Oesophageal cancer is the seventh most common cancer globally, and the sixth most common cause of death from cancer.1 The relative 5-year survival rate is 8% or less for patients diagnosed with metastatic disease.2, 3
Research in context
Evidence before this study
We searched PubMed in July, 2019, using the terms “esophageal OR oesophageal” and “PD-1 OR PD-L1” in the title or abstract, with no time limits, to identify articles published in English about immunotherapies with PD-1/PD-L1 inhibitors in patients with oesophageal cancer. To identify results from clinical trials that were not yet published in peer-reviewed journals, we also searched the American Society of Clinical Oncology and European Society for Medical Oncology congress websites for publications between July 1, 2017, and July 1, 2019, using the key words “esophageal squamous OR oesophageal squamous” and “PD-1 OR PD-L1”. We selected primary publications from phase 2 or phase 3 studies of PD-1 or PD-L1 monotherapy in patients who had previously received treatment for unresectable advanced or recurrent oesophageal squamous cell carcinoma. Using these search criteria, we identified three studies of PD-1 immune checkpoint inhibitors: the phase 2 ONO-4538-07 (ATTRACTION-1) and phase 2 KEYNOTE-180 studies of nivolumab and pembrolizumab monotherapy, respectively, and the phase 3 KEYNOTE-181 study of pembrolizumab. In the ATTRACTION-1 phase 2 study, nivolumab showed promising antitumour activity with a manageable safety profile in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to standard chemotherapies. In the KEYNOTE-180 phase 2 study, pembrolizumab showed durable antitumour activity and manageable safety in heavily pre-treated patients with metastatic oesophageal squamous cell carcinoma. The final analysis of the KEYNOTE-181 phase 3 study reported no significant difference in overall survival for pembrolizumab versus chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma.
Added value of this study
To our knowledge, ATTRACTION-3 is the first randomised phase 3 study to show a significant improvement in overall survival with a PD-1 inhibitor (nivolumab) versus chemotherapy (paclitaxel or docetaxel) in previously treated patients with advanced oesophageal squamous cell carcinoma. A survival benefit with nivolumab was noted irrespective of tumour PD-L1 expression. Nivolumab was well tolerated and showed a favourable safety profile, with numerically fewer treatment-related adverse events versus chemotherapy. Additionally, an exploratory analysis of health-related quality of life showed significant improvements with nivolumab compared with chemotherapy.
Implications of all the available evidence
The results of this study, along with those from previously published studies, suggest that anti-PD-1 monotherapy offers a favourable benefit–risk profile in patients with previously treated, unresectable advanced or recurrent oesophageal squamous cell carcinoma. Nivolumab might represent a new standard second-line treatment option to address the high unmet need for patients with advanced oesophageal squamous cell carcinoma.
Oesophageal squamous cell carcinoma is the dominant histological subtype of oesophageal cancer worldwide (approximately 90%)1, 4 and has a molecular profile distinct from that of oesophageal adenocarcinoma.5, 6 The usefulness of palliative chemotherapy for patients with advanced oesophageal squamous cell carcinoma is not well established.7, 8 Fluoropyrimidine and platinum doublet chemotherapy are considered acceptable first-line therapy options for patients with unresectable advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.7, 8, 9, 10 In the second-line setting, single-agent chemotherapy is an established option based on patient benefit-risk assessment.7, 8, 9, 10 Although second-line treatments with docetaxel and paclitaxel are used for patients with advanced oesophageal squamous cell carcinoma that has progressed after first-line chemotherapy, they are associated with haematological, gastrointestinal, and neurological toxicities11 and with poor long-term survival.12, 13 There is therefore an urgent unmet need for new treatment options for this patient population.
Inhibitors of immune checkpoint protein PD-1 enhance antitumour activity of T cells by blocking the interaction between the PD-1 receptor and its ligands.14, 15 Antitumour activity of PD-1 inhibitors has been reported in studies of several types of squamous cell tumours, including oesophageal, head and neck, non-small cell lung, and anal cancers.16, 17, 18, 19, 20 Until recently, no targeted therapies were approved for treatment of advanced oesophageal squamous cell carcinoma. The US Food and Drug Administration approved the PD-1 inhibitor pembrolizumab in 2019 for the treatment of recurrent locally advanced or metastatic oesophageal squamous cell carcinoma in patients whose tumours express PD-L1 (combined positive score ≥10) and who have progressed beyond one or more previous systemic therapy.
PD-L1 expression is enriched in oesophageal squamous cell carcinoma, which might increase tumour susceptibility in these patients to elimination following immune checkpoint inhibition. The reported prevalence of PD-L1 expression in oesophageal squamous cell carcinoma ranges from 15% to 83% in tumour cells, and from 13% to 31% in immune cells.6, 21, 22, 23, 24 Nivolumab, a human monoclonal anti-PD-1 antibody, has been approved for the treatment of several solid tumours, and showed promising antitumour activity and a manageable safety profile in a phase 2 study (ATTRACTION-1) of patients with advanced oesophageal squamous cell carcinoma who were refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapies.19 In the randomised, open-label, phase 3 ATTRACTION-3 trial, we compared nivolumab with chemotherapy in patients with unresectable advanced or recurrent oesophageal squamous cell carcinoma who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy. Here, we report the results of the final analysis of ATTRACTION-3 (follow-up for long-term outcomes is ongoing).