Tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT in advanced or metastatic
esophageal squamous cell carcinoma (ESCC): PD-L1 biomarker analysis from RATIONALE-306
Authors: Eric Raymond,1 Jianming Xu,2 Ken Kato,3 Richard Hubner,4 Yongqian Shu,5 Sook Ryun Park,6Takashi Kojima,7 Lucjan Wyrwicz,8 David Tougeron,9 Karen Geboes,10 Eric Van Cutsem,11 Roberto
Pazo-Cid,12 Aziz Zaanan,13 Sue-Anne McLachlan,14 Hongqian Wu,15 Jingwen Shi,16 Liyun Li,17 ShicanYan,17 Harry H. Yoon,18Affiliations: 1Centre Hospitalier Paris Saint-Joseph, Paris, France; 2Fifth Medical Center, Chinese PLA
General Hospital, Beijing, China; 3National Cancer Center Hospital, Tokyo, Japan; 4Department ofMedical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University ofManchester, Manchester, UK; 5The First Affiliated Hospital of Nanjing Medical University, Nanjing,
China; 6Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea;
7National Cancer Center Hospital East, Chiba, Japan; 8Maria Sklodowska-Curie National Cancer
Research Institute, Warsaw, Poland; 9Centre Hospitalier Universitaire de Poitiers, Poitiers, France;
10UZ Gent, Gent, Belgium; 11University Hospitals Gasthuisberg / Leuven & KULeuven, Leuven,Belgium; 12Hospital Universitario Miguel Servet, Zaragoza, Spain; 13Hôpital Européen Georges
Pompidou, Digestive Oncology, Paris, France; 14St Vincent’s Hospital Melbourne, Melbourne,Victoria, Australia; 15Global Statistics and Data Science, BeiGene USA, Inc., Ridgefield Park, NJ, USA;
16
Clinical Biomarker, BeiGene (Beijing) Co., Ltd., Beijing, China; 17Clinical Development, BeiGene(Beijing) Co., Ltd., Beijing, China; 18Mayo Clinic, Rochester, MN, USAABSTRACT
Background: TIS (an anti–PD-1 antibody) + CT demonstrated significant overall survival (OS) benefitvs PBO + CT as first-line (1L) therapy for advanced ESCC in all randomized patients (pts; stratified HR0.66) and pts with PD-L1 Tumor Area Positivity (TAP) score ≥10% (stratified HR 0.62) (RATIONALE306; NCT03783442). Sustained survival benefit was observed at 3 yrs follow-up. Here we report
exploratory analyses of OS by PD-L1 expression status and concordance of PD-L1 TAP and combined
positive score (CPS).
Methods: Adults with advanced ESCC were randomized (1:1) to IV TIS 200 mg or PBO every 3 wks +investigator-chosen CT (platinum + fluoropyrimidine or platinum + paclitaxel) until diseaseprogression or intolerable toxicity. The primary endpoint was OS. Tissue samples were stained using
the VENTANA PD-L1 (SP263) assay. PD-L1 expression was assessed by TAP and rescored post hoc byCPS. OS with different PD-L1 cutoffs, concordance between TAP and CPS at multiple cutoffs,
interclass correlation coefficient (ICC), and Cohen’s Kappa were investigated.
Results: Among 647 randomized pts, PD-L1 status was evaluable in 542 for TAP and 537 for CPS.
223/34%, 135/21%, 123/19% and 61/9% of pts had PD-L1 TAP score ≥10%, 5 to <10%, 1 to <5% and<1%, respectively. After a minimum 3-yr follow-up, OS improvement with TIS + CT vs PBO + CT wasseen in PD-L1 subgroups with TAP score ≥1%, while small subgroup size with TAP score <1% limited
interpretation (Table). OS results defined by TAP and CPS were similar. ICC between TAP and CPS
was 0.85 (95% CI 0.80–0.88). TAP and CPS scores showed substantial concordance in overall
percentage agreement and Cohen’s Kappa.
Conclusions: Exploratory PD-L1 subgroup results with prior results from all randomized pts, support
TIS + CT as a new 1L treatment option for pts with advanced ESCC. The concordance of TAP and CPS
scoring methods indicate that both are viable clinical measurements of PD-L1 expression in pts withESCC.

ESMO GIEvent/total
PD-L1 status
TAP score≥10%
5 to <10%
1 to <5%<1%Unknown
CPS≥105 to <10
1 to <5<1UnknownPD-L1 concordance
between TAP andCPSTAP 1% vs CPS 1
TAP 5% vs CPS 5
TAP 10% vs CPS
10ESMO GI

OS, unstratified
hazard ratio (95%CI)

TIS + CTPBO + CT

90/116
38/56
50/59
32/36
40/59

85/107
66/79
56/64
22/25
35/48

0.71 (0.53–0.95)
0.50 (0.33–0.75)
0.86 (0.59–1.26)
1.21 (0.70–2.08)
0.65 (0.41–1.02)

85/115
39/54
52/64
28/31
43/62

93/113
51/61
60/73
23/26
37/50

0.64 (0.48–0.86)
0.72 (0.47–1.09)
0.71 (0.49–1.03)
1.36 (0.78–2.38)
0.66 (0.42–1.02)

Overall % agreement,(95% CI)

Cohen’s Kappa,(95% CI)97 (96–98)
85 (82–88)
89 (87–92)

0.85 (0.77–0.92)
0.67 (0.60–0.73)
0.78 (0.72–0.83)