KEY TAKEAWAYS
- A phase 3, RATIONALE-306 study that was global, randomized, double-blind, parallel-arm, and placebo-controlled was carried out at 162 medical centers in Asia, Europe, Oceania, and North America.
- The present study provides interim analysis outcomes from the RATIONALE-306 trial, which aimed to evaluate the efficacy of tislelizumab.
- Tislelizumab, an anti-PD-1 antibody, has demonstrated antineoplastic effects in patients with advanced oesophageal carcinoma.
- Adults with advanced oesophageal squamous cell carcinoma received tislelizumab or placebo with chemotherapy chosen by the investigator.
- Tislelizumab + chemo improves survival in oesophageal cancer patients compared to placebo + chemotherapy, with some treatment-related adverse events.
The therapeutic options for the primary treatment of advanced oesophageal squamous cell carcinoma are limited, and the prognosis remains unfavorable. Tislelizumab, an anti-PD-1 antibody, has demonstrated antineoplastic effects in patients with advanced oesophageal squamous cell carcinoma who have undergone prior treatment.
The present study provides interim analysis outcomes from the RATIONALE-306 trial, which aimed to evaluate the efficacy of tislelizumab in combination with chemotherapy compared to placebo plus chemotherapy for primary treatment of advanced or metastatic oesophageal squamous cell carcinoma.
The phase 3 global, randomized, double-blind, parallel-arm, and placebo-controlled trial was conducted at 162 medical centers in Asia, Europe, Oceania, and North America. Individuals 18 years or older diagnosed with unresectable, locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma, regardless of PD-L1 expression, have an Eastern Cooperative Oncology Group performance status of 0-1 and were enrolled in the study.
Patients were required to have measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). The patients were randomly assigned in a 1:1 ratio using permuted block randomization with a block size of four. Stratification was done based on the investigator’s choice of chemotherapy, region, and previous definitive therapy. They were given tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, along with an investigator-chosen chemotherapy doublet. The chemotherapy doublet consisted of a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) and a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1).
The therapeutic intervention was sustained until the point of disease advancement or intolerable adverse effects. The treatment was concealed from investigators, patients, and sponsor staff or designees. The main outcome measure was the survival rate of the subjects. The efficacy analysis was conducted on the intention-to-treat population, including all randomly assigned patients. Safety was evaluated in all patients who received at least one dose of the study treatment. During the period spanning from December 12, 2018, to November 24, 2020, a total of 869 patients underwent screening. Of these, 649 patients were randomly selected for administering either tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). The median age of the participants was 64.0 years, with an interquartile range (IQR) of 59.0-69.0. Among the 649 participants, 563 (87%) were male, and 86 (13%) were female. Regarding ethnicity, 486 (75%) were Asian, and 155 (24%) were White. Of 326 patients in the tislelizumab group and 323 in the placebo group, 324 (99%) and 321 (99%) patients were administered at least one dose of the investigational drug as per the study protocol. At the time of data cutoff, which was on February 28, 2022, the median follow-up duration was 16.3 months (interquartile range [IQR] 8.6-21.8) in the tislelizumab group and 9.8 months (IQR 5.8-19.0) in the placebo group. Among the participants, 196 (60%) out of 326 patients in the tislelizumab group and 226 (70%) out of 323 patients in the placebo group had passed away. The tislelizumab group exhibited a median overall survival of 17.2 months (95% CI 15.8-20.1), whereas the placebo group displayed a median overall survival of 10.6 months (9.3-12.1; stratified hazard ratio 0.66 [95% CI 0.54-0.80]; one-sided P<0.0001). Of the 324 patients in the tislelizumab group, 313 (97%) experienced treatment-related treatment-emergent adverse events. Similarly, in the placebo group, out of 321 patients, 309 (96%) reported such events. The prevalent grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count, white blood cell count, and anemia. The tislelizumab group had 31% of individuals experiencing decreased neutrophil count compared to 33% in the placebo group. Similarly, the tislelizumab group had 11% of individuals experiencing decreased white blood cell count compared to 16% in the placebo group. The tislelizumab group had 15% of individuals experiencing anemia compared to 13% in the placebo group. There were six fatalities in the tislelizumab cohort, with causes including gastrointestinal and upper gastrointestinal hemorrhage (n=2), myocarditis (n=1), pulmonary tuberculosis (n=1), electrolyte imbalance (n=1), and respiratory failure (n=1). Additionally, four deaths occurred in the placebo group, with causes including pneumonia (n=1), septic shock (n=1), and unspecified death (n=2), all of which were deemed to be related to the treatment.
The administration of Tislelizumab in combination with chemotherapy as the primary therapy for advanced or metastatic oesophageal squamous cell carcinoma resulted in a superior overall survival rate with a manageable safety profile when compared to the administration of placebo in combination with chemotherapy. An independent data monitoring committee has confirmed that the interim analysis has met its superiority boundary for the primary endpoint.
Source Link: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00108-0/fulltext
Clinical Link: https://clinicaltrials.gov/ct2/show/NCT03783442
Prof Jianming Xu, Ken Kato, Prof Eric Raymond, Richard A Hubner, Prof Yongqian Shu, Yueyin Pan, Prof Sook Ryun Park, Lu Ping, Yi Jiang, Prof Jingdong Zhang, Xiaohong Wu, Yuanhu Yao, Prof Lin Shen, Prof Takashi Kojima, Evgeny Gotovkin, Ryu Ishihara, MD
Prof Lucjan Wyrwicz, Prof Eric Van Cutsem, Paula Jimenez-Fonseca, Chen-Yuan Lin, MD
Lei Wang, Jingwen Shi, Liyun Li, Prof Harry H Yoon/Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomized, placebo-controlled, phase 3 study/doi.org/10.1016/S1470-2045(23)00108-0
