Nivolumab for Recurrent Squamous-Cell

Carcinoma of the Head and Neck

BACKGROUND
Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum
chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti
programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.

METHODS
In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent
squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after
platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight)
every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The
primary end point was overall survival. Additional end points included progressionfree 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 percentage 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 functioning 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.)
Squamous-cell carcinoma of the head and neck is a major cause of cancer-associated illness and death,
with more than 600,000 cases diagnosed annually worldwide.1 Most patients present with
locoregionally advanced disease, and more than 50% have recurrence within 3 years.2-4 Patients with
squamouscell carcinoma of the head and neck who have cancer progression within 6 months after
platinum- based chemotherapy administered in the context of primary or recurrent disease have a
median survival of 6 months or less.5 No therapeutic options prolong survival among these patients.5,6

The recurrence and metastasis of squamouscell carcinoma of the head and neck are facilitated by
immune evasion,7 which is mediated in part by expression of the programmed death ligands (PD-L1
and PD-L2) of the T-cell–suppressive immune- checkpoint receptor programmed death 1 (PD-1).8-11
Nivolumab, a fully human IgG4 anti– PD-1 monoclonal antibody, has shown antitumor efficacy in
multiple tumor types.12,13 We designed a randomized trial to investigate whether overall survival
would be longer with nivolumab therapy than with standard therapy, among patients with platinum-
refractory squamous-cell carcinoma of the head and neck.

Methods
Patients
Eligible patients had histologically confirmed, recurrent squamous-cell carcinoma of the head and neck
(including metastatic disease) of the oral cavity, pharynx, or larynx that was not amenable to curative
treatment; tumor progression or recurrence within 6 months after the last dose of platinum containing
chemotherapy administered as adjuvant therapy or in the context of primary or recurrent disease; an age
of at least 18 years; an Eastern Cooperative Oncology Group performance-status score of 0 or 1 (on a
scale from 0 to 5, with higher numbers indicating greater disability); adequate bone marrow, hepatic,
and renal function; and measurable disease according to Response Evaluation Criteria in Solid Tumors
(RECIST), version 1.1.14 Major exclusion criteria were active brain metastases, autoimmune disease,
or systemic immunosuppression; known human immunodeficiency virus or hepatitis B or C
virusinfection; and previous therapy targeting T-cell costimulating or immune checkpoint pathways.

Trial Design and Treatments

Patients were randomly assigned in a 2:1 ratio to receive intravenous nivolumab (Opdivo, Bristol-
Myers Squibb) or a standard, single-agent therapy of the investigator’s choice, with stratification
according to receipt of previous cetuximab therapy (yes or no). Nivolumab was administered at a dose
of 3 mg per kilogram of body weight every 2 weeks. Standard therapy consisted of weekly intravenous
administration of methotrexate at a dose of 40 to 60 mg per square meter of bodysurface area, docetaxel
at a dose of 30 to 40 mg per square meter, or cetuximab at a dose of 250 mg per square meter after a
loading dose of 400 mg per square meter.
End Points and Assessments
The primary end point was overall survival, which was defined as the time from randomization to the
date of death from any cause. Secondary end points were progression-free survival (time from
randomization to the date of disease progression or death) and the rate of objective response according
to RECIST, version 1.1. Additional prespecified end points included the time to response; associations
between PD-L1 level and human papillomavirus (HPV) status and overall survival, progression-free
survival, and response rate; safety; and quality-of-life assessments.

Tumor response was assessed by investigators according to RECIST, version 1.1, every 6 weeks
beginning at week 9. Patients were treated until an unacceptable level of drug-related toxic effects
occurred or until disease progression. However, nivolumab treatment could be continued beyond
disease progression, as assessed clinically or radiographically, if the investigator assessed that it was
providing clinical benefit. Patients were followed for overall survival every 3 months until death, loss
to follow-up, or withdrawal of consent.

At each treatment visit and for 100 days after receipt of the last dose, acute toxic effects were evaluated
according to the Common Terminology Criteria for Adverse Events, version 4.0. Adverse events with
potential immunologic causes were classified as select adverse events. The criteria for a dose delay or
the discontinuation of nivolumab or standard therapy because of treatment-related adverse events were
specified in the protocol, available with the full text of this article at NEJM.org. Dose modifications
were not permitted for nivolumab but were specified for methotrexate, docetaxel, and cetuximab on the
basis of the type and grade of the toxic effect.

Patient-reported outcomes, including symptoms and health-related quality of life, were exploratory end
points and were evaluated with the use of the European Organization for Research and Treatment of
Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-C30) and the head-and-neck
specific module (QLQ-H&N35). Scores for these modules range from 0 to 100, with higher scores
indicating better functioning or well-being or higher symptom burden, although scales measuring
symptom burden were reversescored to facilitate presentation. The proportion of patients reporting
health problems was assessed with the use of the three-level version of the European Quality of Life 5
Dimensions (EQ-5D-3L) questionnaire. Patients also completed the EQ-5D-3L visual-analo use scale,
for which scores range from 0 to 100 and higher scores indicate better perceived health status.

Biomarker Analysis
Fresh or archived pretreatment tumor specimens were obtained after the last therapy and before trial
entry from 90.6% of the patients. For patients with oropharyngeal cancer, tumor HPV status, assessed
by means of p16 immunohistochemical testing, was required to be documented by local or central
analysis and was defined as positive if diffuse staining was present in at least 70% of the tumor cells.15
Immunochemical testing for p16 was not performed for nonoropharyngeal cancers because of the low
prevalence of HPV-positive tumors and poor specificity for HPV status at these anatomical sites.16
Tumor PD-L1 membrane expression was evaluated centrally by means of immunohistochemical testing
(Dako North America) with the use of a rabbit antihuman PD-L1 antibody (clone28–8, Epitomics) and
was scored at prespecified expression levels, including levels of 1% or more, 5% or more, and 10% or
more in a minimum of 100 tumor cells that could be evaluated.17

Trial Oversight
This trial was registered with the National Cancer Institute and was approved by the institutional review
board at each participating institution. Written informed consent was obtained from all the patients
before enrollment. The trial was designed by the academic authors in collaboration with the sponsor
(Bristol-Myers Squibb). The first and last authors attest to the accuracy and completeness of the data
and analyses and vouch for adherence of the trial to the protocol. Medicalwriting support, funded by
the sponsor, was provided by inScience Communications and Chrysalis Medical Communications.

Statistical Analysis
We calculated the required number of events assuming one planned interim analysis of overall survival
after 70% of the events occurred and stopping boundaries that were based on an O’Brien Fleming alpha-
spending function.18 We calculated that a sample of 360 patients and a total of 278 deaths would be
required to ensure that a two-sided test procedure with one interim analysis, a 2:1 ratio for
randomization, and an experiment-wide false positive rate of 5% would provide the trial with 90%
power to detect a hazard ratio of 0.667 for the comparison of nivolumab with standard therapy.

Analyses of baseline characteristics and efficacy followed the intention-to-treat principle. Analyses of
dosing and safety were restricted to patients who received at least one dose of therapy. The distributions
of overall survival and progression- free survival were estimated by the Kaplan– Meier method and
compared by means of log-rank tests stratified according to previous receipt of cetuximab (yes or no).
Cox proportional-hazards models (stratified according to status with respect to previous receipt of
cetuximab) were used to estimate hazard ratios and compute confidence intervals. A generalization of
the Brookmeyer and Crowley method was used to compute confidence intervals for the median survival
times, and the Borgan and Liest.l method was used to compute confidence intervals for survival at
specific time points.19

A confidence interval of 97.73% was used for the hazard ratio for death in the analysis of overall
survival to reflect the significance level for the interim comparison of overall survival. All other
confidence intervals were calculated at the 95% level. The stratum-adjusted Cochran–Mantel– Haenszel
method was used to compute the odds ratio and the associated confidence interval for tumor response.
The protocol specified that if nivolumab was shown to be superior to standard therapy with respect to
overall survival, then progression- free survival and response rate would each be tested, hierarchically
at an alpha level of 5%, to ensure a false positive rate of no more than 5% for testing all three end points.

Prespecified analyses were performed to assess the consistency of treatment effect on the end points in
a range of baseline subgroups, including subgroups defined according to PD-L1 expression status and
p16 status. A post hoc analysis of treatment effect in PD-L1 expression subgroups (≥1% vs. <1%)
according to p16 status (positive vs. negative) was also performed. In addition, tests for interactions
between treatment and PD-L1 expression level (prespecified) and between treatment and p16 status
(post hoc) were performed. All these analyses were exploratory and descriptive: no adjustments for
multiple comparisons were made, nor was the trial powered to detect interactions.

For patient reported outcomes, a clinically meaningful change in score was regarded as 10 points for
the EORTC QLQ C30 and QLQ-H&N35 and as 7 points for the visual-analogue scale of the EQ-5D-
3L questionnaire.20 22 Analysis of covariance was used to compare the mean score changes between
groups, with a separate analysis being performed for each patient-reported outcome. Each analysis was
adjusted for treatment, visit, status with respect to previous cetuximab use, and the baseline value of the
patient-reported outcome. The data cutoff point for the analyses of overall survival, progression-free
survival, and safety was December 18, 2015, which was the date of the planned interim analysis. Data
on rate of response were based on a database lock on May 5, 2016. At the interim analysis, the
independent data monitoring committee confirmed that the P value for the comparison of overall
survival was below the formal statistical boundary for significance of 0.0227.

Results
Patients and Treatment
From June 2014 through August 2015, we randomly assigned 240 patients to receive nivolumab and
121 to receive standard therapy (Fig. S1 in the Supplementary Appendix, available at NEJM.org).
Previous treatment included radiotherapy in 91.4% of the patients and two or more lines of systemic
therapy in 54.5%. The treatment groups were balanced with respect to most demographic and clinical
characteristics (Table 1), although the standard-therapy group included higher percentages of patients
65 years of age or older and of patients who had never smoked. Tumor p16 status was reported, per
protocol, for 178 patients (113 patients in the nivolumab group and 65 in the standard-therapy group),
and 26.2% of the patients in the nivolumab group and 24.0% in the standard-therapy group had positive
p16 status.
Of 361 patients who underwent randomization, 347 (96.1%) received one or more doses of assigned
therapy (236 patients in the nivolumab group and 111 in the standard-therapy group). Standard therapies
that were administered included methotrexate (in 46 patients), docetaxel (in 52), and cetuximab (in 13).
The median duration of treatment was 1.9 months in each group. Data on dose delays and reductions
according to treatment group are provided in Table S1 in the Supplementary Appendix. At the time of
analysis, 41 of 236 patients (17.4%) were still receiving nivolumab and 3 of 111 (2.7%) were still
receiving standard therapy.

Efficacy
Among 361 patients who underwent randomization, 133 deaths (55.4% of patients) occurred in the
nivolumab group and 85 deaths (70.2% of patients) occurred in the standard-therapy group. The median
duration of follow-up for overall survival was 5.1 months (range, 0 to 16.8).

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 standard-therapy group. Overall survival was
significantly longer with nivolumab than with standard therapy, and nivolumabtreated patients had a
risk of death that was 30% 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 separation of the Kaplan–Meier
curves for overall survival is indicative of nonproportionality, and the hazard ratio should be thought of
as an average over time.23 The estimated rate of overall survival at 1 year among patients treated with
nivolumab (36.0%; 95% CI, 28.5 to 43.4) was more than double the rate with standard therapy (16.6%;
95% CI, 8.6 to 26.8).

Nivolumab was associated with longer median overall survival than all the options for standard
therapy: methotrexate (median, 4.6 months hazard ratio for death, 0.64; 95% CI, 0.43 to 0.96),
docetaxel (median, 5.8 months; hazard ratio, 0.82; 95% CI, 0.53 to 1.28), and cetuximab (median,
4.1 months; hazard ratio, 0.47; 95% CI, 0.22 to 1.01). Across prespecified demographic and
clinical subgroups, the estimate of the hazard ratio for death in the analysis of overall survival
with nivolumab versus standard therapy was less than 1 (Fig. 1C, and Fig. S2 in the
Supplementary Appendix).

No significant difference between groups was observed with regard to the rate of progression- free
survival (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P = 0.32). The
crossing of the Kaplan–Meier curves is indicative of nonproportionality. The median progression-free
survival was 2.0 months (95% CI, 1.9 to 2.1) in the nivolumab group versus 2.3 months (95% CI, 1.9
to 3.1) in the standardtherapy group (Fig. 1B). However, a late separation in the Kaplan–Meier curves
was observed, and the estimated rates of progression-free survival at 6 months were 19.7% (95% CI,
14.6 to 25.4) in the nivolumab group and 9.9% (95% CI, 5.0 to 6.9) in the standard-therapy group.

The response rate among nivolumab-treated patients was 13.3% (95% CI, 9.3 to 18.3), including 6
complete responses and 26 partial responses. In the standard-therapy group, the response rate was 5.8%
(95% CI, 2.4 to 11.6), including 1 complete response and 6 partial responses. The median time to
response was 2.1 months with nivolumab versus 2.0 months with standard therapy. Tumor reductions
were more durable with nivolumab, as indicated by the tumor-burden plots over time for patients who
had either a partial response or a complete response (Fig. S3 in the Supplementary Appendix).

PD-L1 Expression and p16 Status

A prespecified, exploratory analysis was performed to evaluate the consistency of the treatment effect
in subgroups defined according to tumor PD-L1 expression level (≥1% vs. <1%) (Table 2). Tumor PD
L1 expression status could be evaluated in 260 of 361 patients (72.0%) (Table S2 in the Supplementary
Appendix). Among the patients who could be evaluated, 57.3% had a PD-L1 expression level of 1% or
more.

In the analysis of overall survival in the subgroup of patients with a PD-L1 expression level of 1% or
more, the hazard ratio for death among patients treated with nivolumab versus standard therapy was
0.55 (95% CI, 0.36 to 0.83) (Fig. 2A), whereas in the subgroup of patients with a PDL1 expression level
of less than 1%, the hazard ratio was 0.89 (95% CI, 0.54 to 1.45; P = 0.17 for interaction) (Fig. 2B).
The estimates of the hazard ratio for death in the analysis of overall survival in the subgroups of patients
with PD-L1 expression levels of 5% or more and of 10% or more were similar to those among patients
with PD-L1 expression levels of 1% or more (Table 2).

In our post hoc exploratory analysis involving the 178 patients for whom tumor p16 status was reported,
the median overall survival appeared to be longer with nivolumab than with standard therapy regardless
of p16 status (Table 2). Among patients with p16-positive tumors, the median overall survival was 9.1
months in the nivolumab group versus 4.4 months in the standard-therapy group (hazard ratio for death,
0.56; 95% CI, 0.32 to 0.99); among patients with p16-negative tumors, the median overall survival was
7.5 versus 5.8 months (hazard ratio, 0.73; 95% CI, 0.42 to 1.25; P = 0.55 for interaction) (Figs. S4 and
S5 in the Supplementary Appendix).

We further explored the effect of nivolumab versus standard therapy on overall survival in subgroups
defined according to both PD-L1 expression (≥1% vs. <1%) and tumor p16 status (positive vs. negative)
(Table 2). The estimated hazard ratios for death in the analysis of overall survival with nivolumab versus
standard therapy were less than 1 in all four subgroups. Results of the exploratory analysis of the
treatment effect on response rates in the subgroups defined according to tumor PD-L1 level and p16
status are provided in Table S3 in the Supplementary Appendix.

Safety
The most common treatment-related adverse events are shown in Table 3 (see also Tables S4, S5, and
S6 in the Supplementary Appendix). The rates of treatment-related adverse events of any grade were
similar in the two groups, but fewer events of grade 3 or 4 were reported in the nivolumab group than
in the standard-therapy group (occurring in 13.1% vs. 35.1% of patients). In the nivolumab group, the
most frequent adverse events of any grade were fatigue, nausea, rash, decreased appetite, and pruritus.
Among the select adverse events, gastrointestinal events were less common with nivolumab than with
standard therapy (occurring in 6.8% vs. 14.4% of the patients; primarily diarrhea), whereas adverse
events of the skin were more common with nivolumab (in 15.7% vs. 12.6%; primarily rash
and pruritus), as were adverse events of the endocine system (in 7.6% vs. 0.9%; primarily
hypothyroidism). Pneumonitis was observed in 2.1% of the patients treated with nivolumab. Two
treatment-related deaths were reported in the nivolumab group (pneumonitis and hypercalcemia in one
patient each), and one patient in the standard-therapy group died from a treatment- related lung
infection.

Patient-Reported Outcomes
Patient-reported quality-of-life measures were similar at baseline among patients randomly assigned to
the nivolumab group and those assigned to the standard-therapy group (Table S7 in the Supplementary
Appendix). Analyses were limited to data collected through week 15 owing to a low number of
responses to the questionnaires in the standard-therapy group after that time point (Table S8 in the
Supplementary Appendix). Patients in the standard-therapy group reported clinically meaningful
worsening of physical, role, and social functioning (as assessed by means of the QLQ C30), as well as
of pain, sensory problems, and social-contact problems (as assessed by means of the QLQ-H&N35).
Conversely, among patients treated with nivolumab, these measures remained nearly stable or showed
slight improvements. P values showed significant betweengroup differences at both week 9 and week
15 for most comparisons (Fig. 2C). Additional patientreported outcome data, including health problems
and evaluations of health as measured by the EQ-5D-3L questionnaire, are provided in Table S9 in the
Supplementary Appendix.

Discussion
Among patients with recurrent squamous-cell carcinoma of the head and neck who had disease
progression after platinum-based chemotherapy, treatment with nivolumab resulted in significantly
longer survival than treatment with standard therapy. Patients who were treated with nivolumab had
stability in several measures of quality of life, whereas the patients who received standard therapy had
declines in these measures.

Our exploratory biomarker analysis indicated that patients who were treated with nivolumab appeared
to have longer overall survival than those treated with standard therapy, regardless of tumor PD-L1
expression or p16 status. Although we observed preliminary evidence that patients with a tumor PD L1
expression level of 1% or more or p16-positive tumors (or both) may have a greater magnitude of effect
from nivolumab therapy than those whose PD-L1 level was less than 1% or who had p16 negative
tumors, the interactions were not significant and were not corrected for multiple comparisons. The
response data from this trial are consistent with those from a previous phase 1b trial of anti–PD-1
therapy.24,25

In conclusion, nivolumab prolonged survival, as compared with standard therapy, among patients with
platinum-refractory squamous-cell carcinoma of the head and neck. Nivolumab was associated with
fewer toxic effects of grade 3 or 4 than standard therapy (13.1% vs. 35.1%) and with maintenance of
quality of life among patients with a treatment-refractory cancer that otherwise has serious adverse
effects on quality of life as it leads to death.

Supported by Bristol-Myers Squibb. Disclosure forms provided by authors are available with the full
text of this article at NEJM.org. We thank the patients and their families; the study teams involved in
the trial; the staff of Ono Pharmaceutical, Osaka, Japan; the staff of Dako North America for
collaborative development of the automated programmed death 1 ligand immunohistochemical assay;
Ludovic Astier for serving as the Check- Mate 141 protocol manager; Naveed Imshad, M.S., and
Karthik Darbha, M.S., for statistical programming; Kim Cocks, Ph.D., Fiona Taylor, M.Biochem., and
Michael DeRosa, M.A., for inferential patient-reported outcome analyses; and Michelle Daniels, M.D.,
of inScience Communications, Springer Healthcare, and Daniel Hutta, Ph.D., of Chrysalis Medical
Communications, for medical writing and editorial assistance (funded by Bristol-Myers Squibb) with
an earlier version of the manuscript.

Figure 1 (facing page). Overall Survival, Progressionfree 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 proportional- hazards model, and the P values
were from a stratified log-rank test. Panel C shows a forest plot of unstratified hazard ratios for death
in the analysis of the treatment effect according to demographic and clinical subgroups at baseline.
Hazard ratios were not calculated for subgroups that included fewer than 20patients 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).

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
treatment 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 interval