1. Overall survival and progression-free survival were higher for patients on nivolumab plus chemotherapy compared to chemotherapy alone.
2. Severe adverse events occurred more frequently in the nivolumab group and more patients withdrew from treatment due to these events.
Evidence Rating Level: 1 (Excellent)
Study Rundown: The 5-year survival rate of patients with proximal gastric cancer is approximately 10-15%. Nivolumab is a cancer therapy which inhibits PD-ligand 1 (PD-L1), a highly expressed surface molecule on tumour cells that allow them to evade the host immune system. Previous trials of nivolumab in gastric cancer have shown increased efficacy in patients with increased combined positive score (CPS), which is a measure of PD-L1 expression on tumour-related cells. This study was a phase 3 trial comparing the safety and efficacy of chemotherapy alone versus chemotherapy and nivolumab in gastric adenocarcinoma. Patients in 29 countries across Asia, Australia, Europe, North America, and South America were randomized 1:1 to the two treatment groups. Results showed significant reduction in risk of progression and death in the nivolumab group compared to chemotherapy alone, with a greater reduction in patients with CPS of greater than five. However, severe adverse events occurred more frequently in patients on nivolumab plus chemotherapy. While treatment-related risk of death was low, 16 patients died in the nivolumab group versus four in the chemotherapy group. Limitations of this study include an open-label design, variable treatment regimens of nivolumab, and large amounts of patients discontinuing treatment due to adverse events. Nonetheless, this study provides a large dataset which supports the use of nivolumab, especially in patients with high CPS.
Relevant Reading: Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial
In-Depth [randomized controlled trial]: From March 27, 2017 and April 24, 2019, 1581 patients were randomly assigned to receive chemotherapy alone (n=789) or chemotherapy plus 360 mg nivolumab every 3 weeks or 240 mg every 2 weeks (n=789). Eligibility criteria included ages ≥18 years, previously untreated, unresectable, non-HER2-positive gastric, gastro-esophageal junction, or esophageal adenocarcinoma. Primary endpoints were overall survival (OS) or progression-free survival (PFS) in only those patients with PD-L1 combined positive score (CSP) of five or more. Tumours were measured by CT or MRI throughout the study. Compared to chemotherapy alone, in those with CPS ≥5, patients on adjunctive nivolumab had significantly improved OS (HR 0.71, p<0.0001) and PFS (HR 0.68, p < 0.0001). Similar findings were seen in patients with CPS ≥1, though not all outcomes were formally tested for significance. Grade 3-4 treatment-related adverse events were experienced by 59% of those in the nivolumab group and 44% in the chemotherapy group. Treatment-related deaths were 16 in the nivolumab group and 4 in the chemotherapy group alone.
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