Abstract 5239: KRAS wild-type status as detected by circulating tumor DNA analysis may be a prognostic or predictive factor for clinical benefit in patients with unresectable, locally advanced or metastatic pancreatic cancer (PC) treated with the MEK inhibitor refametin
Authors: Teufel Michael , Van Laethem Jean-Luc , Riess Hanno , Giurescu Marius , Garosi Vittorio L. , Schulz Anke , Vonk Richardus , Seidel Henrik , Reischl Joachim , Childs Barrett H. 
Published: August 2015

Background: Mutationally-activated KRAS is present in 90% of pancreatic ductal adenocarcinoma (PDAC) and may represent an early genetic driver, being commonly found in low-grade pancreatic lesions (Eser et al. 2014 BJC 111:817). Refametinib is a potent oral allosteric MEK 1/2 inhibitor with both single-agent activity and synergistic activity in combination with gemcitabine in preclinical models of pancreatic cancer (PC). A Phase 1B/2 study in patients with locally advanced, unresectable or metastatic PC and no prior systemic therapy was conducted and recently reported (Van Laethem et al., ASCO 2014; NCT01251640). We report here on the exploratory biomarker findings from this study.

Methods: KRAS mutational analysis was conducted via liquid biopsy at baseline on circulating tumor DNA (ctDNA) by BEAMing (Sysmex-Inostics) as well as circulating micro RNA (miRNA) from plasma collected at baseline and post-dose and analyzed by qPCR using an Exiqon panel of 752 miRNAs and an innovative data preprocessing method for normalization and imputation of undetermined values. Tumor molecular characterization was performed on archival tumor tissue and included targeted tumor gene next-generation sequencing with FOUNDATION ONE and the analysis of Ki67 proliferation index.

Results: Samples for biomarker analysis were obtained from 69 treated patients. Forty-six (67%) had detectable KRAS mutations by liquid biopsy. KRAS G12D, G12V and G12R were the most frequent mutations. Interestingly, KRAS wild-type patients had better efficacy outcomes compared to mutant KRAS patients (mut/WT, respectively): overall response rate 15%/30% (OR 2.4, p = 0.147), median progression-free survival (mPFS) 3.7/8.8 mo (HR 0.32, p = 0.001), and overall survival (OS) 7.1/18.2 mo (HR 0.28, p = 0.001). There was a trend correlating KRAS mutant allele frequency with response. The CA19.9 levels correlated with KRAS mutational status. Tumor exome sequencing was performed from 16 patients, 15 of which had a KRAS mutation (G12D or G12V). The discordancy rate compared to BEAMing KRAS data was 26% (4/15).

Conclusions: The high prevalence of KRAS mutations in patients with PC has been confirmed using BEAMing technology. In this study, there was an association between improved mPFS and OS in KRAS WT patients. Together with lower baseline levels of CA19.9 in the KRAS WT cohort, we conclude that liquid biopsy may be an approach to identify prognostic or predictive markers in PDAC treated with refametinib and gemcitabine. This hypothesis is sustained by the finding that poor clinical response showed increasing allele frequency of mutant KRAS. These results require confirmation in a larger trial.

Citation Format: Michael Teufel, Jean-Luc Van Laethem, Hanno Riess, Marius Giurescu, Vittorio L. Garosi, Anke Schulz, Richardus Vonk, Henrik Seidel, Joachim Reischl, Barrett H. Childs. KRAS wild-type status as detected by circulating tumor DNA analysis may be a prognostic or predictive factor for clinical benefit in patients with unresectable, locally advanced or metastatic pancreatic cancer (PC) treated with the MEK inhibitor refametin [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5239. doi:10.1158/1538-7445.AM2015-5239