Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum

Abstract

Background:To evaluate the activity and safety of everolimus and identify potential biomarkers for efficacy of everolimus in patients with advanced gastric cancer (AGC), who failed both fluoropyrimidine and platinum.Methods:Fifty-four patients received everolimus (10 mg day−1). The primary objective was to determine the 4-month progression-free survival (PFS) rate, assumed to be 30%. We additionally investigated the potential biomarkers for everolimus as an exploratory endpoint in those who underwent tumour biopsies.Results:Two patients (3.7%) achieved partial response and the disease control rate (DCR) was 38.9%. At a median follow-up duration of 8.7 months, the 4-month PFS rate was 18.4%, not fulfilling the primary hypothesis, with a median PFS of 1.7 months and a median overall survival of 8.3 months. The high expression of pS6Ser240/4 at baseline was significantly associated with higher DCR (P=0.043) and prolonged PFS (P=0.001). Grade 1/2 asthenia (96.3%) recorded as the leading toxicity and hyperglycaemia (20.4%) was the most common non-hematological grade 3/4 toxicity. Three patients experienced grade 3/4 pneumonitis. Notably, two experienced treatment-related deaths.Conclusion:Everolimus is active against a limited number of patients with AGC. pS6Ser240/4 may be a potential predictive biomarker for everolimus, which requires validation. Careful monitoring is necessary despite generally favourable toxicity profile.

Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: A systematic review and meta-analysis.

“…Twenty trials reported pneumonitis events, eight trials reported cough, and twelve trials reported dyspnea. Sixteen trials (seven temsirolimus, eight everolimus, and one ridaforolimus) were single arm studies or randomized patients to different doses/schedules of an mTOR inhibitor (Table 2) [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Six trials (one temsirolimus, four everolimus, and one ridaforolimus) randomized patients to an mTOR inhibitor arm or a non-mTOR inhibitor control arm (Table 3) [22-27].…”

Improving trends in survival of patients who receive chemotherapy for metastatic or recurrent gastric cancer: 12 years of experience at a single institution

“…As an increasing number of targeted agents have been used in recent clinical trials [41], ramucirumab, a new monoclonal antibody VEGFR-2 antagonist, has shown survival benefits after first-line chemotherapy [42]. Further active investigations with target agents are needed based on biomarkerdriven clinical trials [34].…”

“…Targeted therapies such as trastuzumab [10], cetuximab [29,30], sorafenib [31], bevacizumab [32], vorinostat [33] and everolimus [34] were administered to a total of 262 patients (6.7 %) as first-line treatment, and these were also the most commonly used in period 3. Use of oral fluoropyrimidine increased significantly since period 2 (p for trend \0.001) [15-18, 22, 23, 35].…”

How Prognostic and Predictive Biomarkers Are Transforming Our Understanding and Management of Advanced Gastric Cancer

“…It prevents mTOR from phosphorylating S6K1 and 4EBP1, halting protein synthesis and blocking cell cycle progression [112,115]. Higher expression of S6 proteins was associated with a higher disease control rate and longer PFS in a phase II second-line study of everolimus in GC [118]. The phase III Gastric Anti-Tumor Trial with Everolimus (GRANITE-1) study compared everolimus plus best supportive care with placebo plus best supportive care in patients with advanced GC who had progressed after one or two lines of chemotherapy [119].…”