Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes

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: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m² 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.

Keywords: PIPAC; gastric cancer; immunotherapy; intraperitoneal; locoregional therapy; niche; peritoneal metastases; peritoneum; tumor microenvironment.

Figure 1

Study hypothesis and treatment schedule. (A) Study hypothesis: The combination of PIPAC-OX and systemic nivolumab would alter the tumor microenvironment and allow synergistic effects of the two drugs. (B) Treatment schedule: PIPAC-OX was administered at 90 mg/m² once every 6 weeks for 2 doses. I.V. nivolumab at 240 mg started 1-3 days after the first PIPAC procedure, every 2 weeks. A third dose of PIPAC was permitted for patients demonstrating good response to therapy. PIPAC-OX, pressurized intraperitoneal aerosol chemotherapy-oxaliplatin.

Figure 2

Survival and response. (A) Overall change in PCI score from baseline after PIPAC for patients who had PCI results after at least two cycles of PIPAC, color-coded by RECIST response. Green bars represent those with progressive disease, burgundy bars represent partial response, and grey bars represent stable or no change. (B) Kaplan–Meier curves of overall survival and (C) progression-free survival, (D) Kaplan–Meier curves of overall survival and (E) progression-free survival stratified by baseline PCI scores, (F) histological images before PIPAC-OX treatment showing viable tumor cells with mucin with some fibrosis (PRGS 3), (G) histological images after PIPAC-OX treatment showing acellular mucin with some inflammatory response (PRGS 1). CI, confidence interval; NA, not available; OS, overall survival; OX, oxaliplatin; PCI, peritoneal cancer index; PFS, progression-free survival; PIPAC, pressurized intraperitoneal aerosolized chemotherapy; PRGS, peritoneal regression grading score.

Figure 3

Translational analyses. (A) UMAP of peritoneal tumor and normal samples. (B) GSEA pathway comparisons and immune deconvoluted cell type changes before and after PIPAC-OX, i.v. nivolumab treatment. (C) Putative gene changes with treatment in peritoneal tumor samples. P values were retrieved with the Wilcoxon’s test. (D) Gene expression profiles of peritoneal tumor samples. Differential gene expressions were included if log 2-fold change values were >2 or <−2 and adjusted P values were <0.05. FPKM, fragments per kilobase of transcript per million mapped reads; GSEA, gene set enrichment analyses; ICI, immune checkpoint inhibition; PCI, peritoneal cancer index; PIPAC-OX, pressurized intraperitoneal aerosol chemotherapy-oxaliplatin; UMAP, Uniform Manifold Approximation and Projection.