Sintilimab in patients with advanced esophageal squamous cell carcinoma refractory to previous chemotherapy: A randomized, open-label phase II trial (ORIENT-2).

Abstract

4511 Background: Patients (pts) with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line chemotherapy have limited treatment options. The study aims to evaluate the efficacy and safety of sintilimab, a PD-1 inhibitor, versus chemotherapy in these pts, and explore predictive value of PD-L1 and neutrophil-to-lymphocyte ratio (NLR) on efficacy of sintilimab. Methods: The open-label, multi-center phase 2 trial (NCT03116152) enrolled advanced ESCC pts refractory to first-line chemotherapy, and randomly assigned (1:1) them to receive sintilimab (200mg, Q3W) or chemotherapy (paclitaxel, 175mg/m2, Q3W; or irinotecan, 180mg/m2, Q2W), intravenously. The primary endpoint was overall survival (OS). Explorative endpoint were effects of PD-L1 and NLR on efficacy of sintilimab. Results: From May 16, 2017 to Aug 30, 2018, 190 pts were randomly assigned to sintilimab or chemotherapy (n = 95 per group). With the median follow-up of 7.2 months for sintilimab group and 6.2 months for chemotherapy group, the median OS in sintilimab was significantly higher than chemotherapy (7.2m vs. 6.2m, hazard ratio [HR] 0.70, P = 0.034). The objective response rate (ORR) was greater in sintilimab than chemotherapy with 12.6% vs. 6.3%, and the median duration of response was longer (8.3m vs. 6.2m). Incidences of treatment-related adverse events (TRAEs) of any grade (54.3% vs. 90.8%) and of grade 3-5 (20.2% vs. 39.1%) were both numerically less in sintilimab than in chemotherapy. The ORR in sintilimab versus chemotherapy in pts with tumor PD-L1 tumor proportion score (TPS) ≥1% and with TPS ≥10% were 20.2% vs. 0%, and 35.7% vs. 0%, respectively. In sintilimab group, pts with low NLR ( < 3) had a significant longer median OS (HR 0.54, P = 0.019) than with high NLR. Conclusions: Sintilimab was superior to chemotherapy with a significantly prolonged survival benefit and a favorable safety profile in pts with advanced ESCC refractory to first-line chemotherapy. High tumor PD-L1 expression (TPS ≥1% or ≥10%) might indicate more response benefit to sintilimab for these pts, and low NLR might be a positive predictive factor for sintilimab. Clinical trial information: NCT03116152 .

Sintilimab: A Promising Anti-Tumor PD-1 Antibody

“…In a phase II study ORIENT-2, 190 advanced esophageal squamous cell carcinoma (ESCC) patients refractory to first-line chemotherapy were randomly assigned (1:1) to receive sintilimab (200 mg, q3w) or chemotherapy (paclitaxel, 175 mg/m2, q3w; or irinotecan, 180 mg/m2, per 2 weeks), intravenously (55). The median OS was 7.2 versus 6.2 months, and the ORRs were 12.6% (12/95) versus 6.3% (6/95) (55).…”

“…In a phase II study ORIENT-2, 190 advanced esophageal squamous cell carcinoma (ESCC) patients refractory to first-line chemotherapy were randomly assigned (1:1) to receive sintilimab (200 mg, q3w) or chemotherapy (paclitaxel, 175 mg/m2, q3w; or irinotecan, 180 mg/m2, per 2 weeks), intravenously (55). The median OS was 7.2 versus 6.2 months, and the ORRs were 12.6% (12/95) versus 6.3% (6/95) (55). In comparison, ORRs of patients who were refractory to first-line chemotherapy and received pembrolizumab (200 mg q3w) or nivolumab (240 mg every two weeks) alone until disease progression, unacceptable toxic effects, or study withdrawal were 14.3% (9/63) and 19.3% (33/171), respectively; their median OS was 6.8 and 10.9 months (56, 57).…”

PD-1/PD-L1 Inhibitors vs. Chemotherapy For Previously Treated Advanced Gastroesophageal Cancer: A Meta-Analysis of Randomized Controlled Trials

“…After screening the titles and abstracts of these articles, we excluded 3216 studies because they were repetitive or irrelevant. After perusing 121 potentially eligible articles, we eventually included 7 studies [5][6][7][8][9][10][11]. A ow chart of the above screening process is shown in Fig.1.…”

“…A ow chart of the above screening process is shown in Fig.1. Almost all the quality evaluations in the included literature were of low risk except ORIENT-2 [11]. ORIENT-2 had a slightly higher risk of bias, because this study was only presented by a meeting report, and the speci c study process was unknown, and the expression of PD-L1 in patients was not reported.…”

“…However, the ATTRACTION-2 [5] was only viewed as a reference, and didn't be included in the pooled analysis, because this study was designed as an PD-1 inhibitor versus placebo treatment. Of the other six trails, ORIENT-2 [11] was a phase 2 clinical trial, and the rest were phase 3 clinical trials. In terms of research region, three of the seven studies were from east Asia, and the other ve studies were from many countries around the world.…”