TISLELIZUMAB (TIS) + CHEMOTHERAPY (CT) VS PLACEBO (PBO) + CT
IN LOCALLY ADVANCED UNRESECTABLE OR METASTATICESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC)
PD-L1 Biomarker Analysis from RATIONALE-306
Eric Raymond,1 Jianming Xu,2 Ken Kato,3 Richard Hubner,4 Yongqian Shu,5 Sook Ryun Park,6 Takashi Kojima,7Lucjan Wyrwicz,8 David Tougeron,9 Karen Geboes,10 Eric Van Cutsem,11 Roberto Pazo-Cid,12 Aziz Zaanan,13Sue-Anne McLachlan,14 Hongqian Wu,15 Jingwen Shi,16 Liyun Li,17 Shican Yan,17 Harry H. Yoon,18 on behalf ofthe RATIONALE-306 Investigators
1Centre Hospitalier Paris Saint-Joseph, Paris, France; 2Fifth Medical Center, Chinese PLA General Hospital, Beijing, China;

3National Cancer Center Hospital, Tokyo, Japan; 4Department of Medical Oncology, The Christie NHS Foundation Trust/Division ofCancer Sciences, University of Manchester, Manchester, UK; 5The First Affiliated Hospital of Nanjing Medical University, Nanjing,China; 6Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 7National Cancer Center Hospital
East, Chiba, Japan; 8Maria Sklodowska-Curie National Cancer Research Institute, Warsaw, Poland; 9Centre Hospitalier
Universitaire de Poitiers, Poitiers, France; 10UZ Gent, Gent, Belgium; 11University Hospitals Gasthuisberg/Leuven & KU Leuven,Leuven, Belgium; 12Hospital Universitario Miguel Servet, Zaragoza, Spain; 13Hôpital Européen Georges Pompidou, Digestive
Oncology, Paris, France; 14St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia; 15Global Statistics and Data Science,
BeiGene USA, Inc., Ridgefield Park, NJ, USA; 16Clinical Biomarker, BeiGene (Beijing) Co., Ltd., Beijing, China;
17Clinical Development, BeiGene (Beijing) Co., Ltd., Beijing, China; 18Mayo Clinic, Rochester, MN, USA

DECLARATION OF INTERESTS
Eric Raymond reports no conflicts of interest

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TISLELIZUMAB (TIS) + CHEMOTHERAPY (CT)VS PLACEBO (PBO) + CT IN LOCALLY ADVANCED
UNRESECTABLE OR METASTATIC ESOPHAGEALSQUAMOUS CELL CARCINOMA (ESCC)

PD-L1 Biomarker Analysis from RATIONALE-306

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BACKGROUND•••

The PD-L1 Tumor Area Positivity (TAP) score is a newly developed area scoring system evaluating both immune andtumour cells. The TAP score has been analytically developed and validated for advanced ESCC in the RATIONALE-306 study• In RATIONALE-306, tislelizumab (TIS) + chemotherapy (CT) demonstrated a significant improvement in overall
survival (OS) in all randomised patients (HR=0.70; 95% CI: 0.59, 0.83) and patients with PD-L1 TAP score ≥10%(HR=0.70; 95% CI: 0.52, 0.95) compared with placebo (PBO) + CT, with a sustained survival benefit observed after aminimum 3-year follow-up
In advanced ESCC, combined positive score (CPS) as mixed PD-L1 expression in immune and tumour single cells was able
to predict responses to checkpoint inhibitors• In KEYNOTE-590, pembrolizumab showed significant OS benefit in all randomised patients and patients withCPS ≥101
• In CheckMate 648, nivolumab showed significant OS benefit in all randomised patients and enhanced OS benefit inpatients with CPS ≥1, ≥5, and ≥102
In these exploratory post-hoc analyses from a minimum 3-year follow-up, we report OS and progression-free survival (PFS)
results in PD-L1 subgroups defined by TAP score and CPS, as well as concordance of TAP score and CPS at multiple
thresholds in RATIONALE-306

1. Sun JM, et al. Lancet. 2021;398(10302):759-771. 2. Kato K, et al. Cancer Med. 2024;13(9):e7235.
Abbreviations: CI, confidence interval; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; PD-L1, programmed death-ligand 1.

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STUDY DESIGN
Randomised, Double-blind, Global Phase 3 StudyKey Eligibility Criteria• Unresectable locally advanced ormetastatic ESCC
• No prior systemic treatment foradvanced disease• ECOG PS 0 or 1
• Measurable or evaluable disease per
RECIST v1.1

TIS 200 mg IV Q3W +CT (platinum + fluoropyrimidine orplatinum + paclitaxel)aR
1:1

Maintenance treatment until unacceptabletoxicity or disease progression
PBO IV Q3W +CT (platinum + fluoropyrimidine orplatinum + paclitaxel)a

Stratification Factors• Geographic region (Asia [excluding Japan] vs Japan vs Rest of World)• Prior definitive therapy (yes vs no)• Investigator-chosen chemotherapy (platinum/fluoropyrimidine vs platinum/paclitaxel paclitaxel)

Primary Endpoints
OS in ITT analysis set
Secondary Endpoints
OS in TAP score ≥10%, PFS, ORR,DoR, HRQoL, safety
Post Hoc Analysis• Subgroup analysis of OS and PFS
using exploratory PD-L1 TAP scoreand CPS cutoffs• TAP score vs CPS concordance

aThe platinum agent may be cisplatin 60-80 mg/m2 day 1 or oxaliplatin 130 mg/m2 day 1 (except in China, Taiwan, Japan, and countries where oxaliplatin substitution is not permitted) according to site or investigator

preference, or standard practice as determined prior to randomisation. The fluoropyrimidine may be 5-fluorouracil 750-800 mg/m2 days 1-5 or capecitabine 1000 mg/m2 days 1-14 twice a day. Paclitaxel 175 mg/m2 day 1.
Abbreviations: CPS, combined positive score; CT, chemotherapy; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Score performance status; ESCC, esophageal squamous cell carcinoma; HRQoL,
health-related quality of life; ITT, intent-to-treat; IV, intravenous; ORR, objective response rate; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1; PFS, progression-free survival; Q3W, once every 3weeks; R, randomised; RECIST, Response Evaluation Criteria in Solid Tumors; TAP, Tumor Area Positivity; TIS, tislelizumab.

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SCORING METHODS COMPARISON BETWEEN TAP SCORE AND CPS•

PD-L1 expression was stained using VENTANA PD-L1 (SP263) assay (Roche) and determined by TAP inRATIONALE-306•

For exploratory purposes, pathologists in the central laboratory scored the same stained samples according to CPSa
TAP Score (%)

Score Formula

Area occupied by PD-L1 staining
tumour cells and immune cells
Tumour area

CPS
× 100%# PD-L1 staining
tumour cells and immune cells
Total # viable tumour cells

× 100

Cell Types Included in PD-L1 Score• Tumour cells• Immune cells (including lymphocytes,macrophages, histiocytes, reticular dendriticcells, plasma cells, and neutrophils)• Tumour cells• Immune cells (including lymphocytes andmacrophages)

Scoring Method• Visual-based estimation on tumour area

• Cell count (time consuming)aOff-label for the VENTANA PD-L1 (SP263) assay.

Abbreviations: CPS, combined positive score; PD-L1, programmed death-ligand 1; TAP, Tumor Area Positivity.

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PREVALENCE OF PD-L1 SUBGROUPS BY TAP SCORE OR CPS•Of 649 patients randomised, 542 had evaluable TAP scores and 537 had evaluable post hoc CPS•

Prevalence was comparable across arms by TAP score or CPS at different thresholds

PD-L1 Status TAP Score/CPS

TAP Score, n (%)
N=542

CPS, n (%)
N=537

TIS + CT
N=267

PBO + CT
N=275

TIS + CT
N=264

PBO + CT
N=273

≥10%/≥10116 (43.4)

107 (38.9)

115 (43.6)

113 (41.4)

5% to <10%/5 to <1056 (21.0)

79 (28.7)

54 (20.5)

61 (22.3)

1% to <5%/1 to <559 (22.1)

64 (23.3)

64 (24.2)

73 (26.7)<1%/<136 (13.5)

25 (9.1)

31 (11.7)

26 (9.5)

Abbreviations: CPS, combined positive score; CT, chemotherapy; PBO, placebo; PD-L1, programmed death-ligand 1; TAP, Tumor Area Positivity; TIS, tislelizumab.

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OS IMPROVEMENT FOR TIS + CT VS PBO + CT IN PD-L1 SUBGROUPSBY TAP SCORE AND CPS
Event/Total
PD-L1 Status

TIS + CT PBO + CT

HR for Death (95% CI)

OS, Unstratified
HR (95% CI)

TAP score≥10%90/116

85/1070.71 (0.53, 0.95)

5% to <10%38/56

66/79

0.50 (0.33, 0.75)

1% to <5%50/59

56/64<1%32/36

22/25

0.86 (0.59, 1.26)
1.21 (0.70, 2.08)

Unknown

40/59

35/48

0.65 (0.41, 1.02)≥1088/115

93/1130.64 (0.48, 0.86)

5 to <1039/54

51/61

0.72 (0.47, 1.09)

1 to <552/64

60/73

0.71 (0.49, 1.03)<128/31

23/26

1.36 (0.78, 2.38)

Unknown

43/62

37/50

0.66 (0.42, 1.02)

CPSTIS better• After a minimum 3-year follow-up,OS improvement with TIS + CT vs
PBO + CT was seen in PD-L1
subgroups with TAP score ≥1% orCPS ≥1• The small subgroup size with TAPscore <1% or CPS <1 limited
interpretation of efficacy data
• OS results defined by TAP scores
and CPS were similar

PBO better
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Abbreviations: CI, confidence interval; CPS, combined positive score; CT, chemotherapy;
HR, hazard ratio; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1;
TAP, Tumor Area Positivity; TIS, tislelizumab.

Survival Probability

TIS + CT (n=59)

PBO + CT (n=64)

50

56

13.0 (10.8, 18.3)

9.6 (7.9, 13.7)

Events0.8
0.7Median (95% CI)

0.6

HR (95% CI)

0.5
0.4

0.86 (0.59, 1.26)

0.3
0.2
0.1
0.0

TAP Score 5% to <10%1.0
0.9
0.8

TIS + CT (n=56)

PBO + CT (n=79)

3866

Events0.7

Median (95% CI) 23.1 (16.4, 28.3)

0.6HR (95% CI)

0.5
0.4

9.8 (8.0, 13.0)

0.50 (0.33, 0.75)

0.3
0.2
0.1
0.00246Time (Months)

TIS + CT (n=116)

Events0.80.7

PBO + CT (n=107)

9085

Median (95% CI) 16.6 (15.3, 23.4)

0.6

HR (95% CI)

0.5
0.4

10.0 (8.6, 13.3)

0.71 (0.53, 0.95)

0.3
0.2
0.1
0.0

08 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

No. at Risk

TAP Score ≥10%

1.0
0.9Survival Probability

TAP Score 1% to <5%1.00.9Survival Probability

SIMILAR OS TREND IN PD-L1–POSITIVE SUBGROUPS BASED ON
ASSOCIATED CLINICAL CUTOFFS

48121620

No. at Risk

242832Time (Months)

3640

4448520 255

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60

Time (Months)

No. at Risk

TIS + CT5955

49

4644373127242219181311111110976541111000TIS + CT

56544640353025201915109520TIS + CT

116 113 105 98

9485767063525049453835312929252419151287322210

PBO + CT6460

524839282722201818171414121211977443322110

PBO + CT

79694731271914119977200

PBO + CT

107 104 9066

5243403733312725222120191513131396654

11000

PBO + CT (n=73)

52

60

EventsMedian (95% CI) 16.7 (12.3, 20.8)

0.7
0.6

HR (95% CI)

CPS 5 to <10

9.5 (7.7, 13.7)

0.71 (0.49, 1.03)

0.50.40.3
0.2
0.1
0.0

1.0
0.9
0.8

Events3951

Median (95% CI) 16.8 (11.2, 23.9)

0.7
0.6

CPS ≥10TIS + CT (n=54) PBO + CT (n=61)

HR (95% CI)

10.8 (8.0, 16.7)

0.72 (0.47, 1.09)

0.5
0.4
0.3
0.2
0.1

Survival Probability

TIS + CT (n=64)

Survival Probability

Survival Probability

CPS 1 to <51.0
0.9
0.82468 10 12 14 16 18 20 22 27 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

Time (Months)

No. at Risk

1.00.90.8

Events0.70.6HR (95% CI)

TIS + CT (n=115)

PBO + CT (n=113)

8893

Median (95% CI) 17.2 (15.3, 24.1)

9.4 (8.5, 12.3)

0.64 (0.48, 0.86)

0.5
0.4
0.3
0.2
0.1
0.0

0.0
082

04

8121620

2428

32

3640

4448

52

Time (Months)

No. at Risk

0 255

4 6 8 10 12 14 16 18 20 24 27 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60

Time (Months)

No. at Risk

TIS + CT

6461555149

46423432

3126

24

2120

17171613109752111000TIS + CT

5449403328231814131297420

TIS + CT

115 113 106 100 95

84746963535150463936323030262419171498322210

PBO + CT

7370

61

5441312825211616

1413

13

1010101077443211110

PBO + CT

61523828

2419

161310985300

PBO + CT

113 109 94

534441

38

35

32

28

2321201918141212119764311000

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8270Abbreviations: CI, confidence interval; CPS, combined positive score; CT, chemotherapy;
HR, hazard ratio; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1;
TAP, Tumor Area Positivity; TIS, tislelizumab.

PFS IMPROVEMENT FOR TIS + CT VS PBO + CT IN PD-L1
SUBGROUPS BY TAP SCORE AND CPS
Event/Total
PD-L1 Status

TIS + CT PBO + CT

HR for Death (95% CI)

PFS, Unstratified
HR (95% CI)

TAP score≥10%81/116

93/1070.49 (0.36, 0.67)

5% to <10%38/56

60/79

0.52 (0.34, 0.79)

1% to <5%

45/59

52/64

<1%27/36

22/25

0.74 (0.49, 1.11)
0.83 (0.47, 1.46)

Unknown

42/59

34/48

0.79 (0.50, 1.25)≥1080/115

97/1130.45 (0.33, 0.61)

5 to <10

41/54

49/61

0.74 (0.48, 1.12)

1 to <544/64

56/73

0.66 (0.44, 0.98)<123/31

23/26

0.76 (0.42, 1.35)

Unknown

45/62

36/50

0.79 (0.51, 1.23)• After a minimum 3-year follow-up,
PFS improvement with TIS + CT
vs PBO + CT was seen in all PDL1 subgroups• PFS results defined by TAP scores
and CPS were similar

CPS

TIS better

PBO better
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Abbreviations: CI, confidence interval; CPS, combined positive score; CT, chemotherapy;
HR, hazard ratio; PBO, placebo; PD-L1, programmed death-ligand 1; PFS, progression-freesurvival; TAP, Tumor Area Positivity; TIS, tislelizumab.

SUBSTANTIAL CONCORDANCE AND GOOD CORRELATIONBETWEEN TAP AND CPS SCORING IN ESCCGood correlation was observed between TAP score and CPS, as shown by the interclass correlation coefficient (ICC=0.85 [0.80, 0.88])
TAP score and CPS showed substantial concordance at multiple cutoffs in terms of overall percent agreement (OPA) and Cohen’s Kappa (OPA
[95% CI]: 97% [96, 98], 85% [82, 88], 89% [87, 92] at 1%, 5%, and 10% thresholds of each score, respectively)••

TAP Score 5% vs CPS 5

TAP Score 1% vs CPS 1

PD-L1 Expression (%)

100TAP Score 10% vs CPS 10

ICC=0.85 (95 % CI: 0.80, 0.88)
PD−L1CPSTAP75TAPCPS+
1.1% (6)TAP+
CPS+
87.5% (470)

TAP+
CPS+
57.5% (309)TAP+
TAPCPSCPS+
1.9% (10) 6.3% (34)TAP+
CPS8.8% (47)TAPCPS9.5% (51)

50

0200

Agreementn/N

Agreement

98 (97, 99)

PPA, % (95% CI)

309/343

90 (87, 93)

PPA, % (95% CI)

NPA, % (95% CI)

51/57

89 (81, 96)

NPA, % (95% CI)

147/194

76 (70, 82)

OPA, % (95% CI)

521/537

97 (96, 98)

OPA, % (95% CI)

456/537

85 (82, 88)

0.85 (0.77, 0.92)

Cohen’s Kappa (95% CI)

0.67 (0.60, 0.73)

n/N

Agreement

196/228

86 (82, 90)

NPA, % (95% CI)

283/30992 (88, 94)

OPA, % (95% CI)

479/537

89 (87, 92)

Cohen’s Kappa (95% CI)

0.78 (0.72, 0.83)

400

Individual Tumour Samples
Strength of Reliability (ICC)

Poor
<0.50

TAPCPS52.7% (283)n/NCohen’s Kappa (95% CI)
0TAP+
CPS4.8% (26)

TAP+
CPS+
36.5% (196)TAPCPS27.4% (147)

470/480

PPA, % (95% CI)

25

TAPCPS+
6.0% (32)Moderate(0.50-0.75)

Good(0.75-0.90)

Strength of Agreement (Kappa)
Slight(0.01-0.20)

Excellent(≥0.90)

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Fair(0.21-0.40)

Moderate(0.41-0.60)

Substantial(0.61-0.80)

Almost perfect(0.81-1.0)

Abbreviations: CI, confidence interval; CPS, combined positive score; ESCC, esophageal
squamous cell carcinoma; NPA, negative percent agreement; PD-L1, programmed death-ligand 1;
PPA, positive percent agreement; TAP, Tumor Area Positivity.

CONCLUSIONS••

Both TAP score and CPS are viable for PD-L1 expression measurement in patients with ESCC
•TIS + CT improved OS in patients with PD-L1 TAP scores of 1 to <5%, 5 to <10%, as well as theprespecified TAP score ≥10%, and improved PFS regardless of PD-L1 expression•Comparable OS and PFS benefit was observed in PD-L1 subgroups by CPS•TAP score and CPS at matched thresholds (1% vs 1, 5% vs 5, 10% vs 10) exhibited substantial
concordance in ESCC

These findings from the 3-year follow-up provide further support for the therapeutic advantages of TIS +CT over PBO + CT as first-line treatment of ESCC, as well as the interchangeability of TAP score and CPS
in measuring PD-L1 expression in ESCC

Abbreviations: CPS, combined positive score; CT, chemotherapy; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1;
TAP, Tumor Area Positivity; TIS, tislelizumab.

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ACKNOWLEDGEMENTS•We would like to thank the investigators, the site support staff, and especially the patients for participatingin this study•

This study was sponsored by BeiGene•

Medical writing support was provided by Lauren D. Van Wassenhove, PhD, of Parexel, with funding
provided by BeiGene

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THANK YOU

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