Novartis investigational checkpoint inhibitor tislelizumab met primary endpoint of overall survival in pivotal phase III trial of esophageal cancer after systemic therapy.

Results were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. Results from RATIONALE 302 in ESCC showed tislelizumab extended median OS by 2.3 months compared to chemotherapy with a 30% reduction in the risk of death (HR=0.70, 95% CI: 0.57-0.85, p=0.0001).1 In PD-L1 positive patients, tislelizumab extended median OS by 3.5 months with a 46% reduction in the risk of death (HR=0.54, 95% CI: 0.36-0.79, p=0.0006). Treatment with tislelizumab demonstrated median progression-free survival (PFS) of 1.6 months compared to 2.1 months (HR=0.83, 95% CI: 0.67–1.01). Tislelizumab demonstrated a higher and more durable anti-tumor activity than chemotherapy (objective response rate [ORR], 20.3% vs. 9.8%; median duration of response [DoR], 7.1 months vs. 4.0 months). The discontinuation rate due to treatment-related adverse events (TRAEs) was lower in patients who received tislelizumab (6.7%) compared to chemotherapy (13.8%). The most common all-grade TRAEs ( greater than 10%) with tislelizumab were increased aspartate aminotransferase (11.4%), anemia (11%) and hypothyroidism (10.2%). No new safety signals were identified. "Most patients with this type of esophageal cancer are diagnosed with advanced disease, resulting in a poor prognosis for this difficult-to-treat cancer," said Jaffer Ajani, M.D., professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. "The impact tislelizumab had on survival compared to chemotherapy in this study is highly meaningful and encouraging news for patients, caregivers and treating oncologists.” RATIONALE 302 is a randomized, global Phase III study assessing tislelizumab versus chemotherapy in patients with advanced unresectable/metastatic ESCC after prior systemic therapy. The primary endpoint is OS in the intent-to-treat (ITT) population. The key secondary endpoint is OS in PD-L1 positive patients (vCPS greater than 10%). Additional secondary endpoints included PFS, ORR, DoR and safety endpoints. Data on tislelizumab in MSI-H cancers presented; The RATIONALE 209 study reported that tislelizumab showed durable anti-tumor activity in patients with previously treated, locally advanced, unresectable or metastatic microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) cancers, which are known to be more responsive to immune checkpoint modulation. Treatment with tislelizumab demonstrated an ORR of 45.9% among all tumor types, including four complete responses (CR) and 30 partial responses (PR). No disease progression was reported in the 34 responders (CR + PR), with a 12-month DoR rate of 100%). Five percent of patients treated with tislelizumab discontinued treatment due to TRAEs, and no new safety signals were identified. Grade greater than 3 TRAEs occurred in 42.5% of patients. MSI-H cancer cells have a defect in the ability to correct mistakes that occur when DNA is copied, leading to mutations that contribute to cancerous growth. Many types of cancer may have a high level of microsatellite instability, but it is seen most often in CRC, gastric cancer and endometrial cancer. See- Shen L, Kato K, Kim S-B, et al." RATIONALE 302: Randomized, Phase III study of tislelizumab vs chemotherapy as second-line treatment for advanced or metastatic esophageal squamous cell carcinoma ". ePoster presentation at American Society of Clinical Oncology Annual Meeting (ASCO). See-Li J, Xu Y, Zang A, et al." A Phase II study of tislelizumab monotherapy in patients with previously treated, locally advanced unresectable or metastatic microsatellite instability-high/mismatch repair deficient solid tumors"-. ePoster presentation at American Society of Clinical Oncology Annual Meeting (ASCO); June 2021.