DNA-damage repair deficiency (dDDR) and response to nanoliposomal irinotecan (nal-IRI) in metastatic pancreatic ductal adenocarcinoma (mPDAC).

Abstract

731 Background: Chemotherapy is the standard of care for patients with mPDAC but there are no biomarkers to aid in treatment selection. Nal-IRI with 5-fluorouracil/folinic acid (FUFA) improves survival over FUFA in the second-line treatment of mPDAC. Nal-IRI is a topoisomerase inhibitor and its action produces DNA damage leading to cell death. We hypothesize that tumors with dDDR, a process that is altered in a subset of patients with PDAC, may be more sensitive to the effects of nal-IRI. Methods: Utilizing the IRB-approved pancreas cancer databases at the University of Miami and Wake Forest University, we identified patients with mPDAC treated with nal-IRI and FUFA who had germline and/or somatic mutation testing. We conducted a retrospective chart review to extract demographic and clinical characteristics including treatments received, response, and survival. Results: Among 31 patients identified, the median age was 66y and 47% were female. Nine patients had a DDR mutation; 6 germline and 3 somatic. Median progression-free survival (PFS) in patients with any germline or somatic DDR mutation was 3.2m vs 3.9m for those without (log-rank p = 0.7). When restricted to germline DDR mutations only, the median PFS was not reached with germline dDDR vs 4m for those without (log-rank p = 0.22). Presence of dDDR was associated with a higher clinical benefit rate (CBR = partial response + stable disease); a DDR mutation was present in 36% of patients who showed clinical benefit vs 15% in those without clinical benefit (p = 0.21). Conclusions: DDR mutations appear to define a subset of patients with mPDAC who may be more sensitive to nal-IRI and FUFA. The PFS and CBR were numerically but not statistically superior, especially in patients with germline DDR mutations. Larger data sets and longer follow-up are needed to confirm this trend.