Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes.

Session Type and Session Title: 
Oral Abstract Session, Sarcoma
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 10503)
George D. Demetri, Michael Jeffers, Peter Reichardt, Yoon-Koo Kang, Jean-Yves Blay, Piotr Rutkowski, Hans Gelderblom, Peter Hohenberger, Michael Gordon Leahy, Margaret von Mehren, Heikki Joensuu, Giuseppe Badalamenti, Martin E. Blackstein, Axel Le Cesne, Patrick Schoffski, Robert G. Maki, Jian-Ming Xu, Toshirou Nishida, Iris Kuss, Paolo Giovanni Casali; Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA; Bayer HealthCare Pharmaceuticals, Montville, NJ; HELIOS Klinikum Berlin-Buch, Berlin, Germany; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Centre Léon Bérard, Lyon, France; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Department of Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands; Department of Surgery, Mannheim University Medical Center, Mannheim, Germany; The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; Fox Chase Cancer Center, Philadelphia, PA; Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland; Department of Surgical and Oncological Sciences, University of Palermo, Palmero, Italy; Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; Institut Gustave Roussy, Villejuif, France; Laboratory of Experimental Oncology and Department of General Medical Oncology, KU Leuven and University Hospitals, Leuven, Belgium; Mount Sinai School of Medicine, New York, NY; Cancer Center, 307 Hospital, Academy of Military Medical Science, Beijing, China; Department of Surgery, Osaka Police Hospital, Osaka, Japan; Bayer HealthCare Pharmaceuticals, Berlin, Germany; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Abstract Disclosures


Background: The phase III GRID study showed that REG provides a significant improvement in progression-free survival (PFS) compared with PL in pts with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27, p<0.0001). Determining GIST genotype in TKI-refractory disease has proven challenging due to inter-tumoral heterogeneity and pt preference to avoid serial biopsies. To overcome this, we analysed circulating DNA in plasma as a source of tumor DNA and studied the correlation between mutational status and clinical outcome. Methods: DNA was isolated from both archival tumor tissue (n=102) and plasma at baseline (n=163) and analyzed for mutations via Sanger sequencing (tissue) or BEAMing (plasma). Results: Mutational frequencies for tumor tissue samples were: KIT, 66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%. For plasma, frequencies were: KIT, 58%; PDGFRA, 1%; KRAS, 1 out of 2 samples, BRAF, 0%. Detection of primary KIT mutations showed 84% concordance between tissue and plasma. Secondary KIT mutations were more commonly detected in plasma (47%) than in tissue (12%). Subgroup analysis based on mutational status showed an improved PFS in REG-treated pts vs PL in all subgroups by both central and local review of imaging studies. The presence of a secondary KIT mutation in plasma was associated with shorter PFS in pts receiving PL (HR 1.82, p=0.05). Pts with a KIT-exon 9 mutation received IM for a shorter period of time, and SU for a longer period of time, relative to other GIST genotypes. Pts with a PDGFRA mutation showed variable clinical responses, while 1/1 KRAS-mutant GIST did not respond well to IM, SU, or REG. Conclusions: KIT mutational status correlated to IM and SU treatment duration. While consistent with prior reports using tissue sampling, this validates the utility of plasma-based circulating DNA analysis of target oncogenes. Secondary KIT mutations appear to have a negative prognostic impact in GIST, while the clinical benefit of REG vs PL was not influenced by KIT mutational status. Clinical trial information: NCT01271712.