Regional Therapies
Nicholas A. Ullman, MD
Post-Doctorate Research Fellow
University of Rochester Medical Center
Rochester, New York, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Survival outcomes for advanced pancreatic ductal adenocarcinoma (PDAC) remain poor; with first-line therapies resulting in cumulative cytopenias and neuropathy, highlighting the need for effective, less toxic maintenance therapies. There are currently no approved maintenance treatments for PDAC not associated with BRCA or DNA-repair mutations. Here we present pre-clinical data demonstrating synergistic effect of CXC chemokine receptor-2 (CXCR2) inhibition and anti-PD1 as well as a Phase-1 study (NCT04477343) evaluating SX-682, an oral CXCR1/2 inhibitor, and nivolumab as maintenance treatment for advanced PDAC.
Methods:
Preclinical studies utilized the KP2 PDAC cell line. Following orthotopic injection, treatment with FOLFIRINOX was followed by SX-682 and anti-PD1 or 5-FU. The trial is an open-label, dose escalation Phase I trial evaluating the combination of SX-682 and nivolumab. Patients must complete at least 16 weeks of first line therapy without disease progression. Radiographically measurable disease must be present per iRECIST. Baseline and on treatment biopsies are required and used to evaluate the tumor microenvironment (TME). The primary objective is determining maximum tolerated dose using Bayesian optimal interval (BOIN) design. Secondary objectives include pharmacokinetic data and progression free survival. Exploratory objectives include alterations in the TME.
Results:
In the preclinical model of maintenance therapy, SX-682 and anti-PD1 therapy increased overall survival vs 5-FU (p < 0.05). At the time of submission, nine of a planned 20 patients have enrolled. Dose-level 1 completed enrollment without dose-limiting toxicity (DLT). Dose-level 2 is without DLTs, but has not completed enrollment. Flow cytometry analysis of four paired biopsies demonstrate a decrease in CXCR2+ Gr-MDSCs and regulatory T cells within the TME.
Conclusions:
Preclinical PDAC maintenance immunotherapy demonstrates increased survival. Clinical translation of this immunotherapy strategy is underway. At the time of submission there have been no DLTs, and paired tumor biopsies have shown decreased immunosuppressive cell populations within the TME.