Abstract A52: Cell free DNA (cfDNA) to monitor clonal evolution in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary results of a phase I/II clinical trial of the anti-MET multi-kinase inhibitor cabozantinib (C) plus the anti-EGFR monoclonal antibody panitumumab (P)
Authors: Strickler John H. , Zhang Tian , Armstrong Andrew J. , Niedzwiecki Donna , Uronis Hope E. , Morse Michael A. , Zafar S. Yousuf , Hsu Shiao-Wen D. , Arrowood Christy C. , Nagy Rebecca , Talasaz AmirAli , Lanman Richard , Haley Sherri , Hurwitz Herbert I. 
Published: May 2016

Background: Several molecular alterations drive acquired resistance to anti-EGFR therapies in pts with KRAS WT mCRC. We designed a clinical trial to identify and treat MET amplification (amp), a well described driver of acquired EGFR resistance.

Methods: Pts with KRAS WT mCRC were enrolled in 3 cohorts: 1) C+P Dose Finding (Dose Find): 3+3 design to determine the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of C+P; 2) C+P Expansion (Exp): to define the safety, tolerability and activity of C+P; and 3) MET amplified monotherapy (MET Mono): to determine the response rate of C alone in pts with prospectively identified MET amp/ EGFR refractory mCRC. Response assessment occurred every 2 months with computed tomography (CT) using RECIST criteria, version 1.1. cfDNA was collected at baseline and each restaging until progression. In the C+P Dose Find and Exp cohorts, peripheral blood was retrospectively sequenced for 54 gene mutations (mut) and focal amplifications, including MET (Guardant Health, Inc.). MET expressing circulating tumor cells (CTCs) were captured utilizing nanomagnetic particles conjugated to an antibody targeting extracellular MET (Janssen R&D, LLC). Genomic amp was tested in tumor tissue using next generation sequencing (NGS) or FISH. These data allowed subgroup and individual pt profiling.

Results: There were no dose limiting toxicity (DLT) events at the RPTD (C 60mg PO daily and P 6 mg/kg IV Q2 weeks) in the Dose Find cohort (n = 6). Assessment of treatment response in C+P cohorts: As of 7/21/2015, 13 pts were treated at the RPTD. 3 pts had not yet received response assessment; 10 pts (6 Dose Find; 4 Exp) were evaluable for response. 8/10 evaluable pts had failed prior anti-EGFR therapy. 6/10 had reduction in RECIST lesions (2/2 EGFR naïve; 4/8 EGFR refractory). Median change was -10% (range -40% to +18%). 2/2 evaluable pts with MET amp cfDNA had a reduction in target lesions (both EGFR refractory). 7/10 had a decrease in tumor marker (CEA). Median CEA change was -39% (range -86% to +103%). Baseline cfDNA profiling in C+P and MET Mono cohorts: 13 pts with EGFR refractory mCRC (6 Dose Find; 3 Exp; 4 MET mono) had baseline cfDNA profiling. 4/13 BRAF mut (2/4 subclonal), 3/13 KRAS mut (2/3 subclonal), 1/13 NRAS mut (0/1 subclonal), 3/13 HER2 amp (3/3 confirmed in tissue), 4/13 MET amp (0/2 in tissue; 2 not tested). Pt examples: One subject (EGFR refractory) had a lymph node biopsy 3 months prior to C+P that revealed no MET amp by NGS (Foundation Medicine). Pre-treatment cfDNA revealed MET amp. Treatment with C+P resulted in a partial response (-40% in RECIST lesions). MET amp was no longer detected in cfDNA at first restaging. A second subject had MET amp in pre-treatment cfDNA. MET-expressing CTCs were captured from peripheral blood. Single cell FISH on CTCs-but not archival tissue-confirmed MET amp.

Conclusions: This ongoing phase I/II study demonstrates the feasibility of: 1) using cfDNA to detect MET amp in pts with EGFR refractory mCRC, even when archival tissue is negative; and 2) capturing MET-expressing CTCs to confirm MET amp. Preliminary clinical results support prospective cfDNA screening to identify and treat pts with EGFR refractory/ MET amp mCRC.

Citation Format: John H. Strickler, Tian Zhang, Andrew J. Armstrong, Donna Niedzwiecki, Hope E. Uronis, Michael A. Morse, S. Yousuf Zafar, Shiao-Wen D. Hsu, Christy C. Arrowood, Rebecca Nagy, AmirAli Talasaz, Richard Lanman, Sherri Haley, Herbert I. Hurwitz. Cell free DNA (cfDNA) to monitor clonal evolution in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (mCRC): Preliminary results of a phase I/II clinical trial of the anti-MET multi-kinase inhibitor cabozantinib (C) plus the anti-EGFR monoclonal antibody panitumumab (P). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A52.