Treatment options after first-line systemic therapy for patients with oesophageal squamous cell carcinoma (ESCC) are limited.The phase III RATIONALE-302 trial evaluated the safety and efficacy of tislelizumab vs. chemotherapy as second-line treatment for advanced or metastatic ESCC. Tislelizumab significantly improved survival and demonstrated a tolerable safety profile in this setting.
Second-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (ESCC) typically consists of single-agent taxane or irinotecan. However, these are associated with significant toxicities and poor long-term survival. Recently, trials studying the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have demonstrated prolonged survival and safety benefits with anti-PD-1 antibodies vs. chemotherapy in patients with advanced or metastatic ESCC whose disease progressed after first-line systemic therapy. These studies demonstrated a survival benefit, specifically in patients with high PD-L1 expression. In early-phase clinical studies, tislelizumab monotherapy or in combination with chemotherapy demonstrated antitumour activity in patients with solid tumours, including oesophageal cancer, and showed a safety profile similar to other anti–PD-1 antibodies. The randomised phase III RATIONALE-302 study evaluated safety and efficacy of tislelizumab vs. chemotherapy as second-line treatment for advanced or metastatic ESCC.
The open-label phase III RATIONALE-302 study enrolled patients with advanced or metastatic ESCC, whose tumour progressed after first-line systemic treatment. Patients who had tumour progression within six months after definitive chemoradiotherapy, neoadjuvant, or adjuvant therapy were also eligible. Patients were required to have an ECOG performance status of 0-1, at least one measurable/evaluable lesion by RECIST v1.1, and adequate haematologic, hepatic, renal, and coagulation function. Patients were randomised 1:1 to receive intravenous tislelizumab (200 mg once every three weeks) or chemotherapy (investigator’s choice of paclitaxel, docetaxel, or irinotecan). Pre-defined subgroups included race, PD-L1 expression (tumour area positivity, TAP < or ≥ 10%) or region. The primary endpoint was overall survival (OS) in all patients. The key secondary endpoint was OS in patients with PD-L1 TAP score ≥ 10%. Other secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), assessed in the intention-to-treat population and in patients with PD-L1 TAP ≥ 10%, and safety and tolerability.
In total, 512 patients were randomly assigned to receive tislelizumab (N= 256) or chemotherapy (N= 256). Median follow-up was 8.5 vs. 5.8 months, respectively. At final analysis, 77.0% vs. 83.2% deaths occurred in the tislelizumab and chemotherapy arms. Median OS was significantly improved in the tislelizumab arm (8.6 vs. 6.3 months; HR[95%CI]: 0.70[0.57-0.85]; p= 0.0001). The 12-month OS rate was 37.4% vs. 23.7%. The survival benefit of tislelizumab vs. chemotherapy was observed in all predefined subgroups, including those defined by baseline PD-L1 expression status, region, and race. Tislelizumab improved median OS in patients with TAP ≥ 10% (10.3 vs. 6.8 months; HR[95%CI]: 0.54[0.36-0.79]; p= 0.0006), in patients with TAP < 10% (HR[95%CI]: 0.82[0.62-1.09]) and in those with TAP unknown (HR[95%CI]: 0.67[0.41-1.12]. Median PFS was 1.6 vs. 2.1 months in the tislelizumab vs. chemotherapy arms (HR[95%CI]: 0.83[0.67-1.01]. The estimated PFS rates were 21.7% vs. 14.9% at six months and 12.7% vs. 1.9% at twelve months. Treatment with tislelizumab was associated with higher ORR (20.3% vs. 9.8%), with 2.0% vs. 0.4% of the patients having complete response. Median DoR was 7.1 vs. 4.0 months. Fewer patients experienced treatment-related AEs (TRAEs) with tislelizumab vs. chemotherapy (73.3% vs. 93.8%). The most common TRAEs with tislelizumab were increased aspartate aminotransferase (11.4%), anaemia (11.0%), and hypothyroidism (10.2%). The most common TRAEs with chemotherapy were decreased white blood cell count (40.8%), decreased neutrophil count (39.2%), and anaemia (34.6%). Fewer patients had grade ≥3 TRAEs with tislelizumab (18.8% vs. 55.8%), including serious TRAEs (14.1% vs. 19.6%). Fewer patients discontinued tislelizumab vs. chemotherapy (6.7% vs. 13.8%) because of a TRAE. In both treatment arms, the primary cause of death was disease progression, which occurred at a lower frequency with tislelizumab vs. chemotherapy (59.8% vs. 66.0%).
Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated a statistically significant survival benefit with tislelizumab. Tislelizumab was also associated with improved PFS, ORR and DoR. Additionally, fewer patients experienced grade ≥ 3 TRAEs and discontinued treatment due to TRAEs in the tislelizumab vs. chemotherapy arms.
Shen L, Kato K, Kim S-B, et al. Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. J Clin Oncol. 2022;40(26):3065-76.