Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study

Summary

Background

Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients.

Methods

ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m² every 3 weeks) or irinotecan (180 mg/m² every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants.

Findings

From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1–12·8) in the camrelizumab group and 6·2 months (3·6–10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8–9·7) in the camrelizumab group and 6·2 months (5·7–6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57–0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage).

Interpretation

Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China.

Funding

Jiangsu Hengrui Medicine.

Introduction

Oesophageal cancer is the seventh most common malignancy in terms of incidence and the sixth most common leading cause of cancer death worldwide.¹ In 2018, approximately 572 000 new cases of oesophageal cancer were diagnosed and it caused 509 000 cancer deaths globally.¹ Although oesophageal adenocarcinoma is the predominant subtype of oesophageal cancers in non-Asian populations, oesophageal squamous cell carcinoma accounts for 90% of cases in the Asian population.1, 2 Oesophageal squamous cell carcinoma is the fourth most common cancer and the fourth leading cause of cancer-related death in China, and more than half of global oesophageal squamous cell carcinoma cases occur in China.2, 3 Chemotherapy, for example with taxanes, cisplatin, and fluorouracil, is commonly used as the first-line treatment for patients with advanced or metastatic oesophageal squamous cell carcinoma. However, there are few treatment options in second-line setting in patients with advanced or metastatic oesophageal squamous cell carcinoma who progress on or are intolerant to first-line standard chemotherapy.

Research in context

Evidence before this study

We searched PubMed and international conferences (held by the American Society of Clinical Oncology and the European Society for Medical Oncology) for publications of articles and abstracts up to Oct 12, 2019, reporting on immunotherapies in patients with advanced or metastatic oesophageal squamous cell carcinoma using the search terms “esophageal squamous OR oesophageal squamous” and “PD-1 OR PD-L1”. This search was limited to articles and abstracts from phase 3 clinical trials. The search resulted in two studies of immune checkpoint inhibitors including pembrolizumab and nivolumab. In the KEYNOTE-181 phase 3 study, an improvement in survival was observed in patients with pembrolizumab versus chemotherapy whose oesophageal squamous cell carcinoma tumours expressed PD-L1 (combined positive score ≥10) as second-line therapy. The ATTRACTION-3 trial reported that nivolumab significantly improved overall survival versus chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma. Despite the fact that more than half of global cases of oesophageal squamous cell carcinoma occur in China, no randomised study on immunotherapy for such patients has been reported in China. A phase 1 trial showed manageable safety profile and promising antitumour activity of camrelizumab in Chinese patients with recurrent or metastatic oesophageal squamous cell carcinoma. Therefore, we launched this phase 3 randomised study to further investigate the activity and safety of camrelizumab in this population.

Added value of this study

To our knowledge, ESCORT is the first randomised phase 3 trial to report the superiority of camrelizumab (anti-PD-1 inhibitor) versus chemotherapy for overall survival in Chinese patients with advanced or metastatic oesophageal squamous cell carcinoma who progressed on or were intolerant to first-line chemotherapy. Unlike treatment with nivolumab in ATTRACTION-3, camrelizumab was associated with a reduction in risk of progression or death compared with chemotherapy. Camrelizumab was also well tolerated.

Implications of all the available evidence

The results of this study, along with those from previous studies, supported the use of an anti-PD-1 inhibitor in second-line treatment in oesophageal squamous cell carcinoma. Camrelizumab might represent a new standard second-line treatment option for patients with advanced or metastatic oesophageal squamous cell carcinoma.

Several clinical studies have reported promising efficacies and manageable safety profiles of anti-PD-1 antibodies in patients with advanced or metastatic oesophageal squamous cell carcinoma.4, 5, 6 The phase 3 ATTRACTION-3 study⁷ showed an improvement in overall survival with nivolumab compared with chemotherapy (median overall survival 10·9 months vs 8·4 months; hazard ratio [HR] 0·77, 95% CI 0·62–0·96) in patients with advanced oesophageal squamous cell carcinoma. The phase 3 KEYNOTE-181 study⁸ showed an improvement in overall survival in patients with oesophageal squamous cell carcinoma and positive PD-L1 expression (combined positive score [CPS] ≥10) randomised to pembrolizumab compared with those who received chemotherapy (median survival 10·3 months vs 6·7 months; HR 0·64, 95% CI 0·46–0·90). Pembrolizumab was approved by the US Food and Drug Administration for patients with recurrent, locally advanced, or metastatic oesophageal squamous cell carcinoma with a PD-L1 CPS of 10 or higher who had disease progression on previous systemic therapy. Given the high prevalence of oesophageal squamous cell carcinoma in China and the shortage of effective treatment options, there is an unmet medical need to develop novel efficacious drugs for patients in China.

Camrelizumab (SHR-1210), a high-affinity, fully humanised, selective IgG4-κ monoclonal antibody against PD-1, has shown activity across a wide range of solid tumours.9, 10, 11, 12, 13 In a phase 1 study, camrelizumab showed promising antitumour activity and a manageable toxicity profile in previously treated patients with recurrent or metastatic oesophageal squamous cell carcinoma.⁹ Treatment with camrelizumab resulted in an objective response rate of 33·3% and a median progression-free survival of 3·6 months. On the basis of these data, we did a phase 3 study to assess the efficacy and safety of camrelizumab as second-line therapy in patients with advanced or metastatic oesophageal squamous cell carcinoma.