RATIONALE-307 Long-term Outcomes: First-line Tislelizumab (TIS) Plus Chemotherapy (chemo) vs Chemo
Alone for Advanced Squamous (sq) NSCLCZhijie Wang1, Xinmin Yu2, Jun Zhao3, Yan Yu4, Jingxun Wu5, Rui Ma6, Zhiyong Ma7, Jiuwei Cui8, Na Zhao9, Liang Liang10, Jinghui Fan10, Jie Wang1
1Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China; 3Department of Medical Oncology,CONCLUSIONS• Tislelizumab is a humanized monoclonal antibody with high affinity and binding specificity•••

for PD-1, and was specifically engineered to minimize Fcγ receptor binding on
macrophages.1,2 It has demonstrated survival benefits across a variety of advanced solidtumors, including non-small cell lung cancer (NSCLC).3-7
In the phase 3 RATIONALE-307 study (NCT03594747), tislelizumab + chemotherapy(chemo) significantly extended progression-free survival (PFS) vs chemo as first-line
treatment in patients with advanced squamous NSCLC.3
This study led to the approval of tislelizumab + chemo as a standard of care forsquamous NSCLC in the first-line setting in China and Europe.
Here we report the updated outcomes of RATIONALE-307 with approximately 4 years offollow-up.

METHODS••

1:1:1 to receive tislelizumab + chemo (two arms: tislelizumab + PC [paclitaxel andcarboplatin], tislelizumab + nPC [nab-paclitaxel and carboplatin]) or chemo (PC) alone(Fig. 1).
Patients allocated to the chemo arm were allowed to cross over to tislelizumab
monotherapy upon disease progression.
Patients with long-term exposure (LTE) to tislelizumab were defined as those who
received ≥35 cycles of tislelizumab treatment.
Biomarker testing was performed on baseline tumor samples, including PD-L1 protein
expression (VENTANA PD-L1 [SP263] assay), tumor mutational burden (TMB), genomic
alterations (OncoScreen Plus), and gene expression profiling (EdgeSeq Precision IOPanel).

Figure 1. Study design

TIS + PC Arm (n=120)
Tislelizumab 200 mg+
paclitaxel 175 mg/m2 +carboplatin AUC 5

Squamous NSCLC

R
1:1:1

Maintenance
Treatment
Q3W

TIS + nPC Arm(n=118)Tislelizumab 200 mg+
nab-paclitaxel 100
mg/m2+
carboplatin AUC 5

Tislelizumab200 mg

Chemo Arm
Paclitaxel 175 mg/m 2+
carboplatin AUC 5

Cross-overallowedupon diseaseprogression

Stratification factors••• Patients with long-term exposure (≥35 cycles) to tislelizumab achieved high ORR and long-term survival, with higher expression ofPD-L1 and T cell inflammation signature, as well as a FAT1 enriched mutational profile

RESULTSRESULTS••••

Figure 3. Kaplan-Meier curves of two-stage-adjusted OS

Figure 6. Swimmer plot and Kaplan–Meier curve for OS of LTE patientsA

AStage (IIIB vs IV)
PD-L1 TC (<1% vs 1%-49% vs ≥50%)••• 360 patients were randomly assigned (tislelizumab + PC, n=120; tislelizumab + nPC,
•n=119; chemo, n=121).
As of April 28, 2023, median time from randomization to data cutoff was 50.3 mo (range,46.5-57.0).

Updated efficacy and safety• Clinically meaningful OS improvement with tislelizumab + chemo was well maintained vs.

••Initial Treatment
Q3W 4 - 6 cycles

Key eligibility criteria• Treatment-naïve
• Stage IIIB or IV• Ineligible for curativesurgery• ECOG PS ≤1• No known EGFRsensitizing mutations
or ALK genetranslocations- 4-yr OS rates: 32.2% with tislelizumab + PC vs 26.0% with tislelizumab + nPC vs 19.2% with chemo alone

chemo arms, with a median of 58 (range 37-71) treatment cycles .
73.8% of patients had PD-L1 TC ≥1% (TC ≥50%, 50.0%), and 26.2% patients had PD-L1
TC <1%. Other baseline characteristics were generally similar to the total ITT populationof tislelizumab plus chemo arms.
ORR was 100% (CR, n=11; PR, n=31; Fig. 6A), and median DOR was not reached.
Median OS was not reached. 4-year OS rate was 97.5% (95% CI, 83.5%-99.6%) (Fig.
6B).
The profile of imAEs in LTE patients was similar to the overall population of tislelizumab +chemo arms.

Patients• Eligible patients with previously untreated advanced squamous NSCLC were randomized•• Tislelizumab + chemo maintained long-term clinical meaningful survival benefits compared with chemo alone, with no new safety
signals, despite a high in-study cross-over rate of 58.7%

Outcomes in patients who received ≥35 cycles of tislelizumab• A total of 42 (17.6%) patients received ≥35 cycles of tislelizumab (LTE) in tislelizumab +••chemo alone with extended follow-up– Tislelizumab + PC vs. chemo: median 26.1 mo vs 19.4 mo; HR 0.67 (95% CI, 0.49 0.92) (Fig. 2A)– Tislelizumab + nPC vs. chemo: median 23.3 mo vs 19.4 mo; HR 0.82 (95% CI, 0.60 1.11) (Fig. 2B)
OS benefit with tislelizumab + chemo was sustained, with 4-year OS rates of 32.2% (95%CI, 23.8 - 40.9) and 26.0% (95% CI, 18.3 - 34.4), versus 19.2% (95% CI, 12.0 - 27.7),
respectively (Fig. 2).
In the chemo arm, 77 (63.6%) patients received subsequent anti-PD-(L)1 therapy, including
71 (58.7%) who crossed over to tislelizumab in-study; analyses adjusted for in-study crossover effect with the two-stage method further confirmed the OS benefits with tislelizumab +chemo (cross-over adjusted median OS of chemo: 16.0 mo; HRs 0.53 and 0.65,
respectively; Fig. 3A & B).
PFS benefits with tislelizumab + chemo vs. chemo were also maintained at this updated
analysis (Fig. 4).
Tislelizumab plus chemotherapy was tolerable, with no new safety signals identified withextended follow-up.

BB

Figure 2. Kaplan-Meier curves of OSA

Figure 4. Kaplan-Meier curves of PFS

A

Molecular features of LTE patients in tislelizumab + chemo arms
• The baseline tumor tissues from LTE patients had higher PD-L1 expression and T cell

inflammation signature levels, while the TMB status was similar between LTE vs non-LTE(Fig.7A)
FAT1 alterations were enriched in LTE vs non-LTE (34.6% vs 15.4%, P=0.028); A numericallylower frequency was observed in NFE2L2, KEAP1, STK11, JAK1/2, and B2M in LTE vs nonLTE (Fig.7B)•Primary endpoint: PFS per IRC
Key secondary endpoints: ORR,DoR, OS, and safety

Figure 7. Molecular features in LTE patients in tislelizumab + chemo armsAAbbreviations

P=0.010BB

PD-L1 TC (%)

AUC, Area Under the Curve; Chemo, chemotherapy; CI, confidence interval; D, day; DoR, duration of response; ECOG PS,Eastern Cooperative Oncology Group; HR, hazard ratio; im-AE, immune-mediated adverse event; IRC, independent review
committee; ITT, intention-to-treat; LTE, long-term exposure; mo, months; nPC, nab-paclitaxel and carboplatin; NSCLC, non-small
cell lung cancer; ORR, objective response rate; OS, overall survival; PC, paclitaxel and carboplatin; PD, progressive disease; PDL1, programmed death-ligand 1; PFS, progression-free survival; Q3W, every 3 weeks; R, randomized; RECIST, Response
Evaluation Criteria in Solid Tumors; sq, squamous; TC, tumor cell; TIS, tislelizumab; TMB, tumor mutation burden.

References
1. Zhang T, et al. Cancer Immunol Immunother. 2018;67:1079-1090.
2. Hong Y, et al. FEBS Open Bio. 2021;11:782-792.
3. Wang J, et al. JAMA Oncol. 2021 May 1;7(5):709-717
4. Lu S, et al. J Thorac Oncol. 2021 Sep;16(9):1512-1522.
5. Xu J, et al. Lancet Oncol. 2023; 24: 483–95.
6. Qiu M, et al. BMJ. 2024 May 28:385:e078876.
7. Cheng Y, et al. J Thorac Oncol. 2024 Jul;19(7):1073-1085.

Acknowledgments: We would like to thank the investigators, the site support staff, and especially the patientsfor participating in this study. This study was sponsored by BeiGene.

Declaration of interests: Dr Zhijie Wang declares no potential conflict of interest.

LTELTE(n=42)(n=42)

B

Non-LTE
Non-LTE(n=195)(n=195)T cell inflammation signatureBACKGROUNDBACKGROUND

13-17 SEP 2024
ESMO CONGRESS Barcelona Spain

P=0.001

LTE(n=29)

Non-LTE(n=156)

P=0.288

TMB (mutations/Mb)

FPN: 1323P

Beijing Cancer Hospital, Beijing, China; 4Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China; 5Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, China; 6Department of Chest Internal Medicine, Liaoning Cancer Hospital & Institute, Shenyang, China;
7Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China; 8Cancer Center Department, The First Hospital of Jilin University, Changchun, China; 9BeiGene (Shanghai) Co., Ltd., Shanghai, China; 10BeiGene (Beijing) Co., Ltd., Beijing, China

LTE(n=26)

Non-LTE(n=149)