Abstract 4461: Analysis of circulating tumor DNA (ctDNA) identifies on-treatment genomic alterations in a phase 2 study of veliparib plus FOLFIRI ± bevacizumab vs. placebo plus FOLFIRI ± bevacizumab in metastatic colorectal cancer (mCRC)
Authors: Ramathal Cyril Y. , Murphy Erin , Asque Elizabeth , Grundstad Arne Jason , Ansell Peter , He Lei , Luo Yan , Berlin Jordan , Waring Jeff 
Published: August 2019

Changes in plasma ctDNA are used as a surrogate molecular marker of response to determine clinical efficacy and provide insights into potential resistance mechanisms to targeted therapeutics. Detection of genomic alterations in circulating tumor DNA (ctDNA) in colorectal cancer has been widely employed as an approach to measure real-time changes in the tumor genome. In order to understand mechanisms of resistance to the PARP inhibitor, Veliparib (ABT-888), pathogenic alterations in oncogenes and DNA Damage Response (DDR) genes were profiled longitudinally in plasma ctDNA and associated to clinical response to Veliparib concurrent to FOLFIRI +/- Bevacizumab.

Methods: 215 serial plasma samples collected at Baseline, Cycle 2 (28 days post-treatment) and at disease progression (Final Visit) from 78 patients (pts) with mCRC in the NCT02305758 clinical trial were selected for the current study, consisting of ~50% partial responders (PR), ~30% stable disease (SD) pts and 5% Non-responders (PD). Detection of ctDNA mutations was accomplished using a targeted, error-correctible NGS assay encompassing 63 cancer driver genes, tumor suppressors & DDR genes. Paired pre- and on-treatment plasma samples were evaluable from 81% pts selected.

Results: Veliparib (VPRB) pts with longest PFS experienced the largest fold change reductions in total cfDNA concentration by end of treatment (EOT). Interestingly, in both treatment arms, the ctDNA mutant fraction per pt decreased by EOT (median = -41%). In support of this correlation, the ctDNA mutational burden also decreased by 28% in VPRB pts and 39% in PLAC pts, largely driven by PR pts with longer PFS. Overall, tumor-specific mutations detected in ctDNA had 88% concordance with tissue, particularly in common mCRC driver mutations. Baseline KRAS mutations were detected in 46% pts (mostly PR & PD) and are eliminated or diminished in 28% pts (14% VPRB, 14% Placebo) by EOT. 30 DDR & MMR genes were found to be frequently altered in all pts, notably APC & MSH3, at both baseline and EOT. However, by EOT, RAD1, XRCC3, BRCA1 and CHEK1 mutations were acquired or increased, while TP53BP1, POLD1 and ERCC5 mutations were eliminated or reduced, prominently in VPRB PR pts.

Conclusions: Broadly, a reduction in ctDNA fraction and pathogenic mutation burden, notably in KRAS, is evidenced in both treatment arms and appears to trend with longer PFS at least in Veliparib-treated pts. Despite these prognostic ctDNA changes, VPRB-specific DDR mutation changes may provide insight into VPRB mechanism of action and resistance in mCRC and is under further exploration at earlier post-treatment timepoints and in SD pts. These data could add insights into alterations acquired earlier in the treatment regimen and the relationship of these alterations with resistance to PARPi in mCRC.

Citation Format: Cyril Y. Ramathal, Erin Murphy, Elizabeth Asque, Arne Jason Grundstad, Peter Ansell, Lei He, Yan Luo, Jordan Berlin, Jeff Waring. Analysis of circulating tumor DNA (ctDNA) identifies on-treatment genomic alterations in a phase 2 study of veliparib plus FOLFIRI ± bevacizumab vs. placebo plus FOLFIRI ± bevacizumab in metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4461.