Catenacci DVT, et al. - In this randomised, double-blind, placebo-controlled, phase 3 trial, researchers sought 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. Findings revealed no improvement with ligand-blocking inhibition of the MET pathway with rilotumumab regarding clinical outcomes in these patients.

Methods

• Researchers performed this multicentre, randomised, double-blind, placebo-controlled, phase 3 study at 152 centres in 27 countries.
• They included 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.
• Randomization of eligible patients (1:1) via a computerised voice response system was performed 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, rilotumumab or placebo monotherapy was administered to patients until disease progression, intolerability, withdrawal of consent, or study termination.
• As per disease extent and ECOG performance status, randomisation was performed.
• To study treatment assignment, both patients and physicians were masked.
• Overall survival, analysed by intention to treat was observed as the primary endpoint.
• The final analysis was reported.

Results

• 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) from Nov 7, 2012, and Nov 21, 2014.
• After an independent data monitoring committee found a higher number of deaths in the rilotumumab group, study treatment was stopped early than in the placebo group; all study treatment were subsequently discontinued in all patients in the rilotumumab group.
• For patients in the rilotumumab group, median follow-up was 7.7 months (IQR 3.6–12.0) and in the placebo group, median follow-up was 9•4 months (5.3–13.1) for patients.
• As per observations, in the rilotumumab group, median overall survival was 8.8 months (95% CI 7.7–10.2) 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).
• In the rilotumumab and placebo groups, the most common grade 3 or worse adverse events 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%]).
• Similar frequency of serious adverse events were observed in the rilotumumab and placebo groups (142 [48%] vs 149 [50%]).
• The rilotumumab group indicated more deaths due to adverse events in comparison to the placebo group (42 [14%] vs 31 [10%]).
• In the rilotumumab group, fatal adverse events were encountered in 33 (11%) of 298 patients due to disease progression, and nine (3%) patients indicated fatal events due to disease progression.
• In the placebo group, 23 (8%) of 299 patients indicated fatal adverse events due to disease progression, and eight (3%) suffered fatal events not due to disease progression.