Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial

Abstract

Summary Background Rilotumumab is a fully human monoclonal antibody that selectively targets the ligand of the MET receptor, hepatocyte growth factor (HGF). We aimed to assess the efficacy, safety, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine, and to assess potential biomarkers, in patients with advanced MET-positive gastric or gastro-oesophageal junction adenocarcinoma. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 3 study was done at 152 centres in 27 countries. We recruited adults (aged ≥18 years) with unresectable locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, MET-positive tumours (≥25% of tumour cells with membrane staining of ≥1+ staining intensity), and evaluable disease, who had not received previous systemic therapy. Eligible patients were randomly assigned (1:1) via a computerised voice response system to receive rilotumumab 15 mg/kg intravenously or placebo in combination with open-label chemotherapy (epirubicin 50 mg/m2 intravenously; cisplatin 60 mg/m2 intravenously; capecitabine 625 mg/m2 orally twice daily) in 21-day cycles for up to ten cycles. After completion of chemotherapy, patients continued to receive rilotumumab or placebo monotherapy until disease progression, intolerability, withdrawal of consent, or study termination. Randomisation was stratified by disease extent and ECOG performance status. Both patients and physicians were masked to study treatment assignment. The primary endpoint was overall survival, analysed by intention to treat. We report the final analysis. This study is registered with ClinicalTrials.gov, number NCT01697072. Findings Between Nov 7, 2012, and Nov 21, 2014, 609 patients were randomly assigned to rilotumumab plus epirubicin, cisplatin, and capecitabine (rilotumumab group; n=304) or placebo plus epirubicin, cisplatin, and capecitabine (placebo group; n=305). Study treatment was stopped early after an independent data monitoring committee found a higher number of deaths in the rilotumumab group than in the placebo group; all patients in the rilotumumab group subsequently discontinued all study treatment. Median follow-up was 7·7 months (IQR 3·6–12·0) for patients in the rilotumumab group and 9·4 months (5·3–13·1) for patients in the placebo group. Median overall survival was 8·8 months (95% CI 7·7–10·2) in the rilotumumab group compared with 10·7 months (9·6–12·4) in the placebo group (stratified hazard ratio 1·34, 95% CI 1·10–1·63; p=0·003). The most common grade 3 or worse adverse events in the rilotumumab and placebo groups were neutropenia (86 [29%] of 298 patients vs 97 [32%] of 299 patients), anaemia (37 [12%] vs 43 [14%]), and fatigue (30 [10%] vs 35 [12%]). The frequency of serious adverse events was similar in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]). More deaths due to adverse events occurred in the rilotumumab group than the placebo group (42 ...

Cisplatin resistance in gastric cancer cells is involved with GPR30‐mediated epithelial‐mesenchymal transition

“…Cisplatin has been clinically used as a first‐line chemotherapeutic drug for more than 30 years. Cisplatin alone or in combination with other drugs has been shown to be effective in relieving symptoms, improving the quality of life and improving survival in patients with GC . Tumour cells develop resistance to chemotherapeutic drugs including cisplatin via a variety of mechanisms, thereby greatly limiting their therapeutic potential.…”

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

“…Increasingly, genomic profiling is being performed on cancer samples in order to identify pathogenic somatic DNA alterations, with these genomic biomarkers then used to guide selection of targeted therapies toward specific activated oncogenes (3,4). In GEA, with the exception of trastuzumab in ERBB2-amplified (HER2 + , herein ERBB2 + ) tumors (5), clinical testing of targeted therapies guided by molecular testing and directed against targets such as MET, FGFR2, and ERBB2-directed receptor tyrosine kinase (RTK) inhibitors has been disappointing (6)(7)(8)(9). In addition, EGFR-directed therapy failed testing in unselected patient populations with metastatic GEA (10,11).…”

Gastric cancer: Basic aspects

“…Indeed, several agents directed at either the hepatocyte growth factor receptor (HGFR or c‐Met) or its ligand, the hepatocyte growth factor (HGF), are currently under clinical testing for their utility in gastric malignancy. Regrettably, when evaluated during the RILOMET‐1 and RILOMET‐2 phase III clinical trials, rilotumumab, a fully human mAb targeting HGF, led to an inferior OS and severe toxicity of GC patients enrolled in the experimental arm . Similar results were obtained when assessing the clinical performance of onartuzumab, a c‐Met‐targeting humanized mAb, as it failed to prolong the OS and the PFS of HER2‐negative c‐Met‐positive GC patients .…”