Kong, Xuan

381 Background: In RATIONALE-306 (NCT03783442), patients (pts) with LA unresectable or metastatic ESCC who received TIS (intravenously, 200 mg, every 3 weeks) + CT (platinum + fluoropyrimidine or paclitaxel) had longer median overall survival (OS) than pts who received PBO + CT at the interim analysis; improvement was maintained after a ≥3-year follow-up. Post hoc analyses in the PD-L1 TAP ≥1% subgroup showed clinically meaningful improvement with TIS + CT. These data supported the US FDA approval for unresectable or metastatic ESCC. Here we report the subgroup analysis of pts who had LA ESCC with PD-L1 TAP score ≥1%. Methods: Pts who had LA unresectable ESCC with PD-L1 TAP score ≥1% were included in this post hoc analysis. Efficacy outcomes (OS, progression-free survival [PFS], objective response rate [ORR], duration of response [DoR]) and safety were analyzed. Results: At data cutoff (Feb 28, 2022), of 649 pts randomized, 63 had LA ESCC with PD-L1 TAP score ≥1% (TIS + CT n=31; PBO + CT n=32; median age 67.0 years; 85.7% male). At median follow-up (TIS + CT 24.4 months; PBO + CT 24.5 months), efficacy with TIS + CT was improved vs PBO + CT (Table) and was consistent with the intent-to-treat (ITT) population. Efficacy was maintained after a ≥3-year follow-up (data cutoff: Nov 24, 2023; Table). Conclusions: In this post-hoc analysis, the median OS for pts receiving TIS + CT exceeded two years. The regimen was well tolerated. While the findings require validation in future clinical trials, first-line TIS + CT is an encouraging option for pts who have LA unresectable ESCC with PD-L1 TAP score ≥1%. Clinical trial information: NCT03783442 . Interim Analysis 3-Year Follow-up TIS + CT (n=31) PBO + CT (n=32) TIS + CT (n=32) e PBO + CT (n=31) f Median OS, mo(95% CI) 25.6 (15.3, NE) 11.5(9.0, 21.8) 25.6 (15.3, NE) 12.3(9.0, 21.8) HR (95% CI) a 0.36 (0.17, 0.77) – 0.50 (0.26, 0.95) – Median PFS, a mo(95% CI) 13.2(6.8, NE) 6.7(4.2, 9.7) 13.2(6.8, 27.7) 6.7(4.2, 9.7) HR (95% CI) a 0.46 (0.22, 0.96) – 0.47 (0.23, 0.96) – ORR, b,c n (%) 18 (58.1) 10 (31.3) 19 (59.4) 10 (32.3) Median DoR, b,d mo(95% CI) Not reached (8.4, NE) 5.7 (1.5, 9.6) 22.1 (6.1, NE) 5.7 (1.5, 9.6) a Stratified. b Investigator assessed. c Unconfirmed. d Based on unconfirmed ORR. e One patient’s disease status at baseline was changed to LA after interim analysis. f One patient’s disease status at baseline was changed to metastatic after interim analysis. NE, not estimable.

378 Background: RATIONALE-305 (NCT03777657) enrolled the highest number of pts with PM among similar trials and stratified pts with advanced GC/GEJC by presence of PM. We used statistical modeling to evaluate the impact of varying PM levels on outcomes with TIS+CT. Methods: We randomized adults with GC/GEJC (1:1) to TIS or placebo (PBO) + CT. Primary endpoints: OS in intent-to-treat (ITT) population and pts with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥5%. We weighted pts using the method of moments to match a hypothetical population to ITT, with the same distribution of sex, primary tumor location, PD-L1 (TAP score <5% vs ≥5%), number of metastatic sites (0-2 vs 3+), and liver metastasis. PM representation was set from 20% to 45%. Weighted OS, PFS, and objective response rate (ORR) were estimated. Results: Of 997 pts enrolled, 434 (43.5%) had PM. Among pts with PD-L1 TAP scores ≥5% (54.8%), 39.7% had PM, and among pts with scores ≥1% (88.9%), 43.6% had PM (data cutoff Feb 28, 2024). Fewer pts with (+) PM had PD-L1 high tumors (TAP score ≥5%: 50.0%) and more had primary stomach tumors (86.6%) compared to those without (-) PM (58.4% and 75.5%). TIS+CT improved OS, PFS, and ORR in ITT and in pts +/- PM vs PBO+CT (Table). Across 20%–45% PM, TIS+CT showed consistent benefit, with stable HRs for OS and PFS (20% and 45% shown). TIS+CT showed survival benefits in pts with PM and PD-L1 TAP score ≥5% (OS: HR=0.71; PFS: HR=0.65) and ≥1% (OS: HR=0.79; PFS: HR=0.79) vs PBO+CT. ORR was higher with TIS+CT vs PBO+CT in pts + PM and PD-L1 TAP scores ≥5% (47.3% vs 30.8%) and ≥1% (44.2% vs 33.2%). Conclusions: Our analysis showed that lowering PM representation marginally improved OS and ORR, underscoring the poor prognosis of peritoneal disease. In RATIONALE-305, TIS+CT provides clinically meaningful response and survival benefits irrespective of PM, with higher responses in PD-L1+ GC/GEJC. Clinical trial information: NCT03777657 . Arm(95% CI) ITT + PM - PM 20%+ PM 45%+ PM OS, months TIS+CT 15.0 (13.6, 16.5) 12.3 (10.6, 14.3) 17.3 (15.0, 20.3) 15.4 (13.9, 18.0) 15.0 (13.5, 16.5) PBO+CT 12.9 (12.1, 14.1) 11.8 (10.5, 13.0) 14.0 (12.6, 16.0) 13.1 (12.3, 14.5) 12.8 (12.1, 14.1) HR 0.79 (0.69, 0.91) 0.78 (0.64, 0.96) 0.79 (0.65, 0.95) 0.81 (0.69, 0.95) 0.79 (0.69, 0.90) PFS, months TIS+CT 6.9 (5.7, 7.2) 5.8 (5.6, 7.3) 7.0 (5.7, 8.4) 6.9 (5.7, 7.3) 6.9 (5.7, 7.2) PBO+CT 6.2 (5.6, 6.9) 5.7 (5.3, 6.9) 6.9 (5.7, 7.1) 6.5 (5.6, 7.0) 6.2 (5.6, 6.9) HR 0.79 (0.68, 0.91) 0.80 (0.64, 0.98) 0.77 (0.64, 0.94) 0.79 (0.67, 0.94) 0.79 (0.69, 0.91) ORR, % TIS+CT 47.3 (42.9, 51.8) 43.6 (37.0, 50.5) 50.2 (44.2, 56.2) 48.0(42.9, 53.1) 47.3 (42.8, 51.8) PBO+CT 40.5 (36.2, 45.0) 32.2 (26.0, 39.0) 46.8 (40.9, 52.8) 43.1(38.1, 48.3) 40.3(36.0, 44.8) ORR difference, % 6.8 (0.6, 12.9) 11.4 (2.3, 20.3) 3.4 (-4.9, 11.6) 4.9 (-2.2, 11.9) 6.9 (0.8, 13.0)