ctDNA as a Molecular Biomarker in the Phase II Trial of Imatinib plus Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumor

Abstract Purpose: This study investigated factors that affected ctDNA detection and ctDNA as a molecular biomarker in a phase II trial of imatinib and binimetinib in newly diagnosed advanced gastrointestinal stromal tumor, including patients exposed to imatinib within 4 weeks of trial enrollment. Experimental Design: Plasma and tumor tissue samples were collected at baseline, during treatment, and upon progression. DNAs extracted from plasma and tumor tissue were analyzed using genomic assays, Memorial Sloan Kettering Analysis of Circulating cfDNA to Evaluate Somatic Status and Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, respectively. Sequenced ctDNA detection of the primary oncogenic driver was determined and correlated with clinical characteristics. Results: Patients (n = 31) included in this analysis had KIT mutations (n = 29, 94%) and metastatic disease (n = 24, 77%) and achieved the best response of partial response (n = 22, 71%), stable disease (n = 8, 26%), or progressive disease (n = 1, 3%). Sixteen patients (52%) were exposed to imatinib at baseline. The ctDNA detection rate of the primary oncogenic driver at baseline was 39% (n = 12/31) and was significantly more likely in patients who were treatment-naïve (n = 15) or had ≤4.2 weeks of treatment (n = 8) than in those otherwise (48% vs. 13%; P value = 0.004). Baseline ctDNA detection did not correlate with tumor burden or stage. The ctDNA serial analysis of the primary oncogenic driver paralleled and sometimes preceded radiographic response. ctDNA detected resistance mutations in KIT (n = 4). Active treatment influenced the detection of secondary KIT alterations in one patient. Conclusions: Active therapy at the time of ctDNA collection negatively affected the ability to detect primary and secondary KIT alterations in sequenced ctDNA from patients with advanced gastrointestinal stromal tumor. ctDNA responses may precede radiographic responses and merit further investigation.