Evaluating the Novel Combination of Pressurized Intraperitoneal Aerosol Chemotherapy-Oxaliplatin (PIPAC-OX) as an Immunomodulator in Combination with Systemic Nivolumab for Gastric Cancer Peritoneal Metastases – The PIANO Trial

Authors
Daryl K A Chia^1*, Wim Ceelen^2,3*, Claramae S L Chia^4,5*, Kim Guowei^1,6,7, Aileen Pang¹, Asim Shabbir^1,6,7, Wouter Willaert², Johnny C A Ong^4,5,8,9,10, Jolene S M Wong^4,5, Seo Chin Jun^4,5, Tan Hon Lyn¹¹, Gloria Chan¹¹, Cheo Seng Wee¹¹, Eduard Callebout¹², Karen Geboes¹³, Matthew C H Ng¹⁴, Jeffrey H Y Lum¹⁵, Leow Wei Qiang¹⁶, Sathiyamoorthy Selvarajan¹⁶, Anne Hoorens¹⁷, Yong Wei Peng^11,18,19, Raghav Sundar^{11,18,20,21^}, Jimmy B Y So^{1,6,7^}

* Authors contributed equally
^ Co-corresponding authors

Affiliations

1. Division of Upper Gastrointestinal Surgery, Department of Surgery, National University Hospital, National University Health System, Singapore
2. Department of Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium.
3. Department of Human Structure and Repair, Ghent University, Belgium
4. Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore
5. Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
6. Division of Surgical Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore.
7. Yong Loo Lin School of Medicine, National University of Singapore, Singapore
8. Laboratory of Applied Human Genetics, Division of Medical Sciences, National Cancer Centre Singapore, Singapore.
9. SingHealth Duke-NUS Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore.
10. Institute of Molecular and Cell Biology, A*STAR Research Entities, Singapore.
11. Department of Haematology-Oncology, National University Cancer Institute, Singapore.
12. Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium.
13. Department of Gastroenterology, Division of Digestive Oncology, Ghent University Hospital, Ghent, Belgium.
14. Division of Medical Oncology, National Cancer Centre, Singapore; Duke NUS Medical School, Singapore.
15. Department of Pathology, National University Hospital, National University Health System, Singapore, Singapore.
16. Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.
17. Department of Pathology, Ghent University Hospital, Ghent, Belgium.
18. Singapore Gastric Cancer Consortium, Singapore.
19. Cancer Science Institute of Singapore, National University of Singapore, Singapore.
20. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
21. The N.1 Institute for Health, National University of Singapore, Singapore.

Corresponding Authors
Professor Jimmy Bok Yan So (sursbyj@nus.edu.sg)
Asst Professor Raghav Sundar (mdcragh@nus.edu.sg)

Introduction
Combination treatment with locoregional therapies that induce DNA damage may overcome resistance to systemic immune checkpoint inhibitors (ICIs). In gastric cancer patients (pts) with peritoneal metastases (GCPM), PIPAC-OX has been shown to induce direct DNA-damage and immunogenic cell death, but has not been evaluated in combination with ICIs. Hence, we conducted a Phase 1 study (ClinicalTrials.gov Identifier: NCT03172416) evaluating the safety and efficacy of PIPAC-OX in combination with systemic nivolumab.

Methods
Pts with predominant GCPM who had progressed on >1 line(s) of systemic chemotherapy were recruited across 3 centres in Singapore and Belgium. After initial staging laparoscopy, pts received PIPAC-OX at 90mg/m2 every 6 weeks with i.v. nivolumab at 240mg every 2 weeks. Response was evaluated clinically by Peritoneal Carcinomatosis Index (PCI) and Response Evaluation Criteria in Solid Tumours (RECIST) IV.I while histological response was determined with the Peritoneal Regression Grading Score (PRGS).

Results
From 2020, 18 pts were enrolled and received 32 and 110 cycles of PIPAC and i.v. nivolumab respectively with a median follow-up of 7.1 months. The 1^st cycle of PIPAC was successfully administered in all pts while 50% (9/18) and 27.8% (5/18) received 2^nd and 3^rd cycles. Common adverse events including abdominal pain and fatigue occurred in 19.4% and 12.9% of procedures while 3 PIPAC-related severe adverse events including vomiting and transaminitis were reported in 9.4% of all PIPAC procedures. The median PCI was 20 (IQR: 11 – 31) at baseline. At 2^nd and 3^rd PIPAC, the median decrease in PCI was -5 (IQR: -12 to +1) and -7 (IQR: -6 to -20) respectively. PRGS grade 1-2 was seen on pathological assessment in 66.7% (6/9) at 2^nd PIPAC and 100% (3/3) at 3^rd PIPAC. Objective response was seen in 14.3% (2/14) while disease control was achieved in 64.3% (9/14) of pts. The median progression-free survival and overall survival in this cohort was 2.3 (95% CI 1.5 – 3.2) and 6.7 (95% CI 1.7 – 11.8) months. Pts who received 3 cycles of PIPAC had the longest median OS (3 vs. 2 vs.1 cycle(s) of PIPAC, median OS [months, 95% CI]: 19.8 [8.3 – 31.3] vs. 6.7 [0.9 – 12.6] vs. 2.9 [1.4 – 4.4] months (p=0.010).

Conclusion
PIPAC-OX in combination with nivolumab is safe and tolerable with good response seen in some pts. Further studies are required to identify subgroups of GCPM pts who may benefit most from this locoregional and systemic therapy combination.