Elsevier

The Lancet Oncology

Volume 20, Issue 11, November 2019, Pages 1506-1517
The Lancet Oncology

Articles
Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial

https://doi.org/10.1016/S1470-2045(19)30626-6Get rights and content

Summary

Background

Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma.

Methods

We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0–1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing.

Findings

Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5–19·0) in the nivolumab group and 8·0 months (4·6–15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2–13·3 vs 8·4 months, 7·2–9·9; hazard ratio for death 0·77, 95% CI 0·62–0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).

Interpretation

Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients.

Funding

ONO Pharmaceutical Company and Bristol-Myers Squibb.

Introduction

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).

Section snippets

Study design and participants

We did a multicentre, randomised, open-label, phase 3 trial at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA.

Eligible patients were age 20 years or older with unresectable oesophageal cancer, whose major current or previously resected lesion was in the cervical or thoracic oesophagus (including the oesophagogastric junction) and was pathologically confirmed as squamous or adenosquamous cell carcinoma. Patients who were refractory or

Results

Between Jan 7, 2016, and May 25, 2017, we assessed 590 patients for eligibility (figure 1) and randomly assigned 419 to treatment: 210 to nivolumab and 209 to chemotherapy. All patients were included in the ITT population; 417 patients received at least one dose of the assigned treatment (figure 1). At the time of data cutoff on Nov 12, 2018, the median follow-up (ie, time from randomisation to last known date alive or death) for overall survival was 10·5 months (IQR 4·5–19·0) in the nivolumab

Discussion

In this randomised, phase 3 trial, treatment with nivolumab was associated with significant improvement in overall survival and a favourable safety profile versus chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma. The survival benefit with nivolumab occurred regardless of patients' level of tumour PD-L1 expression.

The HR for the risk of death with nivolumab compared with chemotherapy was 0·77, and a 2·5-month difference in median overall survival was

Data sharing

See Bristol-Myers Squibb policy on data sharing.

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