Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study.

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]

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]

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]

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

BackgroundFirst‐line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab‐containing regimens in many countries. We report longer‐term follow‐up data.MethodsThis open‐label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression‐free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD‐L1) expression of ≥1% and then in the overall population.ResultsA total of 970 patients were randomly assigned. After 29 months of minimum follow‐up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46–0.76]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65–0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48–0.80]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65–0.92]). In patients with tumor cell PD‐L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51–0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79–1.36]). Among all treated patients (n = 936), Grade 3–4 treatment‐related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients.ConclusionsNivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow‐up, further supporting use as first‐line standard treatment options for patients with advanced ESCC.

LBA11 - Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): The phase III ATTRACTION-3 study

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 .

353 Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. Results from CheckMate 649 led to approval of 1L NIVO + chemo in multiple countries, including China. We report 3-year follow-up results in Chinese pts. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2-positive GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 37 month (mo) minimum follow-up, NIVO + chemo continued to demonstrate clinically meaningful improvement in OS and PFS vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts. The 36-mo OS rate was 31% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 26% vs 9% in all randomized pts, respectively. Objective response rate (ORR) (95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56-79) with NIVO + chemo and 48% (36-60) with chemo, and in all randomized patients was 66% (55-76) and 45% (35-56), respectively. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, with median duration of response (mDOR) (95% CI) of 12.5 mo (7.2-23.4) vs 6.9 mo (3.9-8.5); in all randomized pts, mDOR was 12.5 mo (7.2-17.7) vs 5.6 mo (4.4-8.3), respectively. No new safety signals were identified. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and durable objective responses vs chemo in Chinese pts, with an acceptable safety profile, consistent with the overall study population with advanced GC/GEJC/EAC. These results further support NIVO + chemo as a 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]

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.

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.

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.

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.

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.

BACKGROUNDPembrolizumab combined with chemotherapy has been proven effective as first-line therapy in patients with advanced esophageal cancer. Few trials have assessed the safety and efficacy of this treatment in patients with locally advanced disease.AIMTo analyze long-term outcomes of pembrolizumab in locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) in the real world.METHODSPatients with advanced ESCC admitted to our center from October 2019 to October 2021 were enrolled in this study. Clinical staging of the patients was based on the 8th edition of the American Joint Committee on Cancer TNM staging system. The patients received different treatments based on clinical stage. In brief, patients with locally advanced and resectable ESCC received neoadjuvant therapy combined with surgery. For those who were not candidates for resection, radical concurrent chemoradiotherapy plus pembrolizumab was more preferable. Patients with metastatic ESCC or who were unsuitable for radiotherapy underwent chemotherapy in combination with pembrolizumab. Long-term survival outcomes such as overall survival (OS), progression-free survival, disease-free survival, long-term adverse effects (AEs), immune maintenance therapy and predictors of immune checkpoint inhibitors (ICIs) efficacy were evaluated.RESULTSA total of 55 patients with advanced ESCC were enrolled in this retrospective, observational study. The median age was 61 years (range 44-74), with 47.3% (26/55) of the patients in stage IV and 45.5% of the patients had the tumor (25/55) located in the middle third of the esophagus. The median OS in all patients was not reached. The 12-mo OS rate among all patients was 78.8% and the 18-mo OS rate was 72.7%. 9 patients died due to tumor progression and 7 patients died due to treatment-related complications. The therapeutic effect evaluated at the interim evaluation was significantly reflected in the long-term outcome. Patients with complete response or partial response in all patients (P = 0.005) and in the chemoradiotherapy plus pembrolizumab group (P = 0.007) obtained a better prognosis than non-responders. A total of 20 patients (20/55, 36%) received immune maintenance therapy. Baseline peripheral blood biomarkers of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and neutrophil-to-(leukocyte-neutrophil) ratio did not predict the efficacy of ICIs.CONCLUSIONPembrolizumab combined with chemotherapy or radiotherapy resulted in favorable long-term survival in patients with locally advanced or metastatic ESCC, with safe and manageable long-term AEs.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m-2 on day 1 plus 5-fluorouracil 800 mg m-2 day-1 on days 1-4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54-0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55-0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 .