SUMMARY: The FDA on March 14, 2024 approved TEVIMBRA® (Tislelizumab-jsgr) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. The American Cancer Society estimates that in 2024, about 22,370 new cases of esophageal cancer will be diagnosed in the US and about 16,130 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases. Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.
Tislelizumab is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.
The present approval was based on RATIONALE 302 study, which is a global, randomized, open-label, Phase III trial, designed to investigate the efficacy and safety of TEVIMBRA® when compared with investigators choice of chemotherapy as a second-line treatment, for patients with unresectable, locally advanced or metastatic ESCC. In this study, 512 patients (N=512) with advanced or metastatic ESCC who had progressed during or after first-line systemic treatment were randomly assigned 1:1 to receive either Tislelizumab 200 mg IV every 3 weeks or investigator’s choice of chemotherapy. Those in the chemotherapy group received one of the following regimens: Paclitaxel 135-175 mg/m2 IV every 3 weeks or 80-100 mg/m2 IV weekly, Docetaxel 75 mg/m2 IV every 3 weeks or Irinotecan 125 mg/m2 IV Day 1 and Day 8 every 3 weeks. Stratification factors included ECOG PS and choice of chemotherapy. The Primary end point of this trial was Overall Survival (OS) in the Intention-to-Treat (ITT) population. Secondary end points included Progression Free Survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.
The trial met its Primary endpoint with a statistically significant and clinically meaningful survival benefit for TEVIMBRA® compared with chemotherapy. The median OS in the TEVIMBRA® group was 8.6 months compared to 6.3 months in the chemotherapy group (HR=0.70; P=0.0001). This survival benefit was noted across the predefined subgroups, including PD-L1 status, race, and region. In the subset of patients with a PD-L1 CPS of at least 10%, the median OS with Tislelizumab was 10.3 months versus 6.8 months with chemotherapy (HR=0.54; P=0.0006). The 6-month PFS rates in the Tislelizumab and chemotherapy groups were 21.7% and 14.9% respectively, 12-month PFS rates were 12.7% and 1.9%. The Overall Response Rate was higher in the Tislelizumab group versus chemotherapy group (20.3% versus 9.8%) and the median Duration of Response was 7.1 months versus 4.0 months, respectively. The safety profile of Tislelizumab was also favorable over chemotherapy.
It was concluded that Tislelizumab significantly improved Overall Survival compared with chemotherapy as second-line therapy in patients with advanced or metastatic Esophageal Squamous Cell Carcinoma, with a tolerable safety profile. This survival benefit was even more in patients with PD-L1 CPS of 10% or more. Studies are underway, evaluating Tislelizumab in combination with chemotherapy in treatment naïve patients with advanced esophageal carcinoma.
Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. Shen L, Kato K, Kim S-B, et al. J Clin Oncol.2022;40:3065-3076.
