Raymond, Eric

4032 Background: RATIONALE-306 (NCT03783442) is the first global study to investigate anti-programmed cell death protein 1 therapy in combination with different chemotherapy (chemo) options in the first-line (1L) treatment of advanced/metastatic esophageal squamous cell carcinoma (ESCC). At interim analysis (IA), tislelizumab (TIS) plus chemo demonstrated a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo (PBO) plus chemo, with a manageable safety profile. Here, we report updated efficacy and safety data with minimum 3 years’ follow-up after study unblinding at IA. Methods: Adults with unresectable locally advanced recurrent/metastatic ESCC and no prior systemic treatment for advanced disease were enrolled and randomized (1:1; stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg (Arm A) or PBO (Arm B) IV every 3 weeks plus chemo (platinum plus fluoropyrimidine or platinum plus paclitaxel), until disease progression or intolerable toxicity. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all per INV, and safety. Results: In total, 649 patients (pts) were randomized (Arm A, n=326; Arm B, n=323). At a minimum study follow-up of 36.0 months, improvements in OS, PFS, and DoR in Arm A versus B (Table) were maintained relative to the IA. The hazard ratio (HR) for OS with TIS plus chemo versus PBO plus chemo was 0.70 (95% confidence interval: 0.59, 0.83). Similar to the IA, incidences of any-grade (96.6% vs 96.3%) or grade ≥3 (67.0% vs 64.5%) treatment-related adverse events (TRAEs) were comparable between Arms A and B, respectively; treatment-emergent adverse events leading to treatment discontinuation were higher in Arm A (32.1%) versus B (22.1%). In Arm A versus B, respectively, serious TRAEs occurred in 29.9% vs 19.6% of pts; TRAEs leading to death occurred in 1.9% and 1.2%. Conclusions: After minimum 3 years’ follow-up, 1L TIS plus chemo continued to demonstrate clinically meaningful improvements in OS and PFS and durable antitumor response benefit versus PBO plus chemo in pts with advanced/metastatic ESCC, with no new safety signals. Clinical trial information: NCT03783442 . [Table: see text]

340 Background: TIS, an anti-programmed cell death protein 1 (PD-1) antibody, + chemo as 1L therapy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) vs PBO + chemo in patients with advanced or metastatic ESCC (hazard ratio [HR] 0.66 [95% confidence interval (CI) 0.54, 0.80]; P< 0.0001), with a manageable safety profile, at interim analysis of the phase 3, double-blind RATIONALE-306 study (NCT03783442). Here, we report data from the non-Asia subgroup (Europe, Northern America, and Oceania). Methods: Adults with advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were randomized 1:1, (stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg intravenously (IV) once every 3 weeks (Q3W) (Arm A) or PBO IV Q3W (Arm B), with platinum + fluoropyrimidine, or platinum + paclitaxel until disease progression by INV per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included: progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) by INV per RECIST v1.1; OS in the programmed death-ligand 1 score ≥10%; and safety. Results: Of 649 randomized patients, 163 (25.1%) were from the non-Asia subgroup (Arm A, n = 83; Arm B, n = 80). At data cutoff (Feb 28, 2022), the median study follow-up time in the non-Asia subgroup was 16.0 months (mo) in Arm A vs 8.4 mo in Arm B. OS (median 16.3 vs 9.0 mo; unstratified HR 0.66 [95% CI 0.45, 0.96]) and PFS (median 7.7 vs 5.5 mo; unstratified HR 0.59 [95% CI 0.41, 0.83]) were improved in Arm A vs Arm B, respectively. Arm A had higher ORR (61.4% vs 41.3%, odds ratio 2.27 [95% CI 1.21, 4.25]) and longer median DoR (7.1 mo [95% CI 5.6, 9.6] vs 5.7 mo [95% CI 3.8, 8.3]) than Arm B. More patients in Arm A vs Arm B experienced ≥1 treatment-related adverse event (TRAE; 94.0% vs 88.5%), serious TRAEs (25.3% vs 17.9%), and discontinuation due to treatment-emergent AEs (42.2% vs 35.9%, respectively). Similar proportions of patients in Arm A vs Arm B had ≥grade 3 TRAEs (56.6% vs 52.6%), and TRAEs leading to death (1.2% vs 1.3%), respectively. Conclusions: In the non-Asia subgroup, 1L TIS + chemo showed a clinically meaningful improvement in OS vs PBO + chemo in patients with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Clinical trial information: NCT03783442 .