Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1.

Abstract

LBA3 Background: The prognosis for patients with AGC after failure of first-line chemotherapy is poor. Currently, there is no level 1 evidence established for second-line treatment. 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 age ≥18 years with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to oral EVE 10 mg/d plus best supportive care (BSC) or placebo (PBO) plus BSC. Randomization was stratified by region (Asia vs rest of world) and previous lines of chemotherapy (1 vs 2). Study drug was discontinued upon progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. The final analysis was performed when 526 deaths occurred. Results: A total of 656 patients from 23 countries were enrolled from Jul 2009 to Dec 2010; 439 were randomized to EVE, 217 to PBO. Baseline characteristics were well balanced between arms; 73.6% were men, 55.3% were enrolled in Asia, 47.7% received 1 previous line of chemotherapy, and 50.6% had a gastrectomy. Median OS was 5.39 months with EVE vs 4.34 months with PBO (HR, 0.90; 95% CI, 0.75-1.08; P=0.1244). Median PFS per local investigator assessment was 1.68 months with EVE vs 1.41 months with PBO (HR, 0.66; 95% CI, 0.56-0.78; p<0.0001). Six-month PFS estimates were 12.0% with EVE and 4.3% with PBO. OS and PFS results were consistent across the various subgroups. ORR (95% CI) was 4.5% (2.6%-7.1%) with EVE vs 2.1% (0.6%-5.3%) with PBO. The most common grade 3/4 adverse events were anemia (16.0% with EVE vs 12.6% with PBO), decreased appetite (11.0% vs 5.6%), and fatigue (7.8% vs 5.1%). Conclusions: EVE monotherapy did not significantly improve OS in patients with AGC previously treated with 1 or 2 lines of systemic chemotherapy. EVE did improve PFS. Results for OS and PFS were consistent across the various subgroups. The safety profile was consistent with that previously observed with EVE.

Optimal chemotherapy for advanced gastric cancer: is there a global consensus?

“…Everolimus, an oral mTOR inhibitor, failed to improve OS in patients treated with 1 or 2 lines of systemic chemotherapy when given as monotherapy, but did improve PFS [64]. A phase III trial of the German Arbeitsgemeinschaft Internistische Onkologie (AIO-STO 0111) is currently evaluating paclitaxel with and without everolimus in patients with GC after initial treatment with a fluoropyrimidine-containing regimen (http://clinicalTrials.…”

Defining treatment standards and novel insights into disease biology

“…5 Although phase II studies of antiEGFR therapy in advanced stage gastric cancer were promising, negative results from two large firstline phase III randomized trials that compared the use of standard firstline chemotherapy plus or minus an antiEGFR antibody were presented in 2012. [6][7][8] The REAL3 study (n = 553) compared the addition of panitu mumab (P) to EOC (epirubicin, oxali platin and capecitabine) chemotherapy (Table 1). 6 Median overall survival was significantly worse in the EOCP combina tion arm (8.8 months versus 11.3 months), and enrolment was terminated early.…”

Biological Mosaics–Oligomerization of G Protein-Coupled Receptors

“…At a median followup duration of 9.6 months, the median OS was 10.1 months and good tolerability was observed [53]. Based on this provocative result, a phase III randomized trial, GRANITE-1 study was conducted to compare everolimus with placebo plus best supportive care in patients with progressive disease after one or two prior lines of chemotherapy [54]. A total of 656 patients from 23 countries were enrolled; 439 were randomized to everolimus, 217 to placebo.…”