Tislelizumab (TIS) + Chemotherapy (CT) vs Placebo (PBO) + CT in HER2-negative Advanced or Metastatic Gastric or
Gastro-oesophageal Junction Adenocarcinoma (GC/GEJC): RATIONALE-305 Study Minimum 3-year Survival Follow-upMarcia Cruz Correa,1* Do-Youn Oh,2 Ken Kato,3 Josep Tabernero,4 Yuxian Bai,5 Jianhua Shi,6 Keun-wook Lee,7 Hidekazu Hirano,8 David Spigel,9 Lucjan Wyrwicz,10 Roberto Pazo-Cid,11 Antonio Cubillo Gracián,12 Liyun Li,13#Yaling Xu,14 Tao Sheng,15 Silu Yang,13 Rui-Hua Xu,16 Markus Möehler,17 on behalf of the RATIONALE-305 Investigators

Poster No: 1437P presented atESMO, Barcelona, Spain,
September 13-17, 2024

University of Puerto Rico, San Juan, Puerto Rico; 2Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea; 3Department of Head and Neck, Esophageal Medical Oncology and Gastrointestinal Medical Oncology, National Cancer Center Hospital,Tokyo, Japan; 4Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain; 5Harbin Medical University Cancer Hospital, Harbin, China; 6Linyi Cancer Hospital, Linyi, China; 7Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; 8Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan;
9Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN, USA; 10Narodowy Instytut Onkologii, Warsaw, Poland; 11Hospital Universitario Miguel Servet, Zaragoza, Spain; 12Hospital Universitario HM Sanchinarro, Madrid, Spain; 13BeiGene (Beijing) Co., Ltd, Beijing, China; 14BeiGene (Shanghai) Co., Ltd, Shanghai, China; 15BeiGene USA, Inc., San Mateo, CA, USA; 16Department of MedicalOncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China; 17Gastrointestinal Oncology, Johannes Gutenberg-University Clinic, Mainz, Germany. *Corresponding author. #Affiliation at the time of the study.
1Conclusions

After a minimum 3-year follow-up, tislelizumab (TIS; BGB-A317) plus chemotherapy (CT) as first-line
treatment for gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJC) continued to demonstrateclinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and duration ofresponse (DoR) compared with placebo (PBO) plus CT, with no new safety signals.

These long-term data further support TIS plus CT as a new
first-line treatment option for advanced human epidermal
growth factor receptor 2 (HER2)-negative GC/GEJC.

Background
TIS (an anti–PD-1 antibody) plus CT demonstrated significant OS benefit vs PBO plus CT as first-line therapy for advanced GC/GEJC in all randomised patients (hazard ratio [HR]=0.80; at final analysis)
and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5% (HR=0.74; at the interim analysis) in the phase 3 RATIONALE-305 study (NCT03777657).2 Two-year OS
rates for TIS plus CT vs PBO plus CT in the RATIONALE-305 study were 32.7% vs 23.4%, respectively.5 Here, we report efficacy and safety from RATIONALE-305 after a minimum 3-year follow-up.

GC/GEJC are among the most common cancer types worldwide, representing the 5th and 7th most common causes of death due to cancer for gastric andoesophageal cancers, respectively.1 Checkpoint inhibition with anti–programmed cell death protein-1 (PD-1) inhibitors in combination with CT has shown improved
survival in GC/GEJC over chemotherapy alone.2-4

Results

All Patientsa

100Figure 1. Study Design

Patient Disposition

80• Among 1657 patients assessed for eligibility, a total of 997 patients were randomised(TIS plus CT, n=501; PBO plus CT, n=496)• At 3-year follow-up (minimum follow-up, 36.6 months), 23 (4.6%) patients treated withTIS plus CT and 10 (2.0%) patients treated with PBO plus CT remain on treatment

Key Eligibility
Criteria

TIS 200 mg IV Q3W+ CT (oxaliplatin +capecitabine or
cisplatin +5-fluorouracil)a• Histologicallyconfirmed
GC/GEJC• Excluded
patients with
HER2-positivetumours• No previous
therapy forunresectable,
locally advanced
or metastatic
GC/GEJCR
1:1

Maintenance treatment
until unacceptable toxicity
or disease progression

PBO IV Q3W+ CT (oxaliplatin +capecitabine orcisplatin +5-fluorouracil)aPrimary
Endpoint• OS in
PD-L1–positive(PD-L1 TAPscore ≥5%)and ITT
analysis sets
SecondaryEndpoints• PFSb• ORR

Table 1. Efficacy Outcomes at 3-year Follow-upab• DoRb• Safety

Median OS, mo (95% CI)
HR (95% CI)

Stratification Factors:• Regions of enrolment: China (including Taiwan) vs Japan andSouth Korea vs US and Europe and other regions• PD-L1 expression (PD-L1 score ≥5% vs PD-L1 score <5%)
• Presence of peritoneal metastasis (yes vs no)• Investigator-chosen CT (oxaliplatin + capecitabine or cisplatin +5-fluorouracil)

OS rate at 36 mo, % (95% CI)
Median PFS, mo (95% CI)cHR (95% CI)

22bPFS rate at 36 mo, % (95% CI)

CT: oxaliplatin 130 mg/m on day 1 + capecitabine 1000 mg/m twice daily on days 1-14, Q3W; cisplatin 80 mg/m on day 1 +5-fluorouracil 800 mg/m2/day on days 1-5, Q3W. b Investigator assessed per Response Evaluation Criteria In Solid Tumors v1.1.
Abbreviations: CT, chemotherapy; DoR, duration of response; GC/GEJC, gastric or gastro-oesophageal junction adenocarcinoma;
HER2, human epidermal growth factor receptor 2; 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 3 weeks; R, randomised; TAP,Tumor Area Positivity; TIS, tislelizumab.

ab2

TIS Plus CT
n=501

PBO Plus CT
n=496

15.0 (13.6, 16.5)

12.9 (12.1, 14.1)

0.79 (0.69, 0.90)
20.7 (17.1, 24.4)

13.4 (10.5, 16.6)

6.9 (5.7, 7.2)

6.2 (5.6, 6.9)

0.79 (0.68, 0.91)
15.0 (11.6, 18.8)

7.5 (5.1, 10.5)

Confirmed ORR, % (95% CI)c47.3 (42.9, 51.8)

40.5 (36.2, 45.0)

Median DoR (confirmed responders), mo (95% CI)

8.6 (7.9, 11.1)

7.2 (6.0, 8.5)

24.5 (18.8, 30.6)

14.4 (9.3, 20.5)

Remaining in response at 36 mo, % (95% CI)

ITT analysis set. b Stratified by region (East Asia vs rest of world), PD-L1 expression, and presence of peritoneal metastasis. c Investigator evaluated.
Abbreviations: CI, confidence interval; CT, chemotherapy; DoR, duration of response; HR, hazard ratio; ITT, intent-to-treat; mo, months; ORR, objective
response rate; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TIS, tislelizumab.
aReferences

1. Bray F, et al. CA Cancer J Clin. 2024;74(3):229-263.
2. Qiu M, et al. BMJ. 2024;385:e078876.
3. Janjigian YY, et al. J Clin Oncol. 2024;42(17):2012-2020.

4. Rha SY, et al. Lancet Oncol. 2023;24(11):1181-1195.
5. Smith D, et al. Presented at JFHOD 2024; Abstract P.005.

Acknowledgements

We would like to thank the investigators, the site support staff, and especially the patients for participating in 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.

396

430

90
80

60

15.0 (13.6, 16.5) 12.9 (12.1, 14.1)

50

HR (95% CI)

0.79 (0.69, 0.90)

404650HR (95% CI)

0.71 (0.59, 0.86)

40TIS Plus CT
PBO Plus CT

1008 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 62
Time (Months)

Number of Patients at Risk:
TIS Plus CT 501 477 445 404 355 316 278 254 226 202 179 165 154 134 127 117 109 103
PBO Plus CT 496 472 431 398 344 304 264 218 186 155 136 119 109 99 85 74 66 60

9459845274
4456
3547273724

33
19241418
1213782411000233

16.4 (13.6, 19.1) 12.8 (12.0, 14.5)20220960200PBO Plus CT(n=272)

Median OS, mo(95% CI)

30TIS Plus CT
PBO Plus CT

TIS Plus CT(n=274)
Events70

300• Improvements in OS, PFS, and DoR with TIS plus CT vs PBO plus CT were maintained
at 3-year follow-up (Table 1)• In all patients, and at the prespecified PD-L1 TAP score cutoff points, OS was improved
with TIS plus CT vs PBO plus CT (Figure 2)• OS benefit was observed across all prespecified subgroups (Figure 3)• Among the 273 (54.5%) patients treated with TIS plus CT vs 300 (60.5%) patients treatedwith PBO plus CT who received subsequent anticancer therapies, 258 (51.5%) vs 286(57.7%) received chemotherapy, 156 (31.1%) vs 165 (33.3%) received targeted therapy,
65 (13.0%) vs 98 (19.8%) received immunotherapy, and 15 (3.0%) vs 19 (3.8%) received
other therapies, respectively

PBO Plus CT(n=496)

Median OS, mo(95% CI)

10Efficacy

TIS Plus CT(n=501)
Events70OS (%)• The RATIONALE-305 study is a randomised, double-blind, global phase 3 study(Figure 1)• TAP score was evaluated in tumour tissue using the VENTANA PD-L1 (SP263) assay

90PD-L1 TAP Score ≥5%100OS (%)

Methods

Figure 2. Kaplan-Meier Curves of OS at 3-year Follow-up

02468 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 62
Time (Months)

Number of Patients at Risk:
TIS Plus CT 274 263 247 228 199 178 156 145 133 120 109 102
PBO Plus CT 272 261 236 215 190 168 148 120 99 83 69 5997538651814477427139693565355630482636222917221419121571269461301000HR values are stratified. a ITT analysis set. Abbreviations: CI, confidence interval; CT, chemotherapy; HR, hazard ratio; ITT, intent-to-treat; mo, months; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1; TAP, Tumor Area Positivity; TIS, tislelizumab.

Figure 3. Forest Plot of OS by Subgroup at 3-year Follow-up

aSubgroupAge<65 years≥65 years
SexMaleFemale
Regionb
East Asia
Rest of world
ECOG performance status01PD-L1 expression
PD-L1 TAP score <5%PD-L1 TAP score ≥5%
Peritoneal metastasis
Yes
NoLiver metastasis
Yes
NoEvents/Total
PBO Plus CT
TIS Plus CT

HR for Death (95% CI)

HR (95% CI)

Safety• Safety was maintained at 3-year follow-up (Table 2)• The numbers of treatment-related adverse events (TRAEs), grade ≥3 TRAEs, andtreatment-emergent adverse events leading to dose modification were similar in both arms
• The most common grade ≥3 TRAEs were neutrophil and platelet count decreased

271/340
125/161279/313151/183

0.79 (0.67, 0.93)
0.80 (0.63, 1.01)269/346
127/155

297/346
133/150

0.79 (0.67, 0.93)
0.79 (0.62, 1.01)

Table 2. Safety at 3-year Follow-upa
TIS Plus CT
n=498

PBO Plus CT
n=494

Patients with ≥1 TRAE for any treatment component

483 (97.0)476 (96.4)

Grade ≥3 TRAEs

269 (54.0)

246 (49.8)

288/376
108/125

320/372
110/1240.79 (0.68, 0.93)
0.73 (0.56, 0.96)

139/169
257/332

134/154
296/3420.77 (0.61, 0.98)
0.80 (0.67, 0.94)

187/227
209/274

197/224233/272

0.89 (0.73, 1.09)
0.72 (0.60, 0.87)

Neutrophil count decreased

59 (11.8)

57 (11.5)

Platelet count decreased

56 (11.2)

57 (11.5)

184/220212/281196/214234/282

0.78 (0.64, 0.96)
0.79 (0.65, 0.95)

Neutropenia

33 (6.6)

34 (6.9)

Anaemia

25 (5.0)37 (7.5)

150/190
246/311165/188
265/308

0.77 (0.62, 0.96)
0.80 (0.67, 0.95)

Serious TRAEs for any treatment component

113 (22.7)

72 (14.6)

TRAEs leading to any treatment discontinuation

83 (16.7)

40 (8.1)

TEAEs leading to dose modification of any treatment
component381 (76.5)375 (75.9)

TRAEs leading to deathb

6 (1.2)c2 (0.4)d0 0.25

0.75 1Occurring at ≥5% incidence

1.5TIS Plus CT Better PBO Plus CT Better
HR values are unstratified. a ITT analysis set. b East Asia includes Japan, Korea, China, and Taiwan. Rest of world includes the US, Russia, France,Spain, Italy, UK, Poland, and Turkey. Abbreviations: CI, confidence interval; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group;HR, hazard ratio; ITT, intent-to-treat; mo, months; OS, overall survival; PBO, placebo; PD-L1, programmed death-ligand 1; TAP, Tumor Area
Positivity; TIS, tislelizumab.

Disclosures

MM reports serving in a consultancy/advisory role for Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Dragonfly, Lilly, Merck Serono,
MSD, Novartis, Pfizer, Roche, Servier Laboratories, and Taiho Pharmaceutical; receiving honoraria from Amgen, Astellas, AstraZeneca/
MedImmune, BMS, Daiichi Sankyo, Falk Foundation, Merck Serono, MSD Oncology, Nordic Pharma, Pierre Fabre, Roche/Genentech, Sanofi,
Servier Laboratories, and Transcenta Holding; receiving grant/research funding from Amgen, Leap Therapeutics, Merck Serono, and MSD; andreceiving other remuneration from Amgen, ASCO, Bayer, BeiGene, EORTC, ESMO, German Cancer Society, Merck Serono, MSD, and Roche.

Patients with ≥2 events for the same preferred term were counted only once for the preferred term. b Excludes death due to disease progression.
cDeath (n=4), colitis (n=1), sepsis (n=1), subdural haematoma (n=1). d Pneumonia (n=2). Abbreviations: CT, chemotherapy; PBO, placebo;
TEAE, treatment-emergent adverse event; TIS, tislelizumab; TRAE, treatment-related adverse event.
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