Research

JAMA Otolaryngology–Head & Neck Surgery | Original Investigation

Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer

A Systematic Review and Meta-analysis
Razan Masarwy, MD, MPH; Liyona Kampel, MD; Gilad Horowitz, MD; Orit Gutfeld, MD; Nidal Muhanna, MD, PhD

Supplemental content
IMPORTANCE The emerging approach of neoadjuvant immunotherapy for solid cancers has
set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1)
inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma (HNSCC)
treatment.

OBJECTIVE To assess the reported efficacy and safety of neoadjuvant immunotherapy for
resectable HNSCC.

DATA SOURCES AND STUDY SELECTION Electronic databases, including PubMed (MEDLINE),
Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched for
published and ongoing cohort studies and randomized clinical trials that evaluate
neoadjuvant immunotherapy for resectable HNSCC. The search results generated studies
from 2015 to July 2021.

DATA EXTRACTION AND SYNTHESIS Two investigators (R.M. and L.K.) independently identified
and extracted articles for potential inclusion. Random and fixed models were used to achieve
pooled odds ratios. All results are presented with 95% CIs. Data quality was assessed by
means of the Cochrane Collaboration’s risk of bias tool.

MAIN OUTCOMES AND MEASURES The primary outcomes were reported efficacy, evaluated by
major pathological response and pathological complete response in the primary tumors and
lymph nodes separately, and safety, assessed by preoperative grade 3 to 4 treatment-related
adverse events and surgical delay rate.

RESULTS A total of 344 patients from 10 studies were included. In 8 studies, neoadjuvant
immunotherapy only was administered, and the other 2 studies combined immunotherapy
with neoadjuvant chemotherapy and/or radiotherapy. The overall major pathological
response rate in the primary tumor sites from studies reporting on neoadjuvant
immunotherapy only was 9.7% (95% CI, 3.1%-18.9%) and the pathological complete
response rate was 2.9% (95% CI, 0%-9.5%). Preoperative grade 3 to 4 treatment-related
adverse events were reported at a rate of 8.4% (95% CI, 0.2%-23.2%) and surgical delay at a
rate of 0% (95% CI, 0%-0.9%). There was a favorable association of neoadjuvant
immunotherapy with all outcome measures. The subgroup analyses did not find one specific
anti–PD-1/PD-L1 agent to be superior to another, and the favorable association was
demonstrated by either immunotherapy alone or in combination with anti–CTLA-4.

CONCLUSIONS AND RELEVANCE In this systematic review and meta-analysis, neoadjuvant Author Affiliations: Department of
anti–PD-1/PD-L1 immunotherapy for resectable HNSCC was well tolerated and may confer Otolaryngology–Head and Neck and
Maxillofacial Surgery, Tel Aviv
therapeutic advantages implied by histopathological response. Long-term outcomes are
Sourasky Medical Center, Sackler
awaited. School of Medicine, Tel Aviv
University, Tel Aviv, Israel (Masarwy,
Kampel, Horowitz, Muhanna);
Institute of Radiation Therapy,
Division of Oncology, Tel Aviv
Sourasky Medical Center, Sackler
School of Medicine, Tel Aviv
University, Tel Aviv, Israel (Gutfeld).
Corresponding Author: Nidal
Muhanna, MD, PhD, Department of
Otolaryngology–Head and Neck and
Maxillofacial Surgery, Tel Aviv
Sourasky Medical Center, Sackler
School of Medicine, Tel Aviv
University, 6 Weizmann St, Tel Aviv
JAMA Otolaryngol Head Neck Surg. 2021;147(10):871-878. doi:10.1001/jamaoto.2021.2191 6423906, Israel (nidalm@
Published online September 2, 2021. tlvmc.gov.il).

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 Research Original Investigation
T
he current standard of care for patients with locore-
gionally advanced head and neck squamous cell carci-
noma (HNSCC) includes surgical resection with adju-
vant therapy or definitive chemoradiotherapy. Despite this
multimodal therapeutic approach, high rates of treatment fail-
ure and disease recurrence are responsible for poor survival
outcomes.1,2 The past decade has witnessed the emergence of
administration of immune checkpoint inhibitors as a promis-
ing approach in the treatment of metastatic or recurrent HN-
SCC. Use of pembrolizumab and nivolumab (anti–pro-
grammed cell death 1 [PD-1] antibodies) have demonstrated
efficacy in platinum-refractory advanced HNSCC, leading to
US Food and Drug Administration approval in this setting.3,4
Induction chemotherapy has been studied for advanced-
stage oral cavity cancer compared with the same therapy ad-
ministered in the adjuvant setting, and it failed to achieve any
beneficial clinical outcome.5
A new approach of neoadjuvant administration of immu-
notherapy with a more favorable toxicity profile compared with
chemotherapy cytotoxic agents has been introduced and has
been shown to bestow a clinical benefit for metastatic or re-
current disease.6 The rationale for neoadjuvant immuno-
therapy derives from the early introduction of systemic therapy
that can potentially reduce the risk of distant metastases and
convert unresectable to resectable disease. Ultimately, it may
modify the extent of surgery and reduce surgical morbidity.
Tumor downstaging can also translate into reduced adjuvant
therapy intensity.
The feasibility of neoadjuvant immunotherapy has al-
ready been evaluated in non–small cell lung cancer and
melanoma.7,8 Several phase 2 trials of neoadjuvant anti–PD-
1/PD-1 ligand 1 [PD-L1] administered several weeks prior to de-
finitive resection in locoregionally advanced, resectable HN-
SCC are ongoing and have provided promising initial results.
We performed a meta-analysis on the available data to evalu-
ate the therapeutic benefit of the neoadjuvant approach while
also assessing the potential associated limitations, such as toxic
effects and delay of curative surgery.
Methods
This systematic review followed the Preferred Reporting Items
for Systematic Reviews and Meta-analyses (PRISMA) reporting
guidelines9 and the Meta-analysis of Observational Studies in
Epidemiology (MOOSE) reporting guidelines.10 The detailed
protocol is documented online in the International Prospective
Register of Systematic Reviews registry (PROSPERO:
CRD42021239707). Because this systematic review and meta-
analysis did not use individualized patient data, no institutional
review board approval was required.
Study Selection
We conducted a systematic search in PubMed (MEDLINE),
Embase, the Cochrane Library, and ClinicalTrials.gov to iden-
tify published studies on neoadjuvant immunotherapy in pa-
tients with HNSCC reported before July 2021 (eMethods in the
Supplement). We also searched unpublished reported data of
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Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer
Key Points
Question What is the efficacy and safety profile of neoadjuvant
programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors in
patients with resectable head and neck cancer?
Findings This systematic review and meta-analysis of 10 clinical
trials of patients with resectable head and neck cancer revealed
that neoadjuvant immunotherapy with PD-1/PD-L1 inhibitors had a
favorable association with outcome measures of efficacy
(pathological complete response) and safety (grade 3-4 adverse
events and surgical delay).
Meaning Neoadjuvant anti–PD-1/PD-L1 immunotherapy for
resectable head and neck cancer appears to be well tolerated and
therapeutically efficacious, as implied by pathological response.
ongoing clinical trials of neoadjuvant immunotherapy in pa-
tients with HNSCC presented at international oncological con-
ferences (eTable 2 in the Supplement).
Data Extraction
Two investigators (R.M. and L.K.) independently identified and
extracted articles for potential inclusion. Disagreements were
resolved by referral to a third reviewer (N.M.). The full texts
of the resulting articles were then retrieved and analyzed. A
summary of the characteristics of the included studies is pro-
vided in the Table.11-20 Additional details of the included stud-
ies are provided in eTable 1 in the Supplement.
Quality Assessment and Risk of Bias
The selected studies were assessed with the Cochrane Col-
laboration’s risk of bias tool, which is used to assign a rating
of high, low, or unclear risk of bias for the domains of selec-
tion, performance, detection, attrition, and reporting. Sum-
mary assessment of the risk of bias (high, low, or unclear) was
derived for each outcome in each trial. Two reviewers (R.M.
and L.K.) independently assessed the risk of bias. Disagree-
ments were resolved through consensus or referral to a third
reviewer (N.M.) (eFigures 8 and 9 in the Supplement).
Data Synthesis and Statistical Analysis
The meta-analysis was performed by means of noncompara-
tive binary data in RevMan software, version 5.4 (Cochrane Col-
laboration), because most of the studies were 1-arm clinical
trials. The odds ratios (ORs) and 95% CIs were the effect
measures.21,22 The Freeman-Tukey double-arcsine transfor-
mation was performed for raw incidence rates. Result hetero-
geneity among the studies was quantified with the heteroge-
neity index (I2). Subgroup analyses were performed for specific
anti–PD-1/PD-L1 or for combined use with other therapies. A
P < .05 was considered statistically significant. For more in-
formation, see eMethods in the Supplement.
Results
The search strategy identified 1407 citations. After screening
the abstracts and reviewing the available full texts, 10 studies
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 Table. Characteristics of Studies of Neoadjuvant Immunotherapy in Head and Neck Cancer
ClinicalTrials.gov Study Randomization
Source identifier phase Intervention model Masking Study type method Main inclusion criteria Article type Outcome reported
Wise-Draper NCT02641093 Phase 2 Single arm Open label Cohort NA Clinically high risk Conference • MPR
et al,11 2021 study (T3 or T4 and/or ≥2 LNs) in abstract • Postoperative TRAEs (grade 3-4)
resectable HNSCC
Uppaluri NCT02296684 Phase 2 Sequential Open label Cohort Nonrandomized Surgically resectable stage Full text • pCR

jamaotolaryngology.com
et al,12 2020 assignment, dual arm study III and IV head and neck • MPR
cancer • Preoperative TRAEs (grade 3-4)
• Surgical delay
• Downstaging
IMCISION trial,13 NCT03003637 Phase Single arm Open label Cohort NA Advanced (T3-4, N0-3, M0) Conference • MPR
2020 1B/2 study HNSCC eligible for abstract • Preoperative TRAEs (grade 3-4)
curative-intent surgical • Surgical delay
resection
Horton NCT03021993 Phase 2 Single arm Open label Cohort NA Stage II-IVA OCSSC Conference • pCR
et al,14 2019 study abstract • Preoperative TRAEs (grade 3-4)
• Surgical delay
CIAO study,15 NCT03144778 Phase 1 Parallel assignment, Open label RCT Randomized Stage II-IVA oropharyngeal Full text • pCR
2019 dual arm SCC • MPR
• Adverse events (grade 3-4)
• Downstaging
CheckMate 358 NCT02488759 Phase 1/2 Single arm Open label Cohort Randomized Resectable SCC of the oral Full text • MPR
Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer

study,16 2021 study cavity, pharynx, or larynx • pCR

with ≥T1 primary lesions • Preoperative TRAEs (grade 3-4)
and ≥N1 nodal disease • Surgical delay
Schoenfeld NCT02919683 Phase 2 Parallel assignment, Open label RCT Randomized ≥T2 and/or evidence of Full text • MPR

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et al,17 2020 dual arm regional nodal involvement • pCR
OCSCC • Preoperative TRAEs (grade 3-4)
• Surgical delay
• Downstaging
Kim NCT03737968 Phase 2 Single arm Open label Cohort Randomized Surgically resectable head Conference • pCR
et al,18 2021 study and neck cancer abstract • Preoperative TRAEs (grade 3-4)
• Surgical delay
Neoadjuvant immunotherapy in combination with chemotherapy or radiation therapy
Leidner NCT03247712 Phase 1/2 Single arm Open label Cohort Nonrandomized Locally advanced Full text • MPR
et al,19 2021 study HPV-associated • pCR
oropharyngeal HNSCC

© 2021 American Medical Association. All rights reserved.

Zinner NCT03342911 Phase 2 Single arm Open label Cohort NA Stage II-III HPV + SCCHN Conference • MPR
et al,20 2020 study without distant metastasis abstract • pCR
and candidates for surgery
Abbreviations: HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; LN, lymph node; pathological complete response; RCT, randomized clinical trial; SCC, squamous cell carcinoma; SCCHN, squamous
MPR, major pathological response; NA, not applicable; OCSSC, oral cavity squamous cell carcinoma, pCR, cell carcinoma of the head and neck; TRAEs, treatment-related adverse event.
Original Investigation Research

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873
 Research Original Investigation
Figure 1. PRISMA Flow Diagram
1407 Records identified through database search
1360 From PubMed, Embase, Cochrane Library,
and ClinicalTrials.gov
47 Oncology conferences abstract publications
1180 Records after duplicates removed
1034 Records excluded based on
inappropriate titles
146 Abstract records screened
37 Records on neoadjuvant immunotherapy
assessed for eligibility
27 Excluded
21 No experimental data
4 Neoadjuvant other than
anti–PD-1/PD-L1
2 Relevant primary outcome
not included
10 Studies included in quantitative
synthesis (meta-analysis)
PD-1/PD-L1 indicates programmed cell death 1/programmed cell death 1 ligand 1.
met the inclusion criteria, yielding a total number of 344 pa-
tients for inclusion in this meta-analysis. Five of those 10 stud-
ies were ongoing trials for which only the abstracts were avail-
able, and the remaining 5 were published as full-length articles.
The selection process is illustrated in Figure 1.
Evaluation of Efficacy Outcomes
Pathological complete response (pCR) and major pathologic
response (MPR) were distinguished in the primary tumor site
(Figure 211-18) vs pCR and MPR in regional lymph nodes (eFig-
ure 4 in the Supplement). The rates of pCR at the primary tu-
mor ranged from 0% to 16.7%. The mean pCR was 2.9% (95%
CI, 0%-9.5%) (eFigure 1A in the Supplement). Pooled results
from the trials using neoadjuvant immunotherapy showed a
statistically significant benefit (OR, 0.07; 95% CI, 0.03-0.18;
Figure 2A). The heterogeneity of the results was low (I2 = 34%).
Significant favorable association was observed in nodal pCR
(eFigure 4C in the Supplement). Zinner et al20 and Leidner
et al19 reported that neoadjuvant immunotherapy combined
with chemotherapy and/or radiation prior to surgery were ana-
lyzed separately with overall pCR of 53% (eFigure 3A in the
Supplement).
The MPR to neoadjuvant immunotherapy, defined as 10%
or less residual viable tumor, was reported in 5 studies, and it
ranged from 2.9% to 31.0%. The mean MPR rate was 9.7% (95%
CI, 3.1%-18.9%; eFigure 1B in the Supplement). Neoadjuvant
immunotherapy had a statistically significantly beneficial as-
sociation in terms of MPR (OR, 0.11; 95% CI, 0.04-0.29;
Figure 2B). There was a high level of heterogeneity, but after
a sensitivity analysis was performed and the IMCISION trial,13
which had the highest weight in the analysis, was excluded
(eTable 3 in the Supplement), the heterogeneity decreased. The
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Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer
remaining trials indicated a favorable association of anti–PD-
1/PD-L1 with MPR (OR, 0.08; 95% CI, 0.04-0.14). Nodal MPR
reported in 3 studies has also shown statistically significant fa-
vorability of neoadjuvant immunotherapy (eFigure 4B in the
Supplement). The studies by Zinner et al20 and Leidner et al19
were analyzed separately with overall pCR of 75.3% (eFig-
ure 3B in the Supplement).
Safety of Neoadjuvant Immunotherapy
Treatment-related adverse events (TRAEs), assessed by the Na-
tional Cancer Institute’s Common Terminology Criteria for Ad-
verse Events, version 4.0, are associated with neoadjuvant im-
munotherapy safety. Preoperative grade 3 to 4 neoadjuvant
immunotherapy–related adverse events include autoim-
mune colitis, duodenal hemorrhage, mucositis, nausea, vom-
iting, and syncope. The incidence of preoperative grade 3 to 4
TRAEs was 8.4% (95% CI, 0.2%-23.2%; eFigure 2 in the Supple-
ment). Neoadjuvant immunotherapy was administered with
an acceptable safety profile, supported by all 6 included
studies12-14,16-18 (OR, 0.17; 95% CI, 0.07-0.41; Figure 3A). Ex-
clusion of the IMCISION trial,13 which had the highest weight
in the analysis, demonstrated a decrease in heterogeneity
(eTable 4 in Supplement). As for surgical delay rate, the pooled
OR was supportive of neoadjuvant immunotherapy (OR, 0.02;
95% CI, 0.01-0.05; Figure 3B12-18).
Subgroup Analyses
The subgroup analyses did not find any specific anti–PD-1/
PD-L1 agent to be superior to another (eFigure 6 in the Supple-
ment). Subgroup analyses of safety and efficacy outcomes
(pCR, MPR, and adverse events) did not demonstrate any dif-
ference in the efficacy and safety of any neoadjuvant anti–PD-
1/PD-L1 agent administered alone or in combination with
CTLA-4 blockage (eFigure 7 in the Supplement). For preop-
erative grade 3 to 4 TRAEs, high heterogeneity was detected
in studies with combined anti–CTLA-4 and anti–PD-1/PD-L1
treatments (IMCISION trial13 and HR Kim et al18), which con-
tributed the most to the heterogeneity of the overall grade 3
to 4 TRAEs results.
Discussion
To the best of our knowledge, this is the first meta-analysis that
evaluated the efficacy and safety of neoadjuvant immuno-
therapy for patients with resectable HNSCC. Results demon-
strated favorable outcomes and acceptable tolerance of the ad-
ministration of neoadjuvant PD-1\PD-L1 inhibitors. The
neoadjuvant approach has been evaluated by pCR and MPR as
indicators of treatment efficacy.23 Several studies distin-
guished between these measures of pathologic response in the
primary tumor and in lymph node metastases, while others
reported these outcomes in primary tumor alone. Concor-
dant MPR and pCR in the tumor and metastasis were consis-
tently observed, except for higher MPR in lymph nodes than
in the primary tumor site, as reported in the CIAO study.15 Over-
all, we found a favorable association of neoadjuvant immu-
notherapy, both in primary site and in nodal disease.
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 Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer Original Investigation Research

Figure 2. Efficacy Evaluation of Neoadjuvant Immunotherapy for Resectable Head and Neck Cancer

A Pathological complete response

Log Odds ratio Favors anti– Does not favor

Study or subgroup (odds ratio) SE (95% CI) PD-1/PD-L1 anti–PD-1/PD-L1 Weight, %
CheckMate 358 study,16 2021 –4.317 1.424 0.01 (0.00-0.22) 1.6
CIAO study,15 2019 –2.442 0.737 0.09 (0.02-0.37) 22.8
Horton et al,14 2019 –2.944 1.451 0.05 (0.00-0.90) 8.8
Kim et al,18 2021 –1.609 0.447 0.20 (0.08-0.48) 35.2
Schoenfeld et al,17 2020 –3.332 1.018 0.04 (0.00-0.26) 15.2
Uppaluri et al,12 2020 –4.29 1.424 0.01 (0.00-0.26) 9.0
Total (95% CI) 0.07 (0.03-0.18) 100.0
Heterogeneity: τ2 = 0.43; χ2 = 7.61, df = 5 (P = .18); I2 = 34%
Test for overall effect: z = 5.65 (P <.001) 0.001 0.01 0.1 1 10 100
Odds ratio (95% CI)

B Major pathological response

Log Odds ratio Favors anti– Does not favor
Study or subgroup (odds ratio) SE (95% CI) PD-1/PD-L1 anti–PD-1/PD-L1 Weight, %
CheckMate 358 study,16 2021 –3.497 1.015 0.03 (0.00-0.22) 12.9
IMCISION trial,13 2020 –0.799 0.401 0.45 (0.20-0.99) 24.8
Schoenfeld et al,17 2020 –2.159 0.61 0.12 (0.03-0.38) 20.2
Uppaluri et al,12 2020 –2.833 0.728 0.06 (0.01-0.25) 17.8
Wise-Draper et al,11 2021 –2.512 0.424 0.08 (0.04-0.19) 24.3
Total (95% CI) 0.11 (0.04-0.29) 100.0
Heterogeneity: τ2 = 0.78; χ2 = 13.90, df = 4 (P = .01); I2 = 71%
Test for overall effect: z = 4.55 (P <.001) 0.001 0.01 0.1 1 10 100
Odds ratio (95% CI)

Pathological complete response (A) and major pathological response (B) at the primary tumor sites in clinical trials. PD-1/PD-L1 indicates programmed cell death
1/programmed cell death 1 ligand 1.

Figure 3. Safety of Neoadjuvant Immunotherapy for Resectable Head and Neck Cancer

A Grade 3 to 4 TRAEs

Log Odds ratio Favors anti– Does not favor

Study or subgroup (odds ratio) SE (95% CI) PD-1/PD-L1 anti–PD-1/PD-L1 Weight, %
CheckMate 358 study,16 2021 –1.705 0.384 0.18 (0.09-0.39) 26.0
Horton et al,14 2019 –2.944 1.451 0.05 (0.00-0.90) 7.5
Kim et al,18 2021 –4.29 1.424 0.01 (0.00-0.22) 7.7
IMCISION trial,13 2020 –0.647 0.372 0.52 (0.25-1.09) 26.3
Schoenfeld et al,17 2020 –1.145 0.434 0.32 (0.14-0.74) 24.8
Uppaluri et al,12 2020 –4.29 1.424 0.01 (0.00-0.22) 7.7
Total (95% CI) 0.17 (0.07-0.41) 100.0
Heterogeneity: τ2 = 0.64; χ2 = 14.38, df = 5 (P = .01); I2 = 65%
Test for overall effect: z = 3.93 (P <.001) 0.01 0.1 1 10 100
Odds ratio (95% CI)

B Surgical delay rate

Log Odds ratio Favors anti– Does not favor
Study or subgroup (odds ratio) SE (95% CI) PD-1/PD-L1 anti–PD-1/PD-L1 Weight, %
CheckMate 358 study,16 2021 –4.317 1.424 0.01 (0.00-0.22) 14.4
CIAO study,15 2019 –3.932 1.428 0.02 (0.00-0.32) 14.3
Horton et al,14 2019 –2.944 1.451 0.05 (0.00-0.90) 13.9
Kim et al,18 2021 –4.29 1.424 0.01 (0.00-0.22) 14.4
IMCISION trial,13 2020 –4.078 1.426 0.02 (0.00-0.28) 14.3
Schoenfeld et al,17 2020 –4.078 1.426 0.02 (0.00-0.28) 14.3
Uppaluri et al,12 2020 –4.29 1.424 0.01 (0.00-0.22) 14.4
Total (95% CI) 0.02 (0.01-0.05) 100.0
Heterogeneity: χ2 = 0.67, df = 6 (P >.99); I2 = 0%
Test for overall effect: z = 7.40 (P <.001) 0.001 0.01 0.1 1 10 100
Odds ratio (95% CI)

Preoperative grade 3 to 4 treatment-related adverse events (TRAEs) (A) and surgical delay rates (B) in clinical trials. PD-1/PD-L1 indicates programmed cell death
1/programmed cell death 1 ligand 1.

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 Research Original Investigation
Combinations of neoadjuvant immunotherapy with che-
motherapy or radiotherapy are being evaluated in clinical
trials.24-27 Whether these combinations have synergistic ef-
fects or provide any therapeutic benefit compared with single-
agent therapy is still under investigation. It has been hypoth-
esized that chemotherapy preceding the administration of
neoadjuvant immunotherapy may increase antigen presenta-
tion by dendritic cells and enhance immune activation against
the tumor, which can potentially increase therapeutic
efficacy.28-31 In this meta-analysis, we analyzed the therapeu-
tic efficacy of the combined approach (neoadjuvant immuno-
therapy with chemotherapy and/or radiation), as reported by
Zinner et al20 and Leidner et al19 separately. Both Zinner et al20
and Leidner et al19 reported higher MPR and pCR than the rest
of the trials included in this meta-analysis. Zinner et al20 re-
ported on 26 patients who received neoadjuvant carboplatin
and paclitaxel in addition to nivolumab and achieved a pCR
rate of 42% and MPR rate of 65%. The remarkable pCR rate of
66.6% and MPR rate of 86.6% observed by Leidner et al19 could
be attributed to the fact that most of the patients included in
the study had tested positive for human papillomavirus (HPV).
These patients greatly responded to irradiation therapy alone,
as demonstrated by an 83% rate of MPR. These results sug-
gest that the superiority of combinatorial neoadjuvant therapy
should be considered with caution owing to the heteroge-
neity of patients’ inclusion criteria (such as HPV status). Other
ongoing trials are NCT03721757, 32 NCT03635164, 33 and
NCT03618134,34 which are investigating the efficacy and safety
outcomes of neoadjuvant immunoradiotherapy and will sub-
mit data in the near future that can help assess the individual
contribution of each modality. Further research is required to
determine the optimal doses, timing, and combinations for best
short- and long-term outcomes.
The present study’s subgroup analyses showed no supe-
riority of immunotherapy alone vs immunotherapy com-
bined with other immune checkpoint inhibitors (CTLA-4
blockade). There was no statistically significant difference
between the various anti–PD-1/PD-L1 agents in terms of effi-
cacy and safety. It has been suggested that downstaging
may decrease the need or the intensity of adjuvant postop-
erative radiation and/or chemotherapy in patients undergo-
ing surgery.6,35 Downstaging was reported in 3 studies in
this analysis (eFigure 5 in the Supplement). The CIAO
study15 even reported reduced intensity of adjuvant radio-
therapy. The risk of severe TRAEs that may delay curative
surgery is a limitation of any neoadjuvant immunotherapy
approach that must be considered. In the present study,
neoadjuvant immunotherapy resulted in almost no TRAEs
that caused surgical delay events.
The use of neoadjuvant chemotherapy prior to surgery in
patients with HNSCC is controversial. Neoadjuvant chemo-
therapy has shown little benefit in a number of reports, with
the pCR rate ranging between 13% and 27%.36-42 In one of the
reports, MPR was observed with neoadjuvant chemotherapy
in 27% of patients.36 Similar rates were reported in neoadju-
vant anti–PD-1/PD-L1 combined with CTLA-4 inhibitors,13,17 and
higher rates were measured when neoadjuvant chemo-
therapy was combined with immunotherapy. In terms of safety,
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Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer
the mean rate of grade 3 to 4 adverse effects in this meta-
analysis was 8.4%, indicating better tolerability compared with
higher rates reported with neoadjuvant chemotherapy (37%).38
Moreover, the death rate with neoadjuvant chemotherapy was
reported to be 3%38 compared with no deaths with neoadju-
vant immunotherapy. This provides further evidence for the
safety of immunotherapy in the neoadjuvant setting.
Early systemic therapy may reduce the risk of distant meta-
static spread and may increase overall survival (OS).6 Neoad-
juvant chemotherapy did not demonstrate survival benefit in
a phase 3 randomized clinical trial with 11.5 years of follow-up.37
As for neoadjuvant immunotherapy, long-term data are still
pending. Schoenfeld et al17 reported an 89% OS rate with 14.2
months of follow-up. At 24 months postsurgery, the Check-
Mate 358 study16 has reported 88.2% and 54.2% recurrence-
free survival (RFS) rates for the HPV-positive and HPV-
negative cohorts, respectively. Association between pathologic
response and long-term outcome was assessed by Wise-
Draper et al,11 who demonstrated considerably improved 1-year
disease-free survival (DFS) in patients with MPR compared with
patients with no pathologic response. Similar association was
reported in the IMCISION trial,13 with considerably better RFS
in patients with more than 90% pathologic response than pa-
tients with less than 90% pathologic response. In the Check-
mate 358 study,16 however, there were no clear associations
between pathologic response and RFS or OS. It should be noted
that these studies have administered different combinatorial
adjuvant therapies and the individual contribution to each mo-
dality in optimizing the long-term outcome should be consid-
ered. Other ongoing clinical trials will report survival data in
the upcoming years. One of these trials is the IMSTAR-HN,43 a
phase 3 clinical trial assessing neoadjuvant nivolumab with and
without ipilimumab as first-line treatment with curative in-
tent for HNSCC. It will report DFS, OS, and progression-free sur-
vival outcomes.
Another potential advantage of the neoadjuvant setting is
the “window” phase that allows the investigation of biomark-
ers that may be associated with treatment response to neoad-
juvant immunotherapy and optimize patient selection.44-47 Po-
tential prognostic biomarkers of HNSCC disease response, such
as PD-L1 expression, tumor immune infiltration, tumor mu-
tational burden, circulating tumor cells or tumor DNA, and
other markers, are currently under evaluation.48,49 Data from
phase 3 randomized trials investigating pembrolizumab in the
recurrent or metastatic setting (KEYNOTE-048 and KEYNOTE-
040) showed considerably increased survival in PD-L1–
positive patients,48-50 suggesting that PD-L1 may be a poten-
tial biomarker. This assoc iation in the neoadjuvant
immunotherapy setting, however, is controversial. Both Up-
paluri et al12 and Wise-Draper et al11 have confirmed an asso-
ciation between PD-L1 expression and improved pathologi-
cal response after neoadjuvant pembrolizumab treatment.
However, PD-L1 expression was not associated with im-
proved pathological response in the trials of Schoenfeld et al,17
Horton et al,14 or the CIAO study,15 suggesting that PD-L1 ex-
pression alone is not sufficient to predict treatment re-
sponse. Further studies are warranted to validate potential pre-
dictive biomarkers.
jamaotolaryngology.com
 Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer Original Investigation Research

Limitations
There are several limitations to this meta-analysis. Half of the
included data were derived from ongoing trials or reported in
conference abstracts, while the results of only 5 of the 10 in-
cluded trials were published in full-text articles. The rela-
tively small number of patients included and the scarcity of
randomized clinical trials are major limitations. Further-
more, the variations in study design, treatment protocols, dif-
ferent immunotherapeutic agents, HPV status, and patient
characteristics all contribute to heterogeneity and limit the
strength of these findings. Lastly, long-term outcomes, such
as DFS and OS, that better indicate treatment efficacy have not
yet been reported.
Conclusions
Results of this systematic review and meta-analysis show that
neoadjuvant immunotherapy demonstrated a therapeutic ben-
efit and that it was well tolerated. Conclusive evidence of its
use awaits more data from trials on neoadjuvant immuno-
therapy in patients with resectable HNSCC.

ARTICLE INFORMATION
Accepted for Publication: July 13, 2021.
Published Online: September 2, 2021.
doi:10.1001/jamaoto.2021.2191
Author Contributions: Dr Muhanna had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Masarwy and
Kampel contributed equally to this work.
Concept and design: Masarwy, Gutfeld, Muhanna.
Acquisition, analysis, or interpretation of data:
Masarwy, Kampel, Horowitz, Muhanna.
Drafting of the manuscript: Masarwy,
Kampel, Muhanna.
Critical revision of the manuscript for important
intellectual content: Masarwy, Horowitz,
Gutfeld, Muhanna.
Statistical analysis: Masarwy, Kampel, Horowitz.
Obtained funding: Muhanna.
Administrative, technical, or material support:
Muhanna.
Supervision: Horowitz, Gutfeld, Muhanna.
Conflict of Interest Disclosures: None reported.
REFERENCES
1. Shin DM, Khuri FR. Advances in the management
of recurrent or metastatic squamous cell carcinoma
of the head and neck. Head Neck. 2013;35(3):443-
453. doi:10.1002/hed.21910
2. Haddad R, O’Neill A, Rabinowits G, et al.
Induction chemotherapy followed by concurrent
chemoradiotherapy (sequential chemoradio-
therapy) versus concurrent chemoradiotherapy
alone in locally advanced head and neck cancer
(PARADIGM): a randomised phase 3 trial. Lancet
Oncol. 2013;14(3):257-264. doi:10.1016/S1470-2045
(13)70011-1
3. Ferris RL, Blumenschein G Jr, Fayette J, et al.
Nivolumab for recurrent squamous-cell carcinoma
of the head and neck. N Engl J Med. 2016;375(19):
1856-1867. doi:10.1056/NEJMoa1602252
and neck squamous cell carcinoma. Oral Oncol.
2017;73:65-69. doi:10.1016/j.oraloncology.2017.08.
008
7. Forde PM, Chaft JE, Smith KN, et al.
Neoadjuvant PD-1 blockade in resectable lung
cancer. N Engl J Med. 2018;378(21):1976-1986.
doi:10.1056/NEJMoa1716078
8. Amaria RN, Prieto PA, Tetzlaff MT, et al.
Neoadjuvant plus adjuvant dabrafenib and
trametinib versus standard of care in patients with
high-risk, surgically resectable melanoma:
a single-centre, open-label, randomised, phase 2
trial. Lancet Oncol. 2018;19(2):181-193. doi:10.1016/
S1470-2045(18)30015-9
9. Moher D, Liberati A, Tetzlaff J, Altman DG;
PRISMA Group. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA
statement. BMJ. 2009;339:b2535. doi:10.1136/
bmj.b2535
10. Stroup DF, Berlin JA, Morton SC, et al.
Meta-analysis of observational studies in
epidemiology: a proposal for reporting.
Meta-analysis Of Observational Studies in
Epidemiology (MOOSE) group. JAMA. 2000;283
(15):2008-2012. doi:10.1001/jama.283.15.2008
11. Wise-Draper TM, Takiar V, Mierzwa ML, et al.
Association of pathological response to
neoadjuvant pembrolizumab with tumor PD-L1
expression and high disease-free survival (DFS) in
patients with resectable, local-regionally advanced,
head and neck squamous cell carcinoma (HNSCC).
J Clin Oncol. 2021;39(suppl 15):6006. doi:10.1200/
JCO.2021.39.15_suppl.6006
12. Uppaluri R, Campbell KM, Egloff AM, et al.
Neoadjuvant and adjuvant pembrolizumab in
resectable locally advanced, human
papillomavirus-unrelated head and neck cancer:
a multicenter, phase II trial. Clin Cancer Res. 2020;
26(19):5140-5152. doi:10.1158/1078-0432.CCR-20-
1695
13. Zuur L, Vos JL, Elbers JB, et al. LBA40
16. Ferris RL, Spanos WC, Leidner R, et al.
Neoadjuvant nivolumab for patients with
resectable HPV-positive and HPV-negative
squamous cell carcinomas of the head and neck in
the CheckMate 358 trial. J Immunother Cancer.
2021;9(6):e002568. doi:10.1136/jitc-2021-002568
17. Schoenfeld JD, Hanna GJ, Jo VY, et al.
Neoadjuvant nivolumab or nivolumab plus
ipilimumab in untreated oral cavity squamous cell
carcinoma: a phase 2 open-label randomized
clinical trial. JAMA Oncol. 2020;6(10):1563-1570.
doi:10.1001/jamaoncol.2020.2955
18. Kim HR, Kim CG, Hong MH, et al. Interim
analysis for window of opportunity trial of single
dose preoperative durvalumab (D) with or without
tremelimumab (T) for operable head and neck
squamous cell carcinoma (HNSCC). J Clin Oncol.
2021;39(suppl 15):e18043. doi:10.1200/JCO.2021.39.
15_suppl.e18043
19. Leidner R, Crittenden M, Young K, et al.
Neoadjuvant immunoradiotherapy results in high
rate of complete pathological response and clinical
to pathological downstaging in locally advanced
head and neck squamous cell carcinoma.
J Immunother Cancer. 2021;9(5):e002485. doi:10.
1136/jitc-2021-002485
20. Zinner R, Johnson JM, Tuluc M, et al. 968P
Neoadjuvant nivolumab (N) plus weekly carboplatin
(C) and paclitaxel (P) outcomes in HPV(-) resectable
locally advanced head and neck cancer. Ann Oncol.
2020;31(suppl 4):S682. doi:10.1016/j.annonc.2020.
08.1083
21. Chen Y-H, Du L, Geng X-Y, Liu G-J. Implement
meta-analysis with non-comparative binary data in
RevMan software. Chin J Evidence-Based Med.
2014;14(7):889-896.
22. Jia XH, Xu H, Geng LY, et al. Efficacy and safety
of neoadjuvant immunotherapy in resectable
nonsmall cell lung cancer: a meta-analysis. Lung
Cancer. 2020;147:143-153. doi:10.1016/j.lungcan.
2020.07.001

4. Haddad R, Seiwert T, Pfister DG, et al.
Pembrolizumab after progression on platinum and
cetuximab in head and neck squamous cell
carcinoma (HNSCC): results from KEYNOTE-055.
Ann Oncol. 2016;27(suppl 6):vi330. doi:10.1093/
annonc/mdw376.09
5. Lau A, Li K-Y, Yang W-F, Su Y-X. Induction
chemotherapy for squamous cell carcinomas of the
oral cavity: a cumulative meta-analysis. Oral Oncol.
2016;61:104-114. doi:10.1016/j.oraloncology.2016.08.
022
6. Hanna GJ, Adkins DR, Zolkind P, Uppaluri R.
Rationale for neoadjuvant immunotherapy in head
Neoadjuvant nivolumab and nivolumab plus
ipilimumab induce (near-) complete responses in
patients with head and neck squamous cell
carcinoma: the IMCISION trial. Ann Oncol. 2020;31
(suppl 4):S1169. doi:10.1016/j.annonc.2020.08.2270
14. Horton JD, Knochelmann H, Armeson K,
Kaczmar JM, Paulos C, Neskey D. Neoadjuvant
presurgical PD-1 inhibition in oral cavity squamous
cell carcinoma. J Clin Oncol. 2019;37(suppl 15):2574.
doi:10.1200/JCO.2019.37.15_suppl.2574
15. Ferrarotto R, Bell D, Rubin ML, et al. Checkpoint
inhibitors assessment in oropharynx cancer (CIAO):
safety and interim results. J Clin Oncol. 2019;37(suppl
15):6008. doi:10.1200/JCO.2019.37.15_suppl.6008
23. Melero I, Berraondo P, Rodríguez-Ruiz ME,
Pérez-Gracia JL. Making the most of cancer surgery
with neoadjuvant immunotherapy. Cancer Discov.
2016;6(12):1312-1314. doi:10.1158/2159-8290.CD-16-
1109
24. Stafford M, Kaczmar J. The neoadjuvant
paradigm reinvigorated: a review of pre-surgical
immunotherapy in HNSCC. Cancers Head Neck.
2020;5:4. doi:10.1186/s41199-020-00052-8
25. Wiegand S, Wichmann G, Dietz A. Perspectives
of induction with chemo and/or immune check
point inhibition in head and neck organ
preservation treatment. Front Oncol. 2019;9:191.
doi:10.3389/fonc.2019.00191

jamaotolaryngology.com (Reprinted) JAMA Otolaryngology–Head & Neck Surgery October 2021 Volume 147, Number 10 877

© 2021 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a Universita Torino User on 05/07/2023

 Research Original Investigation
26. Plavc G, Strojan P. Combining radiotherapy and
immunotherapy in definitive treatment of head and
neck squamous cell carcinoma: review of current
clinical trials. Radiol Oncol. 2020;54(4):377-393.
doi:10.2478/raon-2020-0060
27. Gajewski TF. Fast forward—neoadjuvant cancer
immunotherapy. N Engl J Med. 2018;378(21):
2034-2035. doi:10.1056/NEJMe1803923
28. Liu WM, Fowler DW, Smith P, Dalgleish AG.
Pre-treatment with chemotherapy can enhance the
antigenicity and immunogenicity of tumours by
promoting adaptive immune responses. Br J Cancer.
2010;102(1):115-123. doi:10.1038/sj.bjc.6605465
29. Ramakrishnan R, Gabrilovich DI. Novel
mechanism of synergistic effects of conventional
chemotherapy and immune therapy of cancer.
Cancer Immunol Immunother. 2013;62(3):405-410.
doi:10.1007/s00262-012-1390-6
30. Pasquier E, Kavallaris M, André N. Metronomic
chemotherapy: new rationale for new directions.
Nat Rev Clin Oncol. 2010;7(8):455-465. doi:10.
1038/nrclinonc.2010.82
31. Shurin GV, Tourkova IL, Kaneno R, Shurin MR.
Chemotherapeutic agents in noncytotoxic
concentrations increase antigen presentation by
dendritic cells via an IL-12-dependent mechanism.
J Immunol. 2009;183(1):137-144. doi:10.4049/
jimmunol.0900734
32. CA209-891: Neoadjuvant and adjuvant
nivolumab as immune checkpoint inhibition in oral
cavity cancer (NICO). ClinicalTrials.gov identifier:
NCT03721757. Updated January 5, 2021. Accessed
July 22, 2021. https://clinicaltrials.gov/ct2/show/
NCT03721757
33. Radiotherapy with durvalumab prior to surgical
resection for HPV negative squamous cell
carcinoma. ClinicalTrials.gov identifier:
NCT03635164. Updated May 20, 2021. Accessed
July 22, 2021. https://clinicaltrials.gov/ct2/show/
NCT03635164
34. Stereotactic body radiation therapy and
durvalumab with or without tremelimumab before
surgery in treating participants with human
papillomavirus positive oropharyngeal squamous
cell cancer. ClinicalTrials.gov identifier:
NCT03618134. Updated December 8, 2020.
878 JAMA Otolaryngology–Head & Neck Surgery October 2021 Volume 147, Number 10 (Reprinted)
© 2021 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Universita Torino User on 05/07/2023
Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer
Accessed March 11, 2021. https://clinicaltrials.gov/
ct2/show/NCT03618134
35. Liu J, Blake SJ, Yong MCR, et al. Improved
efficacy of neoadjuvant compared to adjuvant
immunotherapy to eradicate metastatic disease.
Cancer Discov. 2016;6(12):1382-1399. doi:10.1158/
2159-8290.CD-16-0577
36. Zhong LP, Zhang CP, Ren GX, et al. Randomized
phase III trial of induction chemotherapy with
docetaxel, cisplatin, and fluorouracil followed by
surgery versus up-front surgery in locally advanced
resectable oral squamous cell carcinoma. J Clin Oncol.
2013;31(6):744-751. doi:10.1200/JCO.2012.43.8820
37. Bossi P, Lo Vullo S, Guzzo M, et al. Preoperative
chemotherapy in advanced resectable OCSCC:
long-term results of a randomized phase III trial.
Ann Oncol. 2014;25(2):462-466. doi:10.1093/
annonc/mdt555
38. Licitra L, Grandi C, Guzzo M, et al. Primary
chemotherapy in resectable oral cavity squamous
cell cancer: a randomized controlled trial. J Clin Oncol.
2003;21(2):327-333. doi:10.1200/JCO.2003.06.146
39. Marta GN, Riera R, Bossi P, et al. Induction
chemotherapy prior to surgery with or without
postoperative radiotherapy for oral cavity cancer
patients: systematic review and meta-analysis. Eur J
Cancer. 2015;51(17):2596-2603. doi:10.1016/j.ejca.
2015.08.007
40. Wang K, Yi J, Huang X, et al. Prognostic impact
of pathological complete remission after
preoperative irradiation in patients with locally
advanced head and neck squamous cell carcinoma:
re-analysis of a phase 3 clinical study. Radiat Oncol.
2019;14(1):225. doi:10.1186/s13014-019-1428-4
41. Zhang XR, Liu ZM, Liu XK, et al. Influence of
pathologic complete response to neoadjuvant
chemotherapy on long-term survival of patients
with advanced head and neck squamous cell
carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol.
2013;115(2):218-223. doi:10.1016/j.oooo.2012.09.084
42. Kies MS, Boatright DH, Li G, et al. Phase II trial
of induction chemotherapy followed by surgery for
squamous cell carcinoma of the oral tongue in
young adults. Head Neck. 2012;34(9):1255-1262.
doi:10.1002/hed.21906
43. Zech HB, Moeckelmann N, Boettcher A, et al.
Phase III study of nivolumab alone or combined
with ipilimumab as immunotherapy versus
standard of care in resectable head and neck
squamous cell carcinoma. Future Oncol. 2020;16
(36):3035-3043. doi:10.2217/fon-2020-0595
44. Benitez JC, Remon J, Besse B. Current
panorama and challenges for neoadjuvant cancer
immunotherapy. Clin Cancer Res. 2020;26(19):
5068-5077. doi:10.1158/1078-0432.CCR-19-3255
45. Kao H-F, Lou P-J. Immune checkpoint inhibitors
for head and neck squamous cell carcinoma:
current landscape and future directions. Head Neck.
2019;41(suppl 1):4-18. doi:10.1002/hed.25930
46. Wang H-C, Yeh T-J, Chan L-P, Hsu C-M, Cho S-F.
Exploration of feasible immune biomarkers for
immune checkpoint inhibitors in head and neck
squamous cell carcinoma treatment in real world
clinical practice. Int J Mol Sci. 2020;21(20):E7621.
doi:10.3390/ijms21207621
47. Oliva M, Spreafico A, Taberna M, et al. Immune
biomarkers of response to immune-checkpoint
inhibitors in head and neck squamous cell
carcinoma. Ann Oncol. 2019;30(1):57-67. doi:10.
1093/annonc/mdy507
48. Soulieres D, Cohen E, Le Tourneau C, et al.
Updated survival results of the KEYNOTE-040
study of pembrolizumab vs standard-of-care
chemotherapy for recurrent or metastatic head and
neck squamous cell carcinoma. Am Assoc Cancer Res.
2018;78(13). doi:10.1158/1538-7445.AM2018-CT115
49. Cohen EEW, Soulières D, Le Tourneau C, et al;
KEYNOTE-040 investigators. Pembrolizumab
versus methotrexate, docetaxel, or cetuximab for
recurrent or metastatic head-and-neck squamous
cell carcinoma (KEYNOTE-040): a randomised,
open-label, phase 3 study. Lancet. 2019;393
(10167):156-167. doi:10.1016/S0140-6736(18)
31999-8
50. Burtness B, Harrington KJ, Greil R, et al.
KEYNOTE-048: phase III study of first-line
pembrolizumab (P) for recurrent/metastatic head
and neck squamous cell carcinoma (R/M HNSCC).
Ann Oncol. 2018;29(suppl 8):viii729. doi:10.1093/
annonc/mdy424.045
jamaotolaryngology.com