A Study of Tislelizumab (BGB-A317) Versus Chemotherapy as Second Line Treatment in Participants With Advanced Esophageal Squamous Cell Carcinoma

A Randomized, Controlled, Open-label, Global Phase 3 Study Comparing the Efficacy of the Anti-PD-1 Antibody Tislelizumab (BGB-A317) Versus Chemotherapy as Second Line Treatment in Patients With Advanced Unresectable/Metastatic Esophageal Squamous Cell Carcinoma

The purpose of this study was to evaluate the efficacy and safety of tislelizumab as second line treatment in participants with advanced unresectable/metastatic ESCC that had progressed during or after first line therapy.

Study Overview

• Status: Completed
• Conditions: Esophageal Squamous Cell Carcinoma (ESCC)
• Intervention / Treatment: Drug: Tislelizumab; Drug: Irinotecan; Drug: Paclitaxel; Drug: Docetaxel

• Study Type: Interventional
• Enrollment (Actual): 512
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium, 2820
    • Imelda Ziekenhuis Bonheiden
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint Luc
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Leuven, Belgium, 3000
    • University Hospitals Leuven
• China
  • Anhui
    • Hefei, Anhui, China, 230601
      • The Second Hospital of Anhui Medical University
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital
    • Beijing, Beijing, China, 100730
      • Peking Union Medical College Hospital
    • Beijing, Beijing, China, 100050
      • Beijing Friendship Hospital, Capital Medical University
  • Fujian
    • Fuzhou, Fujian, China, 350001
      • Fujian Medical University Union Hospital
    • Fuzhou, Fujian, China, 350014
      • Fujian Cancer Hospital
    • Fuzhou, Fujian, China, 350005
      • The First Affiliated Hospital of Fujian Medical University
    • Xiamen, Fujian, China, 361003
      • The First Affiliated Hospital of Xiamen University
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • The First Affiliated Hospital, Sun Yat Sen University
    • Guangzhou, Guangdong, China, 510655
      • The Sixth Affiliated Hospital, Sun Yat Sen University
    • Shantou, Guangdong, China, 515031
      • Cancer Hospital of Shantou University Medical College
    • Shenzhen, Guangdong, China, 518036
      • Peking University Shenzhen Hospital
  • Hebei
    • Baoding, Hebei, China, 071000
      • Affiliated Hospital of Hebei University
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150000
      • Harbin Medical University Cancer Hospital
  • Henan
    • Xinxiang, Henan, China, 453100
      • The First Affiliated Hospital of Xinxiang Medical University
    • Zhengzhou, Henan, China, 450052
      • The First Affiliated Hospital of Zhengzhou University
    • Zhengzhou, Henan, China, 450000
      • Henan Cancer Hospital
  • Hubei
    • Wuhan, Hubei, China, 430079
      • Hubei Cancer Hospital
    • Xiangyang, Hubei, China, 441021
      • Xiangyang Central Hospital
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital
  • Jiangsu
    • Changzhou, Jiangsu, China, 213000
      • The First Peoples Hospital of Changzhou
    • Huaian, Jiangsu, China, 223002
      • Huaian Second Peoples Hospital
    • Nanjing, Jiangsu, China, 210029
      • Jiangsu Province Hospital
    • Nanjing, Jiangsu, China, 210008
      • Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School
    • Nantong, Jiangsu, China, 226000
      • Nantong Tumor Hospital Branch South
    • Xuzhou, Jiangsu, China, 221000
      • The Affiliated Hospital of Xuzhou Medical University
  • Jiangxi
    • Nanchang, Jiangxi, China, 330029
      • Jiangxi Province Cancer Hospital
  • Jilin
    • Changchun, Jilin, China, 130021
      • The First Hospital of Jilin University
  • Shaanxi
    • Xian, Shaanxi, China, 710004
      • The Second Affiliated Hospital of Xian Jiaotong University
  • Shandong
    • Jinan, Shandong, China, 250117
      • Shandong Cancer Hospital
    • Linyi, Shandong, China, 276001
      • Linyi Cancer Hospital
    • Weifang, Shandong, China, 261000
      • Weifang Peoples Hospital
  • Shanghai
    • Shanghai, Shanghai, China, 200000
      • Fudan University Shanghai Cancer Center
  • Shanxi
    • Taiyuan, Shanxi, China, 030012
      • Shanxi Provincial Peoples Hospital
  • Sichuan
    • Chengdu, Sichuan, China, 610071
      • Sichuan Academy of Medical Sciences and Sichuan Provincial Peoples Hospital
  • Yunnan
    • Kunming, Yunnan, China, 650100
      • Yunnan Cancer Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Zhejiang Cancer Hospital
    • Hangzhou, Zhejiang, China, 310003
      • The First Affiliated Hospital, Zhejiang University School of Medicine
• France
  • Brest, France, 29200
    • Chru de Brest Hospital Morvan
  • Dijon, France, 21079
    • Centre Georges François Leclerc
  • Doubs, France, 25030
    • CHU Besançon Hopital Jean Minjoz
  • Lille, France, 59000
    • Centre Oscar Lambret
  • Lyon, France, 69008
    • Hopital Prive Jean Mermoz
  • Montpellier, France, 34090
    • Icm Val Daurelle
  • Pessac, France, 33600
    • CHU Bordeaux Hopital Haut Leveque
  • Poitiers, France, 86000
    • Chu de Poitiers Site de La Mileterie
  • SaintHerblain, France, 44805
    • Ico Site Rene Gauducheau
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Berlin, Germany, 13353
    • Charité Universitätsmedizin Berlin
  • Leipzig, Germany, 04103
    • Universitares Krebszentrum Leipzig
  • Mainz, Germany, 55131
    • Klinikum Johannes Gutenberg Universitaet Mainz
• Italy
  • Faenza, Italy, 48018
    • Ospedale Di Faenza
  • Meldola, Italy, 47014
    • Istituto Romagnolo Per Lo Studio Dei Tumori Dino Amadori Irst
  • Orbassano, Italy, 10043
    • Azienda Ospedaliero Universitaria San Luigi Gonzaga
  • Pisa, Italy, 56126
    • Aou Pisana, Stabilimento Di Santa Chiara
  • Torino, Italy, 10126
    • Ao Citta Della Salute E Della Scienza Di Torino Presidio O
• Japan
  • Hiroshima, Japan, 734-8551
    • Hiroshima University Hospital
  • Kochi, Japan, 781-8555
    • Kochi Health Sciences Center
  • Kyoto, Japan, 6068507
    • Kyoto University Hospital
  • Akita
    • Akitashi, Akita, Japan, 010-8543
      • Akita University Hospital
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East
  • Ehime
    • Matsuyamashi, Ehime, Japan, 791-0280
      • NHO Shikoku Cancer Center
  • Fukuoka
    • Fukuokashi, Fukuoka, Japan, 811-1395
      • Nho Kyushu Cancer Center
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0047
      • Kobe City Medical Center General Hospital
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 216-8511
      • St Marianna University School of Medicine Hospital
  • Osaka
    • Osakasayama, Osaka, Japan, 589-8511
      • Kindai University Hospital
    • Osakashi, Osaka, Japan, 541-8567
      • Osaka International Cancer Institute
    • Suitashi, Osaka, Japan, 565-0871
      • Osaka University Hospital
    • Takatsukishi, Osaka, Japan, 569-8686
      • Osaka Medical and Pharmaceutical University Hospital
  • Saitama
    • Kitaadachigun, Saitama, Japan, 362-0806
      • Saitama Cancer Center
  • Shizuoka
    • Suntogun, Shizuoka, Japan, 411-8777
      • Shizuoka Cancer Center
  • Tokyo
    • Chuoku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
    • Kotoku, Tokyo, Japan, 135-8550
      • Cancer Institute Hospital Of JFCR
• Korea, Republic of
  • Gyeonggi-do
    • Seongnamsi, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital
  • Incheon Gwang'yeogsi
    • Incheon, Incheon Gwang'yeogsi, Korea, Republic of, 21565
      • Gachon University Gil Medical Center
  • Jeollanam-do
    • HwasunGun, Jeollanam-do, Korea, Republic of, 58128
      • Chonnam National University Hwasun Hospital
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 06351
      • Samsung Medical Center
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 08308
      • Korea University Guro Hospital
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 05505
      • Asan Medical Center
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 8036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall dHebron
  • Barcelona, Spain, 08908
    • Institut Catala Doncologia
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28050
    • Hospital Universitario Hm Madrid Sanchinarro
  • Madrid, Spain, 28041
    • Hospital Universitario de Octubre
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet
• Taiwan
  • Kaohsiung, Taiwan, 83301
    • Kaohsiung Chang Gung Memorial Hospital
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Tainan, Taiwan, 736
    • Chi Mei Hospital Liouying
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Taipei, Taiwan, 100225
    • National Taiwan University Hospital East Campus
• United Kingdom
  • Greater Manchester, United Kingdom, M20 4BX
    • The Christie Hospital
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute UK
  • London, United Kingdom, SE1 9RT
    • Guys and St Thomas Hospital Nhs Foundation Trust
  • London, United Kingdom, W2 1NY
    • St Marys Hospital Imperial College Healthcare Nhs Trust
  • Northwood, United Kingdom, HA6 2RN
    • Mount Vernon Hospital (Mount Vernon Cancer Center)
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Nhs Foundation Royal Marsden Hospital
• United States
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Ohio
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Histologically confirmed diagnosis of esophageal squamous cell carcinoma (ESCC)
2. Tumor progression during or after first-line treatment for advanced unresectable / metastatic ESCC
3. At least one measurable/evaluable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 prior to randomization

Key Exclusion Criteria:

1. Receipt of 2 or more prior systemic treatments for advanced/metastatic unresectable ESCC
2. History of gastrointestinal perforation and /or fistula or aorto-esophageal fistula within 6 months prior to randomization
3. Tumor invasion into organs located adjacent to the esophageal disease site (eg, aorta or respiratory tract) at an increased risk of fistula in the study treatment assessed by investigator
4. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage
5. Received prior therapies targeting programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1)
6. Prior malignancy active within the previous 2 years (exceptions include the tumor under investigation in this trial, and locally recurring cancers that have undergone curative treatment, such as resected basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast)
7. Active brain or leptomeningeal metastasis.
8. Has active autoimmune disease or history of autoimmune diseases at high risk for relapse
9. Known history of, or any evidence of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis diagnosed based on imaging or clinical findings, or uncontrolled systemic diseases, including diabetes, hypertension, acute lung diseases, etc
10. Known history of Human Immunodeficiency Virus (HIV)
11. Has cardiovascular risk factors
12. Pregnant or breastfeeding woman.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tislelizumab; Tislelizumab on Day 1, given every 21 days	Drug: Tislelizumab; 200 mg administered intravenously (IV); Other Names: BGB-A317
Active Comparator: Investigator chosen chemotherapy (ICC); Paclitaxel on Day 1, given every 21 days or on a weekly schedule; OR Docetaxel on Day 1, given every 21 days; OR Irinotecan on Days 1 and 8, given every 21 days	Drug: Irinotecan; 125 mg/m^2 administered IV; Drug: Paclitaxel; 135-175 mg /m² administered IV , or 80-100 mg/m^2 administered IV according to local guidelines for standard of care; Drug: Docetaxel; 75 mg/m^2 administered IV or 70 mg/m^2 IV in Japan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) in the Intent-to-Treat (ITT) Analysis Set	OS is defined as the length of time from the date of randomization until the date of death due to any cause in all randomized participants	Approximately 2 years and 10 months from date of first randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) in the PDL-1 Positive Analysis Set	OS is defined as the time from the date of randomization until the date of death due to any cause in the PD-L1 positive population, defined as vCPS ≥10%.	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Objective Response Rate (ORR) in the ITT Analysis Set	ORR is defined as the percentage of participants who had complete response (CR) or partial response (PR) as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1;	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Overall Response Rate (ORR) in the PD-L1 Positive Analysis Sets	ORR is defined as the percentage of participants who had complete response (CR) or partial response (PR) as assessed by the investigator per RECIST v1.1;	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Progression-free Survival (PFS) in the ITT Analysis Set	PFS is defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the investigator per RECIST v1.1 or death, whichever occurs first; reported for the ITT analysis set	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Progression-free Survival (PFS) in the PDL-1 Positive Analysis Set	PFS is defined as the time from the date of randomization to the date of first documentation of disease progression assessed by the investigator per RECIST v1.1 or death, whichever occurs first; reported for the PDL-1 Positive Analysis Set	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Duration of Response (DOR) in the ITT Analysis Set	DOR is defined as the time from the first determination of an objective response until the first documentation of progression as assessed by the investigator per RECIST v1.1, or death, whichever comes first	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Duration of Response (DOR) in the PDL-1 Positive Analysis Set.	DOR is defined as the time from the first determination of an objective response until the first documentation of progression as assessed by the investigator per RECIST v1.1, or death, whichever comes first	Through End-of-Trial Analysis data cutoff date of 28-Dec-2022 (up to approximately 5 years)
Health-Related Quality of Life (HRQoL) as Assessed by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C-30) in the ITT Analysis Set	Mean change from baseline in EORTC QLQ-C30 index score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of cancer participants. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes	Baseline to Cycle 6 (21 days per cycle)
HRQoL as Assessed by EORTC QLQ-C30 in the PDL-1 Positive Analysis Set	Mean change from baseline in EORTC QLQ-C30 Index score. The EORTC QLQ-C30 v3.0 is a questionnaire that assesses quality of life of cancer participants. It includes global health status and quality of life questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes	Baseline to Cycle 6 (21 days per cycle)
HRQoL as Assessed by EORTC QLQ-Oesophagus Cancer Module (EORTC QLQ-OES18) Reported in ITT Analysis Set	Mean change from baseline in EORTC QLQ-OES18 index score. The EORTC QLQ-OES18 is a questionnaire that assesses overall symptoms in esophageal cancer participants. It includes questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes.	Baseline to Cycle 6 (21 days per cycle)
HRQoL as Assessed by EORTC QLQ-OES18) in the PDL-1 Positive Analysis Set.	Mean change from baseline in EORTC QLQ-OES18 index score. The EORTC QLQ-OES18 is a questionnaire that assesses overall symptoms in esophageal cancer participants. It includes questions related to overall health in which participants respond based on a 7-point scale, where 1 is very poor and 7 is excellent. Raw scores are transformed into a 0 to 100 scale via linear transformation. A higher score indicates better health outcomes.	Baseline to Cycle 6 (21 days per cycle)
HRQoL as Assessed by European Quality of Life 5-Dimensions 5-Level Questionnaire (EQ-5D-5L) in the ITT Analysis Set	Mean change from baseline in EQ-5D-5L visual acuity score (VAS). The EQ-5D-5L measures health outcomes using a VAS to record a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes.	Baseline to Cycle 6 (21 days per cycle)
HRQoL as Assessed by EQ-5D-5L in the PD-L1 Positive Analysis Set	Mean change from baseline in EQ-5D-5L visual acuity score (VAS). The EQ-5D-5L measures health outcomes using a VAS to record a participant's self-rated health on a scale from 0 to 100, where 100 is 'the best health you can imagine' and 0 is 'the worst health you can imagine.' A higher score indicates better health outcomes.	Baseline to Cycle 6 (21 days per cycle)
Number of Participants Experiencing Adverse Events (AEs)	Number of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), which includes laboratory tests, physical exams, electrocardiogram results and vital signs	From the first dose date to 30 days after the last dose date; up to approximately 4 years and 11 months

Collaborators and Investigators

• Sponsor: BeiGene
• Investigators: Study Director: Virginia Paton, Pharm.D., BeiGene

Publications and helpful links

General Publications

• Van Cutsem E, Kato K, Ajani J, Shen L, Xia T, Ding N, Zhan L, Barnes G, Kim SB. Tislelizumab versus chemotherapy as second-line treatment of advanced or metastatic esophageal squamous cell carcinoma (RATIONALE 302): impact on health-related quality of life. ESMO Open. 2022 Aug;7(4):100517. doi: 10.1016/j.esmoop.2022.100517. Epub 2022 Jul 1.
• Shen L, Kato K, Kim SB, Ajani JA, Zhao K, He Z, Yu X, Shu Y, Luo Q, Wang J, Chen Z, Niu Z, Zhang L, Yi T, Sun JM, Chen J, Yu G, Lin CY, Hara H, Bi Q, Satoh T, Pazo-Cid R, Arkenau HT, Borg C, Lordick F, Li L, Ding N, Tao A, Shi J, Van Cutsem E; RATIONALE-302 Investigators. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022 Sep 10;40(26):3065-3076. doi: 10.1200/JCO.21.01926. Epub 2022 Apr 20. Erratum In: J Clin Oncol. 2024 Feb 1;42(4):486. doi: 10.1200/JCO.23.02629.

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2018
• Primary Completion (Actual): December 1, 2020
• Study Completion (Actual): December 28, 2022

Study Registration Dates

• First Submitted: January 29, 2018
• First Submitted That Met QC Criteria: February 6, 2018
• First Posted (Actual): February 13, 2018

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 23, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: chemotherapy; paclitaxel; Unresectable; irinotecan; metastatic; docetaxel; esophagus; squamous; second-line
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Neoplasms, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Carcinoma; Carcinoma, Squamous Cell; Antineoplastic Agents, Immunological; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Phytogenic; Docetaxel; Irinotecan; Tislelizumab; Paclitaxel
• Other Study ID Numbers: BGB-A317-302; 2017-003699-30 (EudraCT Number); CTR20171026 (Registry Identifier: ChinaDrugTrials)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No