ASCO

Immunotherapy and Biomarker Testing in

Recurrent and Metastatic Head and Neck
special articles
Cancers: ASCO Guideline
Emrullah Yilmaz, MD, PhD1; Nofisat Ismaila, MD2; Julie E. Bauman, MPH, MD3; Raetasha Dabney, MD4; Gregory Gan, MD, PhD5;
Richard Jordan, DDS, PhD6; Marnie Kaufman7; Kedar Kirtane, MD8; Sean Matthew McBride, MD, MPH9; Matthew O. Old, MD10;
Lisa Rooper, MD11; Nabil F. Saba, MD12; Siddharth Sheth, DO, MPH13; Rathan M. Subramaniam, MD, PhD, MPH, MBA14,15;
Trisha Michel Wise-Draper, MD, PhD16; Deborah Wong, MD, PhD17; and Loren K. Mell, MD18
abstract

PURPOSE To provide evidence-based recommendations for practicing physicians and other health care pro-
viders on immunotherapy and biomarker testing for head and neck cancers.
METHODS ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radi-
ology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews,
meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational
studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and
locoregional control. Expert Panel members used available evidence and informal consensus to develop
evidence-based guideline recommendations.
RESULTS The literature search identified 28 relevant studies to inform the evidence base for this guideline.
RECOMMENDATIONS When possible, evidence-based recommendations were developed to address biomarker
testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-
refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal
carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence.
Additional information is available at www.asco.org/head-neck-cancer-guidelines.
J Clin Oncol 41:1132-1146. © 2022 by American Society of Clinical Oncology

INTRODUCTION treatment with or without chemotherapy.2-4 With the

Head and neck squamous cell carcinoma (HNSCC) advent of ICIs in cancer treatment, biomarkers such as
ASSOCIATED programmed death ligand-1 (PD-L1) and tumor mu-
CONTENT accounts for approximately 4% of all cancers in the
United States, with an estimated 66,470 new diagnoses tational burden (TMB) are gaining importance in
Appendix
selecting treatment options.5,6 Recently, clinical trials
Data Supplement and 15,050 deaths in 2022.1 HNSCC frequently arises
have begun using PD-L1 scoring systems for stratifi-
Author affiliations from the oral cavity, oropharynx, larynx, hypopharynx, or
cation and patient selection.4,7-9
and support nasopharynx, and more rarely from salivary glands or
information (if paranasal sinuses. Patients with HNSCC commonly The purpose of this guideline is to provide recom-
applicable) appear mendations to health care practitioners and patients
at the end of this
present with locoregionally advanced disease and often
article. receive multimodality treatments, including surgery, regarding immunotherapy and biomarker testing for
Accepted on October radiation therapy, and/or chemotherapy. Although this diverse and complex group of diseases.
27, 2022 and cisplatin is the most commonly used chemotherapy, the
published at GUIDELINE QUESTIONS
choice of chemotherapy depends on several factors,
ascopubs.org/journal/
jco on December 15, including prior use of platinum-based chemotherapy This clinical practice guideline addresses six over-
2022: DOI https://doi. and primary tumor site. arching clinical questions: (1) what biomarkers are
org/10.1200/JCO.22.
Recurrent or metastatic HNSCC is typically treated recommended for selecting HNSCC patients for anti–
02328
with systemic therapy involving chemotherapy and/or PD-1 ICI therapy? (2) What is the optimal first-line
Evidence Based
Medicine Committee immunotherapy. Immune-checkpoint inhibitors (ICIs) treatment regimen for recurrent or metastatic HNSCC
approval: were first approved in the treatment of patients with patients based on PD-L1 status? (3) What is the effect
October 12, 2022 platinum-refractory HNSCC and later in first-line of immunotherapy compared to other systemic

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 Immunotherapy and Biomarker Testing in Head and Neck Cancers

THE BOTTOM LINE

Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline
Guideline Question
What is the role of immunotherapy with checkpoint inhibitors and biomarker testing in recurrent and metastatic head and neck
cancers?
Target Population
Patients with head and neck cancers.
Target Audience
Medical oncologists, radiation oncologists, surgical oncologists, clinical oncologists, radiologists, nurses, pathologists,
oncology pharmacists, caregivers, and patients.
Methods
An Expert Panel was convened to develop clinical practice guideline recommendations based on a systematic review of the
medical literature.
Recommendations
Recommendation 1.1. PD-L1 immunohistochemistry testing should be performed in patients with recurrent or metastatic
HNSCC (Type: Evidence based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong).
Recommendation 1.2. PD-L1 combined positive score (CPS) $ 1 should be interpreted as positive and correlates with a
clinical benefit to programmed cell death protein-1 (PD-1) inhibitors (Type: Evidence based, benefits outweigh harms;
Evidence quality: High; Strength of recommendation: Strong).
Recommendation 1.3. TMB testing may be performed in patients with recurrent or metastatic HNSCC when CPS is not
available or in patients with rare tumors (Type: Evidence based, benefits outweigh harms; Evidence quality: High; Strength of
recommendation: Strong).
Recommendation 1.4. TMB $ 10 should be interpreted as high and correlates with a clinical benefit to PD-1 inhibitors (Type:
Evidence based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong).
Recommendation 2.1. Pembrolizumab monotherapy or pembrolizumab, platinum, and fluorouracil should be offered as first-
line treatment for patients with recurrent or metastatic HNSCC with a CPS $ 1 (Type: Evidence based, benefits outweigh
harms; Evidence quality: High; Strength of recommendation: Strong).
Recommendation 2.2. Pembrolizumab, platinum, and fluorouracil may be offered as first-line treatment for patients with
recurrent or metastatic HNSCC with a CPS , 1 (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate;
Strength of recommendation: Strong).
Recommendation 3.1. Pembrolizumab or nivolumab should be offered to patients with platinum-refractory recurrent or
metastatic HNSCC, regardless of CPS status (Type: Evidence based, benefits outweigh harms; Evidence quality: High;
Strength of recommendation: Strong).
Recommendation 4.1. Toripalimab, camrelizumab, or tislelizumab, with gemcitabine and cisplatin, should be offered as first-
line treatment for patients with recurrent or metastatic nasopharyngeal cancer (Type: Evidence based, benefits outweigh
harms; Evidence quality: High; Strength of recommendation: Strong).
Qualifying statement: Pembrolizumab or nivolumab may be offered with gemcitabine and cisplatin if the ICIs in Recom-
mendation 4.1 are unavailable.
Recommendation 4.2. PD-1 inhibitors may be offered to patients with recurrent or metastatic nasopharyngeal cancer who
have progressed following platinum-based therapy (Type: Informal consensus, benefits outweigh harms; Evidence quality:
Low; Strength of recommendation: Weak).
Recommendation 5.1. For patients with oligometastatic HNSCC, radiation therapy is safe to give concurrently with immu-
notherapy for the purpose of palliation or local control, but should not be given to enhance response to immunotherapy outside
of a clinical trial (Type: Evidence based, no net benefit; Evidence quality: Moderate; Strength of recommendation: Weak).
Recommendation 6.1. Pembrolizumab may be offered to patients with TMB-high recurrent or metastatic rare head and neck
cancers (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Weak).
Recommendation 6.2. Pembrolizumab may be offered to patients with PD-L1–positive recurrent or metastatic salivary gland
cancer (Type: Evidence based, benefits outweigh harms; Evidence quality: Moderate; Strength of recommendation: Weak).
(continued on following page)

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 Yilmaz et al

THE BOTTOM LINE (CONTINUED)

Additional Resources
Definitions for the quality of the evidence and strength of recommendation ratings are available in Appendix Table A1 (online
only). More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is
available at www.asco.org/head-neck-cancer-guidelines. The Methodology Manual (available at www.asco.org/guideline-
methodology) provides additional information about the methods used to develop this guideline. Patient information is
available at www.cancer.net.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients
should have the opportunity to participate.

treatments in platinum-refractory recurrent or metastatic
HNSCC? (4) What is the role of immunotherapy for patients
with recurrent or metastatic nasopharyngeal carcinoma
(NPC)? (5) What is the effect of radiation therapy in
combination with anti–PD-(L)1 immunotherapy compared
to immunotherapy alone for the treatment of locoregionally
recurrent or oligometastatic HNSCC? (6) What is the role of
immunotherapy for rare head and neck cancers?
METHODS
Guideline Development Process
This systematic review-based guideline was developed by a
multidisciplinary Expert Panel, which included a patient
representative and an ASCO guidelines staff member with
health research methodology expertise (Appendix Table A2,
online only). Three full panel meetings were held and
members were asked to provide ongoing input on the quality
and assessment of the evidence, generation of recom-
mendations, draft content, and to review and approve drafts
during the entire development of the guideline. ASCO staff
met routinely with the Expert Panel co-chairs and corre-
sponded with the panel via e-mail to coordinate the process
to completion. The guideline recommendations were sent for
an open comment period of 2 weeks allowing the public to
review and comment on the recommendations after sub-
mitting a confidentiality agreement. These comments were
taken into consideration when finalizing the recommenda-
tions. Members of the Expert Panel were responsible for
reviewing and approving the penultimate version of the
guideline, which was then submitted to the Journal of Clinical
Oncology for editorial review and consideration for publi-
cation. All ASCO guidelines are ultimately reviewed and
approved by the Expert Panel and the ASCO Evidence Based
Medicine Committee before publication. All funding for the
administration of the project was provided by ASCO.
The recommendations were developed through a sys-
tematic review of evidence identified via online searches of
PubMed (January 2000-February 2022) and Cochrane
Library (January 2000-February 2022) of phase III ran-
domized clinical trials (RCTs), selected observational
studies, and clinical experience. Articles were selected for
inclusion in the systematic review based on the following
criteria:
1. Population: patients with HNSCC of the oral cavity,
oropharynx, hypopharynx, or larynx, recurrent or
metastatic disease, NPC, or rare head and neck
cancers.
2. Interventions: immunotherapy, biomarker tests.
3. Comparisons: chemotherapy.
4. Outcomes: survival, response, and locoregional
control.
Articles were excluded from the systematic review if they
were (1) meeting abstracts not subsequently published in
peer-reviewed journals; (2) editorials, commentaries, let-
ters, news articles, case reports, and narrative reviews; and
(3) published in a non-English language. The guideline
recommendations are crafted, in part, using the Guidelines
Into Decision Support methodology and accompanying
BRIDGE-Wiz software.10 In addition, a guideline imple-
mentability review was conducted. Based on the imple-
mentability review, revisions were made to the draft to
clarify recommended actions for clinical practice. Ratings
for type and strength of the recommendation, and evidence
quality are provided with each recommendation. The
quality of the evidence for each outcome was assessed
using the Cochrane Risk of Bias tool and elements of the
GRADE quality assessment and recommendations devel-
opment process.11,12 GRADE quality assessment labels (ie,
high, moderate, low, and very low) were assigned for each
outcome by the project methodologist in collaboration with
the Expert Panel co-chairs and reviewed by the full Expert
Panel.
The ASCO Expert Panel and guidelines staff work with co-
chairs to keep abreast of any substantive updates to the
guideline. Based on formal review of the emerging litera-
ture, ASCO will determine the need to update. The ASCO
Guidelines Methodology Manual (available at
www.asco.org/guideline-methodology) provides additional
information about the guideline update process. This is the
most recent information as of the publication date.

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Immunotherapy and Biomarker Testing in Head and Neck Cancers
Guideline Disclaimer
The Clinical Practice Guidelines and other guidance
published herein are provided by the American Society of
Clinical Oncology, Inc (ASCO) to assist providers in clinical
decision making. The information herein should not be
relied upon as being complete or accurate, nor should it be
considered as inclusive of all proper treatments or methods
of care or as a statement of the standard of care. With the
rapid development of scientific knowledge, new evidence
may emerge between the time information is developed
and when it is published or read. The information is not
continually updated and may not reflect the most recent
evidence. The information addresses only the topics spe-
cifically identified therein and is not applicable to other
interventions, diseases, or stages of diseases. This infor-
mation does not mandate any particular course of medical
care. Further, the information is not intended to substitute
for the independent professional judgment of the treating
provider, as the information does not account for individual
variation among patients. Recommendations specify the
level of confidence that the recommendation reflects the
net effect of a given course of action. The use of words like
“must,” “must not,” “should,” and “should not” indicates
that a course of action is recommended or not recom-
mended for either most or many patients, but there is
latitude for the treating physician to select other courses of
action in individual cases. In all cases, the selected course
of action should be considered by the treating provider in
the context of treating the individual patient. Use of the
information is voluntary. ASCO does not endorse third party
drugs, devices, services, or therapies used to diagnose,
treat, monitor, manage, or alleviate health conditions. Any
use of a brand or trade name is for identification purposes
only. ASCO provides this information on an “as is” basis and
makes no warranty, express or implied, regarding the in-
formation. ASCO specifically disclaims any warranties of
merchantability or fitness for a particular use or purpose.
ASCO assumes no responsibility for any injury or damage to
persons or property arising out of or related to any use of this
information, or for any errors or omissions.
Guideline and Conflicts of Interest
The Expert Panel was assembled in accordance with
ASCO’s Conflict of Interest Policy Implementation for
Clinical Practice Guidelines (“Policy,” found at https://
www.asco.org/guideline-methodology). All members of
the expert panel completed ASCO’s disclosure form, which
requires disclosure of financial and other interests, in-
cluding relationships with commercial entities that are
reasonably likely to experience direct regulatory or com-
mercial impact as a result of promulgation of the guideline.
Categories for disclosure include employment; leadership;
stock or other ownership; honoraria, consulting or advisory
role; speaker’s bureau; research funding; patents, royalties,
other intellectual property; expert testimony; travel, ac-
commodations, expenses; and other relationships. In
Journal of Clinical Oncology
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accordance with the Policy, the majority of the members of
the Expert Panel did not disclose any relationships con-
stituting a conflict under the Policy.
RESULTS
Characteristics of Studies Identified in the
Literature Search
A total of 1,167 citations after duplicate removal were
identified in the literature search. After applying the eligi-
bility criteria, 28 references remained, forming the evi-
dentiary basis for the guideline recommendations.2-4,13-37
The identified trials were published between 2016 and
2022, and included one systematic review,13 eight phase III
RCTs2,14-18 with one study having eight publications3,19-25
and another having two publications,4,26 seven phase II
RCTs,27-33 one phase Ib,34 and three cohort studies.35-37
These studies focused on biomarker testing, first-line
treatment regimens based on PD-L1 scores, immuno-
therapy in platinum-refractory recurrent or metastatic
HNSCC, immunotherapy in NPC, and radiation therapy in
combination with immunotherapy for treatment of local
recurrence. Primary outcomes reported include overall
survival (OS), progression-free survival (PFS), objective
response rate, and overall response rate (ORR).
Details on the study characteristics are included in the Data
Supplement (online only). The systematic review flow di-
agram is shown in the Data Supplement.
Evidence Quality Assessment
The quality of evidence was assessed for each outcome of
interest. This rating includes factors such as study design,
consistency of results, directness of evidence, precision,
publication bias, and magnitude of effect, assessed by one
reviewer. Evidence quality ratings for the outcomes of in-
terest are provided in the Data Supplement. Refer to Ap-
pendix Table A1, for definitions for the quality of the
evidence, and the Methodology Manual for more
information.
RECOMMENDATIONS
Clinical Question 1
What biomarkers are recommended for selecting HNSCC
patients for anti–PD-1 ICI therapy?
Recommendation 1.1. PD-L1 immunohistochemistry test-
ing should be performed in patients with recurrent or
metastatic HNSCC (Type: Evidence based, benefits out-
weigh harms; Evidence quality: High; Strength of recom-
mendation: Strong).
Recommendation 1.2. PD-L1 CPS $ 1 should be inter-
preted as positive and correlates with a clinical benefit to
PD-1 inhibitors (Type: Evidence based, benefits outweigh
harms; Evidence quality: High; Strength of recommenda-
tion: Strong).
1135
 Yilmaz et al
Literature review and clinical interpretation. Expression of
PD-L1 as determined by immunohistochemistry correlates
with clinical response to ICI among multiple tumor types,
including HNSCC. Pathologists can assess PD-L1 positivity
using either CPS, defined as the number of tumor cells,
lymphocytes, and macrophages that express PD-L1 di-
vided by the total number of tumor cells and multiplied by
100, or tumor proportion score (TPS), defined as the
percentage of tumor cells that express PD-L1, at various
cutoff points. Meta-analysis of 11 clinical trials indicated
that PD-L1–positive head and neck cancer treated with ICI
had improved OS at 6 and 12 months compared to tumors
that did not express PD-L1, regardless of either CPS or TPS
scoring or numerical cutoffs used for defining PD-L1
positivity.13 Nevertheless, CPS has emerged as the supe-
rior marker. In post hoc receiver operating characteristic
curve analysis of KEYNOTE-040 data, CPS and TPS
appeared to show equivalent performance at a cutoff
of $ 50; however, CPS was more sensitive than TPS at a
lower cutoff of $ 1.14 As such, CPS scoring is preferred for
maximum sensitivity, although a TPS score
indicating $ 1% positivity is correlated with benefit to ICI
and may be interpreted as positive if available. A lower
threshold for defining CPS positivity of $ 1 is also preferred.
In KEYNOTE-048 and subgroup analysis, CPS cutoffs of
both $ 20 and $ 1 were associated with superior OS,4,26
leading to adoption of the lower cutoff to maximize sensi-
tivity. Some additional variables, including intratumoral
heterogeneity, temporal heterogeneity, size of sample
stained, and type of sample stained, may impact assess-
ment of PD-L1 expression, although variable use of CPS
and TPS and divergent definitions of positivity makes it
challenging to draw definitive conclusions from existing
literature. The relationship between human papillomavirus
(HPV) and P16 status and response to ICI also is not yet
fully established, although a pooled analysis of six clinical
trials recently did not demonstrate a link between HPV
(P16) positivity and PD-L1 expression.38
Recommendation 1.3. TMB testing may be performed in
patients with recurrent or metastatic HNSCC when CPS is
not available or in patients with rare tumors (Type: Evidence
based, benefits outweigh harms; Evidence quality: High;
Strength of recommendation: Strong).
Recommendation 1.4. TMB $ 10 should be interpreted as
high and correlates with a clinical benefit to PD-1 inhibitors
(Type: Evidence based, benefits outweigh harms; Evidence
quality: High; benefits outweighs harms; Strength of rec-
ommendation: Strong).
Literature review and clinical interpretation. TMB was
shown to correlate with clinical response to ICI among
multiple tumor types including HNSCC. Although no ran-
domized trials have been performed in HNSCC, using
patients sequenced on MSK-IMPACT, 138 HNSCC patients
were identified who had nonsynonymous somatic TMB
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performed and received PD-1 inhibitors. The total number
of somatic nonsynonymous mutations was normalized to
the total number of megabases sequenced. Those with
increased TMB were found to have significantly improved
OS. The top 20th percentile for HNSCC for TMB was above
10.3 MB, which significantly correlated with improved OS
with PD-1 inhibitors.39 Therefore, HNSCC patients with
TMB of $ 10 MB should be considered high, and testing
may be performed in patients for whom CPS is not avail-
able, as those with high TMB may benefit from PD-1 in-
hibitors. In addition, retrospective analysis of biomarkers in
192 patients in the KEYNOTE-012 study confirmed an
association between TMB and ICI response and demon-
strated no correlation between TMB and PD-L1.40
Clinical Question 2
What is the optimal first-line treatment regimen for recur-
rent or metastatic HNSCC patients based on PD-L1 status?
Recommendation 2.1. Pembrolizumab monotherapy or
pembrolizumab, platinum, and fluorouracil (5-FU) should
be offered as first-line treatment for patients with recurrent
or metastatic HNSCC with a CPS $ 1 (Type: Evidence
based, benefits outweigh harms; Evidence quality: High;
Strength of recommendation: Strong).
Literature review and clinical interpretation. This recom-
mendation is based on findings from KEYNOTE-048,4
which was a randomized, open-label, phase III clinical
trial comparing the EXTREME regimen consisting of che-
motherapy (platinum, 5-FU) and cetuximab versus pem-
brolizumab monotherapy or pembrolizumab and
chemotherapy in recurrent or metastatic HNSCC. Patients
with a CPS $ 1 had improved OS with pembrolizumab
monotherapy compared to chemotherapy and cetuximab
(hazard ratio [HR], 0.78; 95% CI, 0.64 to 0.96; P 5 .0086).
Median OS was 12.3 months (95% CI, 10.8 to 14.9) in
patients receiving pembrolizumab monotherapy compared
to 10.3 months (95% CI, 9.0 to 11.5) in patients receiving
cetuximab with chemotherapy. However, patients with
CPS $ 20 derived the greatest benefit with pembrolizumab
monotherapy compared to chemotherapy and cetuximab
(HR, 0.61; 95% CI, 0.45 to 0.83; P 5 .0007). Median
OS was 14.9 months (95% CI, 11.6 to 21.5) with
pembrolizumab monotherapy compared to 10.7 months
(95% CI, 8.8 to 12.8) in the cetuximab with chemotherapy
group.
Deciding on the plausibility of chemoimmunotherapy ver-
sus immunotherapy in patients with previously untreated
recurrent or metastatic HNSCC must take into consider-
ation the clinical presentation and urgency for achieving a
response. Chemoimmunotherapy may therefore be a
plausible option even in biomarker-positive disease in case
a rapid reduction in tumor burden is deemed clinically
necessary. Response rates to single-agent pembrolizumab
remain close to 20%, regardless of prior exposure to
therapy or PD-L1 expression,41,42 supporting the
Volume 41, Issue 5
 Immunotherapy and Biomarker Testing in Head and Neck Cancers
chemoimmunotherapy paradigm in situations where early
response is a primary objective.
HPV status may influence response to anti–PD-1 therapy,
with a large meta-analysis reporting greater efficacy of PD-1
inhibitors in smokers and HPV-negative patients.43 How-
ever, current data do not support changing recommen-
dations for the addition or exclusion of anti–PD-1 therapies
in the recurrent and/or metastatic setting with regard to the
HPV status.
Recommendation 2.2. Pembrolizumab, platinum, and 5-FU
may be offered as first-line treatment for patients with re-
current or metastatic HNSCC with a CPS , 1 (Type:
Evidence based, benefits outweigh harms; Evidence quality:
Moderate; Strength of recommendation: Strong).
Literature review and clinical interpretation. Recurrent or
metastatic HNSCC is a heterogeneous disease presenting
many different possible clinical scenarios. Based on the
results of the KEYNOTE-048 phase III trial, the combination
of pembrolizumab, platinum, and 5-FU has been approved
as a therapeutic option for patients with recurrent or
metastatic HNSCC regardless of PD-L1 status or CPS
score.4 Patients in the overall population had prolonged
survival with pembrolizumab and chemotherapy compared
to cetuximab with chemotherapy group (HR, 0.77; 95% CI,
0.70 to 0.99; P 5 .0034). Median OS was 13 months in the
pembrolizumab with chemotherapy group compared to
10.7 months in the cetuximab with chemotherapy group in
the total population regardless of PD-L1 status. Subgroup
analysis was performed by PD-L1 CPS subgroups in
KEYNOTE 048 study.26 Median OS was 11.3 months in the
pembrolizumab with chemotherapy group compared to
10.7 months in the cetuximab with chemotherapy group
(HR, 1.12; 95% CI, 0.76 to 1.94; P 5 .78932). Although a
small number of patients were in the PD-L1 CPS , 1
subgroup (39 and 43 respectively) and the study was not
powered to evaluate efficacy of pembrolizumab with che-
motherapy in this subgroup, cetuximab with chemotherapy
may also be considered for these patients.41,42
Clinical Question 3
What is the effect of immunotherapy compared to other
systemic treatments in platinum-refractory recurrent or
metastatic HNSCC?
Recommendation 3.1. Pembrolizumab or nivolumab
should be offered to patients with platinum-refractory re-
current or metastatic HNSCC, regardless of CPS status
(Type: Evidence based, benefits outweigh harms; Evidence
quality: High; Strength of recommendation: Strong).
Literature review and clinical interpretation. Systemic
therapy with palliative intent is indicated for patients with
platinum-refractory, recurrent or metastatic HNSCC. Two
phase III trials, KEYNOTE-040 and CheckMate 141, eval-
uated anti–PD-1 therapies, pembrolizumab (KEYNOTE-040)
and nivolumab (CheckMate 141), compared to standard-of-
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care single-agent therapy (methotrexate, docetaxel, or
cetuximab).2,3 Both studies enrolled HNSCC patients with
disease progression within 6 months after platinum-based
chemotherapy. A key difference was KEYNOTE-040 ex-
cluded patients with disease progression within 0-3 months.
Major findings from these trials include a statistically sig-
nificant OS benefit (8.4 and 7.5 months, respectively)
compared to the control arm. Additionally, lower rates of
grade 3 and 4 treatment-related adverse events (AEs) were
observed in patients treated with anti–PD-1 therapies
compared to standard of care. Importantly, the OS benefit
was independent of HPV status or PD-L1 expression, which
has been confirmed in a long-term follow up study.21 These
findings supported the US Food and Drug Administration
approval of both pembrolizumab and nivolumab in the
advanced-line setting after progression on or following
platinum-containing therapies, regardless of PD-L1 ex-
pression. Therefore, we recommend single-agent pem-
brolizumab or nivolumab for patients with recurrent or
metastatic HNSCC with disease progression within 6 months
of platinum-based chemotherapy.
The combination of anti–PD-1 inhibitors with other sys-
temic treatments has been investigated in platinum-
refractory disease; however, no combination has become
standard of care to date. The anti–epidermal growth factor
receptor has been one potential target, with data from
multiple single-arm, phase II studies.44-46 A study of
pembrolizumab and cetuximab showed 45% response rate
with a median PFS of 6.5 months and a median OS of
18.4 months in recurrent or metastatic HNSCC.44 This trial
included a high percentage (64%) of patients with
platinum-refractory disease. A study of nivolumab and
cetuximab enrolled patients with recurrent or metastatic
HNSCC with a median PFS of 7.8 months and a median OS
of 14.5 months. In the 12 patients with platinum-refractory
disease, the response rate was 42%.45,46 Additional data
from randomized trials evaluating anti–PD-1 and cetux-
imab combinations in the platinum-refractory, recurrent or
metastatic HNSCC setting are needed prior to incorporation
into standard clinical practice.
The evaluation of an anti–PD-1 inhibitor and cytotoxic T-cell
lymphocyte-4 inhibitor combination in platinum-refractory
HNSCC was conducted in the EAGLE trial.17 Durvalumab
with or without tremelimumab was evaluated versus
standard-of-care therapy.17 There was no significant dif-
ference in OS by treatment arm, indicating the lack of
benefit of adding cytotoxic T-cell lymphocyte-4 inhibition to
this patient population.
Clinical Question 4
What is the role of immunotherapy for patients with re-
current or metastatic NPC?
Recommendation 4.1. Toripalimab, camrelizumab, or
tislelizumab, with gemcitabine and cisplatin, should be
offered as first-line treatment for patients with recurrent or
1137
 Yilmaz et al
metastatic NPC (Type: Evidence based, benefits outweigh
harms; Evidence quality: High; Strength of recommenda-
tion: Strong).
Qualifying statement: Pembrolizumab or nivolumab may be
offered with gemcitabine and cisplatin if the ICIs in Rec-
ommendation 4.1 are unavailable.
Literature review and clinical interpretation. The benefit of
adding anti–PD-1 immunotherapy to gemcitabine-
platinum for recurrent or metastatic NPC as a first-line
treatment has been evaluated. The phase III trial
JUPITER-02 randomized 289 patients 1:1 to gemcitabine
and cisplatin (GC) with either toripalimab, a humanized
IgG4K monoclonal PD-1 antibody, or placebo.15 Patients
with recurrent or metastatic NPC who had not previously
received systemic therapy in the recurrent or metastatic
setting were eligible. Notably, subjects were eligible for
enrollment irrespective of the level of tumor PD-L1 posi-
tivity. Patients received up to six cycles of GC (gemcitabine
1,000 mg/m2 days 1 and 8, cisplatin 80 mg/m2 day 1) with
toripalimab 240 mg or placebo once every 21 days, fol-
lowed by up to 2 years of toripalimab or placebo. The
primary end point was PFS by blinded independent review
committee. Secondary end points were investigator-
assessed PFS, OS, ORR, duration of response (DOR),
disease control rate, and 1- and 2-year PFS and OS rates.
The addition of toripalimab to GC resulted in significantly
improved PFS compared to placebo with GC (11.7 v
8.0 months; HR, 0.52; 95% CI, 0.36 to 0.74). Improved
PFS with toripalimab was seen in both PD-L1–negative
(tumor cell and immune cell PD-L1 immunohistochem-
istry , 1%) and PD-L1–positive (tumor cell or immune cell
PD-L1 immunohistochemistry $ 1%) subgroups. While
median OS had not yet been reached for either arm at the
time of the data cutoff, a 40% reduction in risk of death
was observed in the toripalimab arm compared to the
placebo arm, with a stratified HR for mortality of 0.603
(95% CI, 0.364 to 0.997; P 5 .0462) favoring toripalimab.
While most toxicities were comparable, and the incidence
of AEs leading to discontinuation were similar, for tor-
ipalimab and placebo arms (7.5% v 4.9%), immune-
related AEs were significantly higher in the toripalimab
arm.15
A parallel study, CAPTAIN-1st, was a double-blinded,
placebo-controlled phase III trial evaluating the addition
of camrelizumab, an anti–PD-1 IgG4 monoclonal anti-
body, versus placebo, in combination with GC. The trial
randomly assigned 263 subjects 1:1 to camrelizumab
200 mg IV or placebo plus GC (gemcitabine 1,000 mg/m2
day 1, 8; cisplatin 80 mg/m2 day 1) once every 21 days for
4-6 cycles followed by up to 2 years of camrelizumab or
placebo. Similar to JUPITER-02, eligible subjects had
treatment-naive recurrent or metastatic NPC with any level
of PD-L1 expression. The primary end point was
investigator-assessed PFS. An improvement in median
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PFS (9.7 v 6.9 months; HR, 0.54; 95% CI, 0.39 to 0.76),
with a longer median DOR (9 v 6 months), was seen for the
camrelizumab arm compared to placebo. Median OS had
not been reached at the time of the data cutoff. Given the
strength of the evidence from both JUPITER-02 and
CAPTAIN-1st, where available, toripalimab or camreli-
zumab may be offered in combination with GC for frontline
treatment of recurrent or metastatic NPC, irrespective of
PD-L1 expression levels.16
The RATIONALE-309 trial, presented as an abstract at
ASCO 2022,47 was of similar design to JUPITER-02 and
CAPTAIN-1st. In this trial, 263 subjects with recurrent or
metastatic NPC were randomly assigned 1:1 to six cycles of
GC with either tislelizumab or placebo administered for 4-6
cycles, followed by tislelizumab or placebo once every
3 weeks. In contrast to the aforementioned studies, wherein
up to 2 years of maintenance anti–PD-1 immunotherapy
was administered, treatment with tislelizumab continued
until disease progression, unacceptable toxicity, or subject
withdrawal. Furthermore, crossover to tislelizumab mono-
therapy was allowed for patients allocated to placebo at the
time of independent review committee–assessed disease
progression. With a median follow up of 15.5 months, PFS
was improved in the tislelizumab arm (HR, 0.50; 95% CI,
0.37 to 0.68). Median PFS was 9.6 months (95% CI, 7.6 to
11.7) versus 7.4 months (95% CI, 5.7 to 7.6) in the
tislelizumab versus placebo arm, respectively. This evi-
dence from three different phase III trials of similar size and
design shows improved PFS with the combination of ICI
and GC, with similar effect sizes. Notably, toxicity seems to
be manageable, and the clinical benefit appears to be
independent of tumor PD-L1 status. Further evaluation of
such regimens is needed in Epstein-Barr virus (EBV)–
negative disease.
Given the strength of the evidence from JUPITER-02,
CAPTAIN-1st, and RATIONALE-309, where available,
toripalimab, camrelizumab, or tislelizumab may be offered
in combination with GC for frontline treatment of recurrent
or metastatic NPC, irrespective of PD-L1 expression levels.
Recommendation 4.2. PD-1 inhibitors may be offered to
patients with recurrent or metastatic nasopharyngeal
cancer who have progressed following platinum-based
therapy (Type: Informal consensus, benefits outweigh
harms; Evidence quality: Low; Strength of recommenda-
tion: Weak).
Literature review and clinical interpretation. The benefit of
anti–PD-1 immunotherapy in patients with recurrent or
metastatic NPC who have progressed on frontline platinum-
based chemotherapy has been evaluated in several
studies.18,27,48,49 KEYNOTE-122 randomly assigned 233
patients with recurrent or metastatic NPC who had pro-
gressed on frontline platinum-based chemotherapy 1:1 to
either pembrolizumab 200 mg IV once every 3 weeks up to
35 cycles or investigator’s choice chemotherapy
Volume 41, Issue 5
 Immunotherapy and Biomarker Testing in Head and Neck Cancers
(capecitabine, gemcitabine, or docetaxel). The primary end
point was OS. Secondary end points were PFS, ORR, and
DOR. With a median follow-up of 45 months, median OS
was not statistically different between the two arms:
17.2 months for pembrolizumab versus 15.3 months for
chemotherapy (HR, 0.90; 95% CI, 0.67 to 1.19; P 5 .226).
Median OS for patients with PD-L1 CPS $ 1 was also similar
in the two arms (17.2 months for pembrolizumab v
18.0 months for chemotherapy); however, the incidence of
treatment-related AEs was lower for the pembrolizumab
group compared to the chemotherapy group (61.2% v
87.5%, respectively), as was the incidence of grade 3 to 5
toxicity (10.3% for pembrolizumab v 43.8% for
chemotherapy).18
Two phase II studies of nivolumab for recurrent or metastatic
NPC have been reported.48,49 In NCI-4792, 44 recurrent or
metastatic NPC patients previously treated with platinum-
based chemotherapy received nivolumab 3 mg/kg once
every 2 weeks. Nine objective responses were seen (21%;
one complete and eight partial responses). 1-Year PFS and
OS were 19% and 59%.48 CheckMate-358 was a multi-
cohort study of nivolumab in five virally associated cancers,
including recurrent or metastatic NPC. Twenty-four patients
with nonkeratinizing disease who had received no more than
two prior lines of therapy in the recurrent or metastatic setting
were treated with nivolumab 240 mg IV once every 2 weeks
until progression or unacceptable toxicity. Primary end
points were ORR and safety. At a median follow-up of
26 weeks, ORR was 20.8%; responses were irrespective of
PD-L1 positivity.49
In POLARIS-02, 190 patients with recurrent or metastatic
NPC who had progressed on prior platinum-based che-
motherapy were treated with toripalimab 3 mg/kg once
every 2 weeks until disease progression or unacceptable
toxicity. The primary end point (ORR) was 20.5% (95% CI,
15.0 to 27.0) in the total cohort. Median PFS was
1.9 months (95% CI, 1.8 to 3.5) and median OS was
17.4 months (95% CI, 11.7 to 22.9). For the 92 patients
who had failed at least two lines of prior therapy, ORR was
23.9% (95% CI, 31.1 to 52.1). ORR was similar in PD-L1–
positive (tumor cells . 1) and PD-L1–negative patients
(27.1% and 19.1%, respectively; P 5 .31).27
Although there are no phase III studies showing the ef-
fectiveness of anti–PD-1 immunotherapies in patients with
recurrent metastatic NPC who have progressed on
platinum-based chemotherapy, phase II studies suggest a
clinical benefit with lower toxicity rates when compared to
chemotherapy.48,49
Clinical Question 5
What is the effect of radiation therapy in combination with
anti–PD-(L)1 immunotherapy compared to immunotherapy
alone for the treatment of locoregionally recurrent or oli-
gometastatic HNSCC?
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Recommendation 5.1. For patients with oligometastatic
HNSCC, radiation therapy is safe to give concurrently with
immunotherapy for the purpose of palliation or local control,
but should not be given to enhance response to immu-
notherapy outside of a clinical trial (Type: Evidence based,
no net benefit; Evidence quality: Moderate; Strength of
recommendation: Weak).
Literature review and clinical interpretation. To date, a lone
randomized phase II trial has evaluated the benefit of
adding radiation therapy to anti–PD-(L)1 immunotherapy in
patients with locoregionally recurrent or oligometastatic
HNSCC. McBride et al32 randomly assigned 62 patients
with metastatic HNSCC or WHO grade 1 to 3 NPC—without
restriction according to number of metastases or HPV or
EBV status—to either nivolumab alone or nivolumab with
stereotactic body radiation therapy (SBRT). SBRT was
delivered as 27 Gy in three fractions, was initiated between
the first and second doses of nivolumab, and was directed
at a single metastatic lesion. The primary outcome was
ORR using RECIST 1.1 criteria; PFS and OS were sec-
ondary end points. In brief, there was no significant
difference in ORR (34.5% v 29%, P 5 .86), median PFS
(1.9 v 2.6 months, P 5 .79), or median OS (14.2 v
13.6 months) between the nivolumab alone versus
nivolumab 1 SBRT arms. The 1-year OS was 50.2% with
nivolumab alone versus 54.4% with nivolumab 1 SBRT. In
a preplanned subgroup analysis, a test for interaction
between HPV- or EBV-positive status and treatment arm
was nonsignificant. There was no significant difference in
any AEs or grade 3 to 5 AEs between the two arms.
The CHEERS trial evaluated the addition of SBRT to im-
munotherapy in metastatic solid tumors and included a
small subgroup (n 5 20) of HNSCC patients.50 There were
no restrictions on number of metastases. Investigators
selected the anti–PD-(L)1 immunotherapy, with the timing
and SBRT schema like McBride et al32 (24 Gy in three
fractions, treating up to a maximum of three lesions started
after completion of cycle 1 of immunotherapy). Again, the
authors found no benefit in ORR, PFS, or OS with the
addition of SBRT to anti–PD-(L)1 immunotherapy.
There are at least eight ongoing randomized phase II trials
evaluating anti–PD-(L)1 ICIs plus SBRT in locoregionally
recurrent or metastatic HNSCC.51 To date, however,
evidence indicates that, while safe to deliver concur-
rently, there is no role for SBRT either in inducing an
abscopal response or otherwise augmenting the effects of
immunotherapy in patients with recurrent or metastatic
HNSCC.
Clinical Question 6
What is the role of immunotherapy for rare head and neck
cancers?
Recommendation 6.1. Pembrolizumab may be offered to
patients with TMB-high recurrent or metastatic rare head
1139
 Yilmaz et al
and neck cancers (Type: Evidence based, benefits out-
weigh harms; Evidence quality: Moderate; Strength of
recommendation: Weak).
Literature review and clinical interpretation. TMB-high and
microsatellite instability-high/deficient mismatch repair
(MSI-H/dMMR) have emerged as biomarkers for response
to pembrolizumab immunotherapy, irrespective of tissue
of origin. These biomarkers can be used to select patients
with rare head and neck cancers for immunotherapy. The
phase II study, KEYNOTE-158, evaluated the response of
patients with advanced, incurable solid tumors to pem-
brolizumab.33 Twenty-seven tumor types were enrolled,
including salivary gland carcinomas. In a prespecified
analysis, the association between response to pem-
brolizumab and tissue TMB (tTMB) was assessed. Re-
sponse rates were higher in tTMB-high group (defined
as $ 10 mutations per megabase) when compared to
non-tTMB high group (29% v 6%, respectively). Based on
these data, pembrolizumab is US Food and Drug
Administration–approved and may be offered as systemic
treatment for TMB-high advanced rare head and neck
cancers (eg, salivary, sinonasal, etc).
MSI-H due to deficient DNA mismatch repair (dMMR) leads
to increased somatic mutations and neoantigens, which
increases response to anti–PD-1 inhibitors. KEYNOTE-158
prospectively evaluated response to pembrolizumab in
patients with noncolorectal MSI-H/dMMR cancers who
progressed on or were intolerant to prior standard treat-
ment.52 Response to pembrolizumab in MSI-H/dMMR
cancers was 34.3% and OS was 23.5 months. However,
this cohort did not include any patients with head and neck
cancers, and MSI-H alterations in head and neck cancer
have not been reported to date. Therefore, although
pembrolizumab is approved for any MSI-H tumors, further
studies are needed to establish the incidence of MSI-H al-
terations in rare head and neck cancers, and confirm the role
of pembrolizumab in this setting.
Recommendation 6.2. Pembrolizumab may be offered to
patients with PD-L1–positive recurrent or metastatic sali-
vary gland cancer (Type: Evidence based, benefits out-
weigh harms; Evidence quality: Moderate; Strength of
recommendation: Weak).
Literature review and clinical interpretation. High-grade
salivary gland cancers have been found to express PD-L1,
with 22.8% of samples expressing $ 1% PD-L1 in a ret-
rospective tissue analysis.37 PD-L1 expression was asso-
ciated with poor disease-free survival in this study. The
phase Ib study, KEYNOTE-028, evaluated the effectiveness
of pembrolizumab in patients with advanced solid tumors
expressing 1% or greater PD-L1.34 Of 142 patients with
advanced salivary gland cancers who were screened, 33
had PD-L1–positive tumors (23%), consistent with other
reports. Of the 26 patients treated with pembrolizumab,
three (12%) had a partial response without unexpected
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immune-related AEs. Therefore, pembrolizumab may be
offered to patients with recurrent or metastatic salivary
gland cancers with PD-L1 expression $ 1%.
See the algorithm in Figure 1 for biomarkers and recom-
mendations by PD-L1 status, and the algorithm in Figure 2
for recommendations by subtype.
PATIENT AND CLINICIAN COMMUNICATION
As the advancement of science continues, controversies
around old and new practices continue to arise. Improving
outcomes requires careful consideration in the continuous
balance of literature. With the advancement of science and
technology, additional screening techniques are available
to better treat patients.
Strategies to manage cancer in the head and neck, oral
cavity, and oropharynx naturally vary according to a sur-
geon’s experience and the availability of different tech-
nologies. As surgical techniques and the understanding of
disease pathogenesis improve, patients are given even
more options. However, head and neck cancer clinicians
face a unique set of challenges, given the potential adverse
impacts many of these treatments have on a patient’s
quality of life. The clinician needs to consider how treat-
ment might affect many areas for the patient, such as
speech, taste, saliva, chewing, swallowing, lymphatic
processes, nerve damage, teeth, facial bone structure, and
physical appearance. The clinician needs to discuss these
potential impacts with the patient to balance the most ef-
fective treatment with the patient’s quality-of-life objectives.
Fortunately, many of the screening techniques described in
the guidelines do not place additional burdens on patients.
By recommending which patients would most benefit from
immunotherapy and biomarker testing, the Expert Panel
hopes to give clearer guidelines to treating clinicians. The
goal of these recommendations is so patients will receive
more specific, targeted treatments to manage their cancer,
resulting in higher success rates. This guideline does not
seek to encompass all approaches, but serves as a helpful
framework for discussions among the multidisciplinary
treatment team, the patient, and their families. These
discussions are critical for optimal modern care.
ASCO has always believed that strong and clear commu-
nication between physicians, patients, caregivers, and
families is paramount for delivering the best quality care.
For recommendations and strategies to optimize patient-
clinician communication, see Patient-Clinician Communi-
cation: American Society of Clinical Oncology Consensus
Guideline.
HEALTH DISPARITIES
Although ASCO clinical practice guidelines represent ex-
pert recommendations on the best practices in disease
management to provide the highest level of cancer care, it is
important to note that many patients have limited access to
Volume 41, Issue 5
 Immunotherapy and Biomarker Testing in Head and Neck Cancers

First-line therapy

Pembrolizumab monotherapy

PD-L1 CPS ≥ 1
(positive)
Pembrolizumab, platinum, and
5-FU

Pembrolizumab
Patients with any PD-L1 CPS
Patients with recurrent
PD-L1 IHC testing status and platinum-refractory
or metastatic HNSCC
recurrent or metastatic HNSCC
Nivolumab

Pembrolizumab, platinum, and

PD-L1 CPS < 1
5-FU

TMB testing if CPS is

Intepret as high; correlating
not available or in
TMB ≥ 10 with a clinical benefit to
patients with rare
PD-1 inhibitors
tumors

FIG 1. Algorithm for biomarkers and recommendations by PD-L1 status. 5-FU, fluorouracil; CPS, combined positive score; HNSCC, head and
neck squamous cell carcinoma; IHC, immunohistochemistry; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1;
TMB, tumor mutational burden.

Toripalimab, camrelizumab, or
Nasopharyngeal
tislelizumab, with gemcitabine
cancer
and cisplatin as first-line therapy

Pembrolizumab or nivolumab
Patients with recurrent
with gemcitabine and cisplatin if
or metastatic head and
toripalimab, camrelizumab, or
neck cancer
tislelizumab not available

Salivary gland cancer PD-L1–positive

Pembrolizumab

Rare head and neck

cancers TMB-high
Salivary gland cancer

Radiation therapy is safe to give concurrently with immunotherapy for the

Oligometastatic
purpose of palliation or local control, but should not be given to enhance
HNSCC
response to immunotherapy outside of a clinical trial

FIG 2. Recommendations by cancer subtype. HNSCC, head and neck squamous cell carcinoma; PD-L1, programmed death ligand-1; TMB, tumor
mutational burden.

Journal of Clinical Oncology 1141

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Yilmaz et al
medical care or receive fragmented care. Factors such as
race and ethnicity, age, socioeconomic status, sexual ori-
entation and gender identity, geographic location, and
insurance access are known to impact cancer care out-
comes.53 Racial and ethnic disparities in health care
contribute significantly to this problem in the United States.
Patients with cancer who are members of racial or ethnic
minorities suffer disproportionately from comorbidities,
experience more substantial obstacles to receiving care,
are more likely to be uninsured, and are at greater risk of
receiving fragmented care or poor-quality care than other
Americans.54-57 Many other patients lack access to care
because of their geographic location and distance from
appropriate treatment facilities. Lack of access to care
increases timelines to diagnoses and often results in an
advanced disease state at the time of diagnosis. Awareness
of these disparities in access to care should be considered
in the context of this clinical practice guideline, and health
care providers should strive to deliver the highest level of
cancer care to these vulnerable populations. Additionally,
stakeholders should work toward achieving health equity by
ensuring equitable access to both high-quality cancer care
and research and addressing the structural barriers that
preserve health inequities.53
MULTIPLE CHRONIC CONDITIONS
Creating evidence-based recommendations to inform
treatment of patients with additional chronic conditions, a
situation in which the patient may have two or more such
conditions—referred to as multiple chronic conditions
(MCCs)—is challenging. Patients with MCC are a complex
and heterogeneous population, making it difficult to ac-
count for all of the possible permutations to develop specific
recommendations for care. In addition, the best available
evidence for treating index conditions, such as cancer, is
often from clinical trials whose study selection criteria may
exclude these patients to avoid potential interaction effects
or confounding of results associated with MCC. As a result,
the reliability of outcome data from these studies may be
limited, thereby creating constraints for expert groups to
make recommendations for care in this heterogeneous
patient population.
As many patients for whom guideline recommendations
apply present with MCC, any treatment plan needs to take
into account the complexity and uncertainty created by the
presence of MCC and highlights the importance of shared
decision making regarding guideline use and imple-
mentation. Therefore, in consideration of recommended
care for the target index condition, clinicians should review
all other chronic conditions present in the patient and take
those conditions into account when formulating the treat-
ment and follow-up plan.
In light of these considerations, practice guidelines should
provide information on how to apply the recommendations
for patients with MCC, perhaps as a qualifying statement for
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recommended care. This may mean that some or all of the
recommended care options are modified or not applied, as
determined by best practice in consideration of any MCC.
COST IMPLICATIONS
Increasingly, individuals with cancer are required to pay a
larger proportion of their treatment costs through deduct-
ibles and coinsurance.58,59 Higher patient out-of-pocket
costs have been shown to be a barrier to initiating and
adhering to recommended cancer treatments.60,61
Discussion of cost can be an important part of shared
decision making.62 Clinicians should discuss with patients
the use of less expensive alternatives when it is practical
and feasible for treatment of the patient’s disease and there
are two or more treatment options that are comparable in
terms of benefits and harms.62
Patient out-of-pocket costs may vary depending on in-
surance coverage. Coverage may originate in the medical or
pharmacy benefit, which may have different cost-sharing
arrangements. Patients should be aware that different
products may be preferred or covered by their particular
insurance plan. Even with the same insurance plan, the
price may vary between different pharmacies. When dis-
cussing financial issues and concerns, patients should be
made aware of any financial counseling services available
to address this complex and heterogeneous landscape.62
As part of the guideline development process, ASCO may
opt to search the literature for published cost-
effectiveness analyses that might inform the relative
value of available treatment options. Excluded from
consideration are cost-effective analyses that lack con-
temporary cost data; agents that are not currently avail-
able in either the United States or Canada; or are industry-
sponsored. Three cost-effectiveness analyses were
identified to inform the topic.63-65 Each analysis similarly
dealt with the particular case of nivolumab monotherapy
for recurrent or metastatic HNSCC. Both Haddad et al63
and Ward et al65 found that nivolumab was cost-effective
up to a willingness-to-pay threshold of $150,000 in US
dollars (USD) per quality-adjusted life-year (QALY);63
however, Tringale et al64 concluded nivolumab was not
cost-effective if a threshold of $100,000 (USD) per
quality-adjusted life-year was used.
EXTERNAL REVIEW AND OPEN COMMENT
The draft recommendations were released to the public for
open comment from June 6 to 21, 2022. Response cat-
egories of “Agree as written,” “Agree with suggested
modifications” and “Disagree. See comments” were cap-
tured for every proposed recommendation with 53 written
comments received. A total of 97% of the 29 respondents
either agreed or agreed with slight modifications to the
recommendations and 3% of the respondents disagreed.
Expert Panel members reviewed comments from all
Volume 41, Issue 5
 Immunotherapy and Biomarker Testing in Head and Neck Cancers
sources and determined whether to maintain original draft
recommendations, revise with minor language changes, or
consider major recommendation revisions. All changes
were incorporated prior to ASCO Evidence Based Medicine
Committee review and approval.
GUIDELINE IMPLEMENTATION
ASCO guidelines are developed for implementation across
health settings. Each ASCO guideline includes a member
from ASCO’s Practice Guideline Implementation Network
(PGIN) on the panel. The additional role of this PGIN
representative on the guideline panel is to assess the
suitability of the recommendations to implementation in the
community setting, but also to identify any other barrier to
implementation a reader should be aware of. Barriers to
implementation include the need to increase awareness of
the guideline recommendations among frontline practi-
tioners and survivors of cancer and caregivers, and also to
provide adequate services in the face of limited resources.
The guideline Bottom Line Box was designed to facilitate
implementation of recommendations. This guideline will be
distributed widely through the ASCO PGIN. ASCO guide-
lines are posted on the ASCO website and most often
published in the Journal of Clinical Oncology.
LIMITATIONS OF THE RESEARCH AND FUTURE RESEARCH
Routine use of immunotherapy in HNSCC is currently limited
to the recurrent or metastatic setting. The role of ICIs in
locoregionally advanced disease is not yet established, with
several randomized trials finding no benefit to the addition of
ICIs in combination with definitive (chemo)radiotherapy.66,67
The phase III JAVELIN trial tested the addition of the PD-L1
inhibitor avelumab to standard cisplatin and radiation
therapy for definitive treatment of locally advanced
HNSCC.67 This trial found no benefit to the addition of
avelumab to standard chemoradiation. However, this trial
was not restricted on the basis of PD-L1 status, and the
optimal sequencing of (chemo)radiation with immunother-
apy is not yet defined. A phase II trial of neoadjuvant and
adjuvant pembrolizumab in resectable locally advanced
HNSCC patients indicated that pathologic response could
serve as a potential marker for subsequent response to ICIs
and improved disease-free survival.68 Multiple other recently
completed and ongoing randomized trials are evaluating the
role of immunotherapy in combination with definitive or
adjuvant (chemo)radiation. These include KEYNOTE-412,
GORTEC-REACH, GORTEC 2015-01, NRG HN004 (Clin-
icalTrials.gov identifier: NCT03258554), NRG HN005
(ClinicalTrials.gov identifier: NCT03952585), Imvoke010,
RTOG 1216, ECOG-ACRIN EA3161 (ClinicalTrials.gov
identifier: NCT03811015), KEYCHAIN (ClinicalTrials.gov
identifier: NCT03383094), and CCTG HN.9.66,69-74 To date,
however, the role of immunotherapy, if any, in the treatment
of previously untreated locoregionally advanced HNSCC
remains to be determined.
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GENDER-INCLUSIVE LANGUAGE
ASCO is committed to promoting the health and well-being of
individuals regardless of sexual orientation or gender iden-
tity.82 Transgender and nonbinary people, in particular, may
face multiple barriers to oncology care including stigmatiza-
tion, invisibility, and exclusiveness. One-way exclusiveness or
lack of accessibility may be communicated through gendered
language that makes presumptive links between gender and
anatomy.83-86 With the acknowledgment that ASCO guidelines
may impact the language used in clinical and research set-
tings, ASCO is committed to creating gender-inclusive
guidelines. For this reason, guideline authors use gender-
inclusive language whenever possible throughout the
guidelines. In instances in which the guideline draws upon
data based on gendered research (eg, studies regarding
women with ovarian cancer), the guideline authors describe
the characteristics and results of the research as reported.
ASCO believes that cancer clinical trials are vital to inform
medical decisions and improve cancer care, and that all
patients should have the opportunity to participate.
ADDITIONAL RESOURCES
More information, including a supplement with additional
evidence tables, slide sets, and clinical tools and resources,
is available at www.asco.org/head-neck-cancer-guidelines.
Patient information is available at www.cancer.net.
RELATED ASCO GUIDELINES
• Integration of Palliative Care Into Standard On-
cology Care75 (http://ascopubs.org/doi/10.1200/
JCO.2016.70.1474).
• Patient-Clinician Communication76 (http://
ascopubs.org/doi/10.1200/JCO.2017.75.2311).
• Management of the Neck in Squamous Cell
Carcinoma of the Oral Cavity and Oropharynx77
(http://ascopubs.org/doi/10.1200/
JCO.18.01921).
• Human Papillomavirus Testing in Head and
Neck Carcinomas78 (http://ascopubs.org/doi/
10.1200/JCO.18.00684).
• Diagnosis and Management of Squamous Cell
Carcinoma of Unknown Primary in the Head
and Neck79 (http://ascopubs.org/doi/10.1200/
JCO.20.00275).
• Chemotherapy in Combination with Radiotherapy
for Definitive-Intent Treatment of Stage II-IVA Na-
sopharyngeal Carcinoma80 (http://ascopubs.org/
doi/10.1200/JCO.20.03237).
• Management of Salivary Gland Malignancy81
(http://ascopubs.org/doi/10.1200/
JCO.21.00449).
1143
 Yilmaz et al

EDITOR’S NOTE
AFFILIATIONS
1 This American Society of Clinical Oncology (ASCO) Clinical Practice
Cleveland Clinic, Cleveland, OH
2
Guideline provides recommendations, with comprehensive review and
American Society of Clinical Oncology, Alexandria, VA
3
analyses of the relevant literature for each recommendation. Additional
George Washington University, Washington, DC
4 information, including a supplement with additional evidence tables,
The Center for Cancer and Blood Disorder, Southlake, TX
5
slide sets, clinical tools and resources, and links to patient information at
Kansas University Medical Center, Kansas City, KS
6
www.cancer.net, is available at www.asco.org/head-neck-cancer-
University of California San Francisco, San Francisco, CA
7 guidelines.
Patient Representative, Needham Heights, MA
8
Moffitt Cancer Center, Tampa, FL
9
Memorial Sloan Kettering Cancer Center, New York, NY EQUAL CONTRIBUTION
10
Ohio State University, Columbus, OH E.Y. and L.K.M were Expert Panel co-chairs.
11
Johns Hopkins Medicine, Baltimore, MD
12
Emory University, Atlanta, GA
13
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
University of North Carolina, Chapel Hill, Chapel Hill, NC
14
Otago Medical School, University of Otago, Dunedin, New Zealand
INTEREST
15
Duke University, Durham, NC Disclosures provided by the authors are available with this article at DOI
16
University of Cincinnati, Cincinnati, OH https://doi.org/10.1200/JCO.22.02328.
17
University of California Los Angeles, Los Angeles, CA
18
University of California San Diego, La Jolla, CA AUTHOR CONTRIBUTIONS
Conception and design: All authors
CORRESPONDING AUTHOR Collection and assembly of data: All authors
American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Data analysis and interpretation: All authors
Alexandria, VA 22314; e-mail: guidelines@asco.org. Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

ACKNOWLEDGMENT
The Expert Panel wishes to thank Drs Rohan Garje and Shilpi Gupta, and
the Evidence Based Medicine Committee for their thoughtful reviews and
insightful comments on this guideline.

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 Immunotherapy and Biomarker Testing in Head and Neck Cancers

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Emrullah Yilmaz Nabil F. Saba

Consulting or Advisory Role: Astellas Pharma Honoraria: Merck, EMD Serono, AstraZeneca, ReachMD, Vaccinex, Eisai,
Novartis, Exelixis, GlaxoSmithKline, Inovio Pharmaceuticals, American Journal
Nofisat Ismaila
of Managed Care.
Employment: GlaxoSmithKline
Consulting or Advisory Role: Mirati Therapeutics
Stock and Other Ownership Interests: GlaxoSmithKline
Research Funding: Bristol Myers Squibb, Exelixis
Julie E. Bauman Patents, Royalties, Other Intellectual Property: UpToDate chapter writing and
Consulting or Advisory Role: BlueDot, Exelixis editing, Springer textbook Royalty
Research Funding: Bristol Myers Squibb (Inst), AVEO (Inst), Novartis (Inst), Travel, Accommodations, Expenses: Merck
Celldex (Inst), Moderna Therapeutics (Inst), Lilly (Inst), AstraZeneca (Inst), CUE
Siddharth Sheth
Biopharma (Inst)
Honoraria: Naveris, Medscape
Raetasha Dabney Speakers’ Bureau: Exelixis
Employment: Magellan Health Research Funding: AstraZeneca/MedImmune, Merck (Inst), AstraZeneca (Inst),
Speakers’ Bureau: Myriad Genetics Inovio Pharmaceuticals (Inst)
Gregory Gan Travel, Accommodations, Expenses: AstraZeneca/MedImmune
Honoraria: AstraZeneca Trisha Michel Wise-Draper
Consulting or Advisory Role: IDEO Oncology Stock and Other Ownership Interests: High Enroll
Research Funding: Aclaris Therapeutics Honoraria: Physicians’ Education Resource
Patents, Royalties, Other Intellectual Property: US Patent Application #: Consulting or Advisory Role: Shattuck Labs, Rakuten Medical, Exicure, Merck,
15/506,421 Title: Inhibition of MK2 in Treatment of Cancer. Coinventor: Gregory Caris Life Sciences
Gan, Ellen Beswick Patent filed on Dec 2015 Research Funding: Merck, AstraZeneca/MedImmune, Bristol Myers Squibb,
GlaxoSmithKline, Caris Life Sciences, Janssen Oncology
Richard Jordan
Stock and Other Ownership Interests: Genomic Health Travel, Accommodations, Expenses: Merck, Bristol Myers Squibb, Bexion,
AstraZeneca/MedImmune, Caris Life Sciences, Lilly, Tesaro
Research Funding: Deciper Bio (Inst)
Kedar Kirtane Deborah Wong
Consulting or Advisory Role: Bristol Myers Squibb, Genentech/Roche,
Stock and Other Ownership Interests: Oncternal Therapeutics, Seattle Genetics,
Macrogenics, Immunomedics, Myovant Sciences, Veru, Agenus Sanofi/Aventis, Blueprint Medicines, Regeneron
Consulting or Advisory Role: MyCareGorithm Research Funding: Merck Serono (Inst), Merck Sharp & Dohme (Inst), ARMO
BioSciences (Inst), AstraZeneca/MedImmune (Inst), Kura Oncology (Inst),
Sean Matthew McBride Regeneron (Inst), Genentech/Roche (Inst), Bristol Myers Squibb (Inst), FSTAR
Consulting or Advisory Role: Janssen, AstraZeneca (Inst), Pfizer (Inst), Astellas Pharma (Inst), Enzychem Lifesciences (Inst), Lilly,
Research Funding: Genentech, AstraZeneca Elevar Therapeutics (Inst), TopAlliance Biosciences Inc (Inst), Checkmate
Matthew O. Old Pharmaceuticals (Inst), Bicara Therapeutics (Inst), Gilead Sciences (Inst)
Honoraria: KLS Martin Loren K. Mell
Travel, Accommodations, Expenses: KLS Martin Consulting or Advisory Role: Cel-Sci
Research Funding: Merck, AstraZeneca
Open Payments Link: https://openpaymentsdata.cms.gov/physician/286651
No other potential conflicts of interest were reported.

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Yilmaz et al

APPENDIX

TABLE A1. Recommendation Rating Definitions

Term Definitions
Quality of evidence
High We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of
the effect, but there is a possibility that it is substantially different.
Low Our confidence in the effect estimate is limited: The true effect may be substantially different from the
estimate of the effect.
Very low We have very little confidence in the effect estimate: The true effect is likely to be substantially different
from the estimate of effect.
Strength of recommendation
Strong In recommendations for an intervention, the desirable effects of an intervention outweigh its
undesirable effects.
In recommendations against an intervention, the undesirable effects of an intervention outweigh its
desirable effects.
All or almost all informed people would make the recommended choice for or against an intervention.
Weak In recommendations for an intervention, the desirable effects probably outweigh the undesirable
effects, but appreciable uncertainty exists.
In recommendations against an intervention, the undesirable effects probably outweigh the desirable
effects, but appreciable uncertainty exists.
Most informed people would choose the recommended course of action, but a substantial number
would not.

TABLE A2. Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers Guideline Expert Panel Membership
Name Affiliation Role or Area of Expertise
Emrullah Yilmaz, MD, PhD Cleveland Clinic, Cleveland, OH Medical Oncology
(co-chair)
Loren K. Mell, MD (co-chair) University of California San Diego, La Jolla, CA Radiation Oncology
Julie Bauman, MPH, MD George Washington University, Washington, DC Medical Oncology
Raetasha Dabney, MD The Center for Cancer and Blood Disorder, Southlake, TX PGIN Representation
Gregory Gan, MD, PhD Kansas University Medical Center, Kansas City, KS Radiation Oncology
Richard Jordan, DDS, PhD University of California San Francisco, San Francisco, CA Pathologist
Marnie Kaufman Needham Heights, MA Patient Representation
Kedar Kirtane, MD Moffitt Cancer Center, Tampa, FL Medical Oncology
Sean Matthew McBride, MD, MPH Memorial Sloan Kettering Cancer Center, New York, NY Radiation Oncology
Matthew O. Old, MD Ohio State University, Columbus, OH Surgical Oncology
Lisa Rooper, MD Johns Hopkins Medicine, Baltimore, MD Pathologist
Nabil F. Saba, FACP, MD Emory University, Atlanta, GA Medical Oncology
Siddharth Sheth, DO, MPH University of North Carolina, Chapel Hill, NC Medical Oncology
Rathan M. Subramaniam, Otaga Medical School, University of Otago, Dunedin, NZ Radiologist and Nuclear Medicine
MD, PhD, MPH, MBA Duke University, Durham, NC Physician
Trisha Michel Wise-Draper, University of Cincinnati, Cincinnati, OH Medical Oncology
MD, PhD
Deborah Wong, MD, PhD University of California Los Angeles, Los Angeles, CA Medical Oncology
Nofisat Ismaila, MD American Society of Clinical Oncology, Alexandria, VA ASCO Practice Guideline Staff
(Health Research Methods)

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