Abstract
BACKGROUND: Gastric cancer (GC) with peritoneal dissemination remains a challenge with poor prognosis and limited treatment options. We aimed to compare solvent-based paclitaxel (sb-PTX) + ramucirumab (RAM) vs. nanoparticle-albumin-bound paclitaxel (nab-PTX) + RAM as second-line therapy for unresectable or recurrent GC with peritoneal dissemination. METHODS: This prospective, randomised, open-label, multicentre phase 2 trial was conducted at 58 centres within the West Japan Oncology Group (WJOG) in Japan. Eligible participants were patients with histologically-confirmed GC with peritoneal dissemination refractory or intolerant to first-line therapy. Patients were randomised 1:1 to receive sb-PTX + RAM or nab-PTX + RAM. Primary endpoint was overall survival (OS); key secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), safety, and protocol-specified biomarker analyses including the assessment of stromal caveolin-1 (Cav-1) expression by immunohistochemistry on archival tumour specimens. The data cutoff for the analysis presented herein was January 27, 2021. This trial was registered in the Japan Registry of Clinical Trials (jRCTs031180022). FINDINGS: Between Oct 1, 2018, and Jan 27, 2020, 105 patients were assigned to sb-PTX + RAM (n = 53) or nab-PTX + RAM (n = 52). Median follow-up was 18.1 months. Median OS was 8.1 months with sb-PTX + RAM and 7.2 months with nab-PTX + RAM (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.960; 95% CI, 0.621-1.484; P = 0.631). Median PFS was 5.1 vs. 3.9 months (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.965; 95% CI, 0.642-1.450; P = 0.893). ORR was 20.7% vs. 20.0% (P = 0.993), and DCR was 77.4% vs. 63.5% (P = 0.150), with sb-PTX + RAM and nab-PTX + RAM. Grade≥3 neuropathy occurred in 7.5% with sb-PTX + RAM and 17.6% with nab-PTX + RAM, and febrile neutropenia in 11.3% vs. 5.9%. In biomarker analysis, OS and PFS improved stepwise with increasing Cav-1 expression in patients receiving nab-PTX + RAM (P = 0.007, P = 0.012); no such association was observed with sb-PTX + RAM. Among patients with high stromal Cav-1 expression (IHC score 3+), nab-PTX + RAM showed some evidence of improved OS compared with sb-PTX + RAM (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.371; 95% CI, 0.130-1.060; P = 0.055). The interaction between Cav-1 expression and treatment arm showed a non-significant trend (HR for interaction, 0.364; 95% CI, 0.115-1.152; P = 0.086), consistent with this finding. INTERPRETATION: Treatment with nab-PTX + RAM did not meet the prespecified threshold (HR < 0.90) for promising efficacy in patients with GC and peritoneal dissemination. High stromal Cav-1 expression was associated with improved efficacy of nab-PTX + RAM. Future studies should prospectively validate the predictive value of stromal Cav-1 in patients receiving nab-PTX + RAM. FUNDING: Taiho Pharmaceutical Co. Ltd.