As reported in The Lancet Oncology by Jianming Xu, MD, of Fifth Medical Center, Chinese PLA General Hospital, Beijing, corresponding author Harry H. Yoon, MD, of the Department of Oncology, Mayo Clinic, Rochester, and colleagues, an interim analysis of the phase III RATIONALE-306 trial has shown improved overall survival with the addition of the anti–PD-1 agent tislelizumab to chemotherapy in first-line treatment of advanced or metastatic esophageal squamous cell carcinoma.¹

Jianming Xu, MD

Harry H. Yoon, MD

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 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). Randomization was stratified by investigator-chosen chemotherapy, region, and previous definitive therapy.  A total of 75% of patients were from Asia, 24% from Europe, less than 1% from North America, and less than 1% from Oceania. 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 (end 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% (95% CI = 59.4%–70.0%) vs 44.9% (95% CI = 39.2%–50.3%) and 48.6% (95% CI = 42.9%–54.0%) vs 34.5% (95% CI = 29.2%–39.8%).

Median overall survival was similar in both patients with more than 10% tumor area positivity and in those patients with less than 10% tumor area positivity. Hazard ratios were 0.67 (95% CI = 0.54–0.84) among 243 vs 243 patients from Asia and 0.66 (95% CI = 0.45–0.96) among 83 vs 80 patients from other regions. Hazard ratios were 0.66 (95% CI = 0.49–0.88) among 147 vs 146 patients who received platinum/fluoropyrimidine and 0.69 (95% CI = 0.54–0.89) among 179 vs 177 receiving platinum/paclitaxel chemotherapy. Hazard ratios were 0.67 (95% CI = 0.49–0.90) among 143 vs 141 patients who received previous definitive therapy and 0.68 (95% CI = 0.53–0.87) among 183 vs 182 who did not.

Investigator-assessed objective response was observed in 63% of patients in the tislelizumab group vs 42% of the control group (odds ratio = 2.38, 95% CI = 1.73–3.27, P < .0001). 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 6 and 12 months were 61.1% (95% CI = 55.3%–66.5%) vs 44.5% (95% CI = 38.6%–50.2%) and 30.0% (95% CI = 24.6%–35.6%) vs 15.7% (95% CI = 11.5%–20.4%). Totals of 157 of 326 patients (48%) in the tislelizumab group and 177 of 323 patients (55%) in the control group received subsequent systemic anticancer therapies after discontinuing study treatment, including immunotherapy in 46 patients (14%) vs 72 patients (22%).

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 67% of 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% (most commonly peripheral neuropathy in 7%) vs 19% of patients. Death considered related to treatment occurred in six patients in the tislelizumab group (from gastrointestinal and upper gastrointestinal hemorrhage in two and myocarditis, pulmonary tuberculosis, electrolyte imbalance, and respiratory failure in one each) and in four patients in the control group (from an 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 versus 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.” 

DISCLOSURE: The study was funded by BeiGene. Dr. Xu reported no conflicts of interest. Dr. Yoon has received grants to fund clinical trials from BeiGene, Bristol Myers Squibb, CARsgen Therapeutics, MacroGenics, and Merck; has received a travel grant from BeiGene; and has received honoraria to serve on advisory boards for ALX Oncology, Amgen, AstraZeneca, Astellas, BeiGene, Bristol Myers Squibb, Elevation Oncology, MacroGenics, Merck, OncXerna, Zymeworks, and Novartis. For full disclosures of the study authors, visit thelancet.com. 

REFERENCE

1. Xu J, Kato K, Raymond, E, et al: Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): A global, randomised, placebo-controlled, phase 3 study. Lancet Oncol 24:483-495, 2023.