Comparative Efficacy and Safety of Tislelizumab Versus Anti–PD-1 Treatments in Second-Line Esophageal
Squamous Cell Carcinoma (ESCC): Simulated Treatment Comparisons (STC)
Elizabeth Smyth, Jaffer A. Ajani, Kaijun Wang, JeanPierre Coaquira Castro, * Maximiliano Augusto Novis de Figueiredo, Jong-Mu Sun, Konstantinos Soulanis, Anastasios Tasoulas,
783Georgios F. Nikolaidis, Eugenia Priedane, Lin Zhan
1233,

4566

Poster No: 1417P Presented at the European Society for
Medical Oncology (ESMO) Congress; September 13–17, 2024;
Barcelona, SpainOxford University Hospitals NHS Foundation Trust, Oxford, England, UK; 2Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX, USA; 3BeiGene USA, Inc., Emeryville, CA, USA;
4
Department of Internal Medicine, Faculty of Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil; 5Division of Hem/Oncology, Samsung Medical Center, Seoul, Korea; 6IQVIA, Athens, Greece; 7IQVIA, London, UK; 8BeiGene UK, London, UK.
*Affiliation at the time of study.
1Conclusions

This analysis supports comparable overall survival (OS), progression-free survival(PFS), and toxicities for tislelizumab versus other key anti–programmed cell death
protein-1 (anti–PD-1) immunotherapies (nivolumab and pembrolizumab) for
second-line (2L) therapy in patients with ESCC

Background•

•
•
•

•

Statistical Methods

Esophageal carcinoma (EC) is the seventh leading cause of cancer-related mortality worldwide, exhibiting amortality rate of 5.48 per 100,000 individuals.1 Esophageal squamous cell carcinoma constitutes about 90% ofEC incidences2The aggressive progression of EC is mirrored in low survival rates, with 5-year OS estimated at 10% in Europe,
20% in the US and Eastern Asia, 30% in China, 31%-33% in South Korea, and 36% in Japan3-6
For locally advanced or metastatic ESCC, treatment options include immunotherapy, chemo-radiotherapy,chemotherapy, chemo-immunotherapy, or radiation therapy•

In a recent phase 3 study (RATIONALE-302, N=512, NCT03430843),7 tislelizumab demonstrated a statisticallysignificant and clinically meaningful survival benefit over chemotherapy (median OS of 8.6 vs 6.3 months; hazardratio [HR], 0.70; 95% confidence interval [CI], 0.57-0.85; P=0.0001), regardless of PD-L1 expression level, withan acceptable safety profile for 2L ESCC

•Subsequently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved
tislelizumab for use in 2L ESCC; the National Comprehensive Cancer Network (NCCN) also recommended
tislelizumab in the treatment of unresectable, recurrent, or metastatic ESCC.8-10 While nivolumab andpembrolizumab monotherapies are 2L options, pembrolizumab is only approved for patients with PD-L1combined positive score (CPS) ≥108 in the US. Notably, pembrolizumab monotherapy is pending approval for 2L
ESCC in the European Union (EU)

Nivolumab (ATTRACTION 3)

0.5

0.88 (0.66-1.17)

0.78 (0.58-1.04)

0.90 (0.68-1.20)← Favors tislelizumab

1.0Favors comparator →1.5•

Screening•

A systematic literature review (SLR) was conducted to identify and summarize all available published data on
the clinical efficacy and safety of existing 2L treatment regimens for patients with unresectable, advanced, or
metastatic ESCC. One original and two subsequent SLR updates contributed to the evidence base••

A rigorous process was employed to identify effect-modifying and prognostic variables, which included a thoroughexamination of individual patient data (IPD) from RATIONALE-302, alignment with previous ITCs within the same
medical domain, and consultation with clinical experts

Total records included in• Original SLR: n=19 records reporting on 8 studies• First SLR update: n=13 records reporting on 3 studies• Second SLR update: n=3 records reporting on 3 studies
Included

For the purposes of evidence synthesis, the focus was narrowed to pivotal studies evaluating key
immunotherapies considered in the EU and the UK. These included the following: RATIONALE-302 tislelizumab,7
ATTRACTION 3 (nivolumab),11,12 RAMONA (nivolumab with ipilimumab),13 and KEYNOTE-181 (pembrolizumab)14

Original SLR: n=9a records reporting on 8 unique studies
First SLR update: n=13 records reporting on 3 additional unique studies
Second SLR update: n=3 records reporting on 2 additional unique studies

Outcomes and Interventions•

Primary outcomes of interest were OS, PFS, and the incidence of grade ≥3 treatment-related adverse events(TRAEs). The comparator interventions under scrutiny were nivolumab and pembrolizumab

Total records included: n=25, reporting on 13 unique studies
Nineteen publications from the original SLR were rescreened in the first SLR update, and 10 publications were excluded based on “conference abstract superseded by full text.”
Note: Time frame for database searches: Original SLR: May 2021; first SLR update: May 2021-November 2022; second update: November 2022-October 2023.
PICOS, Population, Intervention, Comparison, Outcomes and Study; SLR, systematic literature review.

aReferences

1.
2.
3.
4.
5.
6.
7.
8.

Fan et al. Cancer Med. 2020;9(18):6875-6887.
Abnet et al. Gastroenterology. 2018;154(2):360-373.
Gavin et al. Cancer Epidemiol. 2012;36(6):505-512.
Allemani et al. Lancet. 2018;391(10125):1023-1075.
Siegel et al. CA Cancer J Clin. 2020;70(1):7-30.
Park et al. J Chest Surg. 2021;54(6):454-459.
Shen et al. J Clin Oncol. 2022;40(26):3065-3076.
NCCN. NCCN Guidelines for Esophageal andEsophagogastric Junction Cancers (2024). 2024.

9.

Drug trials snapshots: TEVIMBRA. US Food and Drug Administration. Accessed August 13,2024. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-tevimbra
10. Tevimbra. European Medicines Agency. Accessed August 13, 2024. https://www.ema.europa.
eu/en/medicines/human/EPAR/tevimbra
11. Kato et al. Lancet Oncol. 2019;20(11):1506-1517.
12. Okada et al. Clin Cancer Res. 2022;28(15):3277-3286.
13. Ebert et al. Lancet Healthy Longev. 2022;3(6):e417-e427.
14. Kojima et al. J Clin Oncol. 2020;38(35):4138-4148.

Favors comparator →1.50.5← Favors tislelizumab

1.0Favors comparator →15. Welton et al. CHTE2020 sources and synthesis of evidence: update to evidence synthesis
methods. NICE Decision Support Unit. Accessed August 13, 2024. https://rees-france.com/
wp-content/uploads/2020/12/CHTE-2020_synthesis-of-evidence.pdf
16. Phillippo et al. NICE DSU technical support document 18: methods for population-adjusted indirect comparisons in submissions to NICE. NICE Decision Support Unit. Accessed August 13,2024. https://research-information.bris.ac.uk/ws/portalfiles/portal/94868463/Population_adjustment_TSD_FINAL.pdf
17. Phillippo et al. Stat Med. 2021;40(11):2759-2763.
18. Remiro-Azócar et al. Res Synth Methods. 2022;13(6):716-744.

Acknowledgements
This study was sponsored by BeiGene,
Ltd. Editorial and submission support wereprovided by Envision Pharma Inc. andfunded by BeiGene.

2.5

All included studies compared an anti–PD-1 antibody with chemotherapy, and clinical consensus anticipated minimalheterogeneity, validating its use as a common anchor. The overlap of populations between RATIONALE-302 andcomparator studies, based on effect-modifying variables, is depicted in Figure 3

RATIONALE-302 VS ATTRACTION 3RATIONALE-302 VS KEYNOTE-181

RATIONALE-302 VS RAMONAAge (median)Age (median)Age (median)

Male

1

Current/former smoker
Male0.75

ECOG 00.5

ECOG 10

Race: Asian11

PD-L1: negative

0.75

PD-L1: negative
0.75

0.5

0.5

Male0.25

PD-L1: positive

ECOG 00

PD-L1: negative
0.25

PD-L1: positive0Lymph node metastasis

Lung metastasis
Liver metastasis
Bone metastasis

ECOG 1

Metastatic disease
Region: Asia

Metastatic disease

PD-L1: positive

Note: PD-L1–negative patients are those with TPS <1% or CPS <10. PD-L1–positive patients are those with TPS ≥1% or CPS ≥10.
CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group Performance Status; PD-L1, programmed death-ligand 1; TPS, tumor positivity score.

The trial design and inclusion criteria of RAMONA significantly diverged from those of RATIONALE-302, precluding its
inclusion in the ITC. Conversely, ATTRACTION 3 and KEYNOTE-181 were sufficiently comparable to RATIONALE-302
in most effect-modifying aspects, despite some differences in baseline characteristics• Following population adjustment, the analyses revealed no significant differences in OS, PFS, or grade ≥3 TRAEs
when comparing tislelizumab with other anti–PD-1 agents (nivolumab and pembrolizumab for survival outcomes; only
nivolumab for safety outcomes)• However, tislelizumab was found numerically favorable over both comparators in OS and PFS [vs nivolumab,
OS HR (95% CI), 0.88 (0.65-1.19) and PFS HR (95% CI), 0.79 (0.59-1.07); vs pembrolizumab, OS HR (95% CI),
0.94 (0.67-1.32) and PFS HR (95% CI), 0.95 (0.63-1.43)]• Both sensitivity and subgroup analyses were consistent with the base case, revealing no significant disparities• Notably, these estimates are not directly comparable due to differing target populations. Specifically, the results of each
STC cannot be compared to the results of other STCs (eg, nivolumab STC results are independent of pembrolizumab
STC results), as RATIONALE-302 data are always adjusted to the average baseline characteristics of the comparator
trial’s population, and therefore, each estimate is only relevant to the enrolled population of that particular study•

Evidence Synthesis Feasibility Assessment•← Favors tislelizumab

1.0Figure 3. Visual Representation of Population Overlap Between RATIONALE-302 (Gray Area) andComparator Studies (Colored Area). The covariate range is normalized across studies.

Total records excluded at full-text screening in• Original SLR (n=39)• First SLR update (n=52)• Second SLR update (n=17)

The SLR yielded 25 records pertaining to 13 distinct trials that were deemed relevant for analysis (Figure 1)

0.5

Results

Total records excluded at title-abstract screening in• Original SLR (n=3190)• First SLR update (n=1082)• Second SLR update (n=1167)

Total records assessed for
eligibility at full-text level in• Original SLR (n=58)• First SLR update (n=65)• Second SLR update (n=20)

1.37 (0.75-2.51)

0.95 (0.63-1.43)

0.25

Systematic Literature Review

1.30 (0.68-2.48)

TRAEs grade ≥3 data were not available for the squamous cell carcinoma subgroup of KEYNOTE-18114 that was used for the comparison with RATIONALE-3027; thus, an STC was not feasible for TRAEs grade ≥3 in the comparison
with pembrolizumab.
STC, simulated treatment comparison; TRAE, treatment-related adverse event.

Duplicates removed before screening in• Original SLR (n=232)• First SLR update (n=308)• Second SLR update (n=926)

Methods

STC
Unadjusteda

Identification of studies via databases (MEDLINE, Embase, Cochrane libraries) and other methods(conferences, trial registries, bibliography hand-searching)Total records identified in• Original SLR (n=3480)• First SLR update (n=1455)• Second SLR update (n=2113)

0.79 (0.59-1.07)

0.89 (0.67-1.19)

Figure 1. Identification of PICOS-Eligible Studies Based on Original SLR and Subsequent Updates(From Database Inception to October 2023)

The objective of this analysis was to identify the evidence on existing 2L treatments for ESCC and derive relative
efficacy and safety estimates versus tislelizumab through indirect treatment comparisons (ITCs)

0.88 (0.65-1.19)

TRAEs Grade ≥3a

Pembrolizumab (KEYNOTE-181)

Analyses were conducted with both available RATIONALE-302 DCOs from December 1, 2020, andDecember 28, 2022; the former was used for the base case and the latter for sensitivity analysis. Subgroup
analyses considered PD-L1 category and baseline ECOG PS
The base case STC analyses are presented in Figure 2, providing HRs for OS and PFS, and odds ratios forgrade ≥3 TRAEs, along with their respective 95% CIs

Progression-Free Survival

0.94 (0.67-1.32)

Simulated treatment comparisons for OS and PFS were adjusted for ECOG Performance Status (PS), diseasestatus, PD-L1 expression, and the presence of liver and lung metastases. Simulated treatment comparisons forgrade ≥3 TRAEs were adjusted for age, ECOG PS, PD-L1 expression, liver metastasis, and prior treatments•

Overall Survival

Tislelizumab(RATIONALE-302) vsUsing IPD from RATIONALE-302, a Cox model was fit to OS and PFS model, and a binomial generalized linear
model was fit to grade ≥3 TRAEs, incorporating effect modifiers as interactions with the treatment arm16•

However, the analysis is limited by the uncertainty surrounding the estimates andthe assumptions inherent to the methodology employed to obtain the indirectcomparisonsFigure 2. Forest Plots of Relative Efficacy and Safety of Tislelizumab Versus Relevant Comparators

Aligned with recent updates to methods guidance, STCs were preferred over matching-adjusted indirectcomparisons (MAICs) for population adjustment in this anchored setting.15 The STC approach, based on NICEDSU TSD18,16 was extended to adjust for both binary and multilevel categorical characteristics and to enable theestimation of population-average treatment effects17,18•

Identification•These findings were consistent across primary, sensitivity, and subgroup analyses.
Specifically, results were similar to the base case when using the latest RATIONALE
data cutoff (DCO), and there were no statistically significant differences in theprogrammed death ligand-1 (PD-L1)– and Eastern Cooperative Oncology Group(ECOG)–specific subgroups

Disclosures
Elizabeth Smyth received payment or honoraria from Amgen, Astellas, AstraZeneca, BeiGene,Bristol Myers Squibb, Daiichi Sankyo, Merck, Mirati, Novartis, Pfizer, T-Cypher Bio, Viracta,and Zymeworks, outside the submitted work; and grants from AstraZeneca and BristolMyers Squibb. She is Chair of the European Organisation for Research and Treatment ofCancer Gastrointestinal Trials Group (2024-2027), and a trustee for the UK and Ireland
Oesophagogastric Cancer Group. She is supported by the National Institute for Health andCare Research Biomedical Research Centre at the University of Oxford.

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