Tislelizumab (TIS) Plus Chemotherapy (Chemo) vs Placebo (PBO)
Plus Chemo as First-Line (1L) Treatment of Advanced Gastric or
Gastroesophageal Junction Adenocarcinoma (GC/GEJC): Health-Related
Quality of Life (HRQoL) Outcomes in the RATIONALE-305 Study
Ken Kato,1 Marcia Cruz Correa,2 Rui-Hua Xu,3 Markus Moehler,4 Do-Youn Oh,5 David Spigel,6 Hendrik-Tobias Arkenau,7 Josep Tabernero,8 Anastasia V. Zimina,9Yuxian Bai,10 Jianhua Shi,11 Keun-Wook Lee,12 Hidekazu Hirano,5 Lucjan Wyrwicz,13 Roberto Pazo Cid,14 Hui Xu,15 Tao Sheng,16 Gisoo Barnes16National Cancer Center Hospital, Department of Gastrointestinal Medical Oncology, Tokyo, Japan; 2University of Puerto Rico, School of Medicine, San Juan, Puerto Rico; 3University Cancer Center State Key Laboratory of Oncology
in South China, Collaborative Innovation Center of Cancer Medicine, Department of Medical Oncology, Guangzhou, China; 4Johannes-Gutenberg University Clinic, Department of Internal Medicine I, Mainz, Germany;
5Seoul National University Hospital Cancer Research Institute, Seoul National University College of Medicine, Department of Internal Medicine, Seoul, South Korea; 6Sarah Cannon Research Institute, Nashville, TN, USA;
7Sarah Cannon Research, London, UK; 8Vall d’Hebron University Hospital, Department of Medical Oncology, Barcelona, Spain; 9BIH of Omsk Region, Clinical Oncology Dispensary, Omsk Oblast, Russia;
10Harbin Medical University Cancer Hospital, Department of Gastrointestinal Oncology, Harbin, China; 11Linyi Cancer Hospital, Department II of Medical Oncology,Linyi, China; 12Seoul National University College of Medicine, Seoul National University Bundang Hospital, Department of Medical Oncology (InternalMedicine), Seongnam, Republic of Korea; 13Maria Sklodowska-Curie National Cancer Research Institute, Department of Oncology and Radiotherapy,
Presented at the Asia Pacific Gastroenterology
Warsaw, Poland; 14Hospital Universitario Miguel Servet, Department of Medical Oncology, Zaragoza, Spain; 15BeiGene (Beijing) Co., Ltd., Beijing, China;
CancerSummit (APGCS); 29-31 August 2024; Singapore
16
BeiGene USA, Inc., San Mateo, CA, USA1

• Advanced or metastatic gastroesophageal junction adenocarcinoma (GC/GEJC) patients had better health-related quality of life (HRQoL) outcomes withtislelizumab plus chemotherapy compared with placebo plus chemotherapy• These better HRQoL outcomes were maintained through Cycles 4 and 6, corresponding to approximately 9 and 15 weeks, respectively• The sustained and improved HRQoL in overall health status, physical functioning, and gastric cancer disease-specific symptoms concurred well with improved
efficacy and safety results of tislelizumab plus chemotherapy• Tislelizumab plus chemotherapy can potentially serve as a 1L treatment for advanced or metastatic GC/GEJC patients

Conclusions

BackgroundResults• Gastric cancer, including GC/GEJC, continues to be one of the most common forms of cancer and aleading cause of cancer death worldwide1• Individuals with gastric cancer commonly experience symptoms such as fatigue, diarrhea, sleep
disorders, and eating difficulties2-4 thus having a detrimental impact on patients’ HRQoL• RATIONALE-305 (NCT03777657), a phase 3 study, examined the efficacy of tislelizumab plus
chemotherapy compared with placebo plus chemotherapy in adults with GC/GEJC
Tislelizumab plus chemotherapy demonstrated significant improvements in overall survival vs placebo
plus chemotherapy in patients with a PD-L1 score ≥5% (median 17.2 months vs 12.6 months; hazard
ratio [HR] 0.74, [95% confidence interval (CI) 0.59–0.94]; P=0.0056 [at interim analysis]) and in all
randomized patients (median 15.0 months vs 12.9 months; HR 0.80
[95% CI 0.70–0.92]; P=0.0011 [at final analysis])
Grade ≥3 treatment-related adverse events were observed in 54% vs 50% of patients in thetislelizumab plus chemotherapy and placebo plus chemotherapy arms, respectively––• The intent-to-treat population consisted of a total of 997 patients randomized to receive eithertislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496)• Patient demographics and baseline disease characteristics were generally balanced across treatment
arms (Table 1)

Adjusted Completion Rates• The adjusted completion rates were high (>91%) and consistent across treatment arms at each
assessment timepoint

Change From Baseline to Cycle 4• Better outcomes were observed in the tislelizumab plus chemotherapy arm vs the placebo plus
chemotherapy arm. The decrease in pain/discomfort of -6.88 (-8.39, -5.36) was clinically meaningful inthe tislelizumab plus chemotherapy arm (Figure 1)

Change From Baseline to Cycle 6• Better outcomes were observed in the tislelizumab plus chemotherapy arm at Cycle 6 (Figure 2)• The decrease in pain/discomfort continued to be observed in the tislelizumab plus chemotherapy arm,
whereas decrease (worsening) of physical functioning was observed in the placebo plus chemotherapy arm

Objective• The purpose of the current analyses was to assess HRQoL in patients treated with tislelizumab orplacebo plus chemotherapy in the RATIONALE-305 studyTime to Deterioration• Results showed patients receiving tislelizumab plus chemotherapy were at a lower risk of deterioration as
indicated by GHS/QoL, physical functioning, QLQ-STO22 symptom index, pain/discomfort, and uppergastrointestinal symptoms (Table 2)
Table 1. Demographics and Baseline Disease Characteristics

Methods

Tislelizumab plus
chemotherapy(n=501)

Placebo plus
chemotherapy(n=496)60.0 (53.0–66.0)

61.0 (54.0–68.0)

Male

346 (69)346 (70)

Female155 (31)150 (30)Asian

376 (75)372 (75)

White116 (23)107 (22)

Other

9 (2)

17 (3)

Study Design and Patients• RATIONALE-305 was a randomized, open-label, multicenter, multiregional phase 3 study• The study population consisted of adults (aged ≥18 years) with previously untreated locally advanced
unresectable or metastatic GC/GEJC• Eligible patients were randomized 1:1 to receive tislelizumab 200 mg or placebo intravenously
once every 3 weeks plus investigator’s choice of chemotherapy regimen until disease progression,unacceptable toxicity, or patient withdrawal• HRQoL was a secondary endpoint and was assessed using patient-reported outcomes (PROs)

Assessments and Analyses

Median age, years (IQR)
SexRacea• The PRO measures were collected at baseline (treatment Cycle 1, Day 1) and then every cycle (each21-day cycle) for the first 6 cycles and every other cycle thereafter• Key clinical cycles were Cycles 4 and 6 and were pre-specified as clinically justifiable for assessing theshort- and long-term treatment effects in both arms5-7• The following key pre-specified PRO endpoints were selected based on their relevance to gastric cancerand treatment side effects, as well as their use in previous studies:
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30(QLQ-C30): global health status/quality of life (GHS/QoL), physical functioning, and fatigue symptom
scales. Higher scores on the GHS/QoL and physical functioning scales indicate better HRQoL orfunctioning, whereas a higher score on the fatigue symptom scale suggests worse symptoms
EORTC Quality of Life Questionnaire – Gastric Cancer Module (QLQ-STO22): symptom index,
dysphagia/odynophagia, pain/discomfort, upper gastrointestinal symptoms, and dietary restrictions
scales. Higher scores on the QLQ-STO22 indicate worse symptoms or problems• Higher scores on the GHS/QoL and physical functioning scales and lower scores on symptom scales
indicate better outcomes

Geographical region

Statistical Analysis––• All analyses were conducted using the data cut-off of February 28, 2023
• All randomized patients who completed the baseline, and at least one post-baseline PRO questionnaire
were included in this analysis• Adjusted completion rates were defined as the number of patients who completed the questionnaires at
each cycle divided by the number still on treatment• Change from baseline in each key PRO endpoint to Cycle 4 and Cycle 6 was analyzed using a constrained
longitudinal data analysis model; differences in the least-squares (LS) mean change (95% CI) from baseline
to key clinical cycles of Cycle 4 and Cycle 6 between the arms were assessed. The model included baseline
score, stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects and visit
as a repeated measure. P-values were 2-sided and nominal
Between-group comparisons were reported as differences in the LS mean change from baseline with
95% CIsA clinically meaningful change was defined as a 5-point mean change from baseline7-10• Time to deterioration was defined as time to first onset of a ≥10-point change in the worsening direction
from baseline with confirmation by a subsequent worsening; the Kaplan-Meier method was used toestimate the deterioration curve in each group
The log-rank test and hazard ratios showed the magnitude of treatment effect

–––

Asia

376 (75)372 (75)China

259 (52)257 (52)

Japan and South Korea

117 (23)115 (23)125 (25)

124 (25)0169 (34)

154 (31)1

332 (66)342 (69)

North America/Europe
ECOG performance status

Primary tumor location
Stomach405 (81)395 (80)

GEJC

96 (19)100 (20)b494 (99)490 (99)

0–2

335 (67)335 (68)≥3

166 (33)

160 (32)

Liver metastases

190 (38)

188 (38)

Peritoneal metastases

220 (44)214 (43)

Prior adjuvant/neoadjuvant treatment

107 (21)100 (20)

Prior gastrectomy/esophagectomy

133 (27)

139 (28)

Metastatic disease
Metastatic sites

MSI or MMR status
MSI-H/dMMR

16 (3)

24 (5)

MSI-L/MSS/pMMR

448 (89)439 (89)

Unknown

37 (7)

33 (7)<5%

227 (45)224 (45)≥5%274 (55)272 (55)

PD-L1 expression score

Data cut-off: February 28, 2023. Data are n (%) unless specified otherwise.
aIncludes not reported, unknown and other.
b
The diagnosis of one patient was updated from gastric adenocarcinoma to pancreatic cancer after randomization.
dMMR, deficient mismatch repair; ECOG, Eastern Cooperative Oncology Group; GEJC, gastroesophageal junction carcinoma; IQR, interquartile range; MSI-H/L, microsatellite instability-high/low;
MSS, microsatellite stable; PD-L1, programmed death-ligand 1; pMMR, proficient mismatch repair.

Table 2. Time to Deterioration for EORTC QLQ-C30 and QLQ-STO22 Scales

Worsened, n (%)
Censored, n (%)
EORTC QLQ-C30
Median time to deterioration, months (95% CI)aGHS/QoL
Stratified HR (95% CI)b
Stratified log-rank test P-value b,cWorsened, n (%)
Number of patients
Censored, n (%)
Median time to deterioration, months (95% CI)a
Physical functioning
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cWorsened, n (%)
Number of patients
Censored, n (%)
Mediantimetodeterioration,months (95% CI)aFatigue
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cWorsened, n (%)
Number of patients
Censored, n (%)
EORTC QLQ-STO22
Median time to deterioration, months (95% CI)a
Symptom index
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cWorsened, n (%)
Number of patients
Censored, n (%)
Dysphagia/
Median time to deterioration, months (95% CI)aodynophagia
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cWorsened, n (%)
Number of patients
Censored, n (%)
Median time to deterioration, months (95% CI)aPain/discomfort
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cWorsened, n (%)
Number of patients
Censored, n (%)
UpperMedian time to deterioration, months (95% CI)agastrointestinal symptoms
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cWorsened, n (%)
Number of patients
Censored, n (%)
Median time to deterioration, months (95% CI)a
Dietary restrictions
Stratified HR (95% CI)b
Stratified log-rank test P-valueb,cNumber of patientsResults
Figure 1. Least-Squares Mean Change From Baseline at Cycle 4 and by Treatment Arm
Mean change frombaseline to Cycle 4(95% CI)

EORTC-QLQ-C30
5Tislelizumab plus chemotherapy

3.07
1.75 (1.23, 4.91)(-0.09, 3.60)

1.35(-0.24, 2.94)

Placebo plus chemotherapy

0-0.45(-2.04, 1.13)-5-10

EMTD (95% CI)

GHS/QoL
1.80 (-0.33, 3.94)
P=0.0979-2.47(-3.77, -1.18) -3.92(-5.21, -2.62)

Physical functioning
1.44 (-0.27, 3.16)
P=0.0990

Fatigue-1.32 (-3.79, 1.15)
P=0.2950

Mean change frombaseline to Cycle 4(95% CI)

EORTC-QLQ-STO22
0.61(-0.82, 2.05)

50-5-10EMTD (95% CI)-0.61-1.71 (-1.66, 0.45)(-2.77, -0.66)-1.27-2.78 (-2.48, -0.06)(-3.99, -1.57)

Symptom index-1.11 (-2.53, 0.31)
P=0.1262

Dysphagia/odynophagia-1.51 (-3.13, 0.11)
P=0.0680-0.31(-1.75, 1.12)-4.64-6.88 (-6.16, -3.13)(-8.39, -5.36)

Pain/discomfort-2.23 (-4.26, -0.20)
P=0.0311

Dietary restrictions-0.93 (-2.85, 0.99)
P=0.3433-1.54-3.14 (-2.80, -0.28)(-4.40, -1.87)

Upper GI symptoms-1.59 (-3.28, 0.09)
P=0.0632

CI, confidence interval; EMTD, estimated mean treatment difference; EORTC, European Organisation for Research and Treatment of Cancer; GHS/QoL, global health status/quality of life; GI, gastrointestinal;
QLQ-C30, Quality of Life Questionnaire – Core 30; QLQ-STO22, Quality of Life Questionnaire – Gastric Cancer Module.

Figure 2. Least-Squares Mean Change From Baseline at Cycle 6 and by Treatment Arm
Mean change frombaseline to Cycle 6(95% CI)

EORTC-QLQ-C30
105

Tislelizumab plus chemotherapy

4.73
1.71 (2.68, 6.77)(-0.32, 3.75)

0.93(-0.71, 2.57)

Placebo plus chemotherapy

0-5

-1.58
(-3.24, 0.07)-10

EMTD (95% CI)

GHS/QoL
2.52 (0.29, 4.74)
P=0.0266-2.76(-4.22, -1.30) -5.22(-6.69, -3.75)

Physical functioning
2.46 (0.49, 4.43)
P=0.0145

Fatigue-3.01 (-5.78, -0.24)
P=0.0330

Mean change frombaseline to Cycle 6(95% CI)

EORTC-QLQ-STO22
1.08(-0.48, 2.63)

50-5-10EMTD (95% CI)-0.22-1.84 (-1.34, 0.89)(-2.95, -0.74)

Symptom index-1.62 (-3.12, -0.12)
P=0.0341-2.01-2.79 (-3.17, -0.86)(-3.93, -1.64)-4.09-5.97 (-5.69, -2.49)(-7.56, -4.38)

Dysphagia/odynophagia
0.77 (-2.31, 0.76)
P=0.3238

Pain/discomfort-1.88 (-4.03, 0.27)
P=0.0862-0.25(-1.79, 1.30)

Dietary restrictions-1.32 (-3.42, 0.77)
P=0.2160-1.49-3.24 (-2.84, -0.14)(-4.58, -1.90)

Upper GI symptoms-1.74 (-3.55, 0.06)
P=0.0584

CI, confidence interval; EMTD, estimated mean treatment difference; EORTC, European Organisation for Research and Treatment of Cancer; GHS/QoL, global health status/quality of life; GI, gastrointestinal;
QLQ-C30, Quality of Life Questionnaire – Core 30; QLQ-STO22, Quality of Life Questionnaire – Gastric Cancer Module.

References
1.
2.
3.
4.

Thrift AP, et al. Nat Rev Clin Oncol. 2023;20(5):338-49.
Choi J, et al. Support Care Cancer. 2022;30(4):3215-24.
Dalhammar K, et al. BMC Cancer. 2022;22(1):434.
Zhang FF, et al. Ann Palliat Med. 2021;10(7):8024-33.

5.

U.S. Food and Drug Administration (FDA). Methods to Identify What is Important toPatients & Select, Develop or Modify Fit-for-Purpose Clinical Outcomes Assessments:Guidance for Industry. 2018.

Tislelizumab plus
Placebo plus
chemotherapy
chemotherapy(n=501)(n=496)121 (24.2)
144 (29.0)
380 (75.8)352 (71.0)
NR (36.0, NE)
38.0 (26.7, NE)
0.77 (0.60, 0.98)
0.0168124 (24.8)
151 (30.4)
377 (75.2)
345 (69.6)
NR (30.4, NE)
37.7 (16.6, NE)
0.72 (0.57, 0.92)
0.0036193 (38.5)
209 (42.1)
308 (61.5)
287 (57.9)
16.9 (9.8, NE)
9.4 (5.4, 17.8)
0.83 (0.68, 1.01)
0.031050 (10.0)72 (14.5)451 (90.0)424 (85.5)
NR (NE, NE)
NR (NE, NE)
0.64 (0.45, 0.92)
0.008048 (9.6)
54 (10.9)453 (90.4)
442 (89.1)
NR (NE, NE)
NR (NE, NE)
0.81 (0.54, 1.19)
0.1387110 (22.0)
134 (27.0)
391 (78.0)
362 (73.0)
NR (28.3, NE)
42.2 (33.1, NE)
0.74 (0.58, 0.96)
0.0109101 (20.2)
127 (25.6)
400 (79.8)
369 (74.4)
NR (NE, NE)
NR (NE, NE)
0.73 (0.56, 0.95)
0.0085100 (20.0)
99 (20.0)401 (80.0)
397 (80.0)
NR (40.3, NE)
NR (NE, NE)
0.96 (0.73, 1.27)
0.3936Percentages were based on n.
a
Estimates are based on Kaplan-Meier method.
bStratified by regions (east Asia versus ROW [rest of the world]), PD-L1 expression and presence of peritoneal metastasis.
cOne-sided P-value was estimated from stratified log-rank test.
CI, confidence interval; EORTC, European Organisation for Research and Treatment of Cancer; GHS/QoL, global health status/quality of life; HR, hazard ratio; NE, not estimable; NR, not reached;
PD-L1, programmed death-ligand 1; QLQ-C30, Quality of Life Questionnaire – Core 30; QLQ-STO22, Quality of Life Questionnaire – Gastric Cancer Module.

Acknowledgments
6.
7.

U.S. Food and Drug Administration (FDA). Core Patient-Reported
Outcomes in Cancer Clinical Trials: Guidance for Industry. 2021.
Patel TH, et al. Curr Treat Options Oncol. 2020;21(9):70.
doi:10.1007/s11864-020-00774-4.

8. Shields A, et al. Expert Rev Pharmacoecon Outcomes Res. 2015;15(6):951-9.
9. Sloan JA, et al. Value Health. 2007;10 Suppl 2:S106-15.
10. Osoba D, et al. J Clin Oncol. 1998;16(1):139-44.

We would like to thank the investigators, site support staff, and especially the patients, for participating in this study. This study was sponsored by BeiGene, Ltd. Medical writing support,
under the direction of the authors, was provided by Jason Allaire of Generativity Solutions Group, funded by BeiGene. Editorial support, under the direction of the authors, was provided byThai Cao, MS, and Smitha Reddy, PhD, of Envision Pharma Inc., and was funded by BeiGene.

Presenter Disclosures
KK: Consultancy/advisory role for ONO Pharmaceutical, Bristol Myers Squibb, Merck and Co, Bayer AG, AstraZeneca, BeiGene, Taiho, Merck Biopharma, Amgen, Novartis, Daiichi Sankyo;
Grant/Research funding from ONO Pharmaceuticals, Merck & Co, Bayer AG, AstraZeneca, BeiGene, Chugai, Taiho, Oncolys Biopharma, Janssen Pharmaceuticals.

Contact: kenkato@ncc.go.jp (Ken Kato)