Multicenter Phase II Study of Everolimus in Patients With Previously Treated Metastatic Gastric Cancer

Abstract

PURPOSE Everolimus, an oral inhibitor of the mammalian target of rapamycin, has shown antitumor activity in gastric cancer in preclinical and phase I studies. This phase II study evaluated the efficacy and safety of everolimus in pretreated patients with advanced gastric cancer. PATIENTS AND METHODS Patients with advanced gastric cancer who experienced progression despite prior chemotherapy received everolimus 10 mg orally daily until disease progression or study discontinuation. The primary end point was disease control rate (DCR; ie, complete response, partial response, or stable disease). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS Fifty-three patients were assessable (median age, 63 years; 51% and 49% received one or two prior chemotherapy regimens, respectively). Although no complete or partial response was obtained, a decrease in tumor size from baseline was observed in 45% of patients by central review. The DCR was 56.0% (95% CI, 41.3% to 70.0%); median PFS was 2.7 months (95% CI, 1.6 to 3.0 months). At a median follow-up time of 9.6 months, median OS was 10.1 months (95% CI, 6.5 to 12.1 months). Common grade 3 or 4 adverse events included anemia, hyponatremia, increased gamma-glutamyltransferase, and lymphopenia. Grade 1 or 2 pneumonitis was reported in eight patients (15.1%). CONCLUSION Everolimus monotherapy resulted in a promising DCR in patients with previously treated advanced gastric cancer. Adverse events are consistent with the reported safety profile of everolimus. These results warrant further evaluation in patients with advanced gastric cancer.

Conversion to everolimus in maintenance liver transplant patients: A multicenter, retrospective analysis

“…[30][31][32] The mode of action of mTOR inhibitors 33 suggests that they may be associated with a direct impact on malignant cells and may also exert an antiangiogenesis effect, 34 as demonstrated in animal models. [35][36][37][38] A phase 3 trial of everolimus in patients with advanced renal cell carcinoma 39 and a series of phase 2 studies in patients with various other types of malignancies [40][41][42][43][44] have consistently demonstrated an antitumor effect of everolimus. Although the data remain preliminary, a series of uncontrolled trials have shown markedly lower rates of HCC recurrence after liver transplantation in patients receiving sirolimus-based immunosuppression versus a standard CNI regimen.…”

The Target of Rapamycin: Structure and Functions

“…Rapamycin and derivatives such as CCI-779 (temsirolimus, Torisel), RAD001 (everolimus), and AP23573 (ridaforolimus) act as cytostatic agents that slow down or arrest the growth of cells derived from several cancer types such as rhabdomyosarcoma (Hosoi et al 1999), prostate cancer (van der Poel et al 2003, breast cancer (Pang & Faber 2001), and Bcell lymphoma (Muthukkumar et al 1995). Early results from clinical trials reveal that they have antiproliferative activity in a subset of cancer, such as endometrial cancer (Oza et al 2011), pancreatic neuroendocrine tumors (Goldstein & Meyer 2011), gastric cancer (Doi et al 2010), and malignant glioma (Reardon et al 2011). However, only a subset of mTORC1 functions is sensitive to rapamycin treatment, hence the antiproliferative properties of this drug can be limited Choo et al 2008;Choo & Blenis 2009).…”

Update on targeted therapy and immune therapy for gastric cancer, 2018

“…Although everolimus in a phase II trial was demonstrated to be significantly beneficial clinically [32] , in a phase III trial, everolimus did not significantly improve OS for AGC after first-or second-line chemotherapy compared with BSC (GRANITE-1) [33] . The reason for these results was discussed to be partially attributable to the slightly higher percentage of placebo groups who initiated antineoplastic therapy after a study on drug discontinuation.…”