Perioperative Immunoagent (Tislelizumab) Plus Chemotherapy for Locally Advanced Resectable Thoracic Oesophageal Squamous Cell Carcinoma Trail:A Prospective Single-arm,Phase II Study (PILOT Trail)
Phase: PHASE2
Conditions: Esophageal Squamous Cell Carcinoma, Neoadjuvant Chemoimmunotherapy, Adjuvant Therapy
Sponsor: Guo Xufeng

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 1 / 21 
 
Protocol study: 
 
Periopearative immunoagent (tislelizumab) plus chemotherapy for locally 
advanced resectable thoracic oesophageal squamous cell carcinoma trail: A 
prospective single-arm, phase II study (PILOT trial) 
 
 
 
Version number: V1.0 
Version date: September 06, 2023 
 
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 2 / 21 
 
 
Objectives: Neoadjuvant immunotherapy with chemotherapy (nICT) has been the 
recommended treatment for locally advanced esophageal squamous cell carcinoma 
(ESCC). However, high-level evidence of nICT followed by esophagectomy in locally 
advanced resectable ESCC patients are still lacking. The aim of this study was to 
analyze esophageal cancer patients who previously underwent nICT followed by 
esophagectomy to determine whether additional adjuvant therapy is associated with 
improved survival outcomes. 
Design and Methods: Seventy-three eligiled patients with pathologically confirmed 
thoracic esophageal squamous cell carcinoma and at clinical T1b-3N1-3M0 or 
T3N0M0 according to the eighth edition of American Joint Committee on Cancer 
staging will be allocated to neoadjuvant immunotherapy (tislelizumab 200mg d1, q3w 
× 2 cycles ) a nd chemotherapy (nad-paclitaxel 260 mg/m2  d1 + carboplatin AUC = 5 
d1, q3w × 2 cycles) treatment.  Patients with resected (R0)  were assigned to receive 
tislelizumab ( at a dose of 200 mg every 3 weeks for 30 weeks) in pCR patients or 
adjuvant immunotherapy and chemothearpy for two cycles, and then tislelizumab ( at 
a dose of 200 mg every 3 weeks for 24 weeks) in non-pCR patients.The primary 
endpoint for this study is 2-year disease-free survival (DFS) in non-pCR patients.The 
secondary endpoints include pCR rate, major pathological response (MPR) rate, 2-
year DFS in pCR patients, R0 resection rate, adverse events, and overall survival (OS). 
Discussion: The results of the PILOT trial will first provide adjuvant immunotherapy 
in neoadjuvant immunotherapy with chemotherapy treatment for ESCC, also to 
explore whether adjuvant immunotherapy offers additional benefit in pCR patients or 
adjuvant immunotherapy and chemothearpy offers additional benefit in non-pCR 
patients after nICT during the perioperative setting. Meanwhile, the treatment 
protocols will be compared in terms of efficacy and safety, and 2-year DFS in non-
pCR patients and pCR petants. We hypothesize that perioperative immunotherapy will 
provide preliminary evidence of the efficacy and safety of adjuvant tislelizumab as an 
innovation therapy for patients with locally advanced ESCC. 
Keywords: Esophageal squamous cell carcinoma (ESCC); nivolumab; neoadjuvant; 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 3 / 21 
 
adjuvant; chemotherapy 
 
 
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 4 / 21 
 
1.0 Background 
According to the latest data from the National Cancer Center of China, the 
incidence and mortality of esophageal cancer (EC) were 25.3 and 19.4 per 10000 
people, respectively, ranking the sixth and fourth among malignant tumors in China 
[1]. About 50% of esophageal cancer cases in the world occur in China, of which 
more than 90% are esophageal squamous cell carcinoma, which is more prone to 
lymph node metastasis than esophageal adenocarcinoma [2]. Approximately 50% of 
EC is diagnosed as locally advanced disease, esophagectomy alone is far from enough 
due to the high recurrence or metastasis rates [3].  
The CROSS study and NEOCRTEC5010 study confirmed that neoadjuvant 
chemoradiotherapy (nCRT) can significantly improve the long-term survival of ESCC 
patients after surgery [4-6]. Patients who received nCRT in the CROSS study had a 
recurrence and metastasis rate of 34.7% during a median follow-up of 2 years after 
surgery, of which hematogenous metastasis was 22% [7]. Similarly, the long-term 
follow-up results of NEOCRTEC5010 study showed that 33.0% of patients who had 
received nCRT still had recurrence and metastasis during the 3-year follow-up after 
surgery, and distant blood metastasis (21.4%) was more common [8]. All these 
evidences suggest that more efficient systemic treatment options are needed to further 
improve the efficacy of locally advanced resectable ESCC in the future. 
Several 
phase 
Ⅱ 
clinical 
studies 
have 
confirmed 
that 
neoadjuvant 
immunotherapy combined with chemotherapy (nICT) is safe and effective in the 
treatment of locally advanced resectable ESCC, which achieves similar pathological 
complete response (pCR) rate (18.8-39.2%) as nCRT [9-12]. In the previous Nice 
study [13], the KEEP G 03 study [14] and the TD-NICE study [9], the pCR rates of 
patients with locally advanced thoracic ESCC treated with neoadjuvant 
immunotherapy combined with chemotherapy were 39.2%, 20.0% and 50.0%, 
respectively. It is even higher than the latest DCF neoadjuvant chemotherapy regimen 
discussed in JCOG1109, with a pCR of 19.8% [15]. The neoadjuvant regimen of 
tislelizumab combined with chemotherapy in the TD-NICE trial resulted in a higher 
pCR rate compared with 49% (CROSS study) and 43.2% (NEOCRTEC5010 study) 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 5 / 21 
 
for preoperative induction chemoradiotherapy. Real-world data show that patients 
with pCR may have better survival benefits, but distant metastasis and recurrence of 
non-pCR patients are still problems that need to be solved, and new methods of 
perioperative treatment are also being explored. 
Patients with non-pCR and positive lymph nodes after neoadjuvant 
chemoradiotherapy have a high risk of recurrence after surgery. Several retrospective 
studies have investigated the effects of adjuvant chemotherapy after neoadjuvant 
therapy followed by surgery reducing the distant metastasis and improving the OS in 
ypT+N+ ESCC patients [16-18]. Similarly, CheckMate577 showed that nivolumab 
could significantly prolong disease free survival (DFS) in non-pCR patients after 
nCRT, and patients with squamous cell carcinoma benefited more than those with 
adenocarcinoma, with a 2-year DFS of 58%[19]. Nevertheless, the question remains 
that whether adjuvant immunotherapy and chemotherapy offer additional benefit in 
patients who have received nCRT/nCT. 
Hence, we launched a prospective single-arm, phase II trial (PILOT trial) to 
assess the safety and  efficacy of neoadjuvant tislelizumab combined with 
chemotherapy for locally advanced resectable ESCC patients. Moreover, we also 
intend to evaluate whether adjuvant administration of immunotherapy combined with 
chemotherapy could bring survival benefit in non-pCR patients after nICT, as 
compared with adjuvant immunotherapy treatment in pCR patients, which will answer 
the questions that CheckMate 577 and TD-NICE did not cover.  
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 6 / 21 
 
2.0 Design and Methods 
2.1 Study design and recruitment 
The PILOT trial was a prospective, single-arm phase II study of neoadjuvant 
tislelizumab combined with chemotherapy in patients with locally advanced 
resectable thoracic ESCC, adjuvant immunotherapy combined with chemotherapy for 
non-pCR patients, and sequential adjuvant immunotherapy therapy for all patients. 
The study will be conducted in Shanghai Chest hospitals in China, recruiting 73 
patients. The trial will be conducted in accordance with the Declaration of Helsinki 
(as revised in 2013). This study protocol has been reviewed and approved by the 
Institution Review Committee [KS(Y)23255]. All patients will provide written 
informed consent before enrollment. The protocol is designated PILOT (version 1.1; 
dated September 6, 2023). Recruitment started in September 2023 and is estimated to 
continue until September 2026. 
 
Figure 1. Study Design Drawing 
This study is a standardized perioperative immunotherapy trial for locally advanced 
resectable thoracic ESCC. Eligible patients received neoadjuvant immunotherapy 
(tislelizumab 200mg d1, q3w× 2 cycles  ) and chemotherapy (nad-paclitaxel 260 
mg/m2 d1 + carboplatin AUC = 3–5 d1, q3w × 2 cycles ) treatment. The efficacy was 
evaluated according to RECIST 1.1. Patients with a clinical complete response (cCR) 
and clinical partial response (cPR) undergo surgery after 4–6 weeks. If patients were 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 7 / 21 
 
evaluated for clinical progressive disease (cPD) and clinically stable disease (cSD), 
they would receive a new treatment regimen after a multidisciplinary team (MDT) 
discussion. Subsequently, all the patients underwent surgery after 4–6 weeks. After 
surgery, patients with pCR would always undergo immunotherapy (Tislelizumab 200 
mg q21d) and maintenance treatment for one year, and patients with non-pCR would 
receive immunotherapy (Tislelizumab 200 mg q21d) and chemotherapy （nad-
paclitaxel 260 mg/m2 d1 + carboplatin AUC = 3–5 d1, q3w × 2 cycles  ）, and then 
sequential maintenance immunotherapy treatment for one year. The other patients 
who did not undergo R0 resection received a new treatment regimen after MDT.  
 
2.2 Study Endpoints 
2-year disease-free survival (DFS) in non-pCR patients was considered the primary 
endpoint and was defined as the time from the first day of surgery to the first 
occurrence of local or distant recurrence and metastasis or death from any cause.The 
secondary endpoints are pCR rate, major pathological response (MPR) rate, 2-year 
DFS in pCR patients, R0 resection rate, adverse events, and overall survival (OS). 
pCR is defined as complete response of both primary tumor and lymph nodes in the 
resected specimen. Exploratory endpoints include quality of life (QOL)  investigation. 
If R0 resection was achieved, disease progression other than distant metastasis during 
neoadjuvant therapy was not considered an event. Recurrence was defined as the 
appearance of one or more new lesions (confirmed by imaging or cytologic or 
pathological assessment, local, regional, or distant from the primary resection site) as 
assessed by the investigator. 
2.4 Study population 
Eligibility criteria 
Patients with locally advanced (T1b-3N1-3M0 or T3N0M0, AJCC 8th) ESCC who 
have been histologically-confirmed, reviewed by two experienced thoracic surgeons 
and considered surgically resectable. 
2.4.1 Inclusion criteria 
1) The patient volunteers to participate in the study, signs a consent form, has good 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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compliance, and obeys the follow-up, and is willing and able to follow the 
protocol during the study; 
2) Histologically-confirmed squamous cell carcinoma; tumors of the esophagus are 
located in the thoracic cavity; 
3)  Have not received systemic and local treatment for esophageal cancer; 
4) Pre-treatment staging as cT1b-3N1-3M0 or T3N0M0, American Joint Committee 
on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition; 
5) Male or female, aged ≥18 and ≤75 years; 
6) The Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 
is 0 –1; 
7) R0 resection is expected; 
8)  Adequate cardiac function. All patients should perform electrocardiogram (ECG), 
and those with a cardiac history or ECG abnormality should perform 
echocardiography with the left ventricular ejection fraction >50%; 
9) Adequate respiratory function with forced expiratory volume in 1 second (FEV1) 
≥ 1.2 L, FEV1% ≥ 50% and lung diffusing capacity for carbon monoxide (DLCO) 
≥ 50% shown in pulmonary function tests; 
10) Adequate bone marrow function (white blood cells > 4×10 9/L, neutrophil > 1.5 
×10 9/L, hemoglobin > 90g/L, platelets > 100×10 9/L). Aspartate aminotransferase 
(AST), alanine aminotransferase (ALT) ≤ 3× upper  level of normal (ULN);  
11) Adequate liver function (total bilirubin <1.5× ULN,  AST and ALT <2.5× ULN);   
12) Adequate renal function (glomerular filtration rate (GFR) >60 mL/min; serum 
creatinine (SCr) ≤120 μmol/L];  
13)  Fertile female subjects are required to have a negative serum or urine pregnancy 
test no later than 72 hours before starting the study drug administration, and to 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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use effective contraception (such as an IUD, contraceptive pill, or condom) 
during the trial period and for at least 3 months after the last dose; For male 
subjects whose partners are women of reproductive age, effective contraception 
should be used during the trial period and within 3 months after the last dose; 
2.4.2 Exclusion criteria 
Patients who meet any of the following conditions will be excluded: 
1) Unresectable factors, including those who are unresectable for tumor reasons or 
have surgical contraindications, or who refuse surgery; 
2) Patients with supraclavicular lymph node metastasis; 
3) Poor nutritional status, BMI<18.5Kg/m2; Patients could continue to be 
considered for enrollment if corrected with symptomatic nutritional support 
before enrollment and after assessment by the principal investigator  
4) Allergy to any drugs; 
5) Have received or are receiving any of the following treatments; a) any 
radiotherapy, chemotherapy or other antineoplastic drugs directed at the tumour; 
b) being treated with an immunosuppressive drug or systemic hormone for 
immunosuppression (at a dose of >10mg/ day of prednisone or equivalent) within 
2 weeks before the first dose of the study drug; Inhaled or topical steroids and 
corticosteroid replacement at doses >10mg/ day of prednisone or equivalent were 
allowed in the absence of active autoimmune disease; c) received live attenuated 
vaccine within 4 weeks before the first dose of study drug; d) major surgery or 
severe trauma within 4 weeks before the first dose of study drug; 
6) Human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C 
virus (HCV) active infection or known HIV seropositivity; including HBV or 
HCV surface antigen positive (RNA) 
7) Uncontrolled cardiac symptoms or diseases, including but not limited to: (1) heart 
failure above NYHA class II, (2) unstable angina, (3) myocardial infarction 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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within 1 year, (4) clinically significant supraventricular or ventricular arrhythmias 
without or poorly controlled after clinical intervention; 
8) Severe infection (CTCAE>2) occurred within 4 weeks before the first dose of 
study drug, such as severe pneumonia requiring hospitalization, bacteremia, and 
infectious complications; Prophylactic antibiotics were excluded if there was 
active pulmonary inflammation on chest imaging at baseline, if there were signs 
and symptoms of infection within 14 days before the first dose of the study drug, 
or if treatment with oral or intravenous antibiotics was required 
9) Participation in other drug clinical studies within 4 weeks before randomization; 
10) Patients with interstitial pneumonia or interstitial lung disease, or previous history 
of interstitial pneumonia or interstitial lung disease requiring hormone therapy, or 
other subjects with pulmonary fibrosis, organized pneumonia (such as 
bronchiolitis obliterans), pneumoconiosis, drug-related pneumonia, idiopathic 
pneumonia that may interfere with the judgment and treatment of immune related 
pulmonary toxicity, or subjects with active pneumonia or severe lung function 
damage revealed by CT during screening; Active pulmonary tuberculosis; 
11) Patients with any active autoimmune disease or history of autoimmune disease 
and possible recurrence [including but not limited to autoimmune hepatitis, 
interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, 
hyperthyroidism, hypothyroidism (patients who can be controlled only by 
hormone replacement therapy can be enrolled)]; Patients with skin diseases that 
do not require systemic treatment, such as leukoplakia, psoriasis, alopecia, 
patients with type I diabetes that can be controlled by insulin treatment, or 
patients with a history of asthma, but have completely relieved in childhood and 
do not need any intervention, can be enrolled; Asthma patients who needed 
bronchodilators for intervention could not be enrolled; Patients have previously 
received an anti-PD-1 ，PD-L1 or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways; 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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12) Other malignancies that had been diagnosed within 5 years before the first dose 
of a study drug were considered unless cancers with a low risk of metastasis or 
death (5-year survival rate, >90%), such as adequately treated basal-cell or 
squamous-cell skin cancer or carcinoma in situ of the cervix, were considered. 
13) Pregnant or lactating women; 
14) The investigators determined that there were other factors that might have led to 
the forced discontinuation of the study, such as other serious medical conditions 
(including mental illness) requiring co-treatment, alcohol, substance abuse, 
family or social factors, and factors that might have affected the safety or 
adherence of the subjects. 
2.5 Intervention（nICT） 
On the first day, a fixed dose of 200mg tislelizumab was injected intravenously for 
about 30-60 min on day 1, followed by sequential nad-paclitaxel (260mg/m2) 
combined with carboplatin (AUC=5), once every 3 weeks for 2 cycles. Dosage 
adjustment is not permitted for tislelizumab, but chemotherapy is allowed in case of 
severe febrileneutropenia or neutropenia, thrombocytopenia and anemia. Treatment 
will be interrupted or postponed if any serious AE (SAE) occurs, and treatment could 
be resumed until the established standards for resumption of treatment are met. 
2.6 Surgery 
Approximately 4–6 weeks after neoadjuvant treatment, patients will be re-evaluated 
by the investigators according to the Response Evaluation Criteria for Solid Tumors 
(RECIST) 1.1.  If there was no evidence of metastatic disease, esophagectomy will be 
performed by two rich experience surgeons. The McKeown procedure can be 
performed using the da Vinci surgical robot, thoracoscope, or laparoscope, or by using 
an open approach, as judged appropriate by the surgeon. 
Two-field thoracoabdominal lymph node dissection was used for patients with middle 
and lower thoracic tumors, and three-field lymph node dissection was used for 
patients with upper thoracic tumors. The lymph nodes dissected groups include: upper 
thoracic esophagus (105), right recurrent laryngeal nerve (106recR), left recurrent 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 12 / 21 
 
laryngeal nerve(106recL), sub-carina (107), right trachea-bronchus (106tbR), left 
trachea-bronchus (106tbL), middle thoracic esophagus (108), lower thoracic 
esophagus (110), supraphrenic (111), right cardia (1), left cardia (2), lesser curvature 
of the stomach (3), and left gastric artery (7). At least dissected lymph nodes were 
dissected. The lymph nodes adjacent to the left and right recurrent laryngeal nerves 
must be dissected and clear exposed. The dissection will be performed in accordance 
with the Japanese Classification of Esophageal Cancer, Eleventh Edition. The total 
number of lymph nodes dissected was no less than 15. 
2.7 Pathology Report 
The pathological report is consulted by two senior pathologists, including the depth of 
infiltration of the primary lesion, histological type, pathological status of the upper 
and posterior margins, and involvement of peripheral and lymph nodes. The 
postoperative pathological evaluation will be based on the CROSS test. The tumor 
regression grade (TRG) [20] and ypTNM staging will be evaluated.  
2.8 Adjuvant immunotherapy 
Patients who underwent R0 resection were divided into pathological complete 
response (pCR) and non-pathological complete response (non-pCR) according to the 
pathological results. Subjects with non-R0 resection will terminate the subsequent 
study treatment program and be given adjuvant radiotherapy. 
pCR group: tislelizumab was administered once every 3 weeks until imaging 
disease recurrence or metastasis, intolerable toxicity, start of new anti-tumor treatment, 
subject's initiative to withdraw, and investigator's decision to withdraw from the study. 
Postoperative adjuvant tislelizumab was administered within 4-8 weeks after surgery, 
and the maximum duration was not more than 1 year. 
Non-pCR group: tislelizumab combined with chemotherapy (albumin-bound 
paclitaxel and carboplatin) for 2 cycles, tislelizumab alone was used from the third 
cycle, once every 3 weeks until disease recurrence or metastasis, subject's initiative 
request to withdraw, and investigator's judge that the subject needs to withdraw from 
the study. The maximum duration of tislelizumab maintenance therapy was not more 
than 1 year. 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 13 / 21 
 
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 14 / 21 
 
3.0 Follow-up 
Follow-up will be first performed 1 month after surgery. From then on, follow-up 
visits will be every 3 months in the first 2 years. The detailed examination items 
include standard laboratory tests (blood routine, tumor biomarker), a CT scan of 
thorax, an ultrasound of the neck and abdomen. 
If the patient has signs of recurrence (such as related clinical manifestations), 
additional tumor evaluations are performed during the treatment; possible 
reoperations and/or further cancer treatments are also documented.   During the 
follow-up period without tumor recurrence, other cytotoxic agents are not allowed. 
Patient recurrence and survival will be followed up to the patient’s death, the last date 
on which the patient is known to survive, or 2 year after the primary effectiveness 
analysis. 
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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4.0 Data monitoring 
The data and safety monitoring board consisted of three physicians who were 
independent of the sponsor and declared no competing interests. Active surveillance 
was conducted every 3 months, and interim analyses were planned after recruitment 
of half the planned patients.  
The safety-related endpoints included neoadjuvant and adjuvant treatment-related 
adverse events (TRAEs), immune-related adverse events (irAEs), resection rate, and 
surgical complications. TRAEs and irAEs were evaluated according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 
(CTCAE5.0). Serious adverse events (SAEs) were defined as grade 3–5 TRAEs. If 
SAEs occur during the trial, the investigator will immediately take appropriate 
protective measures or discontinue the treatment, report to the principal investigator 
within 24 hours, fill out and sign the SAE Report Form. The resection rate referred to 
the ratio of patients who underwent surgical resection to the intention-to-treat 
population. Surgical complications within 30 days after operation were coded using 
the Clavien - Dindo classification. All investigators must comply with the standard 
operating procedures (SOPs) for the management of study drugs. 
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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5.0  Statistical Analysis Plan 
The previous CheckMate577 study suggested that the 2-year DFS was 58% for non-
pcr patients with locally advanced esophageal squamous cell carcinoma who received 
neoadjuvant concurrent chemoradiotherapy followed by radical surgery. Assuming 
that after perioperative chemoimmunotherapy and immune maintenance, the 2-year 
DFS increases to 75%, the trial required 55 eligible non pCR patients with a level of 
significance of 90% (α = 0.2) and a power of 90% (β = 0.05). According to the 
previous retrospective data analysis of our center, the pCR rate of patients with the 
neoadjuvant chemotherapy regimen followed by surgery was 26.5%, referring to the 
published data of multi-center real-world study of neoadjuvant chemotherapy in 
China (pCR 25.8%), and then 18 patients was needed. A total of 73 patients were 
enrolled in this study. 
The statistical analysis for primary endpoint was that 2-year DFS in non-pCR patients 
will be calculated by the Kaplan-Meier method.The statistical analysis for secondary 
endpoints: 2-year DFS in pCR patients, R0 resection rate and overall survival (OS) 
will be calculated by the Kaplan-Meier method and compared by the log-rank test. 
The Cox proportional hazard model will be used to evaluate the survival independent 
factors. Continuous variables were presented as the mean and standard deviation (SD). 
Categorical variables were presented as percentages and compared using the chi-
square test. The differences in proportions between the two groups were evaluated by 
Fisher’s exact test. Wilcoxon test was used to compare the non-parametric datasets. 
All statistical analysis will be calculated using SPSS (version 24.0, Chicago, IL, USA) 
statistical analysis software programming. P values less than 0.05 will be considered 
statistically significant. 
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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6.0 Ethical Statement: The authors are accountable for all aspects of the work in 
ensuring that questions relatedto the accuracy or integrity of any part of the work 
areappropriately investigated and resolved. The trial will beconducted in accordance 
with the Declaration of Helsinki (as revised in 2013). This study protocol has been 
reviewed and approved by the Ethics Committees of Shanghai Chest hospital of 
Shanghai Jiao Tong University (No.IS23059). All patients will provide written 
informed consent before enrollment.  
 
 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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7.0 Reference 
1. Sung H, Ferlay J, Siegel RL,et al. Global Cancer Statistics 2020: GLOBOCAN 
Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 
CA: A Cancer Journal for Clinicians. 2021; 71(3): 209-249. 
2. Zheng R, Zhang S, Zeng H, et al Cancer incidence and mortality in China, 2016. 
Journal of the National Cancer Center. 2022; 2(1): 1-9. 
3. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative 
chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012; 
366:2074-2084.  
4. Shapiro J, van Lanschot JJB, Hulshof M, et al. Neoadjuvant chemoradiotherapy 
plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): 
long-term results of a randomised controlled trial. Lancet Oncol. 2015; 16:1090-
1098. 
5. Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by 
surgery versus surgery alone for locally advanced squamous cell carcinoma of the 
esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label 
clinical trial. J Clin Oncol. 2018; 36:2796-2803. 
6. Yang H, Liu H, Chen Y, et al. Long-term Efficacy of Neoadjuvant 
Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced 
Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized 
Clinical Trial. JAMA Surg. 2022; 157(5):458-459. 
7. Oppedijk, V, van der Gaast, A, van Lanschot, JJ, et al. Patterns of recurrence after 
surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS 
trials. J Clin Oncol. 2014; 32(5):385-91. 
8. Liu S, Wen J, Yang H, et al. Recurrence patterns after neoadjuvant 
chemoradiotherapy compared with surgery alone in oesophageal squamous cell 
carcinoma: results from the multicenter phase III trial NEOCRTEC5010. Eur J 
Cancer. 2020;138:113–21. 
9. Yan X, Duan H, Ni Y, et al. Tislelizumab combined with chemotherapy as 
neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
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single-arm, phase II study (TD-NICE). Int J Surg. 2022; 103:106680. 
10. Liu J, Li J, Lin W, Shao D, Depypere L, Zhang Z, Li Z, Cui F, Du Z, Zeng Y, 
Jiang S, He P, Gu X, Chen H, Zhang H, Lin X, Huang H, Lv W, Cai W, Liang W, 
Liang H, Jiang W, Wang W, Xu K, Cai W, Wu K, Lerut T, Fu J, He J. 
Neoadjuvant camrelizumab plus chemotherapy for resectable, locally advanced 
esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, phase 2 
study. Int J Cancer. 2022;151(1):128-137. 
11. Zhang Z, Hong ZN, Xie S, Lin W, Lin Y, Zhu J, Yang X, Lin Z, Lin J, Kang M. 
Neoadjuvant sintilimab plus chemotherapy for locally advanced esophageal 
squamous cell carcinoma: a single-arm, single-center, phase 2 trial (ESONICT-1). 
Ann Transl Med. 2021;9(21):1623.. 
12. Li C, Zhao S, Zheng Y, Han Y, Chen X, Cheng Z, Wu Y, Feng X, Qi W, Chen K, 
Xiang J, Li J, Lerut T, Li H. Preoperative pembrolizumab combined with 
chemoradiotherapy for oesophageal squamous cell carcinoma (PALACE-1). Eur J 
Cancer. 2021;144:232-241. 
13. Liu J, Yang Y, Liu Z, Fu X, Cai X, Li H, Zhu L, Shen Y, Zhang H, Sun Y, Chen H, 
Yu B, Zhang R, Shao J, Zhang M, Li Z. Multicenter, single-arm, phase II trial of 
camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced 
esophageal squamous cell carcinoma. J Immunother Cancer. 2022;10(3):e004291. 
14. Chen X, Xu X, Wang D, Liu J, Sun J, Lu M, Wang R, Hui B, Li X, Zhou C, Wang 
M, Qiu T, Cui S, Sun N, Li Y, Wang F, Liu C, Shao Y, Luo J, Gu Y. Neoadjuvant 
sintilimab and chemotherapy in patients with potentially resectable esophageal 
squamous cell carcinoma (KEEP-G 03): an open-label, single-arm, phase 2 trial. J 
Immunother Cancer. 2023;11(2):e005830.  
15. Kato K. Ito Y, Daiko H, et al. A randomized controlled phase III trial comparing 
two chemotherapy regimen and chemoradiotherapy regimen as neoadjuvant 
treatment for locally advanced esophageal cancer, JCOG1109 NExT study. J Clin 
Oncol. 2022;40:suppl 238.  
16. Xufeng Guo, Zhexin Wang, Hong Yang, et al. Impact of Lymph Node Dissection 
on Survival after Neoadjuvant Chemoradiotherapy for Locally Advanced 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 20 / 21 
 
Esophageal Squamous Cell Carcinoma: From the Results of NEOCRTEC5010, a 
Randomized Multicenter Study. Ann Surg. 2023; 277(2):p259-266.  
17. Park SY, Kim HK, Jeon YJ, Lee J, Cho JH, Choi YS, Shim YM, Zo JI. The Role 
of Adjuvant Chemotherapy after Neoadjuvant Chemoradiotherapy Followed by 
Surgery in Patients with Esophageal Squamous Cell Carcinoma. Cancer Res Treat. 
2023 Apr 24. 
18. Lee Y, Samarasinghe Y, Lee MH, Thiru L, Shargall Y, Finley C, Hanna W, Levine 
O, Juergens R, Agzarian J. Role of Adjuvant Therapy in Esophageal Cancer 
Patients After Neoadjuvant Therapy and Esophagectomy: A Systematic Review 
and Meta-analysis. Ann Surg. 2022;275(1):91-98.  
19. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, 
Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, 
Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, 
Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 
Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal 
Junction Cancer. N Engl J Med. 2021;384(13):1191-1203. 
20. Chirieac LR, Swisher SG, Ajani JA, Komaki RR, Correa AM, Morris JS, Roth JA, 
Rashid A, Hamilton SR, Wu TT. Posttherapy pathologic stage predicts survival in 
patients with esophageal carcinoma receiving preoperative chemoradiation. 
Cancer. 2005 Apr 1;103(7):1347-55.  
21. Tang H, Wang H, Fang Y, Zhu JY, Yin J, Shen YX, Zeng ZC, Jiang DX, Hou YY, 
Du M, Lian CH, Zhao Q, Jiang HJ, Gong L, Li ZG, Liu J, Xie DY, Li WF, Chen 
C, Zheng B, Chen KN, Dai L, Liao YD, Li K, Li HC, Zhao NQ, Tan LJ. 
Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy followed by 
minimally invasive esophagectomy for locally advanced esophageal squamous 
cell carcinoma: a prospective multicenter randomized clinical trial. Ann Oncol. 
2023 Feb;34(2):163-172. 
22. Reynolds JV, Preston SR, O’Neill B, et al. Neo-AEGIS (Neoadjuvant trial in 
Adenocarcinoma of the Esophagus and Esophago-Gastric Junction International 
Study): preliminary results of phase III RCT of CROSS versus perioperative 

Periopearative immunoagent (tislelizumab) plus chemotherapy for locally advanced resectable thoracic oesophageal squamous cell 
carcinoma trail: A prospective single-arm, phase II study (PILOT trial)     Version number: V1. 0        Version date: September 06, 2023 
 21 / 21 
 
chemotherapy (modifified MAGIC or FLOT protocol) (NCT01726452). J Clin 
Oncol. 2021; 39(15 suppl):4004. 
23. Sun Z, Zheng J, Xu X, Zhao X, Ma X, Ye Q. Comparison of clinical outcomes of 
conservative treatment and surgery for esophageal cancer patients who achieve a 
clinical complete response following neoadjuvant chemoradiotherapy: a 
systematic review and meta-analysis. Ann Transl Med. 2022 Dec;10(24):1378. 
24. Xi M, Yang Y, Zhang L, et al. Multi-institutional Analysis of Recurrence and 
Survival After Neoadjuvant Chemoradiotherapy of Esophageal Cancer: Impact of 
Histology on Recurrence Patterns and Outcomes. Ann Surg 2019;269:663-70.