Tislelizumab plus chemotherapy for advanced or metastatic esophageal squamous-cell carcinoma in patients with PD-L1 Tumor Area Positivity score ≥5%: a post hoc, exploratory, long-term follow-up of RATIONALE-306☆.

BACKGROUND: In the randomized, double-blind, phase III RATIONALE-306 trial, patients with unresectable, locally advanced, recurrent, or metastatic esophageal squamous-cell carcinoma (ESCC) treated with tislelizumab plus chemotherapy in the intent-to-treat population and in the programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5% subgroup experienced clinically meaningful overall survival (OS) benefit compared with placebo plus chemotherapy at the interim analysis and minimum 3-year follow-up. We report post hoc, exploratory, longer-term outcomes at study closeout with minimum 45.2-month follow-up in patients with PD-L1 TAP score ≥5% per European Medicines Agency recommendation. PATIENTS AND METHODS: Patients were randomly assigned (1 : 1) to receive tislelizumab 200 mg or placebo every 3 weeks plus investigator-chosen chemotherapy. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), safety, and quality of life (QoL). RESULTS: Of 649 randomly allocated patients, 55.2% had PD-L1 TAP score ≥5% (tislelizumab plus chemotherapy, n = 172; placebo plus chemotherapy, n = 186). At 45.2-month minimum follow-up, tislelizumab plus chemotherapy improved OS [median 19.1 versus 10.0 months; hazard ratio (HR) 0.61] and PFS (median 8.2 versus 5.5 months; HR 0.50) compared with placebo plus chemotherapy. ORR was 71.5% versus 41.4%; median DoR was 7.1 versus 5.4 months, respectively. QoL was similar overall between arms, with tislelizumab plus chemotherapy trending toward better global health and pain reduction. Any-grade treatment-related adverse events (TRAEs) occurred in 97.7% (tislelizumab plus chemotherapy) versus 98.4% (placebo plus chemotherapy) and grade ≥3 TRAEs in 70.2% versus 66.5%, respectively. The most common grade ≥3 TRAEs were decreased neutrophil count (35.1% versus 31.9%), anemia (13.5% versus 11.4%), and decreased white blood cell count (12.3% versus 17.8%). Treatment-emergent adverse events with ≥5% difference in incidence between arms at interim analysis decreased substantially after 12 months. CONCLUSION: First-line tislelizumab plus chemotherapy provided sustained and clinically meaningful efficacy benefits over placebo plus chemotherapy and was tolerable, with no new safety signals for patients with unresectable, locally advanced, or metastatic ESCC and PD-L1 TAP score ≥5%.