Safety, Activity, and Biomarkers of SHR-1210, an Anti-PD-1 Antibody, for Patients with Advanced Esophageal Carcinoma

Abstract

The current management of advanced esophageal squamous cell carcinoma (ESCC) remains unsatisfactory. We investigated the safety, efficacy, and biomarkers of SHR-1210, an anti-PD-1 antibody, in patients with recurrent or metastatic ESCC. This study was part of a phase I trial in China. Patients with advanced ESCC who were refractory or intolerant to previous chemotherapy were enrolled. Eligible patients received intravenous SHR-1210 at a dose of 60 mg, with escalation to 200 and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The associations between candidate biomarkers (PD-L1 and somatic mutation load) and the efficacy of SHR-1210 were also explored. Between May 11, 2016, and December 9, 2016, a total of 30 patients from one site in China were enrolled. Ten patients (33.3%) had an independently assessed objective response. Median progression-free survival was 3.6 months (95% CI, 0-7.2). Three (10.0%) treatment-related grade 3 adverse events were reported: two (6.7%) pneumonitis and one (3.3%) increased cardiac troponin I. No grade 4 or grade 5 treatment-related adverse events were reported. The exome sequencing and analysis showed that the mutational burden and the potential mutation-associated neoantigen count were associated with better responses. An objective response was more common in patients with PD-L1-positive tumors as defined by ≥5% staining (7 of 15 patients) than in those with PD-L1-negative tumors (1 of 9 patients). In this population of ESCC patients, SHR-1210 had a manageable safety profile and promising antitumor activity. .

Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR‐1210), a novel anti‐PD‐1 antibody

“…Additionally, pembrolizumab in 18 PD‐L1‐positive ESCC patients demonstrated a promising ORR of 28%, while in 23 patients, the median PFS and OS rates were 1.8 and 7.0 months, respectively, including squamous and adenocarcinoma histology . Moreover, we reported the safety and efficacy of treatment with a novel PD‐1 antibody, camrelizumab, from a phase I study . Continued follow‐up of our ESCC cohort verified encouraging ORRs and PFS, consistent with the results of previous reports, while the OS was different, mainly as a result of the variance in patient selection …”

“…However, the clinical benefit is restricted to only a fraction of patients, and biomarkers for both response and survival are under exploration. We previously reported that high PD‐L1 expression, mutation load, and potential mutation‐associated neoantigen count are associated with a better response . In the KEYNOTE‐028 trial, six‐gene interferon‐γ gene expression signature analysis indicated that higher interferon‐γ composite scores may predict delayed progression and an increased response .…”

“…Currently, immune checkpoint inhibitors (ICIs), particularly inhibitors of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4), PD‐1, and its associated ligand (PD‐L1), have been approved for the treatment of many advanced solid tumors . Several phase I/II studies have shown modest efficacy and tolerable toxicity in ESCC patients treated with anti‐PD‐1 antibodies . However, only a small proportion of advanced ESCC patients benefit from ICIs across all trials, and reliable peripheral blood biomarkers for the response and outcome of anti‐PD‐1 immunotherapy have not been defined in ESCC.…”

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

“…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.…”

Ongoing Phase I Studies of Immune Checkpoint Inhibitors in China

“…According to the latest released results of NCT02742935 , treatment with SHR1210 in advanced/refractory ESCC resulted in an objective response rate of 33.3% and a median progression‐free survival of 3.6 months. The most common TRAEs were reactive capillary hemangiomas (76.7%, 23/30), which was believed to be related to the activation of vascular endothelial growth factor (VEGF)/VEGF receptor pathway.…”