Tislelizumab Plus Chemotherapy Improves Overall Survival in ESCC


The phase 3 RATIONALE-306 study displayed encouraging survival and safety data among patients with advanced or metastatic esophageal squamous cell carcinoma who were treated with tislelizumab and chemotherapy.

Ken Kato, MD, PhD

Ken Kato, MD, PhD

The addition of tislelizumab (BGB-A317) to chemotherapy elicited superior overall survival rates and had a manageable safety profile vs placebo plus chemotherapy when administered as a first-line treatment for patients with advanced or metastatic esophageal squamous cell carcinoma.1

Findings come from the phase 3 RATIONALE-306 study (NCT03783442) which combined tislelizumab with chemotherapy vs placebo plus chemotherapy as first-line treatment.

In the trial, the median overall survival in the tislelizumab arm was 17.2 months (95% CI 15.8-20.1) vs 10.6 months (95% CI, 9.3-12.1) in the placebo arm (stratified HR, 0.66; 95% CI, 0.54-0.80; one-sided P < .0001).

“The added effect of tislelizumab to chemotherapy was shown in the patients with chemotherapy naïve advanced and recurred ESCC. The magnitude of efficacy was consistent with the former study with chemotherapy plus an immune checkpoint inhibitor [ICI], but tislelizumab showed efficacy even for the patients who were PD-L1 negative,” Ken Kato, MD, PhD, chief of the department of head and neck, and esophageal medical oncology and gastrointestinal medical oncology at the National Cancer Center Hospital in Tokyo, Japan, told Targeted OncologyTM.

There are limited options available for first-line treatment of advanced esophageal squamous cell carcinoma, and the outcomes among this patient population remain poor.

“Tislelizumab is human IgG4 antibody which targeted to PD-1. The binding site of tislelizumab to PD-1 is similar to nivolumab [Opdivo] and pembrolizumab [Keytruda], but the preclinical data showed higher affinity of tislelizumab compared with nivolumab and pembrolizumab,” said Kato.

To further evaluate the agent in this patient population, investigators began the RATIONALE-306 study.

In the global, randomized, double-blind, parallel-arm, placebo-controlled, phase 3 study, patients aged 18 years and older with unresectable, locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma were enrolled and evaluated at 162 medical centers across Asia, Europe, Oceania, and North America. Patients were required to have an ECOG performance status of 0-1, and measurable or evaluable disease per RECIST v1.1.

Those enrolled were randomized in a 1:1 ratio to receive tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet of either cisplatin 60-80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1, plus a fluorouracil at 750-800 mg/m2 intravenously on days 1-5 or capecitabine at 1000 mg/m2 orally twice daily on days 1-14, or paclitaxel at 175 mg/m2 intravenously on day 1. Patients continued treatment until disease progression or unacceptable toxicity.

The primary end point of the trial was overall survival with secondary end points of progression-free survival, objective response rate, duration of response, health-related quality-of-life, and number of patients with adverse events (AEs).2

A total of 869 patients were screened, and 649 were randomly assigned to the tislelizumab plus chemotherapy arm (n = 326) or placebo plus chemotherapy (n = 323) between December 12, 2018, and November 24, 2020.1 The median age among patients enrolled were 64 years old (interquartile range [IQR] 59.0-69.0), 87% of patients were male, 13% were female, 75% were Asian, and 24% were White. For those given tislelizumab, 99% received at least 1 dose of the study drug, as well as 99% in the placebo group.

At the data cutoff date of February 28, 2022, the median follow-up was 16.3 months (IQR, 8.6-21.8) for patients given tislelizumab and 9.8 months (IQR, 5.8-19.0) with placebo. Sixty percent vs 70% of patients in the tislelizumab vs placebo group had died.

For safety, in the tislelizumab group, 313 (97%) of 324 patients had treatment-emergent AEs vs 309 (96%) of 321 in the placebo group. The most common grade 3 or 4 treatment-related or treatment-emergent AEs were decreased neutrophil count (31% in the tislelizumab group v 33% in the placebo group), decreased white blood cell count (11% v 16%), and anemia (15% v 13%).

There were 6 deaths among patients in the tislelizumab group from gastrointestinal and upper gastrointestinal hemorrhage (n=2), myocarditis (n=1), pulmonary tuberculosis (n=1), electrolyte imbalance (n=1), and respiratory failure (n=1]), as well as 4 deaths in the placebo group from pneumonia (n=1), septic shock (n=1), and unspecified death (n=2). These deaths were determined to be treatment-related.

Overall, the RATIONALE-306 study of the combination of tislelizumab and chemotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma showed promising survival data with a manageable safety profile vs placebo plus chemotherapy.


Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): a global, randomized, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483-495. doi:10.1016/S1470-2045(23)00108-0

A study of tislelizumab (BGB-A317) in combination with chemotherapy as first line treatment in participants with advanced esophageal squamous cell carcinoma. ClinicalTrials.gov. Updated April 18, 2023. Accessed May 9, 2023. https://clinicaltrials.gov/ct2/show/NCT03783442

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