Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study

Mo, Hongnan; Huang, Jing; Xu, Jiachen; Chen, Xuelian; Wu, Dawei; Dong, Qiu‐Ting; Wang, Xi; Lan, Bo; Wang, Xingyuan; Xu, Jianping; Zhang, Honggang; Chi, Yihebali; Yang, Qing; Xu, Binghe

doi:10.1038/s41416-018-0100-3

Cited by 135 publications

(121 citation statements)

References 31 publications

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“…13,14 Interstitial lung disease is an immune-mediated toxicity that resulted in the only drug-related death in this study, and this is consistent with the safety profile in a previous phase 1 study of nivolumab. 13,14 Interstitial lung disease is an immune-mediated toxicity that resulted in the only drug-related death in this study, and this is consistent with the safety profile in a previous phase 1 study of nivolumab.…”

Section: Discussionsupporting

confidence: 88%

“…Most of the toxicity profiles in our study were similar to those previously reported for SHR-1210. 13,14 Interstitial lung disease is an immune-mediated toxicity that resulted in the only drug-related death in this study, and this is consistent with the safety profile in a previous phase 1 study of nivolumab. 15 The clinical manifestations of interstitial lung disease observed in this trial were similar to those previously reported with other anti-PD-1 antibodies in the treatment of advanced tumors.…”

Section: Discussionsupporting

confidence: 88%

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Promising efficacy of SHR‐1210, a novel anti–programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China

Huang

Zhang

et al. 2018

Cancer

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BACKGROUND:The clinical response to anti-programmed cell death 1 (PD-1) antibodies in patients with advanced gastric and gastroesophageal junction (GEJ) cancer in China has not been reported. METHODS: This study evaluated the efficacy and safety of SHR-1210, an anti-PD-1 antibody, in patients with advanced gastric/GEJ cancer in a phase 1 trial. The associations between candidate biomarkers (programmed death ligand 1 [PD-L1] expression, mismatch repair status, tumor mutation load, and lactate dehydrogenase [LDH] levels) and the efficacy of SHR-1210 were also explored. RESULTS: Thirty patients with recurrent or metastatic gastric/ GEJ adenocarcinoma who were refractory or intolerant to previous chemotherapy were enrolled between June 2, 2016, and June 8, 2017. Seven patients (23.3%) demonstrated objective responses, including 1 complete response. The objective response rates for patients with PD-L1-positive and PD-L1-negative tumors were 23.1% (3 of 13) and 26.7% (4 of 15), respectively (P = 1.000). Two treatment-related grade 3 or higher adverse events were reported: one was grade 3 pruritus, and the other (3.3%) was grade 5 interstitial lung disease. All 20 patients tested for the mismatch repair status had mismatch repair-proficient tumors, and the response rate was 30.0% (95% confidence interval, 11.9%-54.3%). Patients with a higher mutation load (4 of 10) tended to have better responses than those with fewer mutations (2 of 10), but the difference was not significant (P = .628). Patients with a >10% relative increase from the baseline LDH level were more likely to experience disease progression (90% [9 of 10]) than patients with a ≤10% change (40% [8 of 20]; P = .017). CONCLUSIONS: Anti-PD-1 antibody SHR-1210 shows encouraging efficacy in patients with advanced gastric/GEJ cancer in China, including mismatch repair-proficient subgroups. Cancer 2019;125:742-749.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

Promising efficacy of SHR‐1210, a novel anti–programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China

Huang

Zhang

et al. 2018

Cancer

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“…In the third study, 36 patients with advanced melanoma or urinary tumors were enrolled, and 36 (100%) had grade 1-5 AEs, and the incidence of grade 3 and grade 3 AEs was 36%. SHR-1210 included four studies and 178 patients [146][147][148][149] . The study involved classic…”

Section: Fixed Effect Model Random Effects Modelmentioning

confidence: 99%

Meta‐analysis of immune‐related adverse events of immune checkpoint inhibitor therapy in cancer patients

et al. 2020

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Background Immune checkpoint inhibitors (ICIs) have significant clinical efficacy in the treatment of non‐small cell lung cancer (NSCLC); however, the incidence of immune‐related adverse events (irAEs) of up to 50% has prevented their widespread use. With the increase in the use of ICIs alone or as combination therapy, clinicians are required to have a better understanding of irAEs and be able to manage them systematically. In this study, we aimed to assess the incidence of irAEs associated with ICIs. Methods We searched PubMed, Embase, and the Web of Science databases, and also included relevant literature references to widen our search. The relevant data with inclusion criteria were performed using RevMan 3.6.0 for meta‐analysis. We undertook a systematic literature search which included published data up to December 2019. Results Overall, 147 articles and 23 761 cancer patients with 11 different ICI treatment‐related (grade 1–5 and 3–5) irAEs were included in the study. There were 46 articles on pembrolizumab (6598 patients), 27 on nivolumab (3576 patients), 13 on atezolizumab (2787 patients), 12 on avelumab (3213 patients), 10 on durvalumab (1780 patients), 22 on ipilimumab (4067 patients), eight on tremelimumab (1158 patients), three on JS001 (223 patients), four on camrelizumab (SHR‐1210) (178 patients), one on sintilimab (96 patients), and one on cemiplimab (85 patients). Grade 1–5 irAEs were: cytotoxic T lymphocyte antigen 4 (CTLA‐4) (82.87%), programmed cell death 1 (PD‐1) (71.89%), and programmed cell death ligand‐1 (PD‐L1) (58.95%). Subgroup analysis was: Avelumab (44.53%), durvalumab (66.63%), pembrolizumab (67.25%), atezolizumab (68.77%), nivolumab (76.25%), Ipilimumab (82.18%), and tremelimumab (86.78%). Grade 3–5 irAEs were: CTLA‐4 (27.22%), PD‐1(17.29%), and PD‐L1(17.29%). Subgroup analysis was: Avelumab (5.86%), durvalumab (13.43%), atezolizumab (14.45%), nivolumab (15.72%), pembrolizumab (16.58%), tremelimumab (22.04%), and ipilimumab (28.27%). Conclusions This meta‐analysis confirmed that anti‐PD‐1 and anti‐PD‐L1 inhibitors had a lower incidence of irAEs compared with anti‐CTLA‐4 inhibitors.

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“…Tumor immunotherapy is an anticancer therapy with the goal of activating the immune system in the hope that its own immune function would inhibit tumor tissues [27]. At present, tumor immunotherapy has been shown to have strong antitumor activities in some tumor types, including melanoma and nonsmall cell lung cancer, and tumor immunotherapy drugs are clinically applied [28][29][30]. This study con rmed that ALOX12B, KRT78, RHOD, and ZNF750, which are related to tumor progression, affected the prognosis of CESC patients.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes in cervical cancer using weighted gene co-expression network analysis

Gong

Han

et al. 2020

Preprint

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Background Cervical cancer ranks second among malignancies in females around the world. Due to the elevated incidence and mortality of this malignancy, deciphering its pathogenesis and identifying related biomarkers is urgently required. Methods First, raw cervical squamous cell carcinoma (CESC) data in GSE63514 were downloaded from the Gene Expression Omnibus (GEO) database. Then, weighted Correlation Network Analysis (WGCNA) was performed to build a co-expression network. Next, comprehensive bioinformatics was performed to determine hub genes, and assess the associated functional annotation, prognostic signature, tumor immunity, DNA mismatch repair, methylation mechanism, candidate molecular drugs, and gene mutations. Results From the key module, ALOX12B, KRT78, RHOD and ZNF750 were selected for validation. K-M plots indicated that these genes had good diagnostic and prognostic values in CESC. Moreover, mutations in these hub genes resulted in the downregulation of most immune genes in CESC. On the other hand, most of the four core genes were negatively correlated with DNA mismatch genes. In addition, we found that RHOD and ZNF750 had decreased methylation in the disease state, while ALOX12B and KRT78 showed no significant differences. Meanwhile, GSVA revealed that most core genes had associations with P53 signaling and the hypoxia signaling pathway. Conclusion WGCNA could identify groups of genes significantly associated with cervical cancer prognosis. These findings provide new insights into CESC pathogenesis, and identify ALOX12B, KRT78, RHOD and ZNF750 as candidate biomarkers for CESC diagnosis and prognosis.

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Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study

Abstract: Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration.

Cited by 135 publications

References 31 publications

Promising efficacy of SHR‐1210, a novel anti–programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China

Promising efficacy of SHR‐1210, a novel anti–programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China

Meta‐analysis of immune‐related adverse events of immune checkpoint inhibitor therapy in cancer patients

Identification of hub genes in cervical cancer using weighted gene co-expression network analysis

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