IS3-3 - Granite-1; Phase III Trial of Everolimus (EVE) in Previously Treated Patients with Advanced Gastric Cancer (AGC): Results of Japanese Population

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ABSTRACT Background There is no level 1 evidence established for patients with AGC after failure of first-line chemotherapy. EVE inhibits the PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, metabolism, and angiogenesis, and has shown efficacy against AGC in preclinical and phase I/II studies. Methods In a randomized, double-blind, multicenter, phase III study, patients aged 18 years or older with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to oral EVE 10 mg/day plus best supportive care (BSC) or placebo (PBO) plus BSC. Randomization was stratified by region (Asia versus rest of world) and previous lines of chemotherapy (1 versus 2). Study drug was discontinued upon progression or unacceptable toxicity. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate (ORR), and safety. The final analysis was carried out when 526 deaths occurred. Results 656 patients from 23 countries were enrolled, 116 patients of which were Japanese; 74 were randomized to EVE, 42 to PBO. 78.4% were men, 75.0% received 2 previous lines of chemotherapy, and 56.0% had a gastrectomy. Median OS was 8.15 months with EVE versus 6.51 months with PBO (HR, 0.90; 95% CI, 0.57-1.41; P = 0.3182). Median PFS per local investigator assessment was 2.76 months with EVE versus 1.41 months with PBO (HR, 0.47; 95% CI, 0.31-0.70; P = 0.0001). ORR (95% CI) was 7.9% (2.6%-17.6%) with EVE versus 0% with PBO. The most common grade 3/4 adverse events were decreased appetite (17.6% with EVE versus 9.8% with PBO), anemia (13.5% versus 9.8%), and thrombocytopenia (6.8% versus 2.4%). Conclusion In Japanese population, the efficacy results were consistent with that of overall; EVE monotherapy improved PFS, but did not significantly improve OS in patients with AGC previously treated with 1 or 2 lines of systemic chemotherapy. The safety profile was also consistent with that previously observed with EVE.