europe 77 (57) 78 (57) 155 (57)
Rest of world§ 15 (11) 16 (12) 31 (11)
Other systemic cancer therapy — no. (%)¶
Bevacizumab 1 (1) 1 (1) 2 (1)
Cetuximab 0 2 (1) 2 (1)
Etoposide 17 (13) 11 (8) 28 (10)
Fluorouracil 1 (1) 0 1 (<1)
Gemcitabine 60 (44) 71 (52) 131 (48)
Paclitaxel 46 (34) 46 (34) 92 (34)
Pemetrexed 3 (2) 3 (2) 6 (2)
Vinorelbine 20 (15) 24 (18) 44 (16)
Table 1. Baseline Characteristics, Stratification Factors, and Prior Therapy.*
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n engl j med 373;2 nejm.org  july 9, 2015 127
Nivolumab vs. Docetaxel in Advanced Squamous-Cell NSCLC
Objective response rates were compared with the
use of a two-sided, stratified Cochran–Mantel–
Haenszel test, with exact 95% confidence intervals
calculated with the use of the Clopper–Pearson
method. Nonconventional benefit (i.e., a
reduction in the size or number [or both] of
target lesions with the simultaneous appearance
of new lesions, initial disease progression followed
by tumor reduction, or no further progression
for at least two tumor assessments) in
patients treated beyond initial progression was
not included in response-based analyses (objective
response rate or progression-free survival).
Prespecified analyses were performed to evaluate
the prognostic and predictive roles of prestudy
status with respect to PD-L1 expression.
Demographic and efficacy analyses included
all the patients who underwent randomization
(intention-to-treat population). Safety analyses
included all the treated patients (those who received
at least one dose of study drug). At the
time of the interim database lock, 199 of the 272
patients who had undergone randomization had
died (86% of the 231 deaths required for the final
analysis). The boundary for declaring superiority
for overall survival at the interim analysis
was a P value of less than 0.03, which was based
on an O’Brien–Fleming alpha-spending function.
If the P value for overall survival indicated statistical
significance, then the key secondary end
points of response rate and progression-free
survival were tested hierarchically at the 5% alpha
level.
Results
Patients and Treatment
A total of 96% of the patients who underwent
randomization (260 of 272 patients) received treatment
with a study drug: 131 with nivolumab and
129 with docetaxel. The minimum follow-up was
approximately 11 months.
The median age of the patients was 63 years.
Most patients were men, had an ECOG performance-status
score of 1, had stage IV cancer,
and were current or former smokers (Table 1,
and Table S1 in the Supplementary Appendix).
All the patients had received platinum-based
therapy previously; 34% had received paclitaxel
previously. The demographic and clinical char-
Characteristic
Nivolumab
(N = 135)
Docetaxel
(N = 137)
Total
(N = 272)
Best response to most recent prior systemic regimen,
according to the investigator — no. (%)‖
Complete or partial response 48 (36) 43 (31) 91 (33)
Stable disease 33 (24) 47 (34) 80 (29)
Progressive disease 44 (33) 41 (30) 85 (31)
Unknown or not reported 10 (7) 6 (4) 16 (6)
Time from completion of most recent prior systemic
regimen — no. (%)
<3 mo 64 (47) 59 (43) 123 (45)
3–6 mo 35 (26) 40 (29) 75 (28)
>6 mo 35 (26) 37 (27) 72 (27)
Unknown 1 (1) 1 (1) 2 (1)
*	Data from all patients who underwent randomization are included. There were no significant differences between the
study groups at baseline.
†	Race was self-reported.
‡	Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher numbers indicating
greater disability; a score of 0 indicates no symptoms, and 1 mild symptoms.
§	The countries in the rest-of-the-world geographic region were Argentina, Australia, Chile, Mexico, and Peru.
¶	Other systemic cancer therapy includes chemotherapy as part of prior first-line therapy.
‖	All but one patient received only one line of prior cancer therapy, which could include multiple agents or a switch of
agents within the first-line regimen.
Table 1. (Continued.)
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n engl j med 373;2 nejm.org  july 9, 2015128
The new engl and jour nal of medicine
acteristics of the patients were generally well
balanced between the groups, with slight between-group
imbalances in the percentages of
female patients, patients 75 years of age or older,
and patients with an ECOG performance-status
score of 1.
A median of 8 doses (range, 1 to 48) of
nivolumab and 3 doses (range, 1 to 29) of docetaxel
were administered. Among the patients in the
nivolumab group, 85% received at least 90% of
their planned dose intensity. Among the patients
in the docetaxel group, 69% received at least
90% of their planned dose intensity, a finding
that is consistent with docetaxel dose reductions
(which occurred in 27% of patients). At least one
dose delay occurred in 37% of the patients in the
nivolumab group and in 31% of those in the
docetaxel group. The majority of patients in each
group had only one dose delay, and the majority
of dose delays were from 4 to 7 days in duration
(in 61% of the total cycles delayed in the nivolumab
group and 71% of those in the docetaxel
group). Most delays of nivolumab therapy were
attributable to personal or administrative reasons,
disease progression, or the administration
of radiotherapy; most delays of docetaxel therapy
were due to adverse events.
At the time of the database lock, 16% of the
patients in the nivolumab group and 2% of those
in the docetaxel group were continuing treatment
(Table S2 in the Supplementary Appendix). After
discontinuation of treatment, 36% of the patients
in the nivolumab group and 30% of those in the
docetaxel group received subsequent systemic
cancer therapy. In the nivolumab group, 24% of
the patients received subsequent docetaxel, reflecting
the open-label nature of the study; 2%
of the patients in the docetaxel group received
subsequent immunotherapy (Table S3 in the Supplementary
Appendix).
Efficacy
The median overall survival was 9.2 months
(95% confidence interval [CI], 7.3 to 13.3) in the
nivolumab group as compared with 6.0 months
(95% CI, 5.1 to 7.3) in the docetaxel group. Overall
survival was significantly longer with nivolumab
than with docetaxel (Fig. 1), with the risk of
death 41% lower with nivolumab (hazard ratio,
0.59; 95% CI, 0.44 to 0.79; P<0.001). The overall
survival rate at 1 year was 42% (95% CI, 34 to 50)
in the nivolumab group versus 24% (95% CI, 17 to
31) in the docetaxel group. The hazard ratios for
death in the analysis of overall survival favored
Figure 1. Kaplan–Meier Curves for Overall Survival.
The analysis included all the patients who underwent randomization. Symbols indicate censored observations, and
horizontal lines the rates of overall survival at 1 year.
OverallSurvival(%ofpatients)
100
80
90
70
60
40
30
10
50
20
0
0 3 6 9 12 15 18 21 24
Months
No. at Risk
Nivolumab
Docetaxel
135
137
69
45
52
30
113
103
86
68
31
14
15
7
7
2
0
0
Docetaxel
Median Overall Survival
mo (95% CI)
1-Yr Overall Survival
% of patients (95% CI)
No. of
Deaths
9.2 (7.3–13.3)
6.0 (5.1–7.3)
42 (34–50)
24 (17–31)
86
113
Nivolumab (N=135)
Docetaxel (N=137)
Hazard ratio for death, 0.59 (0.44–0.79)
P<0.001
Nivolumab
24
42
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n engl j med 373;2 nejm.org  july 9, 2015 129
Nivolumab vs. Docetaxel in Advanced Squamous-Cell NSCLC
nivolumab across all prespecified subgroups,
except for the subgroups of patients in the restof-world
geographic region (Argentina, Australia,
Chile, Mexico, and Peru) and those who were
75 years of age or older (Fig. S2 in the Supplementary
Appendix).
The rate of confirmed objective response was
significantly higher with nivolumab than with
docetaxel (20% [95% CI, 14 to 28] vs. 9% [95%
CI, 5 to 15]; P = 0.008) (Table 2, and Fig. S3 in
the Supplementary Appendix). The median time
to response was 2.2 months (range, 1.6 to 11.8)
in the nivolumab group and 2.1 months (range,
1.8 to 9.5) in the docetaxel group (Fig. 2A). The
median duration of response was not reached in
the nivolumab group (range, 2.9 to 20.5+ months,
with + indicating an ongoing response at the
time of analysis), as compared with 8.4 months
in the docetaxel group (range, 1.4+ [with the +
indicating censored data because the patient received
subsequent therapy] to 15.2+ [with the +
indicating an ongoing response]).
The median progression-free survival was 3.5
months (95% CI, 2.1 to 4.9) in the nivolumab
group and 2.8 months (95% CI, 2.1 to 3.5) in the
docetaxel group (hazard ratio for death or disease
progression, 0.62; 95% CI, 0.47 to 0.81;
P<0.001) (Fig. 2B, and Fig. S4 in the Supplementary
Appendix). The rate of progression-free
survival at 1 year was 21% (95% CI, 14 to 28) in
the nivolumab group and 6% (95% CI, 3 to 12)
in the docetaxel group.
A total of 28 patients were treated with
nivolumab after initial progression as defined by
RECIST, version 1.1, with 9 patients having a
nonconventional pattern of benefit. The characteristics
of the patients who were treated after
progression, including the change in tumor
burden over time, are provided in Figure S5 and
Table S4 in the Supplementary Appendix.
A total of 83% of the patients who underwent
randomization (225 of 272 patients) had quantifiable
PD-L1 expression. Rates of PD-L1 positivity
were balanced between the two treatment
groups (Table S5 in the Supplementary Appendix).
Across the prespecified expression levels
(1%, 5%, and 10%), PD-L1 expression was neither
prognostic nor predictive of any of the efficacy
end points (Fig. 2C, and Table S6 in the
Supplementary Appendix). The rates of overall
survival and progression-free survival in the PDL1
subgroups favored nivolumab and were similar
to those in the primary population. Similar
rates of objective response were observed among
patients with PD-L1–positivetumors and those
with PD-L1–negative tumors and were consistently
higher in the nivolumab group than in the
docetaxel group (Table S5 in the Supplementary
Appendix). Survival outcomes according to PD-L1
expression across all the prespecified expression
levels are provided in Figures S6 and S7 in the
Supplementary Appendix.
Variable
Nivolumab
(N = 135)
Docetaxel
(N = 137)
Objective response†
No. of patients 27 12
% of patients (95% CI) 20 (14–28) 9 (5–15)
Estimated odds ratio (95% CI) 2.6 (1.3–5.5)
P value 0.008
Best overall response — no. (%)
Complete response 1 (1) 0
Partial response 26 (19) 12 (9)
Stable disease 39 (29) 47 (34)
Progressive disease 56 (41) 48 (35)
Could not be determined 13 (10) 30 (22)
Time to response — mo‡§
Median 2.2 2.1
Range 1.6–11.8 1.8–9.5
Duration of response — mo‡¶
Median NR 8.4
Range 2.9 to 20.5+ 1.4+ to 15.2+
*	NR denotes not reached.
†	Confirmed complete and partial responses were assessed by the investigator
according to the Response Evaluation Criteria in Solid Tumors, version 1.1.
The confidence interval is based on the Clopper–Pearson method. The analysis
was stratified according to geographic region (United States or Canada vs.
Europe vs. rest of the world) and prior paclitaxel therapy (yes vs. no). The
strata-adjusted odds ratio (nivolumab vs. docetaxel) and the two-sided P value
were calculated with the use of the stratified Cochran–Mantel–Haenszel
method.
‡	The analysis was performed with data from all the patients who had a response
(27 patients in the nivolumab group and 12 in the docetaxel group).
§	The time to response was defined as the time from randomization to the date
of first documented complete or partial response.
¶	Results were calculated with the use of the Kaplan–Meier method. The duration
of response was defined as the time from the date of first response to
the date of first documented disease progression, death, or last tumor assessment
that could be evaluated. The + symbol indicates a censored value. The
value of 1.4 was censored owing to the start of subsequent therapy in one patient,
and the other values were censored because the response was ongoing
at the time of the analysis.
Table 2. Clinical Activity of Nivolumab versus Docetaxel in Patients with
Advanced Squamous-Cell Non–Small-Cell Lung Cancer.*
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The new engl and jour nal of medicine
B Progression-free Survival
C Overall and Progression-free Survival According to PD-L1 Expression Level
A Duration of Response
Progression-freeSurvival(%ofpatients)
100
80
90
70
60
40
30
10
50
20
0
0 3 6 9 12 15 18 21 24
Months
No. at Risk
Nivolumab
Docetaxel
135
137
33
9
21
6
68
62
48
26
15
2
6
1
2
0
0
0
Docetaxel
NivolumabPD-L1 Expression Level Docetaxel Unstratified Hazard Ratio (95% CI)
no. of patients
Hazard ratio for disease progression or death, 0.62 (0.47–0.81)
P<0.001
Nivolumab
6
21
After discontinuation
of treatment
Ongoing response
During docetaxel treatment
During nivolumab treatment
Time to first response
0.50 1.000.25 2.00
Docetaxel
Better
Nivolumab Better
Overall survival
≥1%
<1%
≥5%
<5%
≥10%
<10%
Not quantifiable at baseline
Progression-free survival
≥1%
<1%
≥5%
<5%
≥10%
<10%
Not quantifiable at baseline
0.70 (0.49–0.99)
0.45 (0.23–0.89)
0.58 (0.33–1.02)
0.54 (0.32–0.90)
0.75 (0.52–1.08)
0.67 (0.44–1.01)
0.39 (0.19–0.82)
0.66 (0.43–1.00)
0.70 (0.48–1.01)
0.53 (0.31–0.89)
0.50 (0.28–0.89)
0.70 (0.47–1.02)
0.69 (0.45–1.05)
0.125
0.58 (0.37–0.92)
63
54
42
75
36
81
18
63
54
42
75
36
81
18
56
52
39
69
33
75
29
56
52
39
69
33
75
29
Median Progression-free Survival
mo (95% CI)
1-Yr Progression-free Survival
% of patients (95% CI)
No. of
Events
3.5 (2.1–4.9)
2.8 (2.1–3.5)
21 (14–28)
6 (3–12)
105
122
Nivolumab (N=135)
Docetaxel (N=137)
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Weeks
Docetaxel
Nivolumab
63%
(17 of 27 patients
with response)
33%
(4 of 12 patients
with response)
Patients with Ongoing
Response
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n engl j med 373;2 nejm.org  july 9, 2015 131
Nivolumab vs. Docetaxel in Advanced Squamous-Cell NSCLC
Safety
Treatment-related adverse events, including both
hematologic and nonhematologic toxic events,
occurred less frequently with nivolumab than with
docetaxel. In the nivolumab group, 58% of the
patients had events of any grade, 7% had events
of grade 3 or 4, and none had grade 5 events;
in the docetaxel group, 86% of the patients had
events of any grade, 55% had events of grade 3
or 4, and 2% had events of grade 5 (Table 3, and
Table S7 in the Supplementary Appendix). The
most frequently reported treatment-related adverse
events with nivolumab were fatigue (in 16%
of the patients), decreased appetite (in 11%), and
asthenia (in 10%); docetaxel-treated patients most
frequently had neutropenia (33%), fatigue (33%),
alopecia (22%), and nausea (23%).
Treatment-related serious adverse events occurred
less frequently with nivolumab than with
docetaxel. In the nivolumab group, 7% of the
patients had serious events of any grade, 2% had
serious events of grade 3 or 4, and none had
grade 5 serious events; in the docetaxel group,
24% of patients had serious events of any grade,
19% had serious events of grade 3 or 4, and 2%
had serious events of grade 5 (Table S8 in the
Supplementary Appendix). The higher rates of
treatment-related serious adverse events of grade
3 or 4 with docetaxel than with nivolumab were
attributable mainly to hematologic toxic events
and infections.
The most frequently reported (in ≥3% of patients)
treatment-related select adverse events of
any grade were hypothyroidism (4% with nivolumab
vs. 0% with docetaxel), diarrhea (8% vs. 20%),
pneumonitis (5% vs. 0%), increased blood creatinine
level (3% vs. 2%), and rash (4% vs. 6%)
(Table S9 in the Supplementary Appendix). Three
treatment-related select adverse events of grade
3 were reported in the nivolumab group, with
one case each of tubulointerstitial nephritis, colitis,
and pneumonitis; no grade 4 events were reported.
The median times to the onset of treatment-related
select adverse events in the nivolumab
group ranged from 0.3 to 17.6 weeks across categories
(Table S10 in the Supplementary Appendix).
Immune-modulating medications, most often
systemic glucocorticoids, were administered for
the management of a percentage (18 to 83%) of
treatment-related adverse events in each category.
Topical preparations were also used for the
management of skin-related events. The median
times to resolution of treatment-related select
adverse events ranged from 0.3 to 5.0 weeks in
the nivolumab group (Table S10 in the Supplementary
Appendix). The median time to onset of
treatment-related pulmonary events was 15.1
weeks (range, 2.6 to 85.1). All but one patient
with pulmonary events received glucocorticoids,
and all cases resolved, with a median time to
resolution of 5.0 weeks (range, 0.6 to 12.1).
Among the patients with resolved cases, one
patient had a subsequent recurrence of pneumonitis,
which was managed appropriately with glucocorticoid
treatment.
Treatment-related adverse events led to treatment
discontinuation less frequently in the
nivolumab group than in the docetaxel group (in
3% vs. 10% of the patients) (Tables S11 and S12
in the Supplementary Appendix). The most common
(in ≥1% of patients) treatment-related
events leading to discontinuation were pneumonitis
in the nivolumab group (in 2%) and peripheral
neuropathy and fatigue in the docetaxel group
(in 3% and 2%, respectively). Two additional patients
in the nivolumab group discontinued treatment
owing to pneumonitis (one for whom the
relationship was changed from not treatmentrelated
to treatment-related after database lock,
and one who discontinued >30 days after the
Figure 2 (facing page). Efficacy of Nivolumab versus
Docetaxel in Patients with Advanced Squamous-Cell
Non–Small-Cell Lung Cancer.
Panel A shows the characteristics of response and disease
progression as assessed by the investigator, according
to the Response Evaluation Criteria in Solid
Tumors, version 1.1. Bars indicate the duration of response.
Arrows indicate ongoing response at the time
of data censoring. Panel B shows the Kaplan–Meier
curves for progression-free survival, defined as the
time from randomization to the date of the first documented
event of tumor progression, death, or last tumor
assessment that could be evaluated (data-censoring
date). The analysis included all the patients who
underwent randomization. Symbols indicate censored
observations, and the horizontal lines the rates of progression-free
survival at 1 year. Panel C shows the plot
of hazard ratios for death (in the analysis of overall
survival) and death or disease progression (in the
analysis of progression-free survival), according to the
level of expression of the ligand for programmed
death 1 (PD-L1) at baseline. The prespecified expression
levels for the PD-L1 biomarker analysis were 1%,
5%, and 10% of cells in a section with at least 100 tumor
cells that could be evaluated.
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n engl j med 373;2 nejm.org  july 9, 2015132
The new engl and jour nal of medicine
most recent dose). Details of the four patients
who discontinued owing to pneumonitis are provided
in the Supplementary Appendix. No deaths
were attributed to nivolumab, as compared with
three deaths that were attributed to docetaxel (one
each from interstitial lung disease, pulmonary
hemorrhage, and sepsis).
Discussion
Previously treated squamous-cell NSCLC represents
an area of unmet need, with little progress
made since the approval of docetaxel in 1999. A
retrospective review of recent U.S. Medicare data
indicates that survival remains poor among patients
receiving second-line treatment for squamous-cell
NSCLC, with a median overall survival
of 6.4 months and survival rates of 22% at 1 year
and 5% at 2 years.17
Here we report results of an
international, prospective, randomized, phase 3
trial that showed superior survival and an improved
safety profile with nivolumab versus standard-of-care
docetaxel in patients with advanced,
previously treated squamous-cell NSCLC.
A phase 3 trial comparing docetaxel with
docetaxel plus ramucirumab showed a significant
but modest improvement in overall survival
(hazard ratio for death, 0.86; 95% CI, 0.75 to
0.98; P = 0.02) when ramucirumab was added to
docetaxel for use in patients with previously
treated squamous-cell and non–squamous-cell
cancers, but the addition of ramucirumab was
associated with added toxicity.18,19
In contrast, in
our trial, nivolumab monotherapy, as compared
with docetaxel, was associated with a 41% lower
risk of death, a 3.2-month longer median survival,
and nearly twice the 1-year survival rate.
Despite the confounding effects of comparisons
with historical data, the outcomes in the docetaxel
group in the current trial were consistent with
Event Nivolumab (N = 131) Docetaxel (N = 129)
Any Grade Grade 3 or 4 Any Grade Grade 3 or 4
number of patients with an event (percent)
Any event 76 (58) 9 (7) 111 (86) 71 (55)
Fatigue 21 (16) 1 (1) 42 (33) 10 (8)
Decreased appetite 14 (11) 1 (1) 25 (19) 1 (1)
Asthenia 13 (10) 0 18 (14) 5 (4)
Nausea 12 (9) 0 30 (23) 2 (2)
Diarrhea 10 (8) 0 26 (20) 3 (2)
Arthralgia 7 (5) 0 9 (7) 0
Pyrexia 6 (5) 0 10 (8) 1 (1)
Pneumonitis 6 (5) 0 0 0
Rash 5 (4) 0 8 (6) 2 (2)
Mucosal inflammation 3 (2) 0 12 (9) 0
Myalgia 2 (2) 0 13 (10) 0
Anemia 2 (2) 0 28 (22) 4 (3)
Peripheral neuropathy 1 (1) 0 15 (12) 3 (2)
Leukopenia 1 (1) 1 (1) 8 (6) 5 (4)
Neutropenia 1 (1) 0 42 (33) 38 (30)
Febrile neutropenia 0 0 14 (11) 13 (10)
Alopecia 0 0 29 (22) 1 (1)
*	Safety analyses included all the patients who received at least one dose of study drug. No treatment-related deaths occurred
in patients treated with nivolumab. Treatment-related deaths were reported in three patients treated with
docetaxel (one death each from interstitial lung disease, pulmonary hemorrhage, and sepsis).
Table 3. Treatment-Related Adverse Events Reported in at Least 5% of Patients.*
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n engl j med 373;2 nejm.org  july 9, 2015 133
Nivolumab vs. Docetaxel in Advanced Squamous-Cell NSCLC
expectations that were based on previous studies
in which subgroup data were available for patients
with squamous-cell tumors.7,18
Early separation
of the Kaplan–Meier estimates favoring
nivolumab indicates an early survival benefit
with nivolumab.
Consistent with the finding of superior overall
survival, nivolumab was associated with a
significant improvement across secondary efficacy
end points. The rate of confirmed objective
response with nivolumab was more than double
that with docetaxel. Most patients in the nivolumab
group had a response by the time the first
scan was obtained, and responses were durable.
The durability of benefit was reflected further in
the significantly longer progression-free survival
than that seen with docetaxel (38% lower risk of
progression). The observed efficacy of nivolumab
was similar to that observed in a phase 2,
single-group trial (CheckMate 063) of nivolumab
in the context of third-line therapy and beyond
for squamous-cell NSCLC.15
In that study,
nivolumab was associated with a response rate
of 15%, a median overall survival of 8.2 months,
and a 1-year survival rate of 41%.15
Together,
these trials formed the basis for the March 2015
approval of nivolumab by the Food and Drug
Administration for the treatment of patients
with metastatic squamous-cell NSCLC who had
disease progression during or after platinumbased
chemotherapy.20
A consistent treatment effect favoring nivolumab
was observed in prespecified subgroups,
except in the group of patients 75 years of age or
older and the group in the rest-of-the-world geographic
region. This result was probably attributable
to small sample sizes, a lack of adjustment
of type I error for multiple comparisons,
and an imbalance in ECOG performance-status
score that favored the docetaxel group in the
subgroup of patients who were 75 years of age
or older (in this subgroup, an ECOG performance-status
score of 1 was assessed in 91% of
the patients in the nivolumab group, vs. 61% of
those in the docetaxel group). Further studies
that are focused on a larger elderly population
than was included in our trial may more fully
characterize the degree of benefit with nivolumab
in this subgroup.
Early-stage trials have suggested that PD-L1
expression on tumor cells or tumor-infiltrating
lymphocytes (or both) may increase the likelihood
of response to PD-1–directed or PD-L1–directed
therapies.21,22
Depending on the chosen assay
and expression levels, response rates as high as
83% have been reported.23
However, responses
are consistently seen in patients with tumors or
tumor-infiltrating lymphocytes that are not positive
for PD-L1.
In this study, the efficacy of nivolumab, including
a survival benefit, was observed regardless
of tumor PD-L1 expression levels, with results
showing that PD-L1 expression was neither
prognostic nor predictive of efficacy in the population
of patients with squamous-cell NSCLC.
Limitations of these analyses were that PD-L1
expression was assessed in archival tumor tissue,
which may not have reflected tumor PD-L1
status at the time of treatment, and that only
83% of the patients who underwent randomization
had quantifiable PD-L1 expression. We think
that the lack of an association between PD-L1
expression and efficacy is probably not related to
the performance of the PD-L1 assay but is rather
a function of complex interactions between tumors
and the immune system.
At least two groups of investigators have suggested
that mutational burden or combinations
of immune markers might predict which patients
would be more likely to benefit from PD-1
checkpoint inhibition.22,24
Data from the current
study indicate that PD-L1 testing is not required
in order to inform treatment decisions regarding
the use of nivolumab in second-line therapy of
squamous-cell NSCLC and that patients may
have a survival benefit that is independent of
PD-L1 expression level.
The safety profile of nivolumab was more
favorable than that of docetaxel, with infrequently
reported toxic effects that are expected
with cytotoxic chemotherapies used as secondline
therapies. The frequencies of both hematologic
and nonhematologic adverse events, including
severe toxic events, were substantially less
with nivolumab than with docetaxel, as were adverse
events leading to discontinuation. No new
safety concerns were identified, and no deaths
were attributed to nivolumab. Immune-mediated
adverse events with immunotherapies such as
nivolumab differ from those seen with traditional
cytotoxic therapies, and particular attention
should be given to rapid evaluation and initiation
of treatment. These adverse events, including
pneumonitis, were infrequent and of low severThe
New England Journal of Medicine
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n engl j med 373;2 nejm.org  july 9, 2015134
The new engl and jour nal of medicine
ity in this study and were managed with the use
of established guidelines.
In conclusion, nivolumab is a PD-1 checkpoint
inhibitor that showed a clinically meaningful
survival benefit, with an improved safety
profile, over that seen with the current standard
of care in patients with advanced, previously
treated squamous-cell NSCLC. The benefit was
observed regardless of prestudy PD-L1 expression
level. Further research is needed to identify
relevant biomarkers that have sufficient sensitivity
and specificity to predict which patients are
most likely to benefit.
Supported by Bristol-Myers Squibb.
Dr. Brahmer reports providing uncompensated consulting for
and receiving grant support from Bristol-Myers Squibb; Dr.
Reckamp, receiving consulting fees from Bristol-Myers Squibb;
Dr. Baas, receiving fees for serving on advisory boards from Merck
Sharp & Dohme, Bristol-Myers Squibb, and Pfizer, and grant
support from Merck Sharp & Dohme and Bristol-Myers Squibb;
Dr. Eberhardt, receiving honoraria and consulting fees from
Bristol-Myers Squibb, Merck, AstraZeneca, GlaxoSmithKline,
Roche, Novartis, Pfizer, Boehringer Ingelheim, Amgen, Eli Lilly,
Bayer, Astellas Pharma, Daiichi-Sankyo, and Teva Pharmaceutical
Industries, and grant support through his institution from
Eli Lilly; Dr. Antonia, receiving honoraria from MedImmune,
Bristol-Myers Squibb, and AstraZeneca, and grant support from
MedImmune; Dr. Pluzanski, receiving fees for serving on advisory
boards from Boehringer Ingelheim and Merck Sharp & Dohme,
consulting fees from Bristol-Myers Squibb and AstraZeneca, and
lecture fees from Bristol-Myers Squibb, Boehringer Ingelheim,
Merck Sharp & Dohme, Roche, AstraZeneca, and Eli Lilly; Dr.
Vokes, receiving fees for serving on advisory boards from AbbVie,
AstraZeneca, and Boehringer Ingelheim, and honoraria
from Celgene, Clovis Oncology, Eli Lilly, GeneCentric, Genentech,
Merck, Synta Pharmaceuticals, Transgene, and VentiRx
Pharmaceuticals; Dr. Holgado, receiving honoraria and consulting
fees from Roche and travel support from Roche and Merck
Serono; Dr. Waterhouse, receiving consulting fees from Celgene
and Genentech, and lecture fees from Bristol-Myers Squibb,
Celgene, and Genentech; Dr. Ready, receiving honoraria from
Bristol-Myers Squibb and Celgene; Dr. Gainor, receiving fees for
serving on advisory boards and consulting from Jounce Therapeutics
and Kyowa Hakko Kirin and travel support from Jounce
Therapeutics, Dr. Arén Frontera, receiving fees for serving on
advisory boards from Roche, Bristol-Myers Squibb, Boehringer
Ingelheim, and Novartis; Dr. Garassino, receiving fees for serving
on an advisory board from Bristol-Myers Squibb; Dr. Aerts,
receiving lecture fees from Merck Sharp & Dohme, Eli Lilly,
Roche, and Bristol-Myers Squibb, and grant support from Eli
Lilly and Roche, and holding a patent (PCT/EP2013/077873) related
to a method for preparing an immunogenic lysate, which
is held by Amphera; Dr. Paz-Ares, receiving fees for serving as a
scientific advisor from Eli Lilly, Pfizer, Bristol-Myers Squibb,
Roche, AstraZeneca, and Clovis Oncology; Dr. Reck, receiving
consulting and lecture fees from Roche, Eli Lilly, Boehringer
Ingelheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme,
AstraZeneca, and Novartis; Drs. Baudelet, Harbison, and Lestini,
being employees of and holding stock in Bristol-Myers Squibb;
and Dr. Spigel, receiving travel support from Bristol-Myers
Squibb. No other potential conflict of interest relevant to this
article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the patients and their families, as well as the study
teams involved in the trial, for making this study possible; the
staff of Dako North America for collaborative development of
the automated immunohistochemical assay for assessing the
programmed death 1 ligand; Haolan Lu, Ph.D., for serving as
lung-indication biostatistics lead; Konstantina Gialelis, B.S., for
serving as the protocol manager; Rosaria Gallucci, B.Sc., for
serving as the study coordinator at Fondazione IRCCS Istituto
Nazionale dei Tumori, Milan; and Michel van den Heuvel, M.D.,
Ph.D., of Netherlands Cancer Institute, Amsterdam, for contributions
to the conduct of the study. Earlier versions of the manuscript
were prepared with medical-writing and editorial assistance
provided by Elyse Mallimo, Ph.D., and Lisa Sullivan, M.A.,
of StemScientific, with funding from Bristol-Myers Squibb.
Appendix
The authors’ affiliations are as follows: the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.B.); the City
of Hope Comprehensive Cancer Center, Duarte, CA (K.L.R.); the Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital,
Amsterdam (P.B.), Erasmus MC Cancer Institute, Rotterdam (J.G.A.), and Ziekenhuis Amphia, Breda (J.G.A.) — all in the Netherlands;
the University Hospital of Perugia, Perugia (L.C.), and the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.C.G.) — both in
Italy; the Department of Medical Oncology, West German Cancer Center, Universitätsklinikum Essen, and the Ruhrlandklinik, Universität
Duisburg–Essen, Essen (W.E.E.E.), the Thoraxklinik, Heidelberg University Hospital, Heidelberg (M.S.), and the LungenClinic
Grosshansdorf, Grosshansdorf (M.R.) — all in Germany; the N.N. Blokhin Russian Cancer Research Center, Moscow (E.P.); the H. Lee
Moffitt Cancer Center and Research Institute, Tampa, FL (S.A.); the Centrum Onkologii-Instytut im. Marii Skłodowskiej-Curie, Warsaw,
Poland (A.P.); the University of Chicago Medicine and Biological Sciences, Chicago (E.E.V.); the Hospital Madrid Norte Sanchinarro
(E.H.), the Hospital Universitario Fundación Jiménez Díaz, Madrid (M.D.), and the Hospital Universitario Virgen Del Rocío, Seville
(L.P.-A.) — all in Spain; Oncology Hematology Care, Cincinnati (D.W.); the Duke University Medical Center, Durham, NC (N.R.); Massachusetts
General Hospital, Boston (J.G.); Centro Internacional de Estudios Clinicos, Santiago, Chile (O.A.F.); Nemocnice Na Bulovce,
Prague, Czech Republic (L.H.); Bristol-Myers Squibb, Princeton, NJ (C.B., C.T.H., B.L.); and the Sarah Cannon Research Institute and
Tennessee Oncology, Nashville (D.R.S.).
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