Phase 3 Study of Tislelizumab Compared with Docetaxel in Advanced NSCLC (RATIONALE 303)

Based on results of the RATIONALE 303 trial, tislelizumab significantly prolonged median overall survival by more than 5 months in patients with advanced non–small-cell lung cancer (NSCLC) compared with docetaxel.

In patients with advanced non–small-cell lung cancer (NSCLC) who progressed after treatment with platinum-based chemotherapy regimens, anti–PD-1 and anti–PD-L1 therapies have been shown to improve overall survival (OS) by 2 to 4 months compared with docetaxel. Tislelizumab is an anti–PD-1 antibody engineered to minimize FcɣR binding on macrophages, which is a mechanism of T-cell clearance and potential anti–PD-1 resistance.1

The phase 3 RATIONALE 303 study compared the efficacy and safety of tislelizumab with docetaxel as second- or third-line therapy for patients with advanced NSCLC. Patients without oncogenic driver mutations who failed at least 1 prior systemic therapy including a platinum regimen were randomized 2:1 to receive intravenous tislelizumab 200 mg every 3 weeks (arm A) or intravenous docetaxel 75 mg/m2 every 3 weeks (arm B).

The primary end points were OS in the intent-to-treat (ITT) analysis set and OS in the PD-L1 high (≥25% in tumor cells [TC]) analysis set. A prespecified interim analysis was conducted after approximately 426 deaths or 76% of planned events. In the interim analysis, formal OS superiority testing was conducted only in the ITT population.1

A total of 805 patients were randomized in the RATIONALE 303 study, 535 to tislelizumab and 270 to docetaxel. Patient demographics were generally balanced between arms. After 19 months median follow-up or 441 OS events in the ITT population, median OS was significantly longer for tislelizumab compared with docetaxel: 17.2 months compared with 11.9 months (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.53-0.78; P <.0001).1

The OS benefit seen with tislelizumab was also observed in the PD-L1 high analysis group: 19.1 months versus 11.9 months (HR, 0.52; 95% CI, 0.38-0.71) and across most subgroups including histology. Progression-free survival (PFS), overall response rate (ORR), and duration of response were also improved in the tislelizumab arm compared with the docetaxel arm.1

The most commonly reported adverse events (AEs) were anemia and increased alanine aminotransferase for tislelizumab, and alopecia and neutropenia for docetaxel. Pneumonia and neutropenia were the most common grade ≥3 AEs in the tislelizumab and docetaxel arms, respectively. Treatment-related AEs leading to death were observed in 1.5% of tislelizumab patients and 1.6% of docetaxel recipients.1

Researchers concluded that the RATIONALE 303 study demonstrated that tislelizumab given as second- or third-line therapy in patients with advanced NSCLC prolonged OS, improved PFS, and increased ORR compared with docetaxel regardless of NSCLC histology or PD-L1 expression level. The safety profile of tislelizumab was deemed tolerable and manageable.1

1. Zhou C, Huang D, Yu X, et al. Results from RATIONALE 303: a global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC. Presented at: American Association of Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT039.