Nivolumab combination therapies improved overall survival in patients with advanced esophageal squamous cell carcinoma

1. Nivolumab in combination with chemotherapy or ipilimumab significantly prolonged overall survival compared to chemotherapy alone.

2. Common treatment-related adverse events in the nivolumab combination groups were nausea, decreased appetite and stomatitis.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Esophageal cancer is known as the 6^th leading cause of cancer-related deaths worldwide. There is scarce knowledge on the treatment for patients who are refractory or intolerant to the standard therapies (fluoropyrimidine plus platinum-based chemotherapy). Nivolumab is a PD-1 inhibitor that is currently approved for use for a variety of cancers such as advanced squamous and non-squamous non-small-cell lung cancer, melanoma, and Hodgkin’s lymphoma. Previously, combination therapy of nivolumab and ipilimumab has led to longer overall survival compared to chemotherapy or nivolumab monotherapy in several solid tumours. Therefore, this study aimed to explore the safety and efficacy of nivolumab in combination with chemotherapy or ipilimumab in patients with advanced esophageal squamous cell carcinoma. Both nivolumab plus chemotherapy and nivolumab plus ipilimumab significantly prolonged overall survival compared to chemotherapy alone in the overall population. Both combination treatments also significantly improved the overall survival in patients with tumour-cell PD-L1 expression of 1 % or greater.  Nausea, decreased appetite and stomatitis were common treatment-related adverse events that were reported in the nivolumab combination groups. Out of the 3 treatment groups, the incidence of grade 3 or 4 treatment-related adverse events was the highest in the nivolumab plus chemotherapy group. The main limitation of the analyses included not comparing the efficacy between the two combination therapy groups. Overall, this study demonstrated that nivolumab plus chemotherapy or ipilimumab could be a potential treatment for advanced esophageal squamous cell carcinoma. However, further investigation is required to examine the difference in efficacy between different combination treatments with nivolumab.

Click to read the study in The New England Journal of Medicine

Relevant Reading: 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

In-Depth [randomized controlled trial]: This was an open-label, global, phase III study. Patients were enrolled if they had unresectable, advanced, recurrent, or metastatic esophageal squamous cell carcinoma. A total of 970 patients were randomized to receive nivolumab plus chemotherapy, nivolumab plus ipilimumab or chemotherapy alone. The patient demographics and clinical characteristics were well-balanced in all three treatment groups. The minimum follow-up period was 13 months. The overall survival was significantly improved in both combination therapy groups compared to chemotherapy alone in the overall population (nivolumab plus chemotherapy: hazard ratio [HR]: 0.74, 99.1%, confidence interval [CI]: 0.58-0.96; nivolumab plus ipilimumab: HR: 0.78, 98.2% CI: 0.62-0.98). Both combination treatments also significantly improved the overall survival in patients with tumour-cell PD-L1 expression of 1% or greater (nivolumab plus chemotherapy: HR: 0.54, 99.5% CI: 0.37-0.80; nivolumab plus ipilimumab: HR: 0.64, 98.6% CI: 0.46-0.90). Common treatment-related adverse events of any grade in the nivolumab combination groups were nausea (nivolumab + chemotherapy: 59%, nivolumab + ipilimumab: 8%), decreased appetite (nivolumab + chemotherapy: 43%, nivolumab + ipilimumab: 6%) and stomatitis (nivolumab + chemotherapy: 32%, nivolumab + ipilimumab: 4%). The incidence of grade 3 or 4 treatment-related adverse events in the nivolumab plus chemotherapy group (47%) was higher compared to the other groups (nivolumab + ipilimumab: 32%, chemotherapy alone: 36%). Immune-related adverse events included rash, pruritis and hypothyroidism occurring most frequently in the dual immunotherapy group. Grade 3-4 immune events mostly occurred in the dual immunotherapy group and included hepatic, dermatological and endocrine dysfunction.

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