SHR-1701 plus chemotherapy as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC).

411 Background: Recently, several clinical trials have demonstrated synergistic efficacy by combining immune checkpoint inhibitors (ICIs) with chemotherapy. However, only a subset of patients (pts) derived benefits. Combining ICIs with agents blocking immunosuppressive pathway may expand the clinical benefit of ICIs to more pts. Transforming growth factor β (TGF-β) participates in tumor immune escape. SHR-1701, a novel bifunctional fusion protein consisting of a monoclonal antibody targeting PD-L1 fused with the extracellular domain of TGF-β receptor II, was evaluated in a phase II trial (ChiCTR2000039909) to assess its efficacy and safety when combined with chemotherapy for pts with unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled treatment-naive pts with histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic ESCC. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) in combination with up to six cycles of albumin-bound paclitaxel (125mg/m 2 , iv, d1, d8, q3w) and cisplatin (75mg/m 2 , iv, d1, q3w). For those without progressive disease, maintenance treatment was administered 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) and safety. Results: At the data cut-off, March 1, 2024, 24 pts had received at least one dose of the study treatment and were included in both the intention-to-treat (ITT) analysis and safety analysis sets. 3 and 12 pts achieved confirmed complete and partial responses, respectively. The confirmed ORR was 62.5% and DCR was 87.5%. With a median follow-up of 20.8 months (95% CI, 15.5-NR), the median duration of response was 9.1 months (95% CI, 6.9-NR). The median PFS was 10.8 months (95% CI, 7.8-NR) and the median OS was 26.1 months (95% CI, 8.6-NR). 12-month PFS and OS rates were 41.4% (95% CI, 22.5-76) and 64.8% (95% CI, 47.8-87.9), respectively. Grade 3-4 treatment-related adverse events occurred in 11 (45.8%) pts and no treatment-related death was observed. Conclusions: The results highlighted that SHR-1701 plus chemotherapy as first-line therapy maintained long-term, durable survival benefit in pts with advanced ESCC. Clinical trial information: ChiCTR2000039909.

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.

e16064 Background: Immune checkpoint inhibitors combined with chemotherapy has become the current first-line standard treatment for advanced ESCC, while still having a lot of room for improvements in objective responses and survival. Cadonilimab, a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumour activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of Cadonilimab combination therapy as the first-line treatment in advanced ESCC. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were eligible for inclusion. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m2, iv, d1, q3w) and cisplatin (65 to 75 mg/m2, iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) 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. Results: At updated analysis (cut-off: February 5, 2024), 35 pts were enrolled with a median age of 61 years (range 44-75), 82.9% were male, 57.1% had PD-L1 CPS<10 and 88.6% had distant metastases. In the efficacy-evaluable population (n = 29), 5 pts reached complete response (CR), 21 pts had partial response (PR) and 3 pts had stable disease (SD). The ORR was 89.7% (95%Cl: 71.5%-97.3%) and the DCR was 100.0% (95%Cl: 85.4%-100.0%). Among evaluable pts with PD-L1 CPS≥10 and PD-L1 CPS<10, the ORR were 100.0% (12/12) and 81.3% (13/16), respectively. SEPT9 methylation was significantly higher in patients with CR or PR compared to patients with SD (33.28% vs 3.87%, p < 0.001). The median PFS and OS was still not reached. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 9 (25.7%) pts. The most common TRAEs were neutropenia (17.1%), leukopenia (5.7%) and hyponatremia (5.7%). Immune-related adverse events were observed in 9 pts (25.7%). Three pts (8.6%) suffered from serious adverse events, and no grade 5 TRAEs or death were observed. Conclusions: The updated results suggested that bispecific antibody AK104 combined with taxane and cisplatin as first-line treatment showed promising anti-tumor activity and manageable safety in patients with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Follow-up is ongoing for survival analysis. Clinical trial information: NCT05522894 .

215 Background: Esophageal squamous cell carcinoma (ESCC) is a lethal cancer with a high unmet medical need. Camrelizumab, an anti-PD-1 monoclonal antibody, significantly improved overall survival (OS) and objective response rate (ORR) in Chinese patients (pts) with advanced ESCC compared with chemotherapy, with a manageable safety profile in phase III randomized trial (ESCORT). However, the absolute long-term survival benefiting from PD-1 inhibitors is limited, and new effective treatments are needed. Here, our study aimed to assess the efficacy and safety of combination with camrelizumab and apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC. Methods: This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg intravenous camrelizumab every two weeks plus 250 mg oral apatinib daily in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results: At data cutoff (Sept 11, 2020), 36 pts were enrolled, 7 females and 29 males, and 25 pts had lymph node metastases. Twelve pts received radiotherapy and 25 underwent surgery. Twenty-five pts were included in the efficacy analysis with median follow-up time of 5.0 months and 36 pts in the safety analysis with median follow-up time of 4.6 months. The primary endpoint ORR without confirmation was 40 % with complete response in two pts (8%) and partial response in eight pts (32%). Thirteen pts (52%) had stable disease, and the DCR was 92%. The median PFS and OS were not reached. A total of 72.2% of pts had AEs, and 30.6% of pts experienced grade 3 AEs. The most common AEs (all grade, grade≥3) were elevated aspartate aminotransferase (30.6%, 19.4%), elevated alanine aminotransferase (30.6%, 13.9%), hypertension (25%, 2.8%),neutrophil (25%, 5.6%), thrombocytopenia (25%, 0%), leukopenia (22.2%, 2.8%), anemia (11.1%, 0%), proteinuria (11.1%, 0%), hematochezia (8.3%, 0%), reactive cutaneous capillary endothelial proliferation (5.6%, 2.8%), pruritus (5.6%, 0%), esophageal fistula (5.6%, 0%), fatigue (2.8%, 0%) and hypothyroidism (2.8%, 0%). Conclusions: This is the first study to explore the combination of PD-1 inhibitor and anti-angiogenesis inhibitor as a second-line treatment for advanced ESCC. Camrelizumab plus apatinib demonstrated encouraging clinical efficacy and acceptable safety as second-line treatment, and might be a favorable option for pts with advanced ESCC. Further phase III randomized trials are warranted. Clinical trial information: NCT03736863.

181 Background: The prognosis of pts with advanced ESCC remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. As a novel multitarget tyrosine kinase inhibitor mainly targeting antiangiogenic single pathway, anlotinib was demonstrated to be an effective second-line monotherapy for pts with advanced or recurrent ESCC in China. Consequently, the aim of this study was to investigate the efficacy and toxicity of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible subjects were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60~75mg/m2, iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with anlotinib monotherapy (10mg, po, d1~14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans every two cycles. And the calculated sample size of this study was 47. The primary endpoint was PFS, secondary endpoints were safety, objective response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: From Oct 2019 to Aug 2020, 27 pts were available for efficacy and safety evaluation. In best overall response assessment, there were 7.4% CR (2/27), 66.7% PR (18/27) and 25.9% SD (7/27). ORR was 74.1% (95%CI: 53.7. ~ 88.9), and DCR was 100.0% (95%CI: 87.2~100.0). The median PFS of the 27 pts was not yet available. The safety profile indicated that the most common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia and hepatotoxicity. The common grade 3-4 treatment-related adverse events were myelosuppression (18.5%), hypertension (7.4%). Conclusions: The current results indicated that paclitaxel and cisplatin combined with anlotinib as first line therapy for advanced ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04063683. [Table: see text]

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

ObjectiveThis study was to investigate the feasibility and safety of anlotinib monotherapy for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) retrospectively.MethodsThis study was designed as a real-world study. A total of 83 patients with advanced or metastatic ESCC who received anlotinib monotherapy were included. Demographic characteristics of the patients, efficacy data of the treatment and adverse reactions during the treatment were documented and analyzed through the electronic medical record system in the hospital. All the patients were followed up regularly. The primary endpoint of this study was progression-free survival (PFS), secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety profile and PFS analysis according to adverse reactions.ResultsA total of 83 patients with ESCC who received anlotinib monotherapy were included. Partial response was observed in 7 patients, stable disease was noted in 51 patients and progressive disease was found in 25 patients, which yielded an ORR of 8.4% (95% CI: 3.5–16.6%), and a DCR of 69.9% (95% CI: 58.8–79.5%). Furthermore, the median PFS of the 83 patients with advanced ESCC was 3.3 months (95% CI: 2.20–4.40) and the median OS was 7.8 months (95% CI: 5.40–10.20). Common adverse reactions among the 83 patients were hypertension (51.8%), fatigue (48.2%), weight loss (41.0%), diarrhea (34.9) and hand-foot syndrome (30.1%). Correlation analysis between hypertension status and PFS suggested that PFS of the patients with hypertension was longer than that of those with non-hypertension (median PFS: 4.5 vs 3.0 months, P = 0.019).ConclusionAnlotinib monotherapy demonstrated promising efficacy and tolerable toxicity for patients with previously treated advanced or metastatic ESCC. Hypertension that occurs during anlotinib administration might be used as a potential biomarker to predict PFS of patients with ESCC. The conclusion should be confirmed in prospective clinical trials subsequently.

463 Background: Immune checkpoint inhibitors combined with chemotherapy had become the first-line standard treatment for advanced ESCC and cadonilimab, as a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumor activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of cadonilimab combination therapy as the first-line treatment in advanced ESCC. The correlation between DNA methylation and clinical response was also investigated. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were enrolled. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m 2 , iv, d1, q3w) and cisplatin (65 to 75 mg/m 2 , iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) 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 methylation level sequencing. Results: As of September 20, 2024, 43 pts were enrolled with a median age of 61 years (range 44-75), 81.4% were male, 39.5% had PD-L1 CPS≥10 and 95.3% had metastatic diseases. All pts were evaluable for safety and efficacy. The ORR was 81.4% (95%Cl: 66.1%-91.1%) and DCR was 97.7% (95%Cl: 86.2%-99.9%). The median PFS (mPFS) was 7.05 months (mo) (95%Cl: 5.86-8.24) and OS analysis was immature. In the PD-L1 CPS≥10 pts, the ORR was 100.0% (95%Cl: 77.1%-100.0%) and mPFS was 7.05 mo (95%Cl: 5.19-8.91). In the PD-L1 CPS＜10 pts, the ORR was 77.3% (95%Cl: 54.2%-91.3%) and mPFS was 7.05 mo (95%Cl: 5.87-8.24). Six hyper-methylated CpG sites, EPTIN9、PKNOX2、DLEU7、SOX7、CNRIP1 and LINC00554 might be the candidate biomarkers as the mean pretreatment methylation levels were significantly higher in the PR pts than those in the non-PR pts (p=7.8×10 -7 ). Grade 3-4 treatment-related adverse events (TRAEs) were reported in 44.2% (19/43) pts, mainly including neutropenia (25.6%), leukopenia (9.3%) and hyponatremia (7.0%). The infusion-related reactions (IRR) occurred in 14.0% (6/43) and grade ≥3 IRR occurred in 4.7% (2/43) pts. 7 pts discontinued cadonilimab administration due to TRAEs. Conclusions: The updated results suggested that bispecific antibody cadonilimab combined with taxane and cisplatin as first-line treatment continued to show encouraging anti-tumor activity and manageable safety in pts with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Clinical trial information: NCT05522894 .

This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2months (95% CI: 5.1-7.3), and the median OS was 15.3months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. The study demonstrated that individuals older than 65years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.

BackgroundThe combination of anti‐PD‐1 antibody serplulimab and chemotherapy is considered standard first‐line therapy for advanced esophageal squamous cell carcinoma (ESCC), but few later‐line treatments are available. Here we evaluated the therapeutic efficacy of the recombinant, humanized anti‐EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC.MethodsThis open‐label, non‐randomized, two‐cohort, phase 2 trial involved patients 18‐75 years old with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC, and an Eastern Cooperative Oncology Group performance status of 0‐1. Patients who had failed first‐line immuno‐chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks (Q2W). Patients with no prior systemic therapy received HLX07 (1,000 mg, day 1) and serplulimab (200 mg, day 1) intravenously Q2W for up to 2 years, concurrently with cisplatin (50 mg/m2, day 1) for up to 8 cycles and 5‐fluorouracil (1,200 mg/m2, days 1‐2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression‐free survival (PFS) and objective response rate (ORR).ResultsOverall, 50 patients were enrolled. In the HLX07 monotherapy group, ORR was 15.0% (3/20), and the median PFS was 1.5 months (95% confidence interval [CI], 1.3 to 3.7). The median duration of response was not reached, and the rate of patients showing an objective response lasting at least 6 months was 66.7% (95% CI, 5.4 to 94.5). Two (10.0%, 2/20) patients experienced grade 3‐4 treatment‐related adverse events (TRAEs), including hypomagnesemia, hypocalcemia, and fatigue. No patient experienced grade 5 TRAEs. In the HLX07 combination group, the ORR was 60.0% (18/30), and the median PFS was 7.8 months (95% CI, 3.3 to 9.1). Fourteen (46.7%, 14/30) patients experienced grade 3‐4 TRAEs, and one (3.3%, 1/30) patient died due to serplulimab‐related pneumonitis.ConclusionsHLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC. Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC.Trial registrationThis trial was registered at Clinicaltrials.gov (NCT05221658).

364 Background: The optimal therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed after immune checkpoint inhibitors (ICIs) are unclear. This phase II single-arm study aimed to assess the efficacy and safety of re-challenge with camrelizumab plus apatinib in this population. Methods: This study enrolled patients with unresectable locally advanced, locally recurrent, or metastatic ESCC who had experienced prior progression on ICI treatment. Enrolled patients received camrelizumab 200 mg intravenously every two weeks along with daily oral apatinib 250 mg. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal of consent. The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DOR), time to response (TOR), progression-free survival (PFS), overall survival (OS), 3- and 6-month PFS rates, 6-, 9- and 12-month OS rates, and safety. Results: From September 1, 2021, to March 29, 2023, 49 eligible patients were enrolled and given treatment. Among 38 treated patients who had at least one post-baseline efficacy measurement, the ORR and confirmed ORR were 36.8% (95% CI 21.8–54.0) and 13.2% (95% CI 4.4–28.1); the DCR was 89.5% (95% CI 75.2–97.1); the median DOR was 3.0 months; and the median TOR was 2.2 months. Among the 49 treated patients, the median PFS was 4.6 months (95% CI 3.8–6.5) and OS was 7.5 months (95% CI 5.5–13.6). Patients who were both PD-L1 positive and had responded to previous ICI therapy had the longest median PFS (5.7 months, 95% CI 3.9–not reached) and OS (9.6 months, 95% CI 7.5–not reached). Grade ≥ 3 treatment-related adverse events occurred in 34.7% of patients (17/49). Conclusions: This study showed promising efficacy and an acceptable safety profile of camrelizumab plus apatinib for patients with advanced ESCC who had progressed after ICI therapy. The subset of patients who were both PD-L1 positive and had a prior ICI response seemed to benefit most. Clinical trial information: NCT03736863 .

Background Platinum plus 5-fluorouracil (FP) is recognized as the standard regimen of palliative chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma (ESCC). Although taxane is widely selected for 2nd line regimen, other options are very limited. In Japan, S-1 is available for esophageal cancer. In this retrospective study, we evaluated the efficacy of S-1 monotherapy for recurrent or metastatic (advanced) ESCC refractory or intolerable to FP. Methods The subjects of this study were 11 patients with advanced ESCC who received S-1 after failure of FP. The endpoints evaluating efficacy were overall survival (OS), progression free survival (PFS), and overall response rate (ORR) in patients with target lesions (TLs). Results The characteristics of the subjects were: median age 69 years, PS (0/1) 5/6, number of prior chemotherapy regimens (1/2/3 ≥ ) 4/4/3. 9 patients were refractory and 2 were intolerant to prior FP. 9 patients had good control of the primary lesions. Only 2 patients received post-S-1 therapy. The median OS and PFS were 11.7and 3.0 months. Two of 9 patients with TLs, one refractory and the other intolerant to prior FP, achieved partial response (PR) while the remaining 7 patients showed progressive disease (ORR 22%). The other 2 patients without TLs showed nonCR/nonPD. Common treatment-related adverse events included grade 3 leukopenia for 1 patients (9.1%), but there were no serious cases. Conclusion ORR of 22% suggests modest activity of S-1 for advanced ESCC refractory or intolerable to platinum plus 5-FU (FP). However, more than half of the patients showed progressive disease. Future study exploring optimal patient selection for S-1 is warranted. Disclosure All authors have declared no conflicts of interest.

Advanced esophageal squamous cell carcinoma (ESCC) patients exhibit a ~ 50% objective response rate (ORR) and median progression-free survival (mPFS) of just 5–7 months when undergoing first-line immune-chemotherapeutic treatment, underscoring pronounced unmet clinical need. We assessed the efficacy and safety of Anlotinib plus Camrelizumab and chemotherapy for advanced, unresectable, or metastatic ESCC. This is an open-label, investigator-initiated, phase 2, non-randomized clinical trial enrolled patients from August 3, 2020, to August 10, 2022. Patients with treatment-naive unresectable stage III or IV ESCC received treatment which was patient-selected, including chemotherapy + camrelizumab + Anlotinib (TCAC group) or chemotherapy + Camrelizumab (TCC group) induction therapy for 4–6 cycles, followed by maintenance therapy. The primary endpoint was ORR, while secondary endpoints included mPFS, median overall survival (mOS), disease control rate (DCR), and treatment-related adverse events (TRAEs). 30 patients were included in each group. Over a median 14.5-month follow-up period, the ORR was 90.0%, 43.3%(P < 0 0.001) and the mPFS was 16.03, 7.30 months (HR 0.35, 95%CI, 0.19–0.65; P < 0 0.001) in TCAC and TCC groups, respectively. Grade 3 TRAEs were experienced by 12 patients (40.0%) in TCAC group, including decreased neutrophil counts (5 [16.7%]), decreased white blood cell counts (4 [13.3%]), reduced platelet counts (3 [10%]), and hypertension (2 [6.7%]). No patients experienced grade 4–5 TRAEs. The combination of Anlotinib plus Camrelizumab and chemotherapy had promising efficacy among patients with advanced ESCC in this study, which may be a promising first-line treatment regimen.Trial registration: Registered with ClinicalTrials.gov, NCT04471480. 15/07/2020.

361 Background: Therapeutic options for metastatic esophageal squamous cell carcinoma (ESCC) primarily involve immunotherapy combined with chemotherapy. For locally advanced ESCC, concurrent chemoradiotherapy (CRT) or radiotherapy is the standard, though outcomes remain suboptimal. Targeted therapies, particularly anti-angiogenic agents, hold promise to enhance CRT efficacy. Anlotinib, a multi-target anti-angiogenic agent inhibiting VEGFR, PDGFR, FGFR, and c-KIT, has shown potential to enhance radiotherapy by alleviating tumor hypoxia. This multicenter, retrospective study evaluates the efficacy and safety of anlotinib combined with radiotherapy in locally advanced or metastatic ESCC. Methods: This study screened patients (pts) with locally advanced or metastatic ESCC treated with anlotinib (8-12 mg, p.o., qd, d1-14, q3w) and radiotherapy from June 2018 to June 2024. Two cohorts were included: Cohort 1 (metastatic ESCC) and Cohort 2 (locally advanced ESCC). Cohort 2 was divided into an observational group (OG, anlotinib + radiotherapy ± chemotherapy) and a control group (CG, radiotherapy ± chemotherapy). Radiotherapy doses for primary lesions were 45-60 Gy (1.8-2.2 Gy per fraction), while metastatic lesions received either standard fractionation (≥45 Gy) or stereotactic body radiotherapy (SBRT, ≥3 Gy per fraction, total dose ≥30 Gy). Chemotherapy regimens were not restricted. Cohort 1 aimed to enroll 50 pts, while Cohort 2 included 100 in the OG and 200 in the CG. The primary endpoint was overall survival (OS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), and safety. Results: By September 10, 2024, 128 pts had been enrolled: 34 in Cohort 1 and 94 in the OG of Cohort 2. In Cohort 1, all 34 pts (100%) were stage IVB, with a median OS of 24.0 months (95% CI: 12.44-35.60) and a median PFS of 9.2 months (95% CI: 7.60-10.80). The 24-month OS and PFS rates were 54.0% (95% CI: 27.20-74.73) and 30.8% (95% CI: 10.21-54.53), respectively. ORR was 52.9% (95% CI: 35.1-70.2), with 1 complete response (CR) and 17 partial responses (PR), DCR was 88.2% (95% CI: 72.5-96.7). In Cohort 2, 50 pts (53.2%) were stage III, and 28 (29.8%) were stage IVA. The median OS is not yet mature, but the median PFS was 20.1 months. The 36-month OS and PFS rates were 61.9% (95% CI: 46.12-74.34) and 48.4% (95% CI: 29.58-64.87). ORR was 46.8% (95% CI: 36.4-57.4), with 6 CRs and 38 PRs, DCR was 95.7% (95% CI: 89.5-98.8). Safety data collection is ongoing. Conclusions: Anlotinib combined with radiotherapy exhibited promising efficacy in locally advanced or metastatic ESCC, though further data are needed to confirm these preliminary findings.

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]