Efficacy and Safety of PD-1 Inhibitor Combined With Chemotherapy in Locally Advanced (III-IVB) Poorly Differentiated Head and Neck Squamous Cell Carcinoma: a Multi Cohort, Prospective Phase II Study
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Beijing Tongren Hospital

Attachment 1: Research Protocol Template 
(Interventional Study) 
 
 
 
 Project Name (Chinese): Efficacy and safety of PD-1 inhibitor 
combined with chemotherapy in locally advanced (III-IVB) poorly 
differentiated head and neck squamous cell carcinoma: a multi cohort, 
prospective phase II study                                  
 Project Name (English): Efficacy and safety of PD-1 inhibitor combined with 
chemotherapy in locally advanced (III-IVB) poorly differentiated head and 
neck squamous cell carcinoma: a multi cohort, prospective phase II study                 
Version Number: V1.3                                
Version Date: 2023-1-18                                  
Department: Otolaryngology Head and Neck Surgery               
Project Leader: Chen Xiaohong                                
 
 
 
 
 
 
 
 
 
 

I. Research Background and Project Basis 
Please briefly describe the 'medical research content' of this study, 
explain the reasons for conducting intervention research, the current 
domestic and international research status, existing problems, and propose 
research hypotheses. 
Background: 
Head and neck squamous cell carcinoma (HNSCC) refers to a series of 
tumors that occur in the head and neck region, with more than 90% of the 
pathological types being squamous cell carcinoma, and most head and neck 
tumor patients are already in the locally advanced (III-IVB) or advanced 
stage when they seek medical treatment. Currently, data shows that the 5-
year survival rates of patients with locally advanced and metastatic head 
and neck squamous cell carcinoma using standard treatment are 50% and 25% 
respectively. 50% to 60% of newly diagnosed subjects will experience 
recurrence or metastasis within 3 years. 
Poorly differentiated squamous cell carcinoma is a pathological subtype 
of HNSCC, which has strong invasiveness, high rates of distant metastasis 
and regional metastasis, and shows completely different characteristics 
from well-differentiated squamous cell carcinoma in terms of biological 
behavior. The treatment effect is poor due to the high rate of distant 
metastasis, and the prognosis is very poor. Studies have shown that there 
is a 30% difference in the overall 5-year survival rate between patients 
with well-differentiated and poorly differentiated throat squamous cell 
carcinoma. 
PD-L1 is a key negative regulatory factor of self-reactive T cells and 
plays a role in maintaining peripheral immune tolerance and inhibiting 
self-immunity in multiple ways, leading to T cell exhaustion and 
dysfunction, and tumor cells evading immune surveillance. PD-1/PD-L1 
monoclonal antibodies restore the function of tumor-specific T cells by 
blocking the binding of PD-1 and PD-L1, and enhance anti-tumor immune 

response. They have been used in the treatment of various tumors. In 2016, 
the FDA approved pembrolizumab for the treatment of platinum-resistant 
recurrent or metastatic head and neck squamous cell carcinoma. In 2020, 
pembrolizumab combined with chemotherapy can be used as a first-line 
treatment for recurrent/metastatic head and neck squamous cell carcinoma. 
Although the efficacy of PD-1 monoclonal antibodies as neoadjuvant therapy 
in head and neck squamous cell carcinoma is not yet clear, considering the 
good effect of immunotherapy in head and neck squamous cell carcinoma, PD-1 
monoclonal antibodies are expected to have promising clinical application 
prospects for the induction therapy of poorly differentiated squamous cell 
carcinoma. In recent years, multiple studies have suggested that 
neoadjuvant therapy using nivolumab combined with cisplatin and paclitaxel 
has good tolerability and satisfactory efficacy. 
Keywords (5): head and neck squamous cell carcinoma, poorly 
differentiated, locally advanced tumor, PD-L1, chemotherapy 
II. Research objectives and research content  
(I) Research objectives  
By conducting comprehensive genomic testing and analysis on patients 
with poorly differentiated head and neck squamous cell carcinoma in stage 
III-IVB (excluding nasopharyngeal carcinoma), personalized guidance for the 
treatment of poorly differentiated squamous cell carcinoma can be provided. 
The combination of PD-1 inhibitors with platinum-based and paclitaxel-based 
regimens may be safer, more effective, and easier to apply in clinical 
practice. By combining tumor tissue CPS expression, TMB, gene expression 
profiles, and peripheral blood lymphocyte immune characteristics, we aim to 
find a more effective and safe treatment regimen for poorly differentiated 
squamous cell carcinoma. 
(II) Research Content 
Patients with locally advanced (III-IVB) poorly differentiated head and neck squamous cell 
carcinoma (excluding nasopharyngeal carcinoma) who meet the inclusion criteria will have their 

blood samples collected, tumor tissue samples or patient paraffin tissue, and slides for 
comprehensive genomic sequencing and analysis. The study is divided into two groups. Arm1 
group: Patients with stage IVB (T4bNxM0) poorly differentiated head and neck squamous cell 
carcinoma (excluding nasopharyngeal carcinoma) will receive PD-1 combined with platinum-based 
chemotherapy and albumin-bound paclitaxel (dose according to the drug instructions) for 2 to 3 
cycles (determined by the researcher based on tumor shrinkage). If the imaging achieves complete 
response (CR) or partial response (PR), suitable patients will undergo surgical treatment. Patients 
who are not suitable for surgery or have stable disease (SD)/progressive disease (PD) will receive 
concurrent chemoradiotherapy or concurrent chemoradiotherapy combined with PD-1 treatment (up 
to a total of 17 cycles). Arm2 group: Patients with stage III and IVA (T3NxM0, T4aNxM0) poorly 
differentiated head and neck squamous cell carcinoma (excluding nasopharyngeal carcinoma) will 
receive PD-1 combined with platinum-based chemotherapy and albumin-bound paclitaxel (dose 
according to the drug instructions) for 2 cycles. Patients who undergo surgery within 2 weeks will 
receive PD-1 monotherapy maintenance treatment or low-dose radiotherapy followed by PD-1 
monotherapy maintenance treatment based on pathological results. Patients who do not achieve 
pathological complete response (pCR) and have positive surgical margins or extracapsular 
extension will receive concurrent chemoradiotherapy followed by PD-1 maintenance treatment (up 
to a total of 17 cycles). Patients without high-risk factors will receive PD-1 maintenance treatment 
after radiotherapy (up to a total of 17 cycles). After completion of treatment, all patients will be 
followed up every 3 months for 1 year. Subsequently, patients will be followed up every 6 months 
for 3 years. Thereafter, patients will be followed up annually. Patient recurrence and survival data 
will be recorded. 
 
(III) Study Outcome Measures  
Primary Study Outcome Measures and Definitions  
Overall Survival (OS), 1-year/2-year Distant Metastasis Rate: Kaplan-Meier analysis will be 
used to analyze the time from the start of PD-1 combined with platinum-based and albumin-
paclitaxel treatment to the end of data collection (including distant metastasis, local treatment 
failure, and death), and Kaplan-Meier curves will be plotted. The difference in median OS (mOS) 
will also be calculated (95% bilateral confidence interval). 

Secondary Study Outcome Measures and Definitions 
Among the secondary efficacy measures, the proportion of infiltrating squamous cell 
carcinoma in the resected primary tumor specimen and all sampled lymph nodes (mPR) will be 
determined based on real-time results, with mPR defined as ≤10%. If further stratified analysis 
is desired for CPS≥1 and CPS＜1, weighted analysis can be performed using the Miettinen 
method with a 95% bilateral confidence interval. PFS analysis will be conducted similarly to OS. 
 
Primary, secondary, and other outcome measures, including 
specific measurement variables (such as systolic blood pressure), 
quantitative analysis (such as changes from baseline),final 
values,time to occurrence of endpoint events, etc.), methods of data 
integration (such as median, proportion), and time points for each 
outcome measure. Strongly recommend explaining the relevance of the 
selected efficacy or harm outcome measures to clinical practice. 
Indicate whether there is involvement of biospecimen collection. 
Describe how various measures are assessed. 
III. Study Design 
(1) Overall Study Design  
Provide a description of the study design, including the type of 
trial design (such as parallel, crossover, factorial design), 
allocation ratio of subjects in each group, and the study type (such 
as superiority, equivalence, non-inferiority, exploratory). 
A prospective, multicenter, non-randomized phase II clinical 
trial. 
√Complete CPS and HPV testing before treatment; 
√Complete genetic testing before treatment: TMB, TP53BP1, KRAS, 
DDR, GEP, EGFR, and other related genes 
√For patients who meet the inclusion criteria: 
1. Locally advanced (stage IVB, T4bNxM0) poorly differentiated 

head and neck squamous cell carcinoma (excluding nasopharyngeal 
carcinoma) patients receive PD-1 inhibitor combined with platinum-
based chemotherapy and albumin-bound paclitaxel (dose according to 
the drug instructions) for 2 to 3 cycles (determined by the 
investigator based on tumor shrinkage),  
2. Locally advanced poorly differentiated head and neck squamous 
cell carcinoma (excluding nasopharyngeal carcinoma) patients with 
stage III and IVA (T3NxM0, T4aNxM0) receive PD-1 inhibitor combined 
with platinum-based chemotherapy and albumin-bound paclitaxel (dose 
according to drug instructions) for 2 cycles. Patients who undergo 
surgery within 2 weeks based on pathological results are given PD-1 
monotherapy maintenance treatment or low-dose radiotherapy followed 
by PD-1 monotherapy maintenance treatment if they achieve 
pathological complete response (pCR). Non-pCR patients with positive 
surgical margins or extracapsular extension after surgery receive PD-
1 maintenance treatment after concurrent chemoradiotherapy (up to a 
maximum of 17 cycles). Patients without high-risk factors receive PD-
1 maintenance treatment after radiotherapy (up to a maximum of 17 
cycles).  
(II) Duration of the study 
Start time, end time, follow-up status, and follow-up interval. 
November 1, 2023 - October 31, 2025. 
Based on enrolling 4-5 patients per month, a total of 100 patients 
are planned to be enrolled. The enrollment period is estimated to 
be around 24 months. The treatment group closely monitors adverse 
reactions to chemotherapy, recording the timing, grading, 
management measures, outcomes, etc. All patients must undergo 
evaluation after receiving 2 cycles of PD-1 combined with 
platinum-based and albumin paclitaxel treatment (Arm 1 may receive 

a third cycle of treatment based on tumor regression). If they 
meet the criteria for surgery, they must undergo surgical 
treatment within 2 weeks and complete the evaluation within 4 
weeks after surgery. PD-1 monotherapy maintenance treatment (up to 
14 cycles), with a follow-up examination every 3 months during the 
maintenance treatment period. After completion of treatment, all 
patients will have a follow-up examination every 3 months for 1 
year. Afterwards, a follow-up examination will be conducted every 
6 months for 3 years. Subsequently, an annual follow-up 
examination will be conducted. Record patient recurrence and 
survival data. 
(3) Brief flowchart and visit table of the study 
 
(4) Study subjects 
1. Inclusion criteria  
√Patients with locally advanced (III-IVB) poorly differentiated 
head and neck tumors (hypopharyngeal cancer, laryngeal cancer, 
oropharyngeal cancer, nasal cavity and sinus cancer, excluding 
nasopharyngeal cancer) with a confirmed diagnosis by histology 
and/or cytology; 

√Patients who can receive systemic treatment or PD-1/L1 
monotherapy before treatment; 
√Patients in arm2 must be evaluated as having resectable tumors 
before treatment; 
√The investigator believes that the patient can safely receive 
PD-1 combined with platinum-based and albumin-bound paclitaxel 
treatment; 
√Age ≥ 18 years; 
√ECOG 0-1； 
√Measurable disease defined by RECIST v1.1; 
√Adequate bone marrow reserve and organ function: absolute 
neutrophil count (ANC) ≥ 1,000/μL, platelets ≥ 75,000/μL, 
hemoglobin ≥ 8g/dL, no transfusion or erythropoietin (EPO) 
dependence (within 7 days of assessment); 
√Renal function: serum creatinine ≤ 1.5X upper limit of normal 
(ULN) OR measured or calculated creatinine clearance ≥ 60mL/min, 
creatinine level > 1.5X institutional ULN. (GFR can also be used 
instead of creatinine or CrCl). Creatinine clearance should be 
calculated according to institutional standards; 
√Liver function: For subjects with total bilirubin levels >1.5 
ULN, serum total bilirubin ≤1.5X ULN or direct bilirubin ≤ULN; 
For patients with liver metastasis, aspartate aminotransferase 
(AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤2.5X ULN or 
≤5X ULN; Albumin > 2.5 mg/dL; 
√Coagulation function: International normalized ratio (INR) or 
prothrombin time (PT) ≤1.5X ULN, if subjects require 
anticoagulant therapy, PT or PTT should be within the allowable 
range of anticoagulant use; 
√Women should agree to use contraception during the study and 

for 6 months after the end of the study (such as intrauterine 
devices (IUDs), contraceptive pills, or condoms); Within 7 days 
before study enrollment, serum or urine pregnancy test should be 
negative, and patients must be non-lactating; Men should agree to 
use contraception during the study and for 6 months after the end 
of the study. 
2. Exclusion criteria  
√Patients who have previously received PD-1/L1 combined 
chemotherapy drugs; 
√Patients with a history of other malignant tumors (including 
unknown primary) within the past 5 years. Note: Excluding stage 1 
or 2 skin basal/squamous cell carcinoma or in situ carcinoma 
receiving potentially curative treatment; 
√Patients who cannot tolerate postoperative radiotherapy; 
√Patients known to be allergic to the study drug or its active 
ingredients or excipients; 
√Patients with any unstable systemic diseases, including but 
not limited to: severe infection, uncontrolled diabetes, unstable 
angina, cerebrovascular accident or transient ischemic attack, 
myocardial infarction, congestive heart failure, severe arrhythmia 
requiring medication, liver, kidney, or metabolic diseases; 
√Patients with underlying immune deficiencies, chronic 
infections, including HIV, hepatitis, tuberculosis (TB), or 
autoimmune diseases; 
√Patients with potential hematologic issues, including bleeding 
diathesis, known prior gastrointestinal bleeding requiring 
intervention within the past 6 months, active pulmonary embolism 
or deep vein thrombosis (DVT) unstable on anticoagulation regimen; 
√History or evidence of active non-infectious pneumonia; 

√Known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis or leptomeningeal disease. Subjects with 
prior treated brain metastases may participate as long as they are 
stable (no evidence of imaging progression for at least four weeks 
prior to the first trial treatment and any neurological symptoms 
have returned to baseline), no new or enlarging brain metastases, 
and no use of steroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous 
meningitis, which will be excluded regardless of clinical 
stability; 
√Within 7 days before the first day of the first cycle, at the 
same time (or receiving) treatment with drugs that may affect drug 
metabolism; 
√Pregnant or breastfeeding, or expecting to become pregnant or 
give birth during the expected trial period; 
√Any uncontrolled concurrent disease, including but not limited 
to persistent or active infection, symptomatic congestive heart 
failure, unstable angina, arrhythmia; 
√Screening EKG> 475 msprolonged corrected QT (QTc) interval; 
√Ejection fraction <40% by 2D echocardiogram (ECHO) during 
screening; 
√Any serious medical or mental illness/symptoms, including 
substance use disorders, may interfere with or limit compliance 
with study requirements/treatments in the investigator's judgment; 
√Having active autoimmune diseases requiring systemic treatment 
in the past 2 years (even with disease-modifying agents, 
corticosteroids, or immunosuppressive drugs). Alternative 
therapies (e.g., thyroid hormone, insulin, or physiological 
corticosteroid replacement therapy for adrenal or pituitary 

insufficiency) are not considered a form of systemic treatment. 
Exclusion criteria: 
1) Does notmeet inclusion criteria; 
2) Did not receive treatment according to the study protocol; 
3) Withdrawal of informed consent. 
3. Withdrawal criteria  
(1) Subjects withdraw informed consent to participate in the study and refuse further 
follow-up; 
(2) The investigator determines other necessary reasons to withdraw from the study, such 
as the subject losing the ability to express their will due to imprisonment or isolation; 
(3) Lost to follow-up; 
(4) Subject death; 
(5) Sponsor terminates the study. 
 
Indicate whether healthy volunteers are accepted and whether 
vulnerable groups are involved. 
(V) Definition of treatment/intervention groups and controls  
Group A: Locally advanced poorly differentiated head and neck squamous cell carcinoma (stage 
IVB, T4bNxM0) patients receive PD-1 inhibitor combined with platinum-based chemotherapy 
and albumin-bound paclitaxel (dose according to drug instructions) for 2 to 3 cycles (determined 
by the investigator based on tumor shrinkage). Patients achieving complete response (CR) or 
partial response (PR) on imaging are suitable for surgical treatment. Patients who are not suitable 
for surgery or have stable disease (SD)/progressive disease (PD) receive concurrent 
chemoradiotherapy or concurrent chemoradiotherapy combined with PD-1 treatment (up to a 
maximum of 17 cycles). 
Group B: Locally advanced (III-IVA) poorly differentiated head and neck squamous cell carcinoma 
patients (excluding nasopharyngeal carcinoma) with stage T3NxM0 or T4aNxM0 receive PD-1 
inhibitor combined with platinum-based chemotherapy and albumin-bound paclitaxel (dose 
according to drug instructions) for 2 cycles. Patients who undergo surgery within 2 weeks based on 
pathological results are given PD-1 monotherapy maintenance treatment or low-dose radiotherapy 

followed by PD-1 monotherapy maintenance treatment if they achieve pathological complete 
response (pCR). Non-pCR patients with positive surgical margins or extracapsular extension after 
surgery receive PD-1 maintenance treatment after concurrent chemoradiotherapy (up to a maximum 
of 17 cycles). Patients without high-risk factors receive PD-1 maintenance treatment after 
radiotherapy (up to a maximum of 17 cycles). After completion of treatment, all patients are 
followed up every 3 months for 1 year. Afterwards, patients are followed up every 6 months for 3 
years. Subsequently, patients are followed up annually. Record patient's recurrence and survival 
data. 
(VI) Randomization, allocation concealment, and blinding method 
1. Methods for generating random sequence allocation  
Describe the specific randomization method used. If 
stratification is used, provide details on the stratification 
factors. 
No randomization method was employed. 
2. Concealment of random allocation  
Describe the method used for executing random allocation, such as 
central randomization, sealed opaque envelopes, etc. 
No random allocation method was employed. 
3. Blinding and unblinding 
Specify who was blinded after implementing the intervention 
(e.g., subjects, healthcare providers, outcome assessors, data 
analysts) and how blinding was implemented. If blinding was 
implemented, describe the circumstances under which unblinding can 
occur and the procedures for emergency unblinding during the trial. 
Not implementedBlind method and unblinding. 
(VII) Study procedures  
1. Study treatment/intervention period  
Describe the interventions in each group, including how and when 
the intervention is administered; It is recommended to include a 

study schedule, which should include screening period, treatment 
period, and follow-up period, etc. 
Patients with locally advanced (III-IVB) poorly differentiated 
head and neck squamous cell carcinoma (hypopharyngeal cancer, 
laryngeal cancer, oropharyngeal cancer, nasal cavity and paranasal 
sinus cancer, oral cancer, excluding nasopharyngeal cancer) receive 
PD-1 inhibitor combined with platinum-based chemotherapy and albumin-
bound paclitaxel (dose according to the drug instructions) for 2 to 3 
cycles (determined by the investigator based on tumor shrinkage in 
patients). If the imaging reaches CR/PR, suitable patients undergo 
surgical treatment, while patients unsuitable for surgery or with 
SD/PD receive subsequent concurrent chemoradiotherapy or concurrent 
chemoradiotherapy combined with PD-1 treatment (total of no more than 
17 cycles). 
Patients with locally advanced poorly differentiated head and neck 
squamous cell carcinoma (III-IVA stage, T3NxM0, T4aNxM0), excluding 
nasopharyngeal carcinoma, including hypopharyngeal cancer, laryngeal 
cancer, oropharyngeal cancer, and nasal cavity and paranasal sinus 
cancer, receive PD-1 inhibitor combined with platinum-based 
chemotherapy and albumin-bound paclitaxel (dose according to drug 
instructions) for 2 cycles. Patients who undergo surgery within 2 
weeks based on pathological results are given PD-1 monotherapy 
maintenance treatment or PD-1 monotherapy maintenance treatment after 
low-dose radiotherapy for pathological complete response (pCR) 
patients. For non-pCR patients with positive surgical margins or 
extracapsular extension after surgery, PD-1 maintenance treatment 
after concurrent chemoradiotherapy (up to a maximum of 17 cycles) is 
given. If there are no high-risk factors, PD-1 maintenance treatment 
after radiotherapy (up to a maximum of 17 cycles) is given. After 

completion of treatment, all patients are followed up every 3 months 
for 1 year. Afterwards, patients are followed up every 6 months for 3 
years. Subsequently, patients are followed up annually. Record 
patient's recurrence and survival data. 
 
2. Administration method and dose adjustment  
Pembrolizumab in combination with cisplatin and albumin-bound 
paclitaxel, with 3 weeks (21 days) as 1 cycle. On the first day (D1) 
of each cycle, intravenous infusion of pembrolizumab injection 200mg 
is given, and chemotherapy can be initiated after completion of 
pembrolizumab infusion. For subsequent adjuvant or maintenance 
therapy, pembrolizumab is administered at 200mg IV Q3W, with a 
maximum duration of 1 year. 
Chemotherapy drug dose adjustment: Dose adjustment of cisplatin 
and albumin-bound paclitaxel should refer to the approved product 
instructions for standardized chemotherapy regimens. During the study, 
if the investigator determines that the subject cannot tolerate the 
toxicity of chemotherapy drugs (such as grade 4 hematologic toxicity, 
grade ≥3 febrile neutropenia, and grade ≥3 non-hematologic toxicity 
excluding nausea and vomiting), the dose of chemotherapy drugs can be 
adjusted based on the investigator's judgment. In principle, two dose 
adjustments are allowed. It is recommended to adjust the dose to 75% 
of the original dose for the first adjustment, and 50% of the original 
dose for the second adjustment. 
Dose adjustment of pembrolizumab: Depending on the individual 
patient's safety and tolerability, administration may need to be 
temporarily suspended or discontinued. It is not recommended to 
increase or decrease the dose. Pembrolizumab may be interrupted for 
reasons other than treatment-related adverse events (such as 

medical/surgical events or logistical reasons unrelated to the study 
treatment). Unless otherwise discussed with the investigator, 
subjects should resume study treatment within 3 weeks after planned 
interruption. The reason for interruption should be documented in the 
subject's study records . 
 
3. Concurrent therapy, follow-up visits  
Describe the relevant interventions allowed or prohibited during 
the trial. 
Concomitant therapy: If it is deemed necessary for the health of 
the subjects to receive a certain drug treatment and it is expected 
not to interfere with the evaluation of pembrolizumab or interact with 
it, it can continue to be used during the study. All concomitant 
medications must be reported in the Case Report Form (CRF). In addition, 
any diagnoses, treatments, or surgeries performed during the trial 
should be recorded, including the dates, indications, interventions, 
and descriptions of any clinical findings. Patients are not allowed to 
receive any other anticancer treatments during the trial. 
Follow-up visit: All patients need to be evaluated after 
receiving 2 cycles of PD-1 combined with platinum-based and albumin 
paclitaxel treatment (Arm 1 will receive a third cycle of treatment 
based on tumor regression). If the surgical indication is met, 
surgery should be performed within 2 weeks and evaluation should be 
completed within 4 weeks after surgery. PD-1 monotherapy 
maintenance treatment (up to 14 cycles), during the maintenance 
treatment re-evaluation every 3 months. After completion of 
treatment, all patients will be re-evaluated every 3 months for 1 
year; Subsequently, re-evaluation will be conducted every 6 months 
for 3 years; Afterwards, re-evaluation will be conducted annually; 

Record patient recurrence and survival data. 
For specific treatment methods of irAEs, please refer to NCCN 
Guidelines Version 3.2023 Management of Immune Checkpoint 
Inhibitor-Related Toxicities. 
 
4. Patient compliance and withdrawal  
Patients who meet the requirements and participate in this study 
will enjoy the following benefits: 
(1) The professional head and neck malignant tumor MTB (Molecular 
Tumor Board, including experts from head and neck surgery, 
pathology, oncology, radiation therapy, imaging, and 
bioinformatics) team will individually analyze your relevant test 
results and provide professional guidance for your treatment plan. 
(2) You can enjoy a free genomic sequencing analysis service once 
(worth about 12,000 yuan/time, 100 cases). 
(3) You can enjoy a free CPS test once (worth 1500/ case) 
(4) PD-1 inhibitor cost discount program: Taking pembrolizumab as 
an example: Induction immunotherapy: 4 courses at own expense + 13 
courses as a gift (worth 460,000); Maintenance immunotherapy: 4 
courses at own expense + 31 courses as a gift (worth 1.06 million). 
 
5. Deviation from the protocol 
When there is a deviation from the protocol, it should be first 
discussed with the relevant parties. If no agreement is reached, the 
trial can be terminated according to the rights of the trial sponsor. 
During the negotiation, the Ethics Committee (EC)/Institutional 
Review Board (IRB) must be notified. If the trial needs to be 
terminated or the trial center needs to be closed prematurely, all 
research materials (except for the documents that must be archived at 

the trial center) must be returned to the trial sponsor. The 
investigator will retain all other documents until notified by the 
trial sponsor to destroy them. Events that may lead to early 
termination of the trial or closure of the trial center include, but 
are not limited to: new drug toxicity results, trial benefits and 
follow-up completion of subjects, non-compliance with the trial 
protocol, changes in the research and development plan of the 
investigational drug, slow progress in subject recruitment, or poor 
data quality.  
 
(VIII) Evaluation  
1. Evaluation of therapeutic efficacy and intervention effects  
1.1 Primary efficacy indicators 
The primary efficacy indicator of this study is ORR, which is the 
proportion of subjects with objective relief evaluated based on 
RECIST 1.1 criteria (Appendix III). 
Objective response rate (ORR): The proportion of subjects with 
best overall response (BOR) assessed as complete response (CR) or 
partial response (PR) according to RECIST 1.1 criteria. 
1.2 Secondary efficacy indicators 
Progression-free survival (PFS): Defined as the time from 
randomization to the date of first disease progression or death due 
to any cause, whichever occurs first. 
Disease Control Rate (DCR): According to RECIST v1.1 criteria, it 
assesses the proportion of subjects with complete response (CR), 
partial response (PR), and stable disease (SD) in terms of overall 
best response (BOR). 
Time to objective response (TTR): Defined as the duration from 
the start of medication to the date of first documented CR or PR 

(whichever occurs first). Tumor response is based on confirmed tumor 
response, and the response date is from the first observation, not 
the confirmed response. 
Duration of Response (DOR): The duration from the date of first 
assessment as CR or PR to the date of first assessment as disease 
progression or death for subjects who achieved complete response or 
partial response (CR or PR). 
 
2. Safety assessment  
2.1 Baseline signs and symptoms  
Vital signs, including temperature, respiratory rate, heart rate, 
blood pressure. If there are any relevant discomfort symptoms during 
treatment, additional tests can be performed at any time. 
Physical examination and weight measurement, including general 
condition, skin, head and neck (including ears, eyes, nose, throat), 
respiratory system, cardiovascular system, lymph nodes, thyroid, 
abdomen, skeletal muscles (including spine and limbs), nervous 
system. Targeted physical examination can be performed if clinically 
indicated during treatment. Weight measurement is performed at each 
follow-up visit during each cycle. 
 
2.2 Laboratory Safety Assessment  
Samples such as blood and urine will be collected according to the experimental 
flowchart and analyzed in the local laboratory. The detailed laboratory examination items 
are shown in Table 2: 
2
 
 
Item 
Content 
Complete Blood 
Count 
Hemoglobin, red blood cells, white blood cells, neutrophil count, 
lymphocyte count, and platelet count
 

Blood 
Biochemistry/Elec
trolytes 
Total bilirubin, conjugated bilirubin, ALT, AST, ALP, γ-GGT, 
total protein, albumin, urea or urea nitrogen, creatinine, uric 
acid, 
lactate 
dehydrogenase, 
fasting 
blood 
glucose, 
triglycerides, 
cholesterol, 
potassium, 
sodium, 
chloride, 
calcium, phosphorus, lipase (only when there are suspected 
symptoms of pancreatitis during screening and follow-up), 
amylase (only when there are suspected symptoms of pancreatitis 
during screening and follow-up) 
Urinalysis 
Urinary protein, glucose, occult blood (red blood cells, white 
blood cells). If the semi-quantitative method during the 
screening phase shows urinary protein 2+ , a 24-hour urinary 
protein quantitative test is required. If the semi-
quantitative method during the treatment phase shows protein 
2+/3+  in two consecutive visits, a 24-hour urinary protein 
quantitative test is required; If the semi-quantitative 
method shows urinary protein > 3+ , a 24-hour urinary protein 
quantitative test should be directly performed.  
Virological 
examination 
Hepatitis B five-item test (HBsAg, HBsAb, HBcAb, HBeAg, HBeAb). If 
hepatitis B surface antigen (HBsAg) is positive, viral load HBV-DNA 
quantitative test should be performed; For individuals with positive anti-
hepatitis C virus antibodies (anti-HCV antibodies), HCV viral load (HCV 
RNA) testing should be conducted; HIV antibody test. 
 
2.3 Physical examination and vital signs  
Vital signs, including temperature, respiratory rate, heart rate, blood pressure. If there 
are any relevant discomfort symptoms during treatment, additional tests can be performed 
at any time. 
Physical examination and weight measurement, including general condition, skin, 
head and neck (including ears, eyes, nose, throat), respiratory system, cardiovascular 
system, lymph nodes, thyroid, abdomen, skeletal muscles (including spine and limbs), 
nervous system. Targeted physical examination can be performed if clinically indicated 
during treatment. Weight measurement is performed at each follow-up visit during each 
cycle. 
 
(9) Adverse event reporting 
1. Adverse events  
Description of the collection, assessment, reporting, and 

handling plan for any adverse events and other unexpected reactions 
during the intervention measures or implementation process. Adverse 
event assessment includes type and severity, timing, relevance, and 
outcome. 
2. Definition of adverse events (AE) 
AE refers to any adverse medical event that occurs in a clinical trial subject after 
receiving a drug, but it does not necessarily have a causal relationship with the treatment. 
AE can be any unfavorable unexpected symptom, sign, laboratory abnormality, or disease, 
including at least the following situations: 
(1) Existing medical conditions/diseases that were present before entering the clinical 
trial are only considered adverse events if they worsen (including worsening of symptoms, 
signs, and laboratory abnormalities) after starting the investigational drug; 
(2) Any newly occurring adverse event: any newly occurring medical condition 
(including symptoms, signs, newly diagnosed diseases); 
(3) Clinically significant abnormal laboratory test results. 
Diagnostic or therapeutic invasive procedures (such as surgery) and non-invasive 
procedures should not be reported as adverse events, but if the disease condition that led to 
such procedures meets the definition of an adverse event, it should be reported. For example, 
acute appendicitis occurring during the reporting period should be reported as an adverse 
event, while the appendectomy performed as a result should be recorded as the treatment 
method for that adverse event. 
Researchers should carefully record any AEs that occur in subjects, including: AE 
name, onset and end time, severity (graded according to version <5.0> of NCI CTCAE), 
AE relatedness to the investigational drug, duration, measures taken for the AE with the 
investigational drug, AE outcome, and whether it is a serious adverse event. 
 
3. Abnormal examination results  
If AST and/or ALT levels are abnormal and accompanied by abnormal elevation of 
total bilirubin levels, and if the following (1), (2), (3) conditions are met without any other 
causes for the abnormalities, the SAE reporting process should be followed. 

Meeting the criteria 
Criteria for judgment 
(1) Abnormal ALT or AST 
Baseline normal: ALT or AST during treatment > 3×ULN; 
Baseline abnormal: ALT or AST during treatment > 2×baseline level, 
and value > 3×ULN; or value > 8×ULN. 
(2) TBIL abnormal 
Baseline normal: TBIL during treatment > 2×ULN; 
Baseline abnormal: TBIL during treatment increased > 1×ULN or its 
value > 3×ULN. 
(3) No hemolysis, and alkaline phosphatase < 2×ULN (or information not available) 
ULN: Upper limit of normal 
If the subject has abnormal levels of AST and/or ALT and concurrent abnormal 
elevation of total bilirubin levels during the safety follow-up period, it is recommended to 
return to the study center for evaluation and confirmation as soon as possible (preferably 
within 48 hours) after learning about the abnormal results. 
 
4. Serious Adverse Events (SAE)  
SAE refers to adverse events that meet one or more of the following criteria during 
the clinical research process: 
•   Events leading to death; 
•   Events that are life-threatening (the term 'life-threatening' refers to the presence 
of a risk of death at the time of the event/reaction; it does not imply that worsening of the 
condition may lead to death); 
•   Events requiring hospitalization or prolongation of hospital stay; 
•   Events leading to permanent or severe disability/loss of function; 
•   Congenital abnormalities or birth defects; 
•   Other important medical events (referring to events/reactions that may not 
immediately endanger life, cause death or hospitalization, but may harm the subjects or 
may require intervention [such as medication or surgery] to prevent the serious 
consequences listed in the above definition, based on reasonable medical and scientific 
judgment). 
5. Severity assessment 

Refer to the grading criteria for drug-related adverse events in NCI-CTCAE version 
5.0. If the observed adverse event is not listed in the CTCAE version 5.0 grading criteria, 
refer to Table 3: 
3
 
 
Grading 
Criteria for judgment 
Grade 1 
Mild; No clinical symptoms or mild clinical symptoms; Only clinical or laboratory 
abnormalities; No treatment required 
Grade 2 
Moderate; Requires minor, local, or non-invasive treatment; Limitation in activities of daily 
living using age-appropriate tools* 
Grade 3 
Severe illness or medically significant symptoms that are not immediately life-threatening; 
Results in hospitalization or prolonged hospital stay; Results in disability; Limitation in 
activities of daily living (ADL) self-care**. 
Grade 4 
Life-threatening; Requires urgent treatment. 
Grade 5 
Adverse events leading to death. 
Activities of daily living (ADL) 
*Activities of daily living using tools refer to cooking, shopping, making phone calls, counting money, etc. 
**Activities of daily living self-care refer to bathing, dressing and undressing, eating, using the toilet, taking medication, etc., 
excluding bedridden individuals. 
Pay attention to the severity and seriousness of adverse events. For example, "severe 
headache" may be severe in terms of severity, but it cannot be classified as a serious adverse 
event (SAE) unless it meets the criteria for SAE. 
 
6. Assessment of relevance  
Researchers should determine the reasonable possibility of the investigational drug 
causing or contributing to adverse events through comprehensive evaluation. Factors to 
consider include the reasonable temporal sequence between the administration of the 
investigational drug and the occurrence of the adverse event, characteristics of the 
investigational drug, its toxicological and pharmacological effects, concomitant medication 
use, subjects' underlying diseases, medical history, family history, as well as provocation 
and rechallenge reactions. Assess the potential association between adverse events and the 
investigational drug using a five-level classification system: definitely related, probably 

related, possibly unrelated, definitely unrelated, indeterminate. Refer to Table 4 for 
assessment criteria. 
Table 4 : Criteria for judging the relationship between AE and drugs 
 
Association 
evaluation 
Time-
relatednes
s 
Is it 
known 
De-
excitation 
Re-
excitatio
n 
Other 
explanation
s 
Definitely 
related 
+ 
+ 
+ 
+ 
-  
Possibly 
related 
+ 
± 
±？ 
？ 
±？ 
Possibly 
unrelated 
±？ 
-  
±？ 
？ 
±？ 
Definitely 
unrelated 
-  
-  
-  
-  
+ 
Unable to 
evaluate 
Required evaluation data cannot be obtained 
1. ＋ indicates positive or affirmative; - indicates negative or negation; ±  indicates 
difficult to judge; ?Indicates unknown. 
2. Time-relatedness: Is there a reasonable time relationship between drug use and adverse reactions. 
3. Is it known: Do the adverse reactions correspond to the known types of adverse reactions for the drug. 
4. De-excitation: After discontinuation or dose reduction, do the adverse reactions disappear or alleviate. 
5. Re-excitation: Whether the same adverse reactions occur again when the suspicious drug is used again. 
6. Other explanations: Whether adverse reactions can be explained by the effect of the drug, the progression of the subject's 
condition, the influence of other treatments, etc. 
 
(10) Data management and statistical analysis 
1. Quality management: The principle of double data entry, quality 
control during data collection in multicenter studies, data cleaning 
and verification work. 
(1) All trial processes are established SOPs. 
(2) Trial unit qualification: Clinical trial units are drug clinical trial bases with clinical 
conditions determined by the National Medical Products Administration. 
(3) Qualifications of trial participants: Trial participants must be physicians who have 
received clinical trial training and work under the guidance of senior professionals. 

(4) Quality control measures in the laboratory: The laboratory should establish 
standard operating procedures and quality control programs for experimental observation 
indicators. 
 
2. Statistical analysis 
2.1 Sample size determination  
The number of subjects required to achieve the research 
objectives and the calculation method should include any clinical and 
statistical hypotheses. Based on the research objectives and relevant 
parameters from pre-experiments or previous studies, sample size 
estimation work should be conducted using statistical software or 
specific formulas. Consider appropriate expansion of sample size 
considering attrition rate or design effect. 
According to the calculation of enrolling 4-5 patients per month, 
it is planned to enroll 100 patients, and the enrollment time is 
expected to be about 24 months. Close monitoring of chemotherapy 
adverse reactions in the treatment group, recording the time, 
grading, treatment measures, outcomes, etc. 
2.2 Analysis Population 
Descriptive statistical analysis of the population definition, 
non-compliant subjects with the study protocol should be specifically 
described in which analysis set they are included, and how to handle 
missing data. 
The following analysis sets will be involved in this study: 
  Full Analysis Set (FAS): defined as all subjects who have been enrolled and have 
taken the investigational drug at least once. 
  Evaluable Set (ES): The Evaluable Set (ES) is a subset of the Full Analysis Set 
(FAS), defined as subjects who have received the study drug at least once after enrollment 
and have at least one post-baseline efficacy assessment. 
  Safety Set (SS): The Safety Set (SS) consists of all subjects who have received at 

least one dose of the investigational drug in this study. 
 
2.3 Efficacy Analysis and Statistical Methods  
Please describe the statistical analysis methods for the primary 
and secondary outcome measures, as well as any additional analyses 
(such as subgroup analysis). What statistical software (such as SAS 
or SPSS) was used for data processing and analysis, and provide a 
detailed statistical description of the primary and secondary outcome 
measures. Specify whether one-sided or two-sided statistical tests 
were used, as well as the choice of α level. 
Principles of basic data analysis: quantitative data is summarized using mean, standard 
deviation, median, maximum value, and minimum value; Qualitative data is summarized 
using frequency and percentage; Time-event data is analyzed using Kaplan-Meier 
estimation to calculate survival rate and median survival time, and survival curves are 
plotted. 
 
2.3.1 Analysis of primary outcome measures  
Overall Survival (OS), 1-year/2-year Distant Metastasis Rate: Kaplan-Meier analysis will be 
used to analyze the time from the start of PD-1 combined with platinum-based and albumin-
paclitaxel treatment to the end of data collection (including distant metastasis, local treatment 
failure, and death), and Kaplan-Meier curves will be plotted. The difference in median OS (mOS) 
will also be calculated (95% bilateral confidence interval). 
2.3.2 Analysis of secondary outcome measures  
Among the secondary efficacy measures, the proportion of infiltrating squamous cell 
carcinoma in the resected primary tumor specimen and all sampled lymph nodes (mPR) will be 
determined based on real-time results, with mPR defined as ≤10%. If further stratified analysis 
is desired for CPS≥1 and CPS＜1, weighted analysis can be performed using the Miettinen 
method with a 95% bilateral confidence interval. PFS analysis will be conducted similarly to OS. 
 

2.4 Safety analysis and statistical methods  
Descriptive statistics are used to summarize safety data, including but not limited to: 
treatment-emergent adverse events (TEAE) defined as adverse events occurring on or after 
the day of drug treatment. Only TEAEs will be summarized. All adverse events will be 
graded according to NCI-CTCAE version 5.0. Descriptive statistics will mainly summarize 
data on TEAEs, treatment-related adverse events (TRAEs), grade ≥3 adverse events, 
grade ≥3 treatment-related adverse events, serious adverse events (SAEs), treatment-
related serious adverse events, TEAEs with an incidence ≥5%, treatment-related adverse 
events with an incidence ≥5%, TRAEs leading to dose interruption or adjustment, and 
TRAEs leading to treatment discontinuation. 
 
2.5 Interim Analysis 
Describes the criteria for interim analysis and stopping 
analysis, including who can access the results of these interim 
analyses and the final decision-making power to terminate the trial. 
 
2.6 Final Analysis 
 
(XI) Data Collection and Management 
1. Case Report Form/Electronic Data Recording  
Describes the plan for assessing and collecting outcome measures, 
baseline, and other trial data, and describes the reliability and 
accuracy of the data entry tool. 
This study uses electronic case report forms (eCRF) for the collection and 
management of clinical research data. 
Study Case Report Completion: 
Study case reports, as original documents of clinical trials, should be kept intact. The 
study case report is filled out and kept by the investigator. Before each entry, the subject's 
information on the cover of the case report should be checked, with neat handwriting that 
is easy to recognize, and facilitate data verification with the eCRF. 

eCRF filling 
Use HRTAU EDC to collect clinical research data. 
Fill in: The data in the eCRF comes from original documents such as medical records 
and laboratory test reports and should be consistent with the original documents. Any 
observations or examination results in the trial should be promptly, accurately, completely, 
clearly, standardized, and truthfully filled in the eCRF, and should not be arbitrarily 
changed. All items in the eCRF must be filled in, and there should be no empty or missing 
items. 
Modification: If necessary, when making data corrections to the eCRF, the reason for 
the data modification should be filled in according to the system prompt. The system's logic 
check program will perform integrity and logic checks on the clinical trial data entered into 
the EDC system, and will issue information prompts for problematic data, allowing the 
Principal Investigator (PI) to modify or explain the problematic data. If necessary, multiple 
challenges can be issued until the problematic data is resolved. 
Data Monitoring: 
The Clinical Research Associate (CRA) is responsible for monitoring whether the 
center complies with relevant regulations, Good Clinical Practice (GCP) for drug clinical 
trials, and the execution of this study; Whether all eCRF entries are correct, complete, and 
consistent with the original documents such as medical records and laboratory test reports, 
and whether there are any errors or omissions in the data. The monitor will review the 
integrity, consistency, and accuracy of the trial data in the clinical database according to the 
monitoring plan, and discuss problematic data with the researchers. If necessary, the 
researchers will make supplements or corrections. Ensure the consistency of data in the 
eCRF with the original data, a process also known as Source Data Verification (SDV). 
 
2. Data management 
Description of the scheme for data entry, coding, 
confidentiality, and storage, including any relevant measures to 
improve data quality (such as double data entry, range checks, etc.) 

 Establish EDC database 
Database design: The data administrator designs the database and 
tests it with simulated data or real eCRF data to ensure its 
accuracy. 
 Data entry 
Data entry and management are the responsibility of the data 
administrator designated by the statistical unit. To ensure data 
accuracy, two data administrators should independently enter and 
verify the data. 
 Data query 
For any questions regarding the case report form, the data 
administrator will generate a Data Query Form (DRQ) and send it to 
the investigator through the clinical monitor. The investigator 
should respond promptly and return the answers. The data 
administrator will then modify, confirm, and enter the data based on 
the investigator's response. If necessary, another DRQ may be sent. 
 Data lock 
After confirming the correctness of the established database, the 
primary investigator, sponsor, and statistical analyst will lock the 
data. The locked data file will no longer be modified. Issues 
discovered after data lock will be corrected in the statistical 
analysis program after confirmation. 
 Data processing 
After all research data has been entered and locked, the database 
will be handed over to the statistical analyst for statistical 
analysis according to the statistical plan. After completing the 
statistical analysis, the statistical analyst will write a 
statistical analysis report, and the principal investigator of this 
clinical trial will write a trial summary report. 

 
3. Protection of subject rights and informed consent 
Researchers have a responsibility to maintain the anonymity of the subjects. Only 
uppercase letters, numbers, and/or codes should be used to identify subjects in case report 
forms or other documents, not the subject's name. Researchers must keep a record of subject 
codes, names, and home addresses in the subject enrollment table. Researchers must strictly 
maintain the confidentiality of documents that can reveal the identity of the subjects. 
Researchers must inform the relevant information about this trial in both oral and 
written forms. Subjects, guardians, and the legally authorized representatives of the 
subjects (if necessary) have the right to know detailed information about this trial. 
The informed consent form (along with the trial protocol) must be reviewed and 
approved by the ethics committee. If necessary, the researcher has the responsibility to 
explain the content of the informed consent form to the subject in a way and wording that 
the subject can understand. Subjects and their representatives should have sufficient time 
to read before formally signing the informed consent form. 
The final text of the informed consent form should include the following: the purpose 
of the trial, the process and duration of the trial, examination procedures, potential benefits 
and risks to the subjects; Treatment and corresponding compensation that the subject can 
receive in case of trial-related harm; Principles of confidentiality of subject's personal 
information. 
The informed consent form must be signed by the subject (and the subject's legal 
guardian), and the date must be indicated. The researcher who conducted the informed 
consent process must also sign their name and date on the informed consent form. The 
informed consent form may also be signed by an independent witness who can attest to the 
subject's agreement to participate in the trial. One copy of the informed consent form should 
be retained by the researcher and one by the subject. If significant new information 
regarding the investigational drug is discovered, the informed consent form must be revised 
in writing and submitted to the ethics committee for approval before obtaining the subject's 
consent again. 

 
4. Definition of study completion  
1. The end of the first phase is defined as the completion of the study's primary 
endpoint-related indicators and data statistics. 
2. The overall study is defined as including all relevant indicators and data statistics, 
including secondary study endpoints and exploratory endpoints, and publishing 
papers.