As reported in The Lancet Oncology by Xu et al, an interim analysis of the phase III RATIONALE-306 trial has shown improved overall survival with the addition of the anti–PD-1 antibody tislelizumab to chemotherapy in the first-line treatment of advanced or metastatic esophageal squamous cell carcinoma.

Study Details

In the double-blind trial, 649 patients from sites in Asia, Europe, Oceania, and North America were randomly assigned between December 2018 and November 2020 to receive tislelizumab at 200 mg (n = 326) or placebo (n = 323) every 3 weeks on day 1, plus an investigator-chosen platinum doublet; options consisted of a platinum (cisplatin at 60–80 mg/m² on day 1 or oxaliplatin at 130 mg/m² on day 1) plus a fluoropyrimidine (fluorouracil at 750–800 mg/m² on days 1–5, or capecitabine at 1,000 mg/m² twice daily on days 1–14) or paclitaxel (175 mg/m² on day 1). A total of 75% of patients were Asian. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival in the intent-to-treat population.

Overall Survival

As of data cutoff (the end of February 2022), median follow-up was 16.3 months (interquartile range [IQR] = 8.6–21.8 months) in the tislelizumab group and 9.8 months (IQR = 5.8–19.0 months) in the control group. Median overall survival was 17.2 months (95% confidence interval [CI] = 15.8–20.1 months) in the tislelizumab group vs 10.6 months (95% CI = 9.3–12.1 months) in the control group (stratified hazard ratio [HR] = 0.66, 95% CI = 0.54–0.80, P < .0001). Rates at 12 and 18 months were 65.0% vs 44.9% and 48.6% vs 34.5%.

Median overall survival was 16.6 vs 10.0 months (HR = 0.62, P = .0029) among patients with PD-L1 tumor area positivity ≥ 10% and 15.8 vs 10.4 months (HR = 0.77, 95% CI = 0.59–1.01) among those with PD-L1 tumor area positivity < 10%. Hazard ratios were 0.67 (95% CI = 0.54–0.84) among patients from Asia and 0.66 (95% CI = 0.45–0.96) among patients from other regions.

Median progression-free survival was 7.3 months (95% CI = 6.9–8.3 months) in the tislelizumab group vs 5.6 months (95% CI = 4.9–6.0 months) in the control group (HR = 0.62, 95% CI = 0.52–0.75, P < .0001). Rates at 12 months were 30.0% vs 15.7%. Subsequent systemic anticancer therapies were received by 48% of patients in the tislelizumab group vs 55% of the control group, including immunotherapy in 14% vs 22%.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 67% of those in the tislelizumab group vs 64% of the control group; the most common grade 3 or 4 events in the tislelizumab group were decreased neutrophil count (31% vs 33% in the control group), anemia (15% vs 13%), and decreased white blood cell count (11% vs 16%). Serious treatment-related adverse events occurred in 29% vs 19% of patients, most commonly pneumonia in seven patients (2%) in each group. Treatment-related adverse events led to discontinuation of treatment in 29% vs 19% of patients. Death considered related to treatment occurred in six patients in the tislelizumab group (due to gastrointestinal and upper gastrointestinal hemorrhage in two patients, and myocarditis, pulmonary tuberculosis, electrolyte imbalance, and respiratory failure in one each) and in four patients in the control group (due to unspecified cause in two and pneumonia and septic shock in one each). 

The investigators concluded, “Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic esophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile vs placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this article represents the primary study analysis.”

Harry H. Yoon, MD, of the Department of Oncology, Mayo Clinic, Rochester, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by BeiGene. For full disclosures of the study authors, visit thelancet.com.