RATIONALE-306 Subgroup Data Further Support First-line Tislelizumab/Chemo in Locally Advanced ESCC

The frontline combination of tislelizumab-jsgr (Tevimbra) plus chemotherapy demonstrated efficacy improvements over chemotherapy alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC), with similar improvements noted in those with locally advanced disease and a tumor PD-L1 tumor area positivity (TAP) score of at least 5%, according to findings from a subgroup analysis of the phase 3 RATIONALE-306 study (NCT03783442).¹

The data, which were shared during the 2025 ESMO Gastrointestinal Cancers Congress, the median overall survival (OS) with tislelizumab plus chemotherapy (n = 49) was 25.6 months (95% CI, 19.4-36.3) in the subgroup of patients with locally advanced disease vs 12.3 months (95% CI, 9.0-21.7) with chemotherapy (n = 39), translating to a 51% reduction in the risk of death (HR, 0.49; 95% CI, 0.29-0.84; P = .0037). The 12- and 24-month OS rates in the tislelizumab arm were 78.5% and 53.5%; in the placebo arm, these rates were 50.9% and 22.6%. The median investigator-assessed progression-free survival (PFS) with tislelizumab was 9.7 months (95% CI, 6.9-19.6) vs 6.9 months (95% CI, 4.2-9.7) with placebo (HR, 0.56; 95% CI, 0.31-1.01; P = .0262); the respective 12-month PFS rates were 46.2% and 18.2%.

Those with locally advanced ESCC and a PD-L1 TAP score of 5% or higher who received tislelizumab plus chemotherapy (n = 25) experienced a median OS of 26.4 months (95% CI, 15.3-not evaluable [NE]) vs 11.5 months (95% CI, 8.6-19.8) with chemotherapy alone (n = 20), translating to a 63% reduction in the risk of death (HR, 0.37; 95% CI, 0.16-0.83; P = .0067). The 12-month OS rates in the tislelizumab and placebo arms were 72.0% and 45.2%, respectively; the rates at 24 months were 56.0% and 16.9%, respectively. The median investigator-assessed PFS in the tislelizumab arm was 13.2 months (95% CI, 6.8-30.2) vs 6.7 months (95% CI, 4.2-8.6) in the placebo arm (HR, 0.44; 95% CI, 0.19-1.02; P = .269; the respective 12-month PFS rates were 52.4% and 14.8%.

“In this subgroup analysis of patients with locally advanced ESCC, first-line tislelizumab plus chemotherapy showed substantial and clinically meaningful improvements in efficacy, consistent with the primary and 3-year long-term follow-up analyses,” Eric Van Cutsem, MD, PhD, of the Division of Digestive Oncology at University Hospitals Gasthuisberg, Leuven, and KU Leuven, in Leuven, Belgium, said in a presentation of the data. “These findings further support the use of tislelizumab plus chemotherapy as a first-line treatment option for patients with locally advanced ESCC.”

Reviewing RATIONALE-306: Design and Prior Data

The double-blind, randomized, global, phase 3 study enrolled patients with unresectable locally advanced or metastatic ESCC who had measurable or evaluable disease by RECIST v1.1 criteria and an ECOG performance status no higher than 1. Patients had not previously received systemic therapy for advanced disease. They were randomized 1:1 to receive placebo or 200 mg of tislelizumab every 3 weeks plus chemotherapy in the form of platinum plus fluoropyrimidine or platinum plus paclitaxel. Maintenance treatment continued until intolerable toxicity or progressive disease. They were stratified by geographic region (Asia excluding Japan vs Japan vs rest of the world), previous definitive therapy (yes vs no), and investigator-selected chemotherapy regimen (platinum plus fluoropyrimidine vs platinum plus paclitaxel).

The primary end point of the study was OS in the intention-to-treat (ITT) population and secondary end points were OS in the subgroup of patients with a PD-L1 TAP score of 10% or higher, PFS, objective response rate (ORR), duration of response (DOR), health-related quality of life, and safety.

Prior data from the study showed that after a minimum follow-up of 3 years, the median OS in all patients who received tislelizumab plus chemotherapy (n = 326) was 17.2 months (95% CI, 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.0) with placebo plus chemotherapy (n = 323), translating to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.59-0.83; P < .0001).² In the tislelizumab arm, the 12-, 24-, and 36-month OS rates were 65.0%, 37.9%, and 22.1%, respectively; in the placebo arm, the respective rates were 44.7%, 24.8%, and 14.1%. In March 2025, the FDA approved tislelizumab plus platinum-containing chemotherapy for first-line use in adult patients with unresectable or metastatic ESCC with a tumor PD-L1 expression of 1 or higher based on RATIONALE-306 data.³

Delving Deeper Into the Current Post Hoc Subgroup Analysis

The subgroup analysis sought to evaluate OS and PFS in patients with locally advanced ESCC, which accounted for 13.6% of the 649 patients, including those with both locally advanced ESCC and a tumor PD-L1 TAP score of 5% or higher, which accounted for 51.1% of 88 patients.¹ Those with nonmetastatic disease who were not fit for surgery or definitive chemoradiation were retrospectively selected and included in the analysis.

The baseline demographic and disease characteristics in the locally advanced ESCC subgroup were consistent with those of the ITT population, Van Cutsem said.

Additional efficacy data showed that in the locally advanced ESCC subgroup, the investigator-assessed ORR with tislelizumab plus chemotherapy was 61.2%, which comprised a complete response (CR) rate of 12.2% and a partial response (PR) rate of 49.0%. With chemotherapy alone, the investigator-assessed ORR was 38.5%, with a CR rate of 12.8% and a PR rate of 25.6%. The time to response (TTR) with tislelizumab was 1.4 months (range, 1.2-23.3) vs 2.6 months (range, 1.2-4.2) with placebo. The median DOR was 12.6 months (95% CI, 6.9-22.1) and 7.1 months (95% CI, 5.5-16.6) in the respective arms.

In the locally advanced ESCC subgroup that also had a PD-L1 TAP score of 5% or higher, the respective ORRs were 68.0% and 30.0%. In the tislelizumab arm, the CR and PR rates were 16.0% and 52.0%, respectively; in the placebo arm, these respective rates were 10.0% and 20.0%. The median TTR was 1.5 months (range, 1.2-23.3) with tislelizumab vs 2.0 months (range, 1.2-2.7) with placebo. The median DOR in the respective arms was 22.1 months (95% CI, 6.1-NE) and 5.7 months (95% CI, 1.5-NE).

Safety Spotlight

The toxicity profile of tislelizumab combined with chemotherapy in the locally advanced subgroup was consistent with that reported in the ITT population, according to Van Cutsem, who added that no new safety signals were observed.

In the locally advanced ESCC subgroup, 100% and 97.4% of those in the tislelizumab and placebo arms experienced at least 1 treatment-emergent adverse effect (TEAE); 65.3% and 74.4% of the cases were grade 3 or higher, 44.9% and 51.3% were serious, and 6.1% and 5.1% proved fatal. Moreover, 100% of those in the tislelizumab arm and 92.3% of those in the placebo experienced at least 1 treatment-related adverse effect; 59.2% and 59.0% were grade 3 or higher, 28.6% and 20.5% were serious, and 28.6% and 20.5% led to death. TEAEs resulted in treatment discontinuation for 40.8% of those in the tislelizumab arm vs 35.9% of those in the placebo arm. In the tislelizumab arm, 42.9% of patients received subsequent anticancer therapy and 18.4% received subsequent radiation; in the placebo arm, these respective rates were 51.3% and 30.8%.

Disclosures: Van Cutsem disclosed having participated in advisory boards for AbbVie, Agenus, ALX, Amgen, Arcus Biosciences, Astellas, AstraZeneca, Bayer, BeOne Medicines, Bexon Clinical, BioNtech, Boehringer Ingelheim, Bristol Myers Squibb, Canfour, Daiichi Sankyo, Debiopharm, Elmedix, Eisai, Galapagos, GSK, Hookipa Pharma, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Simcere, Takeda, Taiho Pharmaceutical, and Terumo.

References

1. Van Cutsem E, Xu J, Raymond E, et al. Tislelizumab + chemotherapy vs placebo + chemotherapy in patients with locally advanced esophageal squamous cell carcinoma: RATIONALE-306 subgroup analysis. Presented at: 2025 ESMO Gastrointestinal Cancers Congress; July 2-5, 2025; Barcelona, Spain. Abstract 389MO.
2. Yoon HH, Kato K, Raymond, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): minimum 3-year survival follow-up. J Clin Oncol. 2024;42(suppl 16):4032. doi:10.1200/JCO.2024.42.16_suppl.4032
3. Tevimbra approved in US for first-line treatment of advanced esophageal squamous cell carcinoma in combination with chemotherapy. News release. BeiGene, Ltd. March 4, 2025. Accessed July 5, 2025. https://hkexir.beigene.com/news/tevimbra-approved-in-u-s-for-first-line-treatment-of-advanced-esophageal-squamous-cell-carcinoma-in-combination/8379a7c3-35ce-45af-82d3-164c64ecf37c/