Neoadjuvant Tislelizumab (TIS) Plus Chemotherapy (CT) With Adjuvant TIS Versus Neoadjuvant Placebo (PBO) Plus CT With Adjuvant
PBO in Resectable Non–Small Cell Lung Cancer (NSCLC): Patient-Reported Outcomes (PROs) in the RATIONALE-315 Trial
Federico Cappuzzo,1 Changli Wang,2 Wenxiang Wang,3 Hongxu Liu,4 Qixun Chen,5 Dongsheng Yue,2 Shengfei Wang,6 Bin Yao,7 Bryant Barnes,8 Gisoo Barnes8Istituto Nazionale Tumori IRCCS Regina Elena, Rome, Italy; 2Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; 3The Second Department of Thoracic Surgery, Hunan Cancer Hospital, Hunan, China;
4Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang, China; 5Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou, China; 6BeiGene (Shanghai) Co., Ltd., Shanghai, China; 7BeiGene (Beijing) Co., Ltd, Beijing, China;
8
BeiGene USA, Inc., San Mateo, CA, USA.
1

Perioperative tislelizumab did not affect health-related quality of life (HRQoL) in patients with resectable NSCLC in either theneoadjuvant or adjuvant treatment phase
Patients in the tislelizumab arm reported improvements in the key symptoms of coughing and chest pain

Poster No: 1213P presented at the European Society for
Medical Oncology (ESMO) Congress; September 13–17, 2024;
Barcelona, Spain

Taken together, the event-free survival (EFS) and overall survival (OS) benefits combined with maintained or improved PROs
support the use of perioperative tislelizumab plus neoadjuvant platinum-based CT for treatment-naïve patients with resectablestage II-IIIA NSCLC

Conclusions

Background– Between-group comparisons were reported as differences in the leastsquares (LS) mean change from baseline with 95% confidence interval (CI)
– A clinically meaningful change was defined as a ≥5-point mean change fromThe prognosis for patients with NSCLC is relatively poor with 5-year survival
rates of 35% and 10%-15% for patients with stage II and stage IIIA disease,respectively1• Symptoms associated with NSCLC also correspond with poor health-related
quality of life (HRQoL)2,3• In the pivotal phase 3 RATIONALE-315 trial (NCT04379635) of patients withresectable stage II-IIIA NSCLC, perioperative TIS plus neoadjuvant platinumbased CT led to a clinically meaningful and statistically significant benefit forEFS as well as an OS benefit trend compared with perioperative PBO plus
neoadjuvant platinum-based CT• The current analyses report the results for PROs from RATIONALE-315•baseline7-10• Time to deterioration (TDD) was defined as time to first onset of a ≥10-point10
change in the worsening direction from baseline and confirmed by asubsequent worsening; the Kaplan-Meier method was used to estimate thedeterioration curve in each group– The log-rank test and hazard ratio (HR) showed the magnitude of treatment effectStudy Design and Patients

TIS arm
R
1:1
PBO arm

2.
3.
4.
5.

Surgery

PBO (IV Q3W)
+ PtDb CTSurgery

Adjuvant phase(up to 8 cyclesb)
TIS(400 mg IV Q6W)PBO
(IV Q6W)

PtDb CT• Squamous: cisplatin/carboplatin plus paclitaxel• Non-squamous: cisplatin/carboplatin plus pemetrexed

TIS arm

PBO arm

EORTC QLQ-C30

0-5-2.21(-4.40 to -0.03)-10-4.56(-6.78 to -2.34)-2.17(-3.37 to -0.96)•PBO Arm(n=227)62.0 (57.0-67.0)
83 (37)63.0 (56.0-68.0)

205 (91)
21 (9)
226 (100)

205 (90)
22 (10)227 (100)

142 (63)
83 (37)154 (68)73 (32)43 (19)150 (66)
33 (15)92 (41)132 (58)
179 (79)
45 (20)2 (1)98 (43)52 (23)138 (61)37 (16)91 (40)133 (59)
175 (77)
50 (22)
2 (1)

-3.11
(-4.34 to -1.88)-1.97(-4.77 to 0.83)-15

GHS/QoL-2.34 (-5.25 to 0.56)

Physical functioning-0.95 (-2.54 to 0.65)

Fatigue-0.29 (-3.01 to 2.42)

GHS/QoL
0.83 (-2.87 to 4.54)

GHS/QoL-3.57(-5.10 to -2.05)

PBO Arm(n=227)

Worsened, n (%)

79 (35.0)

73 (32.2)

Censored, n (%)

147 (65.0)

154 (67.8)

30.2 (30.2-NE)

NR (NE-NE)-3.61(-5.22 to -2.01)

Mean change frombaseline to Cycle 3 (95% CI)

1.87(0.27-3.47)

55.42(2.39-8.44)
0.43(-2.42 to 3.28)

Physicalfunctioning-5-8.96(-11.54 to -6.38)-15-2.56(-4.39 to -0.73)

EMTD (95% CI)

Dyspnea scale
2.05 (-0.01 to 4.12)

Coughing
0.65 (-2.71 to 4.02)-5.63(-8.97 to -2.29)

Pain in chest-1.50 (-3.98 to 0.89)

Dyspnea scale-1.96 (-4.82 to 0.91)

Neoadjuvant

Coughing
1.05 (-3.38 to 5.47)

Pain in chest-4.99 (-9.05 to -0.93)

Fatigue

The worsening in dyspnea experienced by the PBO arm was near the clinically meaningful
threshold (4.56 [95% CI, 2.07- 7.06]) (Figure 3)• The TIS arm experienced a greater level of clinically meaningful improvement in adjuvant Cycle 7for coughing (-12.15 [95% CI, -15.60 to -8.71]) than PBO with the difference reaching close to theclinically meaningful threshold (-4.63 [95% CI, -9.46 to 0.21)]• The levels of chest pain were maintained in both arms
•Figure 3. Mean Change From Baseline to Cycle 7 in the Adjuvant Phase
EORTC QLQ-C30
51.09(-1.34 to 3.53)

1.90(-0.66 to 4.46)

TIS arm-2.60(-4.20 to -1.00)-10

EMTD (95% CI)

EORTC QLQ-LC13
105GHS/QoL-0.81 (-4.17 to 2.56)

3.18(0.82-5.55)

PBO arm

2.54(0.09-4.99)

EORTC QLQ-LC13
Dysphagia

NR (NE-NE)

Physical functioning-0.37 (-2.61 to 1.87)

4.56(2.07-7.06)

104 (46.0)

101 (44.5)

Censored, n (%)

122 (54.0)

126 (55.5)

11.2 (7.6-NE)

6.2 (4.6-NE)

Median time to deterioration (95% CI),* months

Fatigue-0.33 (-3.73 to 3.07)

0.36(-2.34 to 3.05)

Dyspnea scale-1.38 (-4.71 to 1.95)-12.15(-15.60 to -8.71)
Coughing-4.63 (-9.46 to 0.21)

0.86 (0.65-1.13)
0.1353

Worsened, n (%)

105 (46.5)

111 (48.9)

Censored, n (%)

121 (53.5)

116 (51.1)

7.5 (4.8-NE)

5.1 (4.4-6.8)

Median time to deterioration (95% CI),* months

0.87 (0.66-1.14)
0.1514

Number of patients

Coughing

Worsened, n (%)

40 (17.7)

34 (15.0)

Censored, n (%)

186 (82.3)

193 (85.0)

NR (NE-NE)

NR (NE-NE)

Median time to deterioration (95% CI),* months
Stratified HR (95% CI)†1.14 (0.72-1.81)
0.7175Stratified log-rank test P value‡
Number of patients

1.89(-0.96 to 4.75)-7.52(-11.16 to -3.89)-15

0.3480Worsened, n (%)

Chest pain

Worsened, n (%)

35 (15.5)

49 (21.6)

Censored, n (%)

191 (84.5)

178 (78.4)

NR (NE-NE)

NR (NE-NE)

Median time to deterioration (95% CI),* months
Stratified HR (95% CI)†
Stratified log-rank test P value‡-10

0.93 (0.65-1.33)

Stratified log-rank test P value‡-2.23(-3.92 to -0.54)-5

Pain in chest-1.54 (-5.36 to 2.29)

Higher scores on the GHS/QoL and physical functioning scales indicate better HRQoL or functioning, whereas a higher score on the fatigue symptom scale suggests worse symptoms. Higher scores on theQLQ-LC13 indicate worse symptoms or problems.
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;
HRQoL, health-related quality of life; PBO, placebo; QLQ-C30, Quality of Life Questionnaire – Core 30; QLQ-LC13, Quality of Life Questionnaire – Lung Cancer Module; TIS, tislelizumab.

Acknowledgements
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 C. Allaire, PhD, ofGenerativity Solutions Group, and was funded by BeiGene. Editorial support, under thedirection of the authors, was provided by Smitha Reddy, PhD, of Envision Pharma Inc.,and was funded by BeiGene.

NR (20.4-NE)

Median time to deterioration (95% CI),* months

Stratified HR (95% CI)†

2.87(0.30-5.45)

0-20

167 (73.6)

Number of patients-15-20163 (72.1)

Stratified log-rank test P value‡

0-5Censored, n (%)

Stratified HR (95% CI)†

Adjuvant

Higher scores on the GHS/QoL and physical functioning scales indicate better HRQoL or functioning, whereas a higher score on the fatigue symptom scale suggests worse symptoms. Higher scores on theQLQ-LC13 indicate worse symptoms or problems.
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;
HRQoL, health-related quality of life; PBO, placebo; QLQ-C30, Quality of Life Questionnaire – Core 30; QLQ-LC13, Quality of Life Questionnaire – Lung Cancer Module; TIS, tislelizumab.

1060 (26.4)

Number of patients-4.58(-7.75 to -1.42)-9.61(-12.15 to -7.07)-20

63 (27.9)

Stratified log-rank test P value‡-1.06(-2.86 to 0.74)-10Worsened, n (%)

Stratified HR (95% CI)†

0-0.18(-1.75 to 1.39)

0.4477

Number of patients

Fatigue-0.45 (-3.60 to 2.70)

6.57(4.41-8.74)

100.98 (0.71-1.35)

Stratified log-rank test P value‡

Physical functioning
0.04 (-2.08 to 2.17)

4.62(2.57-6.67)

Median time to deterioration (95% CI),* months
Stratified HR (95% CI)†Adjuvant

EORTC QLQ-LC13

EMTD (95% CI)

The adjusted completion rates were high (100%) and consistent across treatment
arms at each assessment timepoint

6. Park et al. J Cancer Surviv. 2020;14(3):363-376.
7. Patel et al. Curr Treat Options Oncol. 2020;21(9):70.
8. Shields et al. Expert Rev Pharmacoecon Outcomes Res. 2015;15(6):951-959.
9. Sloan et al. Value Health. 2007;10(suppl 2):S106-S115.
10. Osoba et al. J Clin Oncol. 1998;16(1):139-144.

-1.14(-3.79 to 1.52)

Neoadjuvant

Mean change frombaseline to Cycle 7 (95% CI)

TIS Arm(n=226)

ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; PBO, placebo; TIS, tislelizumab.

Adjusted Completion Rates

2.52(0.23-4.81)

Change From Baseline to Cycle 7 (Adjuvant Phase)

Table 1. Patient Demographics and Clinical Characteristics

TIS Arm(n=226)
Number of patients

2.97(0.57-5.37)

5.70(3.62-7.78)

5EMTD (95% CI)

The intent-to-treat population consisted of 453 patients randomized to receiveTIS (n=226) or PBO (n=227)• Patient demographics and baseline disease characteristics were generally balanced
across treatment arms (Table 1)

AgeMedian (IQR), years≥65 years, n (%)
Sex, n (%)
MaleFemale
Asian race, n (%)
ECOG performance status, n (%)
01
Smoking status, n (%)
Current
FormerNever
Disease stage, n (%)
IIIIIA
Histology, n (%)
Squamous
Non-squamous
Other

Table 2. Analyses of Time to Deterioration of EORTC QLQ-C30 andQLQ-LC13 Domains-20•

References

Lung cancer: five-year survival rates. National Cancer Institute SEER Training Modules. Accessed August 14, 2024.
https://training.seer.cancer.gov/lung/intro/survival.html
lyer et al. Lung Cancer. 2013;81(2):288-293.
Iyer et al. Support Care Cancer. 2014;22(1):181-187.
Garassino et al. Lancet Oncol. 2020;21(3):387-397.
Steffen McLouth et al. Clin Lung Cancer. 2020;21(3):255-263.e4.

TIS(200 mg IV Q3W)
+ PtDb CT

10Results•

1.

Surgery

5.99(3.95-8.04)

EORTC QLQ-C30

EGFR testing was mandatory for non-squamous NSCLC. bAdjuvant treatment was only administered to patients with an ECOG PS of 0 or 1 and adequate organfunction for ≤8 cycles or until disease recurrence/progression, unacceptable adverse events, or death occurred, or until the patient and/or investigator decided todiscontinue study treatment.
AJCC, American Joint Committee on Cancer; ALK, anaplastic large-cell lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFR,epidermal growth factor receptor; IV, intravenous; NSCLC, non–small cell lung cancer; PBO, placebo; PD-L1, programmed death-ligand 1; PtDb CT, platinum-based doublet
chemotherapy; Q3W, every 3 weeks; Q6W, every 6 weeks; R, randomized; R0, pathological complete resection of the primary tumor; TIS, tislelizumab; WT, wild type.

Statistical Analyses

Analyses were conducted using the data cutoff of August 21, 2023
• All HRQoL measures were summarized in the intent-to-treat analysis set and by
overall phases and adjuvant phase, respectively• 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 3 (bothneoadjuvant and adjuvant) and Cycle 7 (adjuvant) was analyzed using a
constrained longitudinal data analysis model– The model included baseline score, stratification factors, treatment arm, visit,
and treatment arm by visit interaction as fixed effects and visit as a repeatedmeasureNeoadjuvant phase(3-4 cycles)

TTD analysis showed that patients in the TIS arm were at lower risk of worsening
chest pain compared with those in the PBO arm (HR, 0.59 [95% CI, 0.38-0.91])(Table 2)• Risk of worsening was similar between the treatment arms for all other PRO
endpoints

Figure 2. Mean Change From Baseline to Cycle 3 in the Neoadjuvant and Adjuvant Phases

Mean change frombaseline to Cycle 7 (95% CI)

PROs were assessed at baseline (pre dose at Day 1 of Cycle 1) and key clinicalcycles (Cycle 3 of the neoadjuvant phase and Cycles 3 and 7 of the adjuvant phase)– These key clinical cycles were prespecified as clinically justifiable forassessing the short-term and longer-term treatment effects in both arms
• The following key PRO endpoints were pre-selected based on their relevanceto NSCLC and treatment side effects, as well as their use in previous studies4-6:– 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 or functioning, whereas a higher score on the fatigue
symptom scale suggests worse symptoms– EORTC Quality of Life Questionnaire – Lung Cancer Module (QLQ-LC13):
coughing, chest pain, and dyspnea• Higher scores on the QLQ-LC13 indicate worse symptoms or problems•

The difference between the treatment arms in change from baseline to adjuvant Cycle 3 for chest
pain was clinically meaningful (mean difference, -4.99 [95% CI, -9.05 to -0.93]). The level of chest
pain was maintained from baseline at the adjuvant phase for the TIS arm, while patients in thePBO arm reached clinically worsening levels (5.42 [95% CI, 2.39-8.44]). The changes frombaseline for other PRO endpoints were similar between the treatment arms (Figure 2)• Patients in the TIS and PBO arms experienced clinically meaningful improvements in LS meanchange from baseline to neoadjuvant Cycle 3 for coughing (mean change from baseline,-8.96 [95% CI, -11.54 to -6.38] for TIS and -9.61 [95% CI, -12.15 to -7.07] for PBO)

aThe study included treatment-naïve patients with resectable stage II-IIIA
NSCLC who were eligible for platinum-doublet CT and had no known epidermal
growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma
kinase (ALK) gene translocations (Figure 1)– Patients were randomized (1:1) to either 3-4 cycles of neoadjuvant TIS 200 mgor PBO (administered intravenously [IV] every 3 weeks) plus CT, followed bysurgery and up to 8 cycles of adjuvant TIS 400 mg or PBO (IV every 6 weeks)••

Mean change frombaseline to Cycle 3 (95% CI)

Key eligibility criteria• Resectable stage II-IIIA NSCLC per
AJCC 8th edition (eligible forR0 resection)• ECOG PS 0 or 1• EGFR/ALK WTa
Key eligibility criteria• Histology (squamous vsnon-squamous)• Disease stage (II vs IIIA)• PD-L1 expression (≥1% vs <1%/notevaluable/indeterminate)

Assessments

Time to Deterioration

Figure 1. RATIONALE-315 Study DesignMethods•

Change From Baseline to Cycle 3 (Neoadjuvant and Adjuvant Phases)

Presenter Disclosures
Federico Cappuzzo received consulting fees, honoraria, and participated on Data Safety
Monitoring Board or Advisory Board for Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer,Amgen, Sanofi, Pharmamar, Novocure, Mirati, Galecto, OSE, ILLUMINA, Thermofisher,BeiGene, and MSD; served on Advisory Board for Roche, AstraZeneca, BMS, Pfizer, Takeda,Lilly, Bayer, Amgen, Sanofi, Pharmamar, Novocure, Mirati, Galecto, OSE, ILLUMINA,
Thermofisher, BeiGene, and MSD.

0.59 (0.38-0.91)
0.0079Time to deterioration is defined as the time from randomization to the first occurrence of a decrease of <10 scores in GHS/QoL and physical functioning, and an increase of≥10 scores in QLQ-C30 symptom scale scores (fatigue) and QLQ-LC13 symptom scale scores (dysphagia, coughing, chest pain).
A deterioration is not counted as an event if a subsequent improvement returned the overall worsening from baseline to <10 points.
If a patient does not have an event (10% deterioration), they are censored at their last clinic visit at which HRQoL is measured.
*Estimates are based on Kaplan-Meier method. †Hazard ratio was based on Cox regression model stratified by histology (squamous vs non-squamous), disease stage (stage II vsstage IIIA), and PD-L1 expression (<1%, not evaluable, or indeterminate vs ≥1%) from interactive response technology. ‡The descriptive 1-sided P value was calculated using alog-rank test stratified by histology (squamous vs non-squamous), disease stage (stage II vs stage IIIA), and PD-L1 expression (<1%, not evaluable, or indeterminate vs ≥1%) frominteractive response technology.
CI, confidence interval; EORTC, European Organisation for Research and Treatment of Cancer; GHS/QoL, global health status/quality of life; HR, hazard ratio; HRQoL, health-related
quality of life; NE, not estimable; NR, not reached; PBO, placebo; PD-L1, programmed death-ligand 1; QLQ-C30, Quality of Life

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