Abstract
Objective:The open-label,phase Ⅱ RATIONALE-209 study evaluated tislelizumab(anti-programmed cell death protein 1 antibody)as a tissue-agnostic monotherapy for microsatellite instability-high(MSI-H)/mismatch repair-deficient(dMMR)tumors.Methods:Adults with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR solid tumors were enrolled.Patients received tislelizumab 200 mg intravenously every 3 weeks.Objective response rate(ORR;primary endpoint),duration of response(DoR),and progression-free survival(PFS)were assessed by independent review committee(Response Evaluation Criteria in Solid Tumors v1.1).Results:Eighty patients were enrolled and treated;75(93.8％)patients had measurable disease at baseline.Most had metastatic disease and received at least one prior therapy for advanced/metastatic disease(n=79;98.8％).At primary analysis(data cutoff July 8,2021;median follow-up 15.2 months),overall ORR[46.7％;95％confidence interval(95％CI),35.1-58.6;one-sided P＜0.0001]and ORR across tumor-specific subgroups[colorectal(n=46):39.1％(95％CI,25.1-54.6);gastric/gastroesophageal junction(n=9):55.6％(95％CI,21.2-86.3);others(n=20):60.0％(95％CI,36.1-80.9)]were significantly greater with tislelizumab vs.a prespecified historical control ORR of 10％;five(6.7％)patients had complete responses.Median DoR,PFS,and overall survival were not reached with long-term follow-up(data cutoff December 5,2022;median follow-up 28.9 months).Tislelizumab was well tolerated with no unexpected safety signals.Treatment-related adverse events(TRAEs)of grade＞3 occurred in 53.8％of patients;7.5％of patients discontinued treatment due to TRAEs.Conclusions:Tislelizumab demonstrated a significant ORR improvement in patients with previously treated,locally advanced unresectable or metastatic MSI-H/dMMR tumors and was generally well tolerated.
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