DNA Repair Deficiency, Genomic Instability and Immune Profiling in a Phase 1 Study of Locally Advanced Pancreatic Cancer Patients Treated with Veliparib, Gemcitabine and Radiation Therapy

Abstract

Locally advanced pancreatic cancer (LA) has a dismal prognosis with current treatment modalities. Preclinical studies have demonstrated radiosensitization of orthotopic pancreatic tumors with the PARP-1/2 inhibitor, veliparib. A phase I trial of veliparib (V), gemcitabine (G) and radiation therapy (RT) was conducted to determine the maximum tolerated dose (MTD), safety and clinical activity of this regimen in patients with LA with and without DNA damage repair (DDR) defects. LA patients were treated with weekly G (1000 mg/m2), daily RT (36 Gy/15 fractions) and daily V 20 mg BID for 3 weeks escalated per a novel Bayesian method followed by standard chemotherapy. DAVID was used to interpret differential gene expression. Cox regression model was used to identify DDR pathways associated with survival. Next generation sequencing (NGS) identified genetic mutations involved in DDR, tumor mutation burden (TMB) and microsatellite instability (MSI) status. Blood samples were interrogated for PAR protein and cytokines using an ELISA and electrochemiluminescent array, respectively. The log-rank test was used to evaluate differences in PFS and OS. A total of 34 patients were enrolled from 2013 to 2016. MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15). 12 patients experienced DLT (83.3% lymphopenia, 8.3% neutropenia). Median PFS and OS were 10 and 15 months, respectively. Gene expression analysis identified DDR defects in 50% of patients. Median PFS and OS were significantly higher for these biomarker positive patients (17 vs. 8 mos, p<.01; 22 vs. 12 mos, p<.001, respectively). NGS identified 10 DDR mutations which were not prognostic of outcome. median TMB was 1.8 mut/Mb. A single MSI high patient was identified who was also TMB high (>20 mut/MB) and harbored DDR deficiency by NGS. Lower PAR levels were associated with borderline statistically significant improvements in both PFS and OS (p<.06). Higher levels of IL2 and IL12 and lower levels of FLT1 were associated with improved PFS and OS (p<.05). The combination of V, G and RT was well tolerated. DDR alterations were identified in a large proportion of patients and were associated with significantly improved PFS and OS. Whereas most patients were MSS and had low TMB, those with higher levels of pro-inflammatory cytokines were likely to harbor DDR alterations both of which were associated with improved outcomes.