Everolimus Does Not Improve Overall Survival in Previously Treated Advanced Gastric Cancer
In a phase III trial (GRANITE-1 study) reported in Journal of Clinical Oncology by Atsushi Ohtsu, MD, PhD, of the National Cancer Center Hospital East in Kashiwa, Japan, and colleagues, everolimus (Afinitor) plus best supportive care did not prolong overall survival compared with placebo plus best supportive care in patients with previously treated advanced gastric cancer.
Study Details
In this double-blind trial conducted in 23 countries, 656 patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to receive everolimus at 10 mg/d (n = 439) or placebo (n = 217), both with best supportive care. Patients were stratified by previous chemotherapy lines (one vs two) and region (Asia vs rest of the world).
Median age in the everolimus and placebo groups was 57 years, 73% and 74% of patients were male, 57% and 58% were Asian, and 38% and 35% were white. The groups were generally well matched for baseline characteristics, except for a greater proportion of the placebo group having proximal stomach tumor location (43% vs 37%), Eastern Cooperative Oncology Group performance status of 2 (12% vs 6%), and liver metastases (50% vs 43%). Overall, 48% of patients had received one previous line of chemotherapy and 52% had received two.
Survival Outcomes
Median overall survival was 5.4 months in the everolimus group vs 4.3 months in the placebo group (hazard ratio [HR] = 0.90, P = .124). Trends toward reduction in risk of death with everolimus were observed in patients enrolled in non-Asian countries (HR = 0.85, 95% confidence interval [CI] = 0.65–1.10) and patients from non-Asian countries who had received two previous lines of chemotherapy (HR = 0.74, 95% CI = 0.50–1.09); these trends appeared to be driven by outcomes in patients enrolled outside of Europe. Overall, 39% of everolimus patients and 45% of placebo patients received another antineoplastic therapy after study treatment discontinuation.
Median progression-free survival was 1.7 months in the everolimus group vs 1.4 months in the placebo group. Although this represented a reduction in risk for death or progression with everolimus (HR = 0.66, P < .001), formal statistical significance was not achieved due to use of a hierarchical testing strategy in which significance in progression-free survival could be declared only if significance in overall survival was achieved. At 6 months, 12% of the everolimus group and 4% of the placebo group were progression-free.
Adverse Events
The most common adverse events of any grade with everolimus were decreased appetite (48%), stomatitis (40%), and fatigue (34%), and the most common grade 3 or 4 adverse events were anemia (16%), decreased appetite (11%), and fatigue (8%). Pneumonitis of any grade occurred in 3% of everolimus patients (grade 3 or 4 in 0.7%) and in no placebo patients.
Adverse events led to study drug discontinuation in 21.5% of everolimus patients (most commonly fatigue, gastrointestinal hemorrhage, and abdominal pain) vs 16% of placebo patients and to dose adjustment/interruption in 55% (most commonly, thrombocytopenia, stomatitis, and neutropenia) vs 21%. Death in three everolimus patients and two placebo patients was suspected to be due to study treatment.
The safety profile of everolimus was similar in patients from Asia and those from the rest of the world.
The investigators concluded, “Compared with [best supportive care], everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.”
The study was supported by Novartis Pharmaceuticals.
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