Role of Immunotherapy in Head and

Neck Cancer
Diane C. Ling, MD,* Chris J. Bakkenist, PhD,* Robert L. Ferris, MD, PhD,†,‡,§
and David A. Clump, MD, PhD*,†

Immune system dysfunction plays a role in both the development and progression of head and
neck squamous cell carcinoma (HNSCC), highlighting the potential role for immunotherapy to
improve outcomes in this disease. The application of anti-PD-1 therapies for recurrent or
metastatic HNSCC has found promising results. This has led to interest in combining
immunotherapy with radiation therapy (RT) for the primary treatment of locally advanced
HNSCC. RT with concurrent cetuximab is an option for patients who are medically unfit to
receive cisplatin, and ongoing trials seek to determine to role of cetuximab-RT in treatment de-
intensification for HPV+ oropharyngeal HNSCC. Other ongoing trials are evaluating the use of
anti-PD-1 and anti-PD-L1 therapies in the upfront setting for newly diagnosed high-risk, locally
advanced HNSCC, in an effort to improve disease control. Finally, early phase I studies are
now investigating the use of anti-PD-1 therapy in conjunction with RT for refractory recurrent or
metastatic HNSCC.
Semin Radiat Oncol 28:12-16 C 2017 Published by Elsevier Inc.

Background worse survival outcomes.1 Cetuximab, a mouse-human chi-

meric IgG1 monoclonal antibody targeted against EGFR, has

I mmune system dysfunction appears to play a role in both

the development and progression of head and neck cancer.
Immunosurveillance is mediated largely by cytotoxic T-
lymphocytes, and the presence of tumor cell antigens triggers
a natural T-cell response, which could potentially target and
kill tumor cells. Disruption of this T-cell response, whether by
immunosuppression or various tumor immune evasion mech-
anisms, may play an integral role in the progression of head
and neck squamous cell carcinoma (HNSCC).
Many human tumor cells express high levels of growth factor
receptors, which can be targeted with tumor antigen-specific
monoclonal antibodies. Epidermal growth factor receptor
(EGFR) overexpression can be identified in 80%-90% of
HNSCC and is associated with tumor cell proliferation and
*Department of Radiation Oncology, University of Pittsburgh Medical Center,
Pittsburgh, PA.
†
Division of Head and Neck Surgery, Department of Otolaryngology,
University of Pittsburgh Medical Center, Pittsburgh, PA.
‡
§
Department of Immunology, University of Pittsburgh, Pittsburgh, PA.
Cancer Immunology Program, University of Pittsburgh Cancer Institute,
Pittsburgh, PA.
Conflict of interest: none.
Address reprint requests to David A. Clump, MD, PhD, 5230 Centre Avenue
Pittsburgh, PA 15232. E-mail: clumpda2@upmc.edu
been increasingly utilized for neck squamous cell carcinoma in
recent years.2 Antitumor antigen monoclonal antibodies such as
cetuximab stimulate an antigen-specific immune response via 2
main mechanisms. First, tumor lysis can be directly induced via
antibody-dependent cellular cytotoxicity, mediated by NK cells
and likely monocytes and neutrophils as well.3 Secondly, tumor
antigen-specific monoclonal antibodies interact with FcγRs on
antigen-presenting cells to promote the opsonization of tumor
for phagocytosis and antigen processing. This, in turn, elicits a
tumor antigen-specific cytotoxic CD8þ T-cell response.4
Blockade of immune checkpoints, which regulate the dura-
tion and extent of immune responses, is another approach by
which antitumor T-cell immunity may be activated. Immune
checkpoints serve to modulate physiologic immune responses in
order to prevent excessive inflammatory responses or the
development of autoimmunity. For instance, interaction
between programmed death receptor-1 (PD-1) and its ligands
PD-L1 and PD-L2 has been shown to downregulate T-cell
activation in both mouse models and human systems, and has
been implicated in tumor immune evasion in HNSCC.5 PD-1 is
a member of the CD28 family of T-cell costimulatory receptors
that is expressed on activated T-cells, B-cells, and myeloid cells.
Overexpression of PD-L1 by tumor cells, or immune
infiltration by PD-1þ T-lymphocytes, can result in immune

12 http://dx.doi.org/10.1016/j.semradonc.2017.08.009
1053-4296/& 2017 Published by Elsevier Inc.
Immunotherapy in Head and Neck Cancer
evasion. PD-L1 is overexpressed in 450%-60% of HNSCC.6 It
has been reported that among head and neck cancer patients,
there is higher expression of immune checkpoint inhibitors
such as CTLA-4 and PD-1 in intratumoral regulatory T-cells
compared to peripheral blood samples.7 Others have reported
that tumor infiltration by PD-1þ CD8þ/CD4þ lymphocytes is
paradoxically more common in human papilloma virus (HPV)-
positive than HPV-negative tumors, and is a favorable prog-
nostic biomarker in HPV-positive disease.8 This finding may
reflect a previous immune response against tumor that might
be reactivated by PD-1/PD-L1 blockade. Together, these
findings point to the PDL-1 pathway as promising potential
target in the treatment of HNSCC.
Clinical Application of
Immunotherapy for Recurrent or
Metastatic HNSCC
Patients with recurrent or metastatic HNSCC who fail plati-
num-based chemotherapy have a dismal survival of o6
months,9 and historically, no therapy has been able to prolong
survival in this subset of patients. Recently, the application of
immunotherapy for this population has found promising
results. In a single-arm phase II trial of cetuximab monotherapy
in 103 patients with recurrent or metastatic HNSCC
after failure of platinum-based chemotherapy, the objective
response rate was 12.6% with a median survival of
5.9 months.10 There was no relationship between the level of
baseline EGFR expression and response to cetuximab. The
EXTREME randomized trial found that the addition of
cetuximab to platinum-fluorouracil chemotherapy signifi-
cantly prolonged median overall survival from 7.4 months to
10.1 months, when given as first-line therapy for recurrent or
metastatic HNSCC.11 This trial established a new standard of
care, although survival remains poor.
The anti-PD-1 monoclonal antibodies nivolumab and
pembrolizumab have been shown to improve progression-
free survival and overall survival in advanced melanoma,
nonsmall cell lung cancer, and urothelial cancer, compared
to standard systemic therapy.12-17 Utilization of these agents
has also been investigated in HNSCC. The recently published
KEYNOTE-012 trial was the first to demonstrate the efficacy of
immune checkpoint inhibition in HNSCC. This was a phase
1b trial aimed at evaluating the clinical efficacy and safety of
pembrolizumab for advanced solid tumors, including recur-
rent or metastatic HNSCC. In the initial cohort of 60 HNSCC
patients, all of whom had at least 1% PD-L1 expression in
tumor and stromal cells, patients received pembrolizumab at
10 mg/kg IV once every 2 weeks. The objective response rate
was 21% by clinician review, the median duration progression-
free survival was 2 months, and overall survival was 13
months.18 Grade 3 drug-related adverse events occurred in
17% of patients.
In a subsequent expansion cohort, 132 additional patients
with HNSCC were enrolled regardless of PD-L1 expression
status, and a less frequent dosing schedule of 200 mg IV once
13
every 3 weeks was used.19 The overall response rate was 18%
by central imaging review, at the cost of grade 3 drug-related
adverse events in 9% of patients. The 6-month progression-
free survival was 23%. The degree of PD-L1 expression was
found to be strongly predictive of best overall response,
progression-free survival, and overall survival. The overall
response rate was 22% for patients who were PD-L1 positive
(≥1%), compared to 4% for patients who were PD-L1 negative
(o1%) (p ¼ 0.021). In addition, patients with HPV-associated
disease had a higher overall response rate of 32%, compared to
14% for those with HPV-negative disease. Median overall
survival was 8 months, which approaches the 10-month
overall survival achieved with first-line cisplatin, 5-FU, and
cetuximab for recurrent or metastatic HNSCC,11 despite the
fact that the majority of patients in this trial had already
received 2 or more lines of prior therapy.
Although cross-trial comparisons should be interpreted
with caution, these promising survival data suggest that future
studies investigating pembrolizumab as a first-line therapy are
indicated. Based on the early results of KEYNOTE-012, the
FDA granted accelerated approval of pembrolizumab for
recurrent and metastatic HNSCC in August 2016. The utility
of pembrolizumab for recurrent or metastatic HNSCC is to be
confirmed in a randomized phase III study, KEYNOTE-040,
which assigns patients to pembrolizumab or standard single-
agent methotrexate, docetaxel, or cetuximab. This study is
ongoing, but closed to recruitment,20 with results eagerly
awaited.
The recently published Checkmate-141 randomized phase
III trial assigned 361 patients with recurrent HNSCC who had
progressed within 6 months after platinum-based chemo-
therapy to nivolumab at 3 mg/kg once every 2 weeks, or
standard second-line single-agent systemic therapy consisting
of either docetaxel, methotrexate, or cetuximab, as per inves-
tigator choice.21 This study demonstrated that compared to
standard therapy, nivolumab significantly improved overall
survival from a median of 5.1 to 7.5 months (HR ¼ 0.70, CI:
0.51–0.96), with the 1-year overall survival rate nearly doubled
for those treated with nivolumab (16.6% vs 36.0%). The
response rate was 13.3% for nivolumab, compared to 5.8% for
standard therapy. Exploratory biomarker analysis showed that
the overall survival benefit remained, regardless of PD-L1
expression or p16 status, although those with PD-L1 positive
or HPV-associated disease benefited the most. Among patients
receiving nivolumab, overall response rates were 17% vs
12.3% if PD-L1 positive (≥1%) vs PD-L1 negative (o1%),
and 15.9% vs 8.0% if p16 positive vs p16 negative.
With the exception of Grades 1-2 rash, all treatment-related
toxicities were less frequent in the nivolumab arm. Grades 3-4
toxicities occurred in 13.1% of nivolumab-treated patients,
compared to 35.1% of those receiving standard therapy, with
the most common nivolumab-related adverse events consist-
ing of fatigue, nausea, rash, decreased appetite, and pruritus.
This trial also included a patient-reported quality-of-life
analysis, wherein patients receiving standard therapy reported
worsening quality-of-life in multiple domains, while these
measures were stable or slightly improved in those receiving
nivolumab. This is a significant finding considering the
14
quality-of-life implications of otherwise living with persistent,
treatment-refractory disease for which few other therapeutic
options are available.
Combining Radiation Therapy
and Immunotherapy
Cetuximab þ RT
In the landmark randomized phase III trial published by
Bonner et al, the combination of radiation therapy (RT) with
cetuximab was shown to offer superior locoregional control
and overall survival compared to radiation alone for locore-
gionally advanced HNSCC, without increasing the incidence
of acute mucositis, hematologic toxicity, or gastrointestinal
toxicity.22,23 Unplanned subgroup analysis at 5 years sug-
gested that oropharyngeal primary site, AJCC stage T1-3,
stage N1-3, and age o65 were associated with increased
benefit from the addition of cetuximab. As a result of this
study, cetuximab has been increasingly used for the treatment
of patients who are medically unfit to receive cisplatin.
Because high EGFR expression is associated with poor
response to chemoradiation (CRT),24 and preclinical evidence
showed that EGFR inhibitors sensitize tumors to cisplatin or
RT,25,26 it was hypothesized that the addition of cetuximab to
concurrent CRT for locoregionally advanced HNSCC may
improve outcomes. A pilot phase II trial of cetuximab in
combination with CRT showed promising rates of 3-year overall
survival and locoregional control at 76% and 56%, respec-
tively.27 This led to the phase III RTOG 0522 trial on concurrent
accelerated RT plus cisplatin with or without cetuximab, which
unfortunately found that adding cetuximab to cisplatin-based
CRT did not improve outcome. Patients on the cetuximab-CRT
arm experienced more frequent interruptions in RT, similar
cisplatin delivery, and more acute toxicities such as grades 3-4
radiation mucositis, rash, fatigue, and hypokalemia, although
not more late toxicity. Thus, the authors concluded that this
combination should not be prescribed routinely.28
Thus far, there have been no published phase III random-
ized trials comparing concurrent cetuximab-RT to standard of
care cisplatin-RT. An Italian phase II randomized study of
concurrent weekly cisplatin vs concurrent cetuximab with RT
was discontinued early due to slow accrual, after the enroll-
ment of 70 patients.29 In contrast to the study by Bonner et al,
this study unexpectedly showed that cetuximab was associated
with greater acute toxicity and a higher rate of RT discontinua-
tion (13% vs 0%). The grade 5 toxicity rate for cetuximab was
12.5%, compared to 0% in Bonner et al’s trial. Two-year local
control rates were 53% and 80% for the cetuximab and
cisplatin arms, respectively, although this difference was non-
significant, highlighting the lack of adequate statistical power.
Nevertheless, efforts to investigate the combination of
cetuximab-RT as a possible alternative treatment strategy
continue. As it is now well-established that HPV positivity
confers an excellent prognosis for patients with oropharyngeal
HNSCC, there is strong interest in using treatment de-
intensification strategies to potentially decrease the morbidity
D.C. Ling et al.
of treatment toxicity associated with concurrent cisplatin and
RT. The ongoing RTOG 1016 is a randomized trial that seeks
to determine whether treatment for patients with HPVþ
oropharyngeal HNSCC can be de-intensified with cetuxi-
mab-RT, vs standard cisplatin-RT. Thus far, more than 800
patients have been enrolled. The UK De-ESCALaTE trial and
the Australian TROG 12.01 are two other ongoing phase III
trials assigning patients to cisplatin-RT vs cetuximab-RT, both
with endpoints focused on treatment toxicity.30,31
Improving on Cetuximab-RT
Although EGFR overexpression is present in the majority of
HNSCC, the efficacy of cetuximab is limited. There is
increasing evidence that cetuximab induces not only tumor
antigen-specific cytotoxic T lymphocyte responses, but also
immunosuppressive regulatory T-cells that express CTLA-4,
thus limiting the efficacy of cytotoxic T-lymphocytes.32 Block-
ade of CTLA-4 could prevent activation of this inhibitory
pathway and potentially enhance the efficacy of cetuximab.
UPCI 12-084 was a phase I dose-escalation trial that integrated
ipilimumab, an anti-CTLA-4 monoclonal antibody, into a
standard regimen of cetuximab plus RT in patients with
previously untreated, locally advanced HNSCC. Eligible
patients had stage III-IVB SCC of the larynx or pharynx.
Ipilimumab was delivered at weeks 5, 8, 11, and 14.
Preliminary results were presented at ESMO 2016.33 Among
18 enrolled patients, 6 patients were in cohort 1 and received
ipilimumab at 3 mg/kg. Two of these 6 patients developed
grade 3 immune-related dermatologic dose-limiting toxicities
unique to ipilimumab, consisting of perforating folliculitis and
autoimmune dermatitis. No patients in cohort 1 (n ¼ 12), who
received ipilimumab 1 mg/kg, experienced any dose-limiting
toxicities. Therefore, the recommended phase II dose for
ipilimumab is 1 mg/kg.
Ongoing Clinical Trials
RTOG 3504
Based on RTOG 0522, 40% of patients with intermediate or
high-risk locoregionally advanced HNSCC develop progres-
sive disease at 3 years following completion of definitive
CRT.28 This has led to interest in investigating whether the
addition of novel immunotherapeutic agents to standard
definitive CRT may improve disease control, especially con-
sidering the early success reported for anti-PD-1 targeted
agents such as pembrolizumab and nivolumab in the recurrent
or metastatic setting.
It has been shown in a prior phase I study that nivolumab
can be safely combined with high-dose cisplatin for NSCLC.34
RTOG 3504 is an ongoing trial for newly diagnosed, locore-
gionally advanced HNSCC, seeking to integrate nivolumab
with standard definitive concurrent CRT. The phase I, dose-
finding portion of the trial includes 3 randomized arms:
nivolumab (240 mg q 14 days × 10, starting on day 14) with
weekly cisplatin (40 mg/m2 × 7)-based CRT, nivolumab
(240 mg on day -14 followed by 360 mg q 21 days × 7) with
Immunotherapy in Head and Neck Cancer
high-dose cisplatin (100 mg/m2 IV on days 1, 22, and 43)-
based CRT, or nivolumab (240 mg q 14 days × 10) with
weekly cetuximab and RT. Patients who are age 470 years, or
with Zubrod score of 2, ≥Grade 3 neuropathy, ≥Grade
2 hearing loss, or CrCl o 50 ml/min, will be enrolled onto a
fourth, nonrandomized arm, which consists of nivolumab
240 mg q 14 days for 10 cycles, along with concurrent IMRT.
All treatment arms will receive adjuvant nivolumab consisting
of 480 mg q 28 days × 7, for a total of 1 year of nivolumab
therapy.
NRG-HN003
NRG-HN003 is a phase I trial that seeks to determine the
optimal dosing of pembrolizumab when given in combination
with cisplatin and RT in the adjuvant setting for high-risk, stage
III–IV HNSCC. The primary outcome is dose-limiting toxic-
ities up to 4 weeks posttreatment. Secondary outcome
measures include change in expression of peripheral immune
inflammatory biomarkers, levels of PDL-1, and disease control
and survival outcomes at 1 year. Inclusion criteria include
pathologically confirmed diagnosis of stage III–IV HNSCC
involving the oral cavity (excluding lips), oropharynx (p16
negative), larynx, or hypopharynx, status post definitive gross
total surgical resection, with at least one high-risk pathologic
feature, defined as extracapsular nodal extension or positive
margins. This trial is currently on hold nationally for scheduled
interim monitoring.35
JAVELIN
Avelumab is a human IgG1 monoclonal antibody against
PD-L1. Unlike anti-PD-1 antibodies, which target T-cells, thus
affecting both the PD-L1 and PD-L2 pathways, avelumab
selectively targets PD-L1 on tumor cells. Therefore, avelumab
may be associated with a lower risk of immune-related adverse
events, as the PD-L2/PD-1 pathway is left intact to promote
peripheral self-tolerance.36 The JAVELIN trial is a phase III
randomized, double-blind, international multicenter trial aim-
ing to demonstrate that the combination of avelumab with
standard of care CRT offers superior progression-free survival
compared to CRT alone for the definitive treatment for
patients with high-risk, locally advanced HNSCC. The primary
endpoint is progression-free survival per modified RECIST
criteria.
Regeneron
The R2810-ONC-1423 trial is a phase I, multicenter dose-
escalation study investigating the use of REGN2810, a novel
anti-PD-1 monoclonal antibody, in the treatment of advanced
solid tumors with no alternative standard of care therapeutic
options. In the dose-escalation phase, safety will be assessed in
3 þ 3 dose-escalation cohorts with REGN2810 used as
monotherapy, in combination with RT, combination with
cyclophosphamide, and combination with RT þ cyclophos-
phamide. After the dose-escalation phase, 26 expansion
cohorts categorized based on primary site and histology
will be explored. Patients in the HNSCC expansion cohort
15
(cohort 3) must have recurrent or metastatic disease refractory
to at least first-line therapy, for which palliative radiation
therapy is indicated. Primary tumor sites may include oral
cavity, oropharynx, larynx, or hypopharynx. In the expansion
cohorts, REGN2810 can be given as monotherapy, or in
combination with targeted radiation, low-dose cyclophospha-
mide, both radiation and cyclophosphamide with or
without GM-CSF, or with various combinations of carboplatin,
docetaxel, paclitaxel, or pemetrexed. The primary objective is
to determine the safety, tolerability, and dose-limiting
toxicities of REGN2810. For selected expansion cohorts,
including the HNSCC cohort, a co-primary objective is to
determine the efficacy of REGHN2810 by measuring overall
response rate.
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