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
Abstract
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 progression-free 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.
Address reprint requests to Dr. Gillison at the Ohio State University Comprehensive Cancer Center, Ohio State University, 420 W.
12th Ave., Rm. 690, Columbus, OH 43210, or at maura.gillison@osumc.edu.
Drs. Ferris and Gillison contributed equally to this article.
The authors’ full names, academic degrees, and affiliations are listed in the Appendix.
Disclosure forms provided by authors are available with the full text of this article at NEJM.org.
HHS Public Access
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N Engl J Med
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Published in final edited form as:
N Engl J Med
. 2016 November 10; 375(19): 1856–1867. doi:10.1056/NEJMoa1602252.
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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 squamous-cell 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 squamous-cell 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 virus infection; 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 body-surface area, docetaxel at a dose of 30 to 40 mg per square meter, or
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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 pre-specified 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 reverse-scored
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-analogue 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
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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 (clone 28–8,
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. Medical-writing 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 Liestøl 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.
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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.
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