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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.
J Clin Oncol 31, 2013 (suppl; abstr 10503)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
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.
Abstracts by G. D. Demetri:
A randomized, double-blind, placebo (Pbo)-controlled phase III study of ombrabulin plus cisplatin in patients (pts) with advanced-stage soft-tissue sarcoma after failure of anthracycline and ifosfamide chemotherapies.Category: Sarcoma - Soft Tissue
In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST).Category: Sarcoma - GIST
Educational Book Articles by G. D. Demetri:
A New Model: Physician-Patient Collaboration in Online Communities and the Clinical Practice of OncologyCategory: Lung Cancer
How to Decide Whether to Offer and Use "Nonstandard" Therapies in Patients with Advanced Sarcomas and Gastrointestinal Stromal Tumors: Global Variations in Clinical Practice, Assessment, and Access to Therapies in Diseases with Limited Incidence and DataCategory: Sarcoma
Presentations by G. D. Demetri:
Dynamics of Partnerships between Professionals and Patient Online Communities to Accelerate Clinical Research and Improve CareSession: Leveraging Virtual Patient Communities for Optimal Clinical Care and Research (Education Session)
Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.Session: Sarcoma (Oral Abstract Session)
Meeting: 2012 ASCO Annual Meeting
Session: Global Variations in Access to New Therapies for Sarcomas and Gastrointestinal Stromal Tumor (Education Session)