关键词: 原发性肝癌, 抗PD-1单抗／SHR-1210, 皮肤毛细血管增生症（CCEP）, 临床试验, 免疫相关不良反应

Abstract: ObjectiveTo observe and analyze the appearance of cutaneous capillary endothelial proliferation（CCEP） in clinical trials of primary hepatic carcinoma treated with domestic antiPD-1 monoclonal antibody SHR-1210. 
MethodsFrom Nov 1, 2016 to Sep 30, 2017， SHR-1210 was used to treat primary hepatic carcinoma in our hospital. Among them， single drug group： SHR-1210 3 mg／kg iv q2W or 3 mg／kg iv q3W. The combined group A： SHR-1210 3 mg／kg iv q2W； apatinib starting dose 125 mg po qd. The combined group B： SHR1210 3 mg／kg iv q2W； FOLFOX 4 regimen（oxaliplatin 85 mg／m2 iv d1； leucovorin 200 mg／m2 iv d1， d2； fluorouracil 400 mg／m2 iv d1，d2； fluorouracil 600 mg／m2 CIV d1，d2， q2W）. The incidence of CCEP was observed during SHR-1210 treatment and classified according to the shape. Pathological examinations were performed in some patients and 2 typical cases were shared. 
ResultsThirtyeight patients received SHR1210 monotherapy， including 2 weeks group（n=16） and 3 weeks group（n=22）， all of which were hepatocellular carcinoma. There were 6 cases in SHR1210 combined with apatinib group， including 2 cases of hepatocellular carcinoma， and 4 cases of cholangiocarcinoma. There were 18 cases in SHR1210 combined with FOLFOX 4 regimen group， including 8 cases of hepatocellular carcinoma and 10 cases of cholangiocarcinoma. CCEP can be observed in 59 patients treated with SHR1210 at least 2 times. CCEP were divided into “rednevus”， “pearl”， “mulberry”， “patch” and “tumor type” according to morphological features. The total incidence rate of CCEP of SHR1210 monotherapy was 77.1％（27／35）. The incidence of CCEP in the combined A group and the combined B group was 33.3％（2／6） and 611％（11／18）， respectively. Among the 45 patients could be evaluated, CCEP was found in 35 cases. Patients with CCEP achieved PR 31.4％（11／35）， SD 14.3％（5／35） and PD 543％（19／35）， while those without CCEP got SD 40％ and PD 60％. The response rate of patients with CCEP was significantly higher than those without CCEP， but there was no statistical difference（P=0.105）， which may be related to the small sample size. 
ConclusionCCEP is the most common and drugrelated adverse event in clinical trials of SHR1210 for primary hepatic carcinoma. Its pathogenesis is still unclear and maybe related to the immune response caused by SHR1210. CCEP often take place on the skin of face and body surface, never on the mucosa of respiratory tract and digestive tract. It is preliminarily observed that patients with CCEP tend to have higher response rate during SHR1210 monotherapy. SHR1210 combined with apatinib or FOLFOX 4 regimen can reduce the incidence of CCEP， and the specific mechanism of it needs further study.

Key words: Primary hepatic carcinoma, AntiPD-1 monoclonal antibody／SHR-1210, Cutaneous capillary endothelial proliferation（CCEP）, Clinical trial, Immunerelated adverse events