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

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 tria...

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Published in:	ESMO open Vol. 9; no. 9; p. 103681
Main Authors:	Sundar, R., Chia, D.K.A., Zhao, J.J., Lee, A.R.Y.B., Kim, G., Tan, H.L., Pang, A., Shabbir, A., Willaert, W., Ma, H., Huang, K.K., Hagihara, T., Tan, A.L.K., Ong, C.-A.J., Wong, J.S.M., Seo, C.J., Walsh, R., Chan, G., Cheo, S.W., Soh, C.C.C., Callebout, E., Geboes, K., Ng, M.C.H., Lum, J.H.Y., Leow, W.Q., Selvarajan, S., Hoorens, A., Ang, W.H., Pang, H., Tan, P., Yong, W.P., Chia, C.S.L., Ceelen, W., So, J.B.Y.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-09-2024 Elsevier
Subjects:	gastric cancer immunotherapy intraperitoneal locoregional therapy niche Original Research peritoneal metastases peritoneum PIPAC tumor microenvironment PIPAC peritoneum peritoneal metastases intraperitoneal gastric cancer immunotherapy niche tumor microenvironment locoregional therapy
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Summary:	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). 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. 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. 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. •First-in-human study combining PIPAC-OX with immunotherapy for gastric cancer with peritoneal metastases (GCPM).•This therapeutic regimen demonstrated safety and tolerability with reduction in peritoneal tumor burden.•Molecular profiling of GCPM samples showed enhancement in T-cell infiltration within peritoneal tumors.•This trial provides rationale for future systemic immunotherapies to be combined with intraperitoneal treatments for GCPM.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-last authors. Co-first authors.
ISSN:	2059-7029 2059-7029
DOI:	10.1016/j.esmoop.2024.103681