Phase I PIANO trial—PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes
Raghav Sundar, Daryl Kai Ann Chia, Jing Zhao, Ainsley Ryan Yan Bin Lee, Gyuri Kim, Hon Lyn Tan, Angel Pang, Asim Shabbir, Wouter Willaert, Hu Ma, Kie Kyon Huang, Takeshi Hagihara, Angie Tan, C-A J Ong, Jolene Si Min Wong, Chin Jin Seo, Robert Walsh, Gary Chan, Seng Wee Cheo, C C C Soh, Eduard Callebout, Karel Geboes, Matthew Chau Hsien Ng, Huey Yew Jeffrey Lum, Wei Qiang Leow, Sathiyamoorthy Selvarajan, Anne Hoorens, Wee Han Ang, Hui Pang, Patrick Tan, Wei Peng Yong, Claramae S. Chia, Wim Ceelen, Jimmy Bok Yan So
Abstract
INTRODUCTION: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416). METHODS: every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures. RESULTS: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased. CONCLUSIONS: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments.