Esophagus to Small Intestine
Lancet Oncol. 2023;24(5):483−95
Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or meta-static esophageal squamous cell carcinoma (RATIONALE-306): A global, randomized, placebo-controlled, phase 3 study
Background: The options for first-line treatment of advanced esophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumor activity in previously treated patients with advanced esophageal squamous cell carci-noma (ESCC). The authors report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic ESCC.
Methods: This global, randomized, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centers across Asia, Europe, Oceania, and North America. Patients (aged ≥ 18 years) with unresectable, locally advanced, recurrent or metastatic ESCC (regard-less of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomization (block size of 4) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60−80 mg/m2 i.v. on day 1 or oxaliplatin 130 mg/m2 i.v. on day 1) plus a fluoropyrimidine (fluorouracil [750−800 mg/m2 i.v. on days 1−5] or capecita-bine [1000 mg/m2 orally twice daily on days 1−14]) or paclitaxel (175 mg/m2 i.v. on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary end point was overall sur-vival. The efficacy analysis was done in the intention-to-treat population (i.e., all randomly assigned patients) and safety was assessed in all pa-tients who received at least 1 dose of study treatment.
Findings: Between December 12, 2018, and November 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tisleli-zumab plus chemotherapy (n = 326) or placebo plus chemotherapy (n = 323). Median age was 64.0 years (interquartile range [IQR], 59.0−69.0), 563 of 649 participants (87%) were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 of 326 patients (99%) in the tislelizumab group and 321 of 323 (99%) in the placebo group received at least 1 dose of the study drug. As of data cut-off (February 28, 2022), median follow-up was 16.3 months (IQR, 8.6−21.8) in the tislelizumab group and 9.8 months (IQR, 5.8−19.0) in the placebo group, and 196 of 326 patients (60%) in the tislelizumab group versus 226 of 323 (70%) in the placebo group had died. Median overall survival in the tisleli-zumab group was 17.2 months (95% confidence interval [CI]: 15.8−20.1) and in the placebo group was 10.6 months (95% CI: 9.3−12.1; strati-fied hazard ratio = 0.66 [95% CI: 0.54−0.80]; 1-sided p < 0.0001). 313 of 324 patients (97%) in the tislelizumab group and 309 of 321 (96%) in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treat-ment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs. 105 [33%] in the placebo group), de-creased white blood cell count (35 [11%] vs. 50 [16%]), and anemia (47 [15%] vs. 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal hemorrhage [n = 2], myocarditis [n = 1], pulmonary tuberculosis [n = 1], electrolyte imbalance [n = 1], and respiratory failure [n = 1]) and 4 deaths in the placebo group (pneumonia [n = 1], septic shock [n = 1], and unspecified death [n = 2]) were determined to be treatment-related.
Interpretation: 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 end point, as confirmed by the independent data monitoring committee, this article represents the primary study analysis.