Nivolumab plus chemotherapy or ipilimumab versus chemotherapy in patients with advanced esophageal squamous cell carcinoma (CheckMate 648): 29‐month follow‐up from a randomized, open‐label, phase III trial

4035 Background: NIVO + chemo and NIVO + IPI demonstrated significant overall survival (OS) benefit vs chemo in previously untreated patients (pts) with advanced ESCC in the phase 3 CheckMate 648 study. We report expanded results from the primary analysis with 13-month (mo) minimum follow-up. Methods: Pts with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR) in pts with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Secondary endpoints planned for hierarchical testing included OS, PFS, and objective response rate (ORR) per BICR in all randomized pts. Duration of response (DOR) per BICR and PFS2 per investigator (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) were exploratory endpoints. Results: Among all pts randomized to NIVO + chemo (n = 321), NIVO + IPI (n = 325), or chemo (n = 324), PFS2 favored NIVO + chemo (HR 0.64, 95% CI 0.54–0.77) and NIVO + IPI (HR 0.74, 95% CI 0.62–0.88) vs chemo. ORR (95% CI) was 47% (42–53), 28% (23–33), and 27% (22–32), respectively. More responders with NIVO + chemo or NIVO + IPI vs chemo had prolonged DOR (≥12 mo; 39%, 48%, and 23%, respectively). Efficacy data by tumor cell PD-L1 and PD-L1 combined positive score will be presented. Grade 3/4 treatment-related adverse events with potential immunologic etiology (select TRAEs) occurred in ≤ 6% of pts with NIVO + chemo and NIVO + IPI, and non-endocrine select TRAEs resolved in 57%–95% of pts across organ categories (Table). Conclusions: NIVO + chemo and NIVO + IPI demonstrated favorable PFS2 and a higher proportion of pts with prolonged DOR vs chemo, as well as acceptable safety profiles. These results provide further support for each regimen as a new potential 1L standard of care in advanced ESCC. Clinical trial information: NCT03143153. [Table: see text]

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

LBA4001 Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46–0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1–27.4), and 5.7 (4.4–8.7) mo and for all randomized pts: 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153. [Table: see text]

4034 Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

TPS370 Background: The programmed death-1 (PD-1)/PD-L1 pathway plays an important role in tumor induced immunosuppression. PD-L1 overexpression is observed in approximately 30–60% of esophageal cancers and is associated with poor prognosis. Anti-PD-1 agents demonstrate moderate efficacy in PD-L1-positive esophageal cancer in terms of response rate and overall survival, however, long-term outcomes remain poor due to primary and secondary resistance driven by tumor immune escape. The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-203 is a Phase 2, global, randomized, double-blind, placebo-controlled study (NCT04732494) of patients with unresectable, locally advanced, recurrent or metastatic ESCC, who progressed on or after 1st line systemic therapy and whose tumors express PD-L1 (visually-estimated combined positive score ≥ 10%). After stratification by Eastern Cooperative Oncology Group performance status (0 or 1), number of metastatic sites (≤ 1 or ≥ 2) and region (Asian or non-Asian), 280 patients will be randomized (1:1) to either ociperlimab 900 mg intravenous (IV) plus tislelizumab 200 mg IV every 3 weeks (Q3W), or tislelizumab plus placebo Q3W, until disease progression (per RECIST v1.1), unacceptable toxicity, death or withdrawal of consent. Co-primary endpoints are investigator-assessed overall response rate (ORR) and overall survival (OS) in the intention-to-treat population. A sample size of 280 patients was estimated to provide approximately 94.8% power to detect a 20% difference in ORR at a one-sided significance level of 0.025. With 198 deaths, the study was estimated to provide approximately 86% power to detect a hazard ratio of 0.65 for OS. Secondary endpoints are ORR by independent review, progression-free survival, duration of response, disease control rate, and clinical benefit rate per investigator and independent assessment, cancer-specific health-related quality of life (HRQoL), and safety. Exploratory endpoints include but are not limited to expression of TIGIT, CD226, CD155, CD112, and PD-L1, pharmacokinetics, immunogenicity, and generic HRQoL measures. Clinical trial information: NCT04732494.

TPS255 Background: ESCC is the predominant histological subtype of esophageal cancer, particularly in Asian countries. Platinum-based chemotherapy is the first-line standard therapy for patients with unresectable, locally advanced, recurrent or metastatic ESCC. The FP regimen is recommended as the preferred treatment by guidelines. However, the survival benefit conferred by this therapy leaves considerable space for improvement, with median OS being less than 1 year. Blockade of the immune checkpoint receptors has shown clinical benefits in multiple tumor types. Recent studies combining standard treatments with checkpoint inhibitors have shown encouraging efficacy and favorable safety profile in patients with unresectable, locally advanced, recurrent or metastatic ESCC. CS1001 (sugemalimab) is the first full-length, fully human immunoglobin G4 (IgG4, s228p) anti-programmed death-ligand 1 (PD-L1) monoclonal antibody developed by the OMT transgenic rat platform. In an ongoing Phase Ib trial, CS1001 in combination with FP regimen demonstrated an ORR of 67.6% (25/37) and an mPFS of 9.0 months with a manageable safety profile in unresectable, locally advanced or distantly metastatic ESCC (19 Feb 2020 data cutoff; Shen, L., et al, ESMO 2020). Methods: CS1001-304 is a randomized, double-blind Phase III study to compare the efficacy and safety of FP regimen with CS1001 or placebo as first-line treatment in ESCC. The study enrolls patients with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1, patients are not eligible for curative therapy (curative surgery or definitive chemoradiotherapy), and have not received any prior systemic anti-tumor therapy for locally advanced or metastatic disease. Approximately 540 patients will be randomized at 2:1 into CS1001 + FP and placebo + FP arms respectively, stratified by PD-L1 expression status (PD-L1 expression < 1% vs ≥ 1% and < 10% vs ≥10%), ECOG PS (0 vs 1) and distant metastasis (no vs yes). Patients randomized to either arm will receive FP regimen (fluorouracil: 800 mg/m2/day, continuous intravenous infusion [IV], D1-4 of each cycle; cisplatin: 80 mg/m2, IV, D1 of each cycle), Q3W for up to 6 cycles in combination with CS1001 1200 mg or placebo (IV, D1 of each cycle), Q3W for up to 24 months. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Tumor response will be assessed by RECIST v1.1 every 6 weeks in the first 12 months, and every 12 weeks thereafter. The primary endpoints are blinded independent central review (BICR)-assessed PFS and OS. Secondary endpoints include investigator-assessed PFS, BICR and investigator-assessed ORR and DoR, safety, PK profile, and immunogenicity. The study is actively enrolling patients in over 60 sites in China. Clinical trial information: NCT04187352.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study

BackgroundThe published evidence from several randomized controlled clinical trials of immunotherapy for advanced esophageal squamous cell carcinoma has shown promising results. This study aimed to investigate the efficacy and safety of immune checkpoint inhibitor treatment in esophageal squamous cell carcinoma.MethodsPubMed, Web of Science, Cochrane Library, and Embase databases were searched for relevant articles published before December 30, 2020. The data for efficacy and safety of immune checkpoint inhibitor treatment were subjected to meta-analysis.ResultsSeven clinical trials comprising 1733 patients were included. The results showed that immune checkpoint inhibitor treatment as second- or later-line treatment was associated with an increased risk of the objective response rate (relative risk: 1.82, 95% confidence interval: 0.82–4.04; P=0.002) and median overall survival (hazard ratio: 0.75, 95% confidence interval: 0.67–0.85; P<0.001) compared with chemotherapy in locally advanced or metastatic esophageal squamous cell carcinoma. Moreover, immune checkpoint inhibitor treatment was associated with significant improvement in median overall survival (hazard ratio: 0.61, 95% confidence interval: 0.48–0.77, P<0.001) compared with chemotherapy in the programmed death-ligand 1 (PD-L1)-positive population. However, immune checkpoint inhibitor treatment was also effective in all patients independent of PD-L1 expression. The most common grade ≥3 treatment-related adverse events with immune checkpoint inhibitor therapy were anemia, asthenia, rash, fatigue, decreased appetite, diarrhea, pneumonia, decreased neutrophil count, and vomiting. Patients undergoing immune checkpoint inhibitor therapy was associated with a decreased risk of treatment-related adverse events (relative risk: 0.82, 95% confidence interval: 0.62–1.08; P<0.001) and grade ≥3 treatment-related adverse events (relative risk: 0.50, 95% confidence interval: 0.42–0.60; P<0.001) compared with those undergoing chemotherapy.ConclusionsImmune checkpoint inhibitors as second- or later-line therapy may improve overall response rate and overall survival but not all oncological outcomes for patients with locally advanced or metastatic esophageal squamous cell carcinoma. Patients treated with immune checkpoint inhibitors might experience fewer treatment-related adverse events of any grade, but specifically grade ≥3, compared with those treated with chemotherapy.

TPS4150 Background: The programmed death-1 (PD-1)/PD-L1 pathway plays an important role in tumor induced immunosuppression. PD-L1 overexpression is observed in approximately 30–60% of esophageal cancers and is associated with poor prognosis. Anti-PD-1 agents demonstrate moderate efficacy in PD-L1-positive esophageal cancer in terms of response rate and overall survival, however, long-term outcomes remain poor due to primary and secondary resistance driven by tumor immune escape. The T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is upregulated on T-cells and natural killer cells in multiple solid tumors, which can inhibit anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-203 is a phase 2, global, randomized, double-blind, placebo-controlled study (NCT04732494) of patients with unresectable, locally advanced, recurrent or metastatic ESCC, who progressed on or after 1st line systemic therapy and whose tumors express PD-L1 (visually estimated combined positive score ≥10%). After stratification by Eastern Cooperative Oncology Group performance status (0 or 1), number of metastatic sites (≤1 or ≥2) and region (Asian or non-Asian), 280 patients will be randomized (1:1) to either ociperlimab 900 mg intravenous (IV) plus tislelizumab 200 mg IV every 3 weeks (Q3W), or tislelizumab plus placebo Q3W, until disease progression (per RECIST v1.1), unacceptable toxicity, death or withdrawal of consent. Co-primary endpoints are investigator-assessed overall response rate (ORR) and overall survival (OS) in the intention-to-treat population. A sample size of 280 patients was estimated to provide approximately 94.8% power to detect a 20% difference in ORR at a one-sided significance level of 0.025. With 198 deaths, the study was estimated to provide approximately 86% power to detect a hazard ratio of 0.65 for OS. Secondary endpoints are ORR by independent review, progression-free survival, duration of response, disease control rate, and clinical benefit rate per investigator and independent assessment, cancer-specific health-related quality of life (HRQoL), and safety. Exploratory endpoints include but are not limited to expression of TIGIT, CD226, CD155, CD112, and PD-L1, pharmacokinetics, immunogenicity, and generic HRQoL measures. Clinical trial information: NCT04732494.

Patients with advanced esophageal squamous cell carcinoma (SCC) have a poor prognosis when treated with standard chemotherapy. Programmed death ligand 1 (PD-L1) expression in esophageal cancer has been associated with poor survival and more advanced stage. Immune checkpoint inhibitors, such as PD-1 inhibitors, showed benefits in advanced esophageal cancer in clinical trials. We analyzed the prognosis of patients with unresectable esophageal SCC who received nivolumab with chemotherapy, dual immunotherapy (nivolumab and ipilimumab), or chemotherapy with or without radiotherapy. Patients who received nivolumab with chemotherapy had a better overall response rate (ORR) (72% vs. 66.67%, p = 0.038) and longer overall survival (OS) (median OS: 609 days vs. 392 days, p = 0.04) than those who received chemotherapy with or without radiotherapy. In patients receiving nivolumab with chemotherapy, the duration of the treatment response was similar regardless of the treatment line they received. According to clinical parameters, liver and distant lymph nodes metastasis showed a trend of negative and positive impacts, respectively, on treatment response in the whole cohort and in the immunotherapy-containing regimen cohort. Nivolumab add-on treatment showed less gastrointestinal and hematological adverse effects, compare with chemotherapy. Here, we showed that nivolumab combined with chemotherapy is a better choice for patients with unresectable esophageal SCC.

363 Background: Platinum-based chemotherapy is the standard first-line treatment for advanced or metastatic ESCC. Recently, the combination of PD-(L)1 pathway blockade with chemotherapy has shown synergistic efficacy in a few clinical trials. SHR-1701 is a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II. The purpose of this ongoing phase II trial (ChiCTR2000039909) was to evaluate the efficacy and safety of SHR-1701 combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled systemic treatment-naive patients(pts) with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who had ECOG PS of 0-1. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) combined with up to 6 cycles of albumin-bound paclitaxel (125mg/m2, iv, d1, d8, q3w) and cisplatin (75mg/m2, iv, d1, q3w). For those without progressive disease, maintenance treatment was administrated with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), safety and biomarkers. Results: As of September 21, 2022, 18 pts were enrolled. The median age was 67.5 years (range: 46–75 years) and 16 (88.9%) were male. 10 of the pts (55.6%) presented with distant metastasis. 14 pts were included in the efficacy analysis and 17 were in the safety analysis. The ORR and DCR were 85.7% and 100.0%, respectively. One patient achieved a complete response (CR) which will reach confirmation at next visit. 11 pts had partial response (PR), including 9 confirmed PR, one pending confirmation PR, and one unconfirmed PR. In addition, one PR patient got a CR target lesion. Grade 3-4 treatment-related adverse events (AEs) were observed in 23.5% of pts, including neutropenia (11.8%), leukopenia (5.9%), anemia (5.9%), emesis (5.9%) and rash (5.9%). Immune-related AEs (irAEs) were observed in 52.9%, and only one grade 3 irAE of rash occurred. Conclusions: SHR-1701 plus chemotherapy showed potential clinical benefits with acceptable toxicity as first-line treatment, and it might be a favorable option for pts with advanced ESCC. Clinical trial information: ChiCTR2000039909 .

BackgroundCadonilimab, a bispecific antibody simultaneously targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4, may further boost antitumor activity compared with PD-1 or programmed cell death ligand 1 (PD-L1) inhibitors. Here, we evaluated the safety and efficacy of cadonilimab combined with chemotherapy as the first-line treatment in advanced esophageal squamous cell carcinoma (ESCC).MethodsTreatment-naïve patients with unresectable locally advanced or metastatic ESCC were eligible. Cadonilimab combined with paclitaxel or nab-paclitaxel and cisplatin was administrated for up to six cycles, then cadonilimab monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for DNA methylation level sequencing.ResultsAs of September 27, 2024, 43 patients were enrolled with a median age of 61 years (range 44–75), 39.5% had PD-L1 combined positive score ≥10 and 95.3% had distant metastases. The ORR was 81.4% (95% CI 66.6% to 91.6%) and DCR was 97.7% (95% CI 86.2% to 99.9%). The median PFS was 7.10 months (95% CI 5.68 to 8.48) while OS remained immature. The mean pretreatment cytosine-phosphate-guanine (CpG) site methylation levels of APBA2, EPAS1, TRIM58, ITPKA and LINC00554 were significantly higher in responders than those in non-responders. Grade 3–4 treatment-related adverse events were reported in 53.5% (23/43) patients.ConclusionsCadonilimab combined with taxane and cisplatin as first-line treatment revealed encouraging antitumor activity and manageable safety in patients with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes.Trial registration numberNCT05522894.

Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, + chemotherapy (chemo) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo + chemo, with a manageable safety profile, as a first line (1L) treatment for patients (pts) with advanced or metastatic esophageal squamous cell carcinoma (ESCC) at interim analysis of the phase 3 RATIONALE-306 study. We report data from the China subgroup analysis. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Pts were randomized (1:1); stratified by region, prior definitive therapy, and investigator-chosen chemo (platinum + fluoropyrimidine or platinum + paclitaxel). Pts received tislelizumab (T) 200 mg intravenously + chemo (C) (Arm T+C) or placebo (P) + chemo (Arm P+C) once every three weeks; treatment continued until disease progression by investigator per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included investigator-assessed progression-free survival (PFS) per RECIST v1.1, objective response rate (ORR), and duration of response (DoR), in addition to safety. Results: Of 649 pts in the overall population, 370 (57.0%) were enrolled from China. At data cutoff (Feb 28, 2022), the median study follow-up in the China subgroup (ITT population) was 15.8 months (mo) in Arm T+C (n=182) and 10.6 mo in Arm P+C (n=188). Longer OS (median OS 16.6 mo vs 11.2 mo; unstratified hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54, 0.89) and PFS (median PFS 8.3 mo vs 5.6 mo; unstratified HR 0.58, 95% CI 0.45, 0.75) indicate survival benefit in Arm T+C vs P+C, respectively. Arm T+C had higher response rates and more durable responses than Arm P+C; ORR was 64.8% vs 44.1% (odds ratio 2.33 [95% CI 1.53, 3.55]) respectively, and median DoR was 7.4 mo (95% CI 5.6, 9.5) vs 5.7 mo (95% CI 4.3, 7.5), respectively. Similar proportions of pts in Arm T+C vs P+C had ≥1 treatment-related adverse event (TRAE; 98.8% vs 98.9%) and ≥grade 3 TRAEs (72.9% vs 73.4%). Serious TRAEs occurred in 27.6% vs 21.2% of pts in Arm T+C vs P+C, and TRAEs leading to death occurred in 2.9% vs 1.6% of pts, respectively. Treatment-emergent adverse events leading to discontinuation occurred in 28.2% vs 17.4%, in Arm T+C vs P+C. Conclusions: In the China subgroup, 1L tislelizumab + chemo demonstrated clinically meaningful improvement in OS, PFS, ORR, and DoR vs placebo + chemo in pts with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Emma Ashman, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Citation Format: Yongqian Shu, Yueyin Pan, Ping Lu, Yi Jiang, Jingdong Zhang, Xiaohong Wu, Yuanhu Yao, Lin Shen, Yi Ba, Zhiyong He, Yuxian Bai, Jianhua Chen, Guohua Yu, Yanyan Peng, Hongqian Wu, Lei Wang, Liyun Li, Jianming Xu. Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT076.

4062 Background: The prognosis of pts with advanced esophageal squamous cell carcinoma (ESCC) remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. Recently, the combination of PD-1/PD-L1 pathway blockades with chemotherapy has shown synergistic efficacy in a few clinical trials. KN046 is the world's first dual immune checkpoint inhibitor, which can block PD-1/PD-L1 and CTLA-4 pathways at the same time. The purpose of this ongoing phase II trial (NCT03925870) in China was to evaluate the efficacy and safety of KN046 monotherapy or combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC. Methods: This trial included 3 cohorts, one of which enrolled systemic treatment naïve pts with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1. Eligible subjects were given paclitaxel (135-175mg/m2, iv, d1, q3w) and cisplatin (75mg/m2, iv, d2-4, q3w) plus KN046 (5mpk, iv, d1, q3w) for 4̃6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with KN046 monotherapy (5mpk, iv, q2w) until progression or unacceptable toxicity. Tumour response was assessed according to RECIST 1.1 every 6 weeks. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DCR, safety, PK profile, and immunogenicity. Results: As of December 14, 2020, 15 pts were enrolled, all of them were male, 52.3% ≥60 years, 64% ECOG 1, 80% with distant metastasis. Median exposure time to KN046 was 11.4 wks and average KN046 treatment was 2.4 cycles. 12 pts were included in the efficacy analysis and 15 pts in the safety analysis. The overall response rate (ORR) and disease control rate (DCR) were 58.3% and 91.6%, respectively. 7 pts (58.3%) had partial response (PR) including one complete response of target lesion. 4 pts (33.3%) had stable disease (SD) with 3 pts showing more than 20% of tumor burden reduction. The overall incidence of KN046 related adverse events was 80.0%, with 13.3% Gr 3 or above TRAE. Infusion-related adverse events occurred during 7.8% and most were mild. Immune related adverse events（irAE）were seen in 53.3% and the most common Gr 3 irAE were nausea (n＝1, 6.7%) and rash (n＝1, 6.7%). Conclusions: KN046 plus paclitaxel/cisplatin demonstrated clinical efficacy and acceptable safety as first-line treatment, and might be a favorable option for pts with advanced ESCC. Clinical trial information: NCT03925870. Research Sponsor: Jiangsu Alphamab Biopharmaceuticals Co., Ltd. Clinical trial information: NCT03925870.