Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study

Abstract

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m 2 ] plus docetaxel [25 mg/m 2 ] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9–24.5), OS and PFS time ranged from 8.2–28.5 and 4.0–28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c + dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.

Spatial Distribution and Predictive Significance of Dendritic Cells and Macrophages in Esophageal Cancer Treated With Combined Chemoradiotherapy and PD-1 Blockade

“…Using multi-immunofluorescence assay, we could identify the PD-L1 expression on tumor cells, DCs, and macrophages simultaneously ( 4 ) ( Figures 1C–G ). Of the total PD-L1 expressed cells, the median percentages of tumor cells, DCs, and macrophages were 30.48%, 28.54%, and 15.44%, individually (Additional file 1: Figure S1A ).…”

“…The phase Ib study evaluating the safety and feasibility of definitive chemoradiotherapy combined with an anti-PD-1 antibody, camrelizumab, as the first-line therapy in locally advanced ESCC (ClinicalTrials.gov NCT03671265) ( 4 ). Specifically, camrelizumab (SHR1210, Jiangsu Hengrui Medicine Co. Ltd., China) was given on day 1 of every 2-week period from the beginning of radiotherapy up to 32 weeks, concurrently with radiotherapy for 6 weeks, and with chemotherapy for 4 weeks ( 4 ). The exploratory endpoints of this phase Ib study were local and systematical immune characteristics, and potential predictive biomarkers for combination treatment outcome.…”

“…To investigate the tumor mutation at baseline, the biopsy specimens from 14 patients before the combination were sequenced by using FoundationOne CDx (F1CDx) and FDA-approved 324-gene panel assay conducted by DIAN (Hangzhou Lab) with licensed technologies, to assess the tumor mutation burden (TMB) ( 4 , 20 ).…”

“…We first conducted a clinical trial of first-line chemoradiotherapy combined with anti-PD-1 antibody camrelizumab in locally advanced ESCC. A total of 65% patients survived for at least 2 years, but partial patients did not benefit from this combination ( 4 ). It urgently needs to identify potential biomarkers in patients treated with chemoradiotherapy combined with PD-1 blockade.…”

“…In the present study, we collected paired tumor biopsy samples from the phase Ib clinical trial of chemoradiotherapy combined with anti-PD-1 antibody camrelizumab as the first-line therapy in locally advanced ESCC (ClinicalTrials.gov NCT03671265) at baseline and during combination (after radiation, 40 Gy) ( 4 ). We prospectively identified the DCs and macrophages in the tumor microenvironment to illustrate the dynamic spatial location of DCs and macrophages responding to chemoradiotherapy combined with PD-1 blockade, which provides predictive candidates for clinical outcome of the combination in ESCC.…”