The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Nivolumab for Recurrent Squamous-Cell

Carcinoma of the Head and Neck
R.L. Ferris, G. Blumenschein, Jr., J. Fayette, J. Guigay, A.D. Colevas, L. Licitra,
K. Harrington, S. Kasper, E.E. Vokes, C. Even, F. Worden, N.F. Saba,
L.C. Iglesias Docampo, R. Haddad, T. Rordorf, N. Kiyota, M. Tahara, M. Monga,
M. Lynch, W.J. Geese, J. Kopit, J.W. Shaw, and M.L. Gillison​​

A BS T R AC T

BACKGROUND
The authors’ full names, academic degrees, Patients with recurrent or metastatic squamous-cell carcinoma of the head and
and affiliations are listed in the Appendix. neck after platinum chemotherapy have a very poor prognosis and limited thera-
Address reprint requests to Dr. Gillison at
the Ohio State University Comprehensive peutic options. Nivolumab, an anti–programmed death 1 (PD-1) monoclonal anti-
Cancer Center, Ohio State University, 420 body, was assessed as treatment for this condition.
W. 12th Ave., Rm. 690, Columbus, OH
43210, or at ­maura​.­gillison@​­osumc​.­edu. METHODS
Drs. Ferris and Gillison contributed equal- In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients
ly to this article. with recurrent squamous-cell carcinoma of the head and neck whose disease had
This article was published on October 9, progressed within 6 months after platinum-based chemotherapy to receive nivolu­
2016, at NEJM.org. mab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard,
N Engl J Med 2016;375:1856-67. single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary
DOI: 10.1056/NEJMoa1602252 end point was overall survival. Additional end points included progression-free
Copyright © 2016 Massachusetts Medical Society.
survival, rate of objective response, safety, and patient-reported quality of life.
RESULTS
The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1)
in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that
received standard therapy. Overall survival was significantly longer with nivolumab
than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96;
P = 0.01), and the estimates of the 1-year survival rate were approximately 19 percent-
age points higher with nivolumab than with standard therapy (36.0% vs. 16.6%).
The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with
nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard
ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P = 0.32). The
rate of progression-free survival at 6 months was 19.7% with nivolumab versus
9.9% with standard therapy. The response rate was 13.3% in the nivolumab group
versus 5.8% in the standard-therapy group. Treatment-related adverse events of
grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus
35.1% of those in the standard-therapy group. Physical, role, and social function-
ing was stable in the nivolumab group, whereas it was meaningfully worse in the
standard-therapy group.
CONCLUSIONS
Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the
head and neck, treatment with nivolumab resulted in longer overall survival than
treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb;
CheckMate 141 ClinicalTrials.gov number, NCT02105636.)

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 Nivolumab for Recurrent Carcinoma of Head and Neck

S
quamous-cell carcinoma of the head Trial Design and Treatments
and neck is a major cause of cancer-asso- Patients were randomly assigned in a 2:1 ratio to
ciated illness and death, with more than receive intravenous nivolumab (Opdivo, Bristol-
600,000 cases diagnosed annually worldwide.1 Myers Squibb) or a standard, single-agent therapy
Most patients present with locoregionally ad- of the investigator’s choice, with stratification
vanced disease, and more than 50% have recur- according to receipt of previous cetuximab ther-
rence within 3 years.2-4 Patients with squamous- apy (yes or no). Nivolumab was administered at a
cell carcinoma of the head and neck who have dose of 3 mg per kilogram of body weight every
cancer progression within 6 months after plati- 2 weeks. Standard therapy consisted of weekly
num-based chemotherapy administered in the con- intravenous administration of methotrexate at a
text of primary or recurrent disease have a medi- dose of 40 to 60 mg per square meter of body-
an survival of 6 months or less.5 No therapeutic surface area, docetaxel at a dose of 30 to 40 mg per
options prolong survival among these patients.5,6 square meter, or cetuximab at a dose of 250 mg
The recurrence and metastasis of squamous- per square meter after a loading dose of 400 mg
cell carcinoma of the head and neck are facili- per square meter.
tated by immune evasion,7 which is mediated in
part by expression of the programmed death End Points and Assessments
ligands (PD-L1 and PD-L2) of the T-cell–suppres- The primary end point was overall survival, which
sive immune-checkpoint receptor programmed was defined as the time from randomization to
death 1 (PD-1).8-11 Nivolumab, a fully human IgG4 the date of death from any cause. Secondary end
anti–PD-1 monoclonal antibody, has shown anti- points were progression-free survival (time from
tumor efficacy in multiple tumor types.12,13 We randomization to the date of disease progres-
designed a randomized trial to investigate wheth- sion or death) and the rate of objective response
er overall survival would be longer with nivolumab according to RECIST, version 1.1. Additional pre-
therapy than with standard therapy, among pa- specified end points included the time to re-
tients with platinum-refractory squamous-cell sponse; associations between PD-L1 level and
carcinoma of the head and neck. human papillomavirus (HPV) status and overall
survival, progression-free survival, and response
rate; safety; and quality-of-life assessments.
Me thods
Tumor response was assessed by investigators
Patients according to RECIST, version 1.1, every 6 weeks
Eligible patients had histologically confirmed, beginning at week 9. Patients were treated until
recurrent squamous-cell carcinoma of the head an unacceptable level of drug-related toxic effects
and neck (including metastatic disease) of the occurred or until disease progression. However,
oral cavity, pharynx, or larynx that was not ame- nivolumab treatment could be continued beyond
nable to curative treatment; tumor progression disease progression, as assessed clinically or
or recurrence within 6 months after the last dose radiographically, if the investigator assessed that
of platinum-containing chemotherapy adminis- it was providing clinical benefit. Patients were
tered as adjuvant therapy or in the context of followed for overall survival every 3 months until
primary or recurrent disease; an age of at least death, loss to follow-up, or withdrawal of consent.
18 years; an Eastern Cooperative Oncology Group At each treatment visit and for 100 days after
performance-status score of 0 or 1 (on a scale receipt of the last dose, acute toxic effects were
from 0 to 5, with higher numbers indicating evaluated according to the Common Terminology
greater disability); adequate bone marrow, he- Criteria for Adverse Events, version 4.0. Adverse
patic, and renal function; and measurable dis- events with potential immunologic causes were
ease according to Response Evaluation Criteria classified as select adverse events. The criteria
in Solid Tumors (RECIST), version 1.1.14 Major for a dose delay or the discontinuation of nivolu­
exclusion criteria were active brain metastases, mab or standard therapy because of treatment-
autoimmune disease, or systemic immunosup- related adverse events were specified in the pro-
pression; known human immunodeficiency virus tocol, available with the full text of this article at
or hepatitis B or C virus infection; and previous NEJM.org. Dose modifications were not permit-
therapy targeting T-cell costimulating or immune- ted for nivolumab but were specified for metho-
checkpoint pathways.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

trexate, docetaxel, and cetuximab on the basis of ration with the sponsor (Bristol-Myers Squibb).
the type and grade of the toxic effect. The first and last authors attest to the accuracy
Patient-reported outcomes, including symp- and completeness of the data and analyses and
toms and health-related quality of life, were ex- vouch for adherence of the trial to the protocol.
ploratory end points and were evaluated with the Medical-writing support, funded by the sponsor,
use of the European Organization for Research was provided by inScience Communications and
and Treatment of Cancer (EORTC) Quality of Life Chrysalis Medical Communications.
Questionnaire–Core 30 module (QLQ-C30) and
the head-and-neck–specific module (QLQ-H&N35). Statistical Analysis
Scores for these modules range from 0 to 100, We calculated the required number of events as-
with higher scores indicating better functioning suming one planned interim analysis of overall
or well-being or higher symptom burden, although survival after 70% of the events occurred and
scales measuring symptom burden were reverse- stopping boundaries that were based on an
scored to facilitate presentation. The propor- O’Brien–Fleming alpha-spending function.18 We
tion of patients reporting health problems was calculated that a sample of 360 patients and a
assessed with the use of the three-level version total of 278 deaths would be required to ensure
of the European Quality of Life–5 Dimensions that a two-sided test procedure with one interim
(EQ-5D-3L) questionnaire. Patients also com- analysis, a 2:1 ratio for randomization, and an
pleted the EQ-5D-3L visual-analogue scale, for experiment-wide false positive rate of 5% would
which scores range from 0 to 100 and higher provide the trial with 90% power to detect a
scores indicate better perceived health status. hazard ratio of 0.667 for the comparison of
nivolumab with standard therapy.
Biomarker Analysis Analyses of baseline characteristics and effi-
Fresh or archived pretreatment tumor specimens cacy followed the intention-to-treat principle.
were obtained after the last therapy and before Analyses of dosing and safety were restricted to
trial entry from 90.6% of the patients. For pa- patients who received at least one dose of ther­
tients with oropharyngeal cancer, tumor HPV apy. The distributions of overall survival and
status, assessed by means of p16 immunohisto- progression-free survival were estimated by the
chemical testing, was required to be documented Kaplan–Meier method and compared by means
by local or central analysis and was defined as of log-rank tests stratified according to previous
positive if diffuse staining was present in at least receipt of cetuximab (yes or no). Cox proportional-
70% of the tumor cells.15 Immunochemical test- hazards models (stratified according to status
ing for p16 was not performed for nonoropha- with respect to previous receipt of cetuximab)
ryngeal cancers because of the low prevalence of were used to estimate hazard ratios and com-
HPV-positive tumors and poor specificity for HPV pute confidence intervals. A generalization of the
status at these anatomical sites.16 Tumor PD-L1 Brookmeyer and Crowley method was used to
membrane expression was evaluated centrally by compute confidence intervals for the median sur-
means of immunohistochemical testing (Dako vival times, and the Borgan and Liestøl method
North America) with the use of a rabbit antihu- was used to compute confidence intervals for
man PD-L1 antibody (clone 28–8, Epitomics) and survival at specific time points.19
was scored at prespecified expression levels, in- A confidence interval of 97.73% was used for
cluding levels of 1% or more, 5% or more, and the hazard ratio for death in the analysis of
10% or more in a minimum of 100 tumor cells overall survival to reflect the significance level
that could be evaluated.17 for the interim comparison of overall survival.
All other confidence intervals were calculated
Trial Oversight at the 95% level. The stratum-adjusted Cochran–
This trial was registered with the National Can- Mantel–Haenszel method was used to compute
cer Institute and was approved by the institu- the odds ratio and the associated confidence
tional review board at each participating institu- interval for tumor response. The protocol speci-
tion. Written informed consent was obtained fied that if nivolumab was shown to be superior
from all the patients before enrollment. The trial to standard therapy with respect to overall sur-
was designed by the academic authors in collabo- vival, then progression-free survival and response

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 Nivolumab for Recurrent Carcinoma of Head and Neck

rate would each be tested, hierarchically at an ment groups were balanced with respect to most
alpha level of 5%, to ensure a false positive rate demographic and clinical characteristics (Table 1),
of no more than 5% for testing all three end although the standard-therapy group included
points. higher percentages of patients 65 years of age or
Prespecified analyses were performed to assess older and of patients who had never smoked.
the consistency of treatment effect on the end Tumor p16 status was reported, per protocol, for
points in a range of baseline subgroups, includ- 178 patients (113 patients in the nivolumab
ing subgroups defined according to PD-L1 expres- group and 65 in the standard-therapy group),
sion status and p16 status. A post hoc analysis and 26.2% of the patients in the nivolumab group
of treatment effect in PD-L1 expression subgroups and 24.0% in the standard-therapy group had
(≥1% vs. <1%) according to p16 status (positive positive p16 status.
vs. negative) was also performed. In addition, Of 361 patients who underwent randomiza-
tests for interactions between treatment and tion, 347 (96.1%) received one or more doses of
PD-L1 expression level (prespecified) and be- assigned therapy (236 patients in the nivolumab
tween treatment and p16 status (post hoc) were group and 111 in the standard-therapy group).
performed. All these analyses were exploratory Standard therapies that were administered in-
and descriptive: no adjustments for multiple com- cluded methotrexate (in 46 patients), docetaxel
parisons were made, nor was the trial powered (in 52), and cetuximab (in 13). The median dura-
to detect interactions. tion of treatment was 1.9 months in each group.
For patient-reported outcomes, a clinically Data on dose delays and reductions according to
meaningful change in score was regarded as treatment group are provided in Table S1 in the
10 points for the EORTC QLQ-C30 and QLQ- Supplementary Appendix. At the time of analy-
H&N35 and as 7 points for the visual-analogue sis, 41 of 236 patients (17.4%) were still receiving
scale of the EQ-5D-3L questionnaire.20-22 Analy- nivolumab and 3 of 111 (2.7%) were still receiv-
sis of covariance was used to compare the mean ing standard therapy.
score changes between groups, with a separate
analysis being performed for each patient-reported Efficacy
outcome. Each analysis was adjusted for treat- Among 361 patients who underwent randomiza-
ment, visit, status with respect to previous cetux- tion, 133 deaths (55.4% of patients) occurred in
imab use, and the baseline value of the patient- the nivolumab group and 85 deaths (70.2% of
reported outcome. patients) occurred in the standard-therapy group.
The data cutoff point for the analyses of over- The median duration of follow-up for overall
all survival, progression-free survival, and safety survival was 5.1 months (range, 0 to 16.8).
was December 18, 2015, which was the date of The median overall survival was 7.5 months
the planned interim analysis. Data on rate of (95% confidence interval [CI], 5.5 to 9.1) in the
response were based on a database lock on May nivolumab group versus 5.1 months (95% CI,
5, 2016. At the interim analysis, the independent 4.0 to 6.0) in the standard-therapy group. Overall
data monitoring committee confirmed that the survival was significantly longer with nivolumab
P value for the comparison of overall survival was than with standard therapy, and nivolumab-
below the formal statistical boundary for signifi- treated patients had a risk of death that was 30%
cance of 0.0227. lower than the risk among patients assigned to
standard therapy (hazard ratio, 0.70; 97.73% CI,
0.51 to 0.96; P = 0.01) (Fig. 1A). The delayed
R e sult s
separation of the Kaplan–Meier curves for over-
Patients and Treatment all survival is indicative of nonproportionality,
From June 2014 through August 2015, we ran- and the hazard ratio should be thought of as an
domly assigned 240 patients to receive nivolu­ average over time.23 The estimated rate of overall
mab and 121 to receive standard therapy (Fig. S1 survival at 1 year among patients treated with
in the Supplementary Appendix, available at nivolumab (36.0%; 95% CI, 28.5 to 43.4) was
NEJM.org). Previous treatment included radio- more than double the rate with standard therapy
therapy in 91.4% of the patients and two or more (16.6%; 95% CI, 8.6 to 26.8).
lines of systemic therapy in 54.5%. The treat- Nivolumab was associated with longer median

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Characteristics at Baseline and Previous Therapy.*

Nivolumab Standard Therapy Total

Characteristic (N = 240) (N = 121) (N = 361)
Age
Median (range) — yr 59 (29–83) 61 (28–78) 60 (28–83)
≥75 yr — no. (%) 12 (5.0) 6 (5.0) 18 (5.0)
Male sex — no. (%) 197 (82.1) 103 (85.1) 300 (83.1)
Race — no. (%)†
White 196 (81.7) 104 (86.0) 300 (83.1)
Asian 29 (12.1) 14 (11.6) 43 (11.9)
Black 10 (4.2) 3 (2.5) 13 (3.6)
Other 5 (2.1) 0 5 (1.4)
Smoking or tobacco use — no. (%)
Current or former 191 (79.6) 85 (70.2) 276 (76.5)
Never 39 (16.2) 31 (25.6) 70 (19.4)
Not reported 10 (4.2) 5 (4.1) 15 (4.2)
ECOG performance-status score — no. (%)‡
0 49 (20.4) 23 (19.0) 72 (19.9)
1 189 (78.8) 94 (77.7) 283 (78.4)
≥2 1 (0.4) 3 (2.5) 4 (1.1)
Not reported 1 (0.4) 1 (0.8) 2 (0.6)
Site of primary tumor — no. (%)
Larynx 34 (14.2) 15 (12.4) 49 (13.6)
Oral cavity 108 (45.0) 67 (55.4) 175 (48.5)
Pharynx 92 (38.3) 36 (29.8) 128 (35.5)
Other§ 6 (2.5) 3 (2.5) 9 (2.5)
No. of previous lines of systemic cancer
therapy — no. (%)¶
1 106 (44.2) 58 (47.9) 164 (45.4)
2 80 (33.3) 45 (37.2) 125 (34.6)
≥3 54 (22.5) 18 (14.9) 72 (19.9)
Context of previous systemic therapy
regimen — no. (%)‖
Adjuvant therapy 37 (15.4) 21 (17.4) 58 (16.1)
Neoadjuvant therapy 17 (7.1) 16 (13.2) 33 (9.1)
Primary disease 173 (72.1) 83 (68.6) 256 (70.9)
Metastatic disease 112 (46.7) 59 (48.8) 171 (47.4)
Previous receipt of cetuximab — no. (%) 150 (62.5) 72 (59.5) 222 (61.5)

* There were no significant (P<0.05) between-group differences in the characteristics listed here, except for smoking
(P = 0.047). Percentages may not total 100 because of rounding.
† Race was self-reported.
‡ Eastern Cooperative Oncology Group (ECOG) performance status is scored on a scale from 0 to 5, with higher num-
bers indicating greater disability.
§ The “Other” category included patients with a tumor in more than one of the categories (i.e., larynx, oral cavity, or pharynx).
¶ A line of systemic chemotherapy was defined as any chemotherapy that was administered as part of primary therapy for
squamous-cell carcinoma of the head and neck (e.g., induction or concurrent chemoradiotherapy) or any single-agent
or multiple-agent chemotherapy regimen that was administered after a diagnosis of recurrent squamous-cell carcinoma
of the head and neck.
‖ Patients may have received previous systemic therapy in more than one context.

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 Nivolumab for Recurrent Carcinoma of Head and Neck

overall survival than all the options for standard group of patients with a PD-L1 expression level
therapy: methotrexate (median, 4.6 months; haz- of 1% or more, the hazard ratio for death among
ard ratio for death, 0.64; 95% CI, 0.43 to 0.96), patients treated with nivolumab versus standard
docetaxel (median, 5.8 months; hazard ratio, therapy was 0.55 (95% CI, 0.36 to 0.83) (Fig. 2A),
0.82; 95% CI, 0.53 to 1.28), and cetuximab (me- whereas in the subgroup of patients with a PD-
dian, 4.1 months; hazard ratio, 0.47; 95% CI, L1 expression level of less than 1%, the hazard
0.22 to 1.01). Across prespecified demographic ratio was 0.89 (95% CI, 0.54 to 1.45; P = 0.17 for
and clinical subgroups, the estimate of the haz- interaction) (Fig. 2B). The estimates of the haz-
ard ratio for death in the analysis of overall ard ratio for death in the analysis of overall
survival with nivolumab versus standard therapy survival in the subgroups of patients with PD-L1
was less than 1 (Fig. 1C, and Fig. S2 in the expression levels of 5% or more and of 10% or
Supplementary Appendix). more were similar to those among patients with
No significant difference between groups was PD-L1 expression levels of 1% or more (Table 2).
observed with regard to the rate of progression- In our post hoc exploratory analysis involving
free survival (hazard ratio for disease progres- the 178 patients for whom tumor p16 status was
sion or death, 0.89; 95% CI, 0.70 to 1.13; P = 0.32). reported, the median overall survival appeared
The crossing of the Kaplan–Meier curves is in- to be longer with nivolumab than with standard
dicative of nonproportionality. The median pro- therapy regardless of p16 status (Table 2). Among
gression-free survival was 2.0 months (95% CI, patients with p16-positive tumors, the median
1.9 to 2.1) in the nivolumab group versus 2.3 overall survival was 9.1 months in the nivolumab
months (95% CI, 1.9 to 3.1) in the standard- group versus 4.4 months in the standard-therapy
therapy group (Fig. 1B). However, a late separa- group (hazard ratio for death, 0.56; 95% CI, 0.32
tion in the Kaplan–Meier curves was observed, to 0.99); among patients with p16-negative tu-
and the estimated rates of progression-free sur- mors, the median overall survival was 7.5 versus
vival at 6 months were 19.7% (95% CI, 14.6 to 5.8 months (hazard ratio, 0.73; 95% CI, 0.42 to
25.4) in the nivolumab group and 9.9% (95% CI, 1.25; P = 0.55 for interaction) (Figs. S4 and S5 in
5.0 to 16.9) in the standard-therapy group. the Supplementary Appendix).
The response rate among nivolumab-treated We further explored the effect of nivolumab
patients was 13.3% (95% CI, 9.3 to 18.3), includ- versus standard therapy on overall survival in
ing 6 complete responses and 26 partial respons- subgroups defined according to both PD-L1 ex-
es. In the standard-therapy group, the response pression (≥1% vs. <1%) and tumor p16 status
rate was 5.8% (95% CI, 2.4 to 11.6), including (positive vs. negative) (Table 2). The estimated
1 complete response and 6 partial responses. The hazard ratios for death in the analysis of overall
median time to response was 2.1 months with survival with nivolumab versus standard therapy
nivolumab versus 2.0 months with standard were less than 1 in all four subgroups. Results
therapy. Tumor reductions were more durable of the exploratory analysis of the treatment ef-
with nivolumab, as indicated by the tumor-burden fect on response rates in the subgroups defined
plots over time for patients who had either a according to tumor PD-L1 level and p16 status
partial response or a complete response (Fig. S3 are provided in Table S3 in the Supplementary
in the Supplementary Appendix). Appendix.

PD-L1 Expression and p16 Status Safety

A prespecified, exploratory analysis was per- The most common treatment-related adverse
formed to evaluate the consistency of the treat- events are shown in Table 3 (see also Tables S4,
ment effect in subgroups defined according to S5, and S6 in the Supplementary Appendix). The
tumor PD-L1 expression level (≥1% vs. <1%) rates of treatment-related adverse events of any
(Table 2). Tumor PD-L1 expression status could grade were similar in the two groups, but fewer
be evaluated in 260 of 361 patients (72.0%) events of grade 3 or 4 were reported in the
(Table S2 in the Supplementary Appendix). Among nivolumab group than in the standard-therapy
the patients who could be evaluated, 57.3% had a group (occurring in 13.1% vs. 35.1% of patients).
PD-L1 expression level of 1% or more. In the nivolumab group, the most frequent ad-
In the analysis of overall survival in the sub- verse events of any grade were fatigue, nausea,

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Overall Survival B Progression-free Survival

No. of No. of 1–Yr Overall Median Overall No. of No. of Median Progression-free
Patients Deaths Survival Rate Survival Patients Events Survival (95% CI)
% (95% CI) mo (95% CI) mo
Nivolumab 240 133 36.0 (28.5–43.4) 7.5 (5.5–9.1) Nivolumab 240 190 2.0 (1.9–2.1)
Standard Therapy 121 85 16.6 (8.6–26.8) 5.1 (4.0–6.0) Standard Therapy 121 103 2.3 (1.9–3.1)

100 Hazard ratio for death, 0.70 100

90 90 Hazard ratio for disease progression

Progression–free Survival (%)

(97.73% CI, 0.51–0.96)
80 P=0.01 80 or death, 0.89 (95% CI, 0.70–1.13)
Overall Survival (%)

P=0.32
70 70
60 60
50 50
40 40
Nivolumab
30 30
20 Standard 20
therapy Standard
10 10 Nivolumab
therapy
0 0
0 3 6 9 12 15 18 0 3 6 9 12 15 18
Months Months
No. at Risk No. at Risk
Nivolumab 240 167 109 52 24 7 0 Nivolumab 240 79 32 12 4 1 0
Standard 121 87 42 17 5 1 0 Standard 121 43 9 2 0 0 0
therapy therapy

C Treatment Effect on Overall Survival, According to Subgroup

Subgroup Nivolumab Standard Therapy Unstratified Hazard Ratio (95% CI)

no. of patients
Overall 240 121 0.69 (0.53–0.91)
Age
<65 yr 172 76 0.64 (0.45–0.89)
≥65 yr and <75 yr 56 39 0.93 (0.56–1.54)
≥75 yr 12 6 —
ECOG performance-status score
0 49 23 0.60 (0.30–1.23)
≥1 190 97 0.71 (0.53–0.96)
Not reported 1 1 —
Previous cetuximab use
Yes 147 74 0.81 (0.57–1.15)
No 93 47 0.55 (0.35–0.86)
Intended standard therapy
Cetuximab 33 15 0.47 (0.22–1.01)
Methotrexate 119 52 0.64 (0.43–0.96)
Docetaxel 88 54 0.82 (0.53–1.28)
Site of primary tumor
Larynx 34 15 0.75 (0.36–1.59)
Oral cavity 108 67 0.73 (0.51–1.07)
Pharynx 92 36 0.71 (0.42–1.19)
Other 6 3 —
No. of previous lines of systemic therapy
1 106 58 0.72 (0.48–1.07)
2 80 45 0.64 (0.40–1.00)
≥3 54 18 0.77 (0.38–1.57)
Platinum-refractory disease in context
of primary therapy
Yes 52 26 0.63 (0.35–1.12)
No 188 95 0.71 (0.52–0.97)

0.125 0.25 0.50 1.00 2.00 4.00 8.00

Nivolumab Better Standard Therapy Better

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 Nivolumab for Recurrent Carcinoma of Head and Neck

Figure 1 (facing page). Overall Survival, Progression-free Survival, and Treatment Effect on Overall Survival
According to Subgroup.
Panel A shows the Kaplan–Meier curves for overall survival among all the patients who underwent randomization
and were assigned to receive either nivolumab or standard therapy. In the planned interim analysis, the boundary
for statistical significance for overall survival required the P value to be less than 0.0227. Panel B shows the Kaplan–
Meier curves for progression-free survival among all the patients who underwent randomization. Symbols indicate
censored observations. Hazard ratios (and confidence intervals) were computed with the use of a stratified Cox pro-
portional-hazards model, and the P values were from a stratified log-rank test. Panel C shows a forest plot of un-
stratified hazard ratios for death in the analysis of the treatment effect according to demographic and clinical sub-
groups at baseline. Hazard ratios were not calculated for subgroups that included fewer than 20 patients across the
two groups. Platinum-refractory disease in the context of primary therapy refers to cancer progression within 6 months
after platinum therapy administered in the context of primary or adjuvant therapy (a post hoc derived analysis).

rash, decreased appetite, and pruritus. Among crine system (in 7.6% vs. 0.9%; primarily hypo-
the select adverse events, gastrointestinal events thyroidism). Pneumonitis was observed in 2.1%
were less common with nivolumab than with of the patients treated with nivolumab. Two
standard therapy (occurring in 6.8% vs. 14.4% of treatment-related deaths were reported in the
the patients; primarily diarrhea), whereas ad- nivolumab group (pneumonitis and hypercalce-
verse events of the skin were more common with mia in one patient each), and one patient in the
nivolumab (in 15.7% vs. 12.6%; primarily rash standard-therapy group died from a treatment-
and pruritus), as were adverse events of the endo- related lung infection.

Table 2. Exploratory Analysis of Overall Survival According to Tumor PD-L1 Expression and p16 Status Subgroups.*

Nivolumab Standard Therapy Hazard Ratio for Death

Variable (N = 240) (N = 121) (95% CI)

Patients Median Survival Patients Median Survival

no. (%) mo no. (%) mo

All patients 240 (100.0) 7.5 121 (100.0) 5.1 0.69 (0.53–0.91)
PD-L1 expression level
≥1% 88 (36.7) 8.7 61 (50.4) 4.6 0.55 (0.36–0.83)
≥5% 54 (22.5) 8.8 43 (35.5) 4.6 0.50 (0.30–0.83)
≥10% 43 (17.9) 8.7 34 (28.1) 5.2 0.56 (0.31–1.01)
<1% 73 (30.4) 5.7 38 (31.4) 5.8 0.89 (0.54–1.45)
<5% 107 (44.6) 7.0 56 (46.3) 5.1 0.81 (0.55–1.21)
<10% 118 (49.2) 7.2 65 (53.7) 4.6 0.73 (0.50–1.06)
Not quantifiable 79 (32.9) 7.8 22 (18.2) 5.8 0.79 (0.44–1.44)
p16 status
Positive 63 (26.2) 9.1 29 (24.0) 4.4 0.56 (0.32–0.99)
Negative 50 (20.8) 7.5 36 (29.8) 5.8 0.73 (0.42–1.25)
Combined subgroup
PD-L1 ≥1% and p16-positive 23 (9.6) 8.8 14 (11.6) 3.9 0.50 (0.21–1.19)
PD-L1 ≥1% and p16-negative 17 (7.1) 8.8 16 (13.2) 5.6 0.44 (0.18–1.10)
PD-L1 <1% and p16-positive 24 (10.0) 10.0 10 (8.3) 6.4 0.55 (0.22–1.39)
PD-L1 <1% and p16-negative 14 (5.8) 7.1 12 (9.9) 7.4 0.82 (0.31–2.19)

* Expression of the programmed death 1 ligand 1 (PD-L1) was measured in 260 patients (161 patients in the nivolumab group and 99 in the
standard-therapy group), and the p16 level in 178 patients (113 in the nivolumab group and 65 in the standard-therapy group). Hazard ratios
are from unstratified Cox proportional-hazards models.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A Overall Survival among Patients with Baseline PD-L1 ≥1% B Overall Survival among Patients with Baseline PD-L1 <1%
No. of No. of Median Overall No. of No. of Median Overall
Patients Deaths Survival Patients Deaths Survival
mo (95% CI) mo (95% CI)
Nivolumab 88 49 8.7 (5.7–9.1) Nivolumab 73 45 5.7 (4.4–12.7)
Standard Therapy 61 45 4.6 (3.8–5.8) Standard Therapy 38 25 5.8 (4.0–9.8)
100 100
90 90
80 80
Overall Survival (%)

Overall Survival (%)

70 70
60 60
50 50
40 40
Nivolumab
30 30 Nivolumab
20 20
Hazard ratio for death, 0.55 Standard therapy Hazard ratio for death, 0.89
10 (95% CI, 0.36–0.83) 10 (95% CI, 0.54–1.45) Standard therapy
0 0
0 3 6 9 12 15 18 0 3 6 9 12 15 18

Months Months
No. at Risk No. at Risk
Nivolumab 88 67 44 18 6 0 Nivolumab 73 52 33 17 8 3 0
Standard 61 42 20 6 2 0 Standard 38 29 14 6 2 0 0
therapy therapy

Nivolumab Standard Therapy

C Quality of Life and Symptom Burden

Physical Functioning Role Functioning Social Functioning

40 40 40
Week 9 Week 15 Week 9 Week 15 Week 9 Week 15
30 30 30
Mean Change from

Mean Change from

Mean Change from

20 20 20
Better

Better

Better
10 10 10
Baseline

Baseline

Baseline

0 0 0
Worse

Worse

Worse
−10 −10 −10
−20 −20 −20
−30 −30 −30
−40 P=0.01 P<0.001 −40 P=0.003 P<0.001 −40 P=0.002 P<0.001

Pain Sensory Problems Social-Contact Problems

40 40 40
Week 9 Week 15 Week 9 Week 15 Week 9 Week 15
30 30 30
Mean Change from

Mean Change from

Mean Change from

20 20 20
Better

Better

10 10 10 Better
Baseline

Baseline

Baseline

0 0 0
Worse

Worse

Worse

−10 −10 −10

−20 −20 −20
−30 −30 −30
−40 P<0.001 P=0.02 −40 P=0.01 P<0.001 −40 P=0.26 P<0.001

Figure 2. Overall Survival According to Baseline PD-L1 Status and Quality of Life and Symptom Burden.
Kaplan–Meier curves for overall survival according to tumor programmed death 1 ligand 1 (PD-L1) expression of 1% or higher and of less than
1% are shown in Panels A and B, respectively. Symbols indicate censored observations. Hazard ratios (and 95% confidence intervals) were
computed with the use of a Cox proportional-hazards model. Panel C shows the results of multivariable analyses of adjusted mean changes
from baseline in patient-reported outcomes at weeks 9 and 15, stratified according to treatment group, for 129 patients with questionnaire
responses. Least-squares mean estimates were based on analyses of covariance of changes in scores from baseline with adjustment for treat-
ment group, visit, status with respect to previous cetuximab use, and baseline score. Physical, role, and social functioning were assessed by
means of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-
C30), and pain, sensory problems, and social-contact problems were assessed by means of the EORTC head-and-neck–specific module
(QLQ-H&N35). All scales range from 0 to 100 and were scored such that higher values indicated better functioning or lower symptom burden.
A clinically meaningful score change was regarded as one of 10 points (dashed lines) or more.21,22 I bars indicate 95% confidence intervals.

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 Nivolumab for Recurrent Carcinoma of Head and Neck

Table 3. Treatment-Related Adverse Events Occurring in at Least 5% of the Patients in Either Group.

Event Nivolumab (N = 236) Standard Therapy (N = 111)

Any Grade Grade 3 or 4 Any Grade Grade 3 or 4

number of patients (percent)

Any event 139 (58.9)* 31 (13.1) 86 (77.5)† 39 (35.1)
Fatigue 33 (14.0) 5 (2.1) 19 (17.1) 3 (2.7)
Nausea 20 (8.5) 0 23 (20.7) 1 (0.9)
Rash 18 (7.6) 0 5 (4.5) 1 (0.9)
Decreased appetite 17 (7.2) 0 8 (7.2) 0
Pruritus 17 (7.2) 0 0 0
Diarrhea 16 (6.8) 0 15 (13.5) 2 (1.8)
Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5)
Asthenia 10 (4.2) 1 (0.4) 16 (14.4) 2 (1.8)
Vomiting 8 (3.4) 0 8 (7.2) 0
Dry skin 7 (3.0) 0 10 (9.0) 0
Stomatitis 5 (2.1) 1 (0.4) 10 (9.0) 3 (2.7)
Weight loss 4 (1.7) 0 6 (5.4) 0
Mucosal inflammation 3 (1.3) 0 14 (12.6) 2 (1.8)
Peripheral neuropathy 1 (0.4) 0 7 (6.3) 0
Alopecia 0 0 14 (12.6) 3 (2.7)
Neutropenia 0 0 9 (8.1) 8 (7.2)

* Data include one patient with a grade 5 event of hypercalcemia and one patient with grade 3 pneumonitis who subse-
quently died of a grade 5 pulmonary embolism.
† Data include one patient with a grade 5 event of lung infection.

Patient-Reported Outcomes measured by the EQ-5D-3L questionnaire, are

Patient-reported quality-of-life measures were provided in Table S9 in the Supplementary Ap-
similar at baseline among patients randomly as- pendix.
signed to the nivolumab group and those as-
signed to the standard-therapy group (Table S7 Discussion
in the Supplementary Appendix). Analyses were
limited to data collected through week 15 owing Among patients with recurrent squamous-cell
to a low number of responses to the question- carcinoma of the head and neck who had dis-
naires in the standard-therapy group after that ease progression after platinum-based chemo-
time point (Table S8 in the Supplementary Ap- therapy, treatment with nivolumab resulted in
pendix). Patients in the standard-therapy group significantly longer survival than treatment with
reported clinically meaningful worsening of phys- standard therapy. Patients who were treated with
ical, role, and social functioning (as assessed by nivolumab had stability in several measures of
means of the QLQ-C30), as well as of pain, quality of life, whereas the patients who received
sensory problems, and social-contact problems standard therapy had declines in these measures.
(as assessed by means of the QLQ-H&N35). Con- Our exploratory biomarker analysis indicated
versely, among patients treated with nivolumab, that patients who were treated with nivolumab
these measures remained nearly stable or showed appeared to have longer overall survival than
slight improvements. P values showed significant those treated with standard therapy, regardless of
between-group differences at both week 9 and tumor PD-L1 expression or p16 status. Although
week 15 for most comparisons (Fig. 2C). Addi- we observed preliminary evidence that patients
tional patient-reported outcome data, including with a tumor PD-L1 expression level of 1% or
health problems and evaluations of health as more or p16-positive tumors (or both) may have

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 The n e w e ng l a n d j o u r na l of m e dic i n e

a greater magnitude of effect from nivolumab tients with a treatment-refractory cancer that
therapy than those whose PD-L1 level was less otherwise has serious adverse effects on quality
than 1% or who had p16-negative tumors, the of life as it leads to death.
interactions were not significant and were not Supported by Bristol-Myers Squibb.
Disclosure forms provided by authors are available with the
corrected for multiple comparisons. The response full text of this article at NEJM.org.
data from this trial are consistent with those We thank the patients and their families; the study teams in-
from a previous phase 1b trial of anti–PD-1 volved in the trial; the staff of Ono Pharmaceutical, Osaka,
Japan; the staff of Dako North America for collaborative devel-
therapy.24,25 opment of the automated programmed death 1 ligand immuno-
In conclusion, nivolumab prolonged survival, histochemical assay; Ludovic Astier for serving as the Check-
as compared with standard therapy, among pa- Mate 141 protocol manager; Naveed Imshad, M.S., and Karthik
Darbha, M.S., for statistical programming; Kim Cocks, Ph.D.,
tients with platinum-refractory squamous-cell Fiona Taylor, M.Biochem., and Michael DeRosa, M.A., for infer-
carcinoma of the head and neck. Nivolumab was ential patient-reported outcome analyses; and Michelle Daniels,
associated with fewer toxic effects of grade 3 or M.D., of inScience Communications, Springer Healthcare, and
Daniel Hutta, Ph.D., of Chrysalis Medical Communications, for
4 than standard therapy (13.1% vs. 35.1%) and medical writing and editorial assistance (funded by Bristol-Myers
with maintenance of quality of life among pa- Squibb) with an earlier version of the manuscript.

Appendix
The authors’ full names and academic degrees are as follows: Robert L. Ferris, M.D., Ph.D., George Blumenschein, Jr., M.D., Jerome
Fayette, M.D., Ph.D., Joel Guigay, M.D., A. Dimitrios Colevas, M.D., Lisa Licitra, M.D., Kevin Harrington, Ph.D., F.R.C.P., F.R.C.R.,
Stefan Kasper, M.D., Everett E. Vokes, M.D., Caroline Even, M.D., Francis Worden, M.D., Nabil F. Saba, M.D., Lara C. Iglesias Docampo,
M.D., Robert Haddad, M.D., Tamara Rordorf, M.D., Naomi Kiyota, M.D., Ph.D., Makoto Tahara, M.D., Ph.D., Manish Monga, M.D., Mark
Lynch, Ph.D., William J. Geese, Ph.D., Justin Kopit, Ph.D., James W. Shaw, Pharm.D., Ph.D., M.P.H., and Maura L. Gillison, M.D., Ph.D.
The authors’ affiliations are as follows: the University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh (R.L.F.); the
Department of Thoracic–Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston (G.B.); Centre
Leon Berard, Lyon (J.F.), Centre Antoine Lacassagne, Nice (J.G.), and Institut Gustave Roussy, Villejuif (C.E.) — all in France; Stanford
Cancer Institute, Stanford, CA (A.D.C.); Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan
(L.L.); Institute of Cancer Research–Royal Marsden National Institute for Health Research Biomedical Research Centre, London (K.H.);
University Hospital Essen, Essen, Germany (S.K.); University of Chicago, Chicago (E.E.V.); University of Michigan, Ann Arbor (F.W.);
Winship Cancer Institute of Emory University, Atlanta (N.F.S.); Hospital Universitario 12 de Octubre, Madrid (L.C.I.D.); Dana–Farber
Cancer Institute, Boston (R.H.); Universitätsspital Zurich, Zurich, Switzerland (T.R.); Kobe University Hospital, Kobe (N.K.), and Na-
tional Cancer Center Hospital East, Kashiwa (M.T.) — both in Japan; Bristol-Myers Squibb, Princeton, NJ (M.M., M.L., W.J.G., J.K.,
J.W.S.); and Ohio State University, Columbus (M.L.G.).

References
1. Ferlay J, Soerjomataram I, Dikshit R, 6. Machiels JP, Haddad RI, Fayette J, et al. PD-L1 expression in head and neck can-
et al. Cancer incidence and mortality Afatinib versus methotrexate as second- cer. Cancer Res 2016;​76:​1031-43.
worldwide: sources, methods and major line treatment in patients with recurrent 12. Brahmer J, Reckamp KL, Baas P, et al.
patterns in GLOBOCAN 2012. Int J Can- or metastatic squamous-cell carcinoma of Nivolumab versus docetaxel in advanced
cer 2015;​136(5):​E359-86. the head and neck progressing on or af- squamous-cell non–small-cell lung cancer.
2. Pignon JP, le Maître A, Maillard E, ter platinum-based therapy (LUX-Head & N Engl J Med 2015;​373:​123-35.
Bourhis J. Meta-analysis of chemotherapy Neck 1): an open-label, randomised phase 13. Borghaei H, Paz-Ares L, Horn L, et al.
in head and neck cancer (MACH-NC): an 3 trial. Lancet Oncol 2015;​16:​583-94. Nivolumab versus docetaxel in advanced
update on 93 randomised trials and 7. Ferris RL. Immunology and immuno- nonsquamous non–small-cell lung cancer.
17,346 patients. Radiother Oncol 2009;​92:​ therapy of head and neck cancer. J Clin N Engl J Med 2015;​373:​1627-39.
4-14. Oncol 2015;​33:​3293-304. 14. Eisenhauer EA, Therasse P, Bogaerts J,
3. Bernier J, Domenge C, Ozsahin M, et 8. Topalian SL, Drake CG, Pardoll DM. et al. New response evaluation criteria in
al. Postoperative irradiation with or with- Immune checkpoint blockade: a common solid tumours: revised RECIST guideline
out concomitant chemotherapy for locally denominator approach to cancer therapy. (version 1.1). Eur J Cancer 2009;​45:​228-47.
advanced head and neck cancer. N Engl J Cancer Cell 2015;​27:​450-61. 15. Jordan RC, Lingen MW, Perez-Ordonez
Med 2004;​350:​1945-52. 9. Li J, Jie HB, Lei Y, et al. PD-1/SHP-2 B, et al. Validation of methods for oropha-
4. Cooper JS, Pajak TF, Forastiere AA, et inhibits Tc1/Th1 phenotypic responses and ryngeal cancer HPV status determination
al. Postoperative concurrent radiotherapy the activation of T cells in the tumor micro- in US cooperative group trials. Am J Surg
and chemotherapy for high-risk squamous- environment. Cancer Res 2015;​75:​508-18. Pathol 2012;​36:​945-54.
cell carcinoma of the head and neck. 10. Badoual C, Hans S, Merillon N, et al. 16. Castellsagué X, Alemany L, Quer M,
N Engl J Med 2004;​350:​1937-44. PD-1-expressing tumor-infiltrating T cells et al. HPV involvement in head and neck
5. Saloura V, Cohen EE, Licitra L, et al. are a favorable prognostic biomarker in cancers: comprehensive assessment of bio-
An open-label single-arm, phase II trial of HPV-associated head and neck cancer. markers in 3680 patients. J Natl Cancer
zalutumumab, a human monoclonal anti- Cancer Res 2013;​73:​128-38. Inst 2016 January 28 (Epub ahead of print).
EGFR antibody, in patients with platinum- 11. Concha-Benavente F, Srivastava RM, 17. Cogswell JP, Goldberg SM, Gupta AK,
refractory squamous cell carcinoma of Trivedi S, et al. Identification of the cell- Jure-Kunkel M, Wang XT, Wiggington JM.
the head and neck. Cancer Chemother intrinsic and -extrinsic pathways down- Cancer immunotherapy by disrupting
Pharmacol 2014;​73:​1227-39. stream of EGFR and IFNγ that induce PD-1/PD-L1 signaling. FreePatentsOnline

1866 n engl j med 375;19 nejm.org  November 10, 2016

The New England Journal of Medicine

Downloaded from nejm.org on August 22, 2018. For personal use only. No other uses without permission.
Copyright © 2016 Massachusetts Medical Society. All rights reserved.
 Nivolumab for Recurrent Carcinoma of Head and Neck

.com. November 21, 2013 (http://www​ Pater J. Interpreting the significance of zumab for treatment of recurrent or meta-
.freepatentsonline​.com/​20130309250​.pdf). changes in health-related quality-of-life static squamous cell carcinoma of the
18. O’Brien PC, Fleming TR. A multiple scores. J Clin Oncol 1998;​16:​139-44. head and neck (KEYNOTE-012): an open-
testing procedure for clinical trials. Bio- 22. Bottomley A, Tridello G, Coens C, et al. label, multicentre, phase 1b trial. Lancet
metrics 1979;​35:​549-56. An international phase 3 trial in head and Oncol 2016;​17:​956-65.
19. Klein JP, Moeschberger ML. Survival neck cancer: quality of life and symptom 25. Mehra R, Seiwert TY, Mahipal A, et al.
analysis: techniques for censored and trun- results: EORTC 24954 on behalf of the Efficacy and safety of pembrolizumab in
cated data. New York:​Springer-Verlag, EORTC Head and Neck and the EORTC recurrent/metastatic head and neck squa-
1997. Radiation Oncology Group. Cancer 2014;​ mous cell carcinoma (R/M HNSCC): pooled
20. Pickard AS, Neary MP, Cella D. Esti- 120:​390-8. analyses after long-term follow-up in
mation of minimally important differ- 23. Allison PD. Survival analysis using SAS: KEYNOTE-012. Presented at the Ameri-
ences in EQ-5D utility and VAS scores in a practical guide. Cary, NC:​SAS Institute, can Society of Clinical Oncology Annual
cancer. Health Qual Life Outcomes 2007;​ 1995. Meeting, Chicago, June 3–7, 2016. ab-
5:​70. 24. Seiwert TY, Burtness B, Mehra R, et al. stract.
21. Osoba D, Rodrigues G, Myles J, Zee B, Safety and clinical activity of pembroli- Copyright © 2016 Massachusetts Medical Society.

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