The rates of most potentially immune\related AEs were comparable to those reported for single\agent camrelizumab in a phase 1 trial [33], except that the rate of grade 3\4 hepatitis ( em n? /em =?3, 10.0%) seemed higher in the present trial. (ORR) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Tolvaptan Secondary endpoints included disease control rate (DCR), progression\free survival (PFS), overall survival (OS), and safety. Results We enrolled 30 patients between August 7, 2018 and February 23, 2019. The median follow\up was 24.98 months (95% confidence interval [CI]: 23.05\26.16 months). The centrally assessed ORR was 80.0% (95% CI: 61.4%\92.3%), with a median duration of response of 9.77 months (range: 1.54 to 24.82+ months). The DCR reached 96.7% (95% CI: 82.8%\99.9%). The median PFS was 6.85 months (95% CI: 4.46\14.20 months), and the median OS was 19.43 months (95% CI: 9.93 months C not reached). The most common grade 3\4 treatment\related adverse events (AEs) were leukopenia (83.3%), neutropenia (60.0%), and increased aspartate aminotransferase level (26.7%). Treatment\related serious AEs included febrile neutropenia, leukopenia, and anorexia in one patient (3.3%), and single cases of increased blood bilirubin level (3.3%) and Tolvaptan toxic epidermal necrolysis (3.3%). No treatment\related deaths occurred. Conclusions Camrelizumab plus apatinib combined with liposomal paclitaxel and nedaplatin as first\line treatment demonstrated feasible anti\tumor activity and manageable safety in patients with advanced ESCC. Randomized trials to evaluate this new combination strategy are warranted. Trial registration This trial was registered on July 27, 2018, at ClinicalTrials.gov (identifier: “type”:”clinical-trial”,”attrs”:”text”:”NCT03603756″,”term_id”:”NCT03603756″NCT03603756). strong class=”kwd-title” Keywords: anti\angiogenesis, apatinib, camrelizumab, chemotherapy, esophageal squamous cell carcinoma, first\line, immunotherapy, liposomal paclitaxel, nedaplatin, objective response rate AbbreviationsAEadverse eventCPScombined positive scoreCRcomplete responseDCRdisease control rateDoRduration of responseESCCesophageal squamous cell carcinomaICIimmune checkpoint inhibitorORRobjective response rateOSoverall survivalPFSprogression\free survivalPRpartial responseRECISTResponse Evaluation Criteria in Solid TumorsSDstable diseaseTKItyrosine kinase inhibitorVEGFRvascular endothelial growth factor receptor 1.?BACKGROUND Esophageal cancer remains a common malignancy worldwide, with an estimated 572,034 new cases and 508,585 deaths in 2018 [1]. Esophageal squamous cell carcinoma (ESCC) is the predominant histologic subtype globally, and the incidence of ESCC is the highest in East and Southeast Asia [2]. Nearly half of esophageal cancer patients present with metastatic disease at the time of diagnosis [3]. However, the standard of care for patients with metastatic ESCC in the front\line setting Tolvaptan has not yet been established. Currently, 5\fluorouracil and platinum are the therapeutic combination recommended in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines [4] and the Pan\Asian adapted European Society of Medical MAPT Oncology (ESMO) Clinical Practice Guidelines [5] as the first\line treatment for patients with metastatic ESCC, while newer agents including paclitaxel, docetaxel, and irinotecan are also acceptable options although lack of solid evidence from phase III clinical trials. The response rates ranged between 35%\56.5% with doublet chemotherapy [6, 7, 8, 9, 10, 11] and 43.9%\72.7% with triplet regimens [12, 13, 14]. The survival outcomes of patients treated with these combinations have been unsatisfactory, as the median progression\free survival (PFS) ranged between 4.5 and 7 months, and the median overall survival (OS) was typically around 1 year [6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. Hence, there is an unmet need for novel anti\tumor agents to treat patients with advanced ESCC. Improved understanding of the tumor immune escape and angiogenesis Tolvaptan mechanisms has revealed new possibilities for anti\cancer treatments. Specifically, several immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy on advanced ESCC; response rates to different anti\program death\1 (anti\PD\1) antibodies in patients with previously treated ESCC were reported to be 14.3%\33.3% [16, 17, 18]. Recently, two randomized phase III trials (ATTRACTION\3 [19] and ESCORT [20]) showed that PD\1 blockade, compared with chemotherapy, could significantly prolong the OS of advanced ESCC patients as the second\line treatment. Regarding anti\angiogenesis treatment, a few tyrosine kinase inhibitors (TKIs) that target vascular endothelial growth factor receptor (VEGFR) have shown modest activity during the management of ESCC patients [21, 22, 23]. In a Chinese prospective phase II trial, the response rate with anlotinib was 7% in advanced ESCC patients whose disease had progressed after platinum\ or taxane\containing chemotherapy []. Although the efficacy of both PD\1 blockade and VEGFR inhibition as monotherapy has been limited in the management of patients with metastatic ESCC, it is possible that the combination of these agents with chemotherapy may have synergistic effects. This.