1471 Maintenance ipilimumab + nivolumab post induction chemotherapy + SBRT for first line treatment stage IV pancreatic cancer

<h3>Background</h3> Pancreatic adenocarcinoma (PDAC) patients are usually diagnosed at an advanced stage, resistance to standard and immune mediated therapies and poor overall survival. However, a subset of patients demonstrates favorable response to chemotherapy and may benefit from an alternative therapeutic strategy. Radiotherapy can augment T-cell priming and activation in humans, leading to elimination of cancer cells by T-cells.¹ The ability of radiation to prime antitumor responses may be key in obtaining a therapeutic synergy with immunotherapies that can unleash the lack of immune responses in PDAC. We hypothesize that for selected patients with prolonged durable response to first-line treatment a maintenance approach of hypo-fractionated radiotherapy followed by combined PD-1 and CTLA4 blockade will improve clinical outcome. <h3>Methods</h3> In this open-label, single arm phase-2 study, we enrolled 10 metastatic PDAC patients in a pilot cohort (NCT05088889). Eligible patients had histologically confirmed PDAC, ECOG PS 0-1, and partial response (confirmed by RECIST) on first-line mFOLFIRINOX treatment. Study regimen: SBRT (24Gy/3Fx) followed by Ipilimumab (1 mg/kg every 6 weeks) and Nivolumab (3mg/kg every 2 weeks). Ipi/Nivo treatment continued until PD, discontinuation or withdrawal. Primary endpoint was overall response rate (ORR) secondary endpoints included progression free survival (PFS) calculated from initiation of maintenance treatment and exploratory endpoints. <h3>Results</h3> Ten patients were enrolled and evaluable from Dec-2022 to Sep-2024; All patients had stage IV disease and received first-line treatment with mFOLFIRINOX (median 10.7 cycles range 6–15); Median age 62.5 years (51–75), 60% male and all patients had MSS and BRCA WT. Patients received radiotherapy to dominant lesion (primary pancreatic tumor (n=5), liver (n=2), lung (n=1) or peritoneum (n=1) metastasis). Disease control rate was 90% (9/10). One patient (10%) had durable ongoing CR for 616 days, 8 patients had SD (80%) as best response at 56 days. Four of these patients continued to demonstrate SD for at least 120 days. Median PFS was 153 days (figure 1). No Treatment-related adverse events ≥ grade 2 were reported. <h3>Conclusions</h3> In our pilot study, patients with metastatic PDAC and favorable response to first-line treatment demonstrate clinical benefit from radiotherapy followed by maintenance dual immune checkpoint inhibition. Based on the initial results of this pilot study, we are expanding this cohort. A parallel exploratory analysis is being conducted on blood, tumor and microbiome to characterize the mechanisms of response in this selected study population. <h3>Trial Registration</h3> NCT05088889. <h3>Reference</h3> Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. <i>J Immunol</i> 2008;<b>180</b>:3132–9. <h3>Ethics Approval</h3> ISRAEL IRB - 7484