Circulating tumor DNA (ctDNA) analyses of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor (GIST).

101 Background: The genotype of primary mutations predicts imatinib response in untreated metastatic GIST. However, the sequence salvage treatments GIST is based solely on chronological order registration trials. ctDNA sequencing offers a powerful diagnostic tool to detect resistance but has not been shown correlate with outcomes clinical trials pretreated patients (pts). We analyzed samples collected at baseline phase III VOYAGER trial (NCT03465722) describe landscape KIT alterations and its association pts treated avapritinib or regorafenib. Methods: In VOYAGER, 476 advanced KIT-mutant were randomly assigned (240 pts) regorafenib (236 3rd-4th line. Baseline plasma was Guardant 360 (G360), 74-gene panel. molecular subgroups determined correlated outcomes. PDGFRA-mutant GISTs excluded from analysis. Results: analysis performed 386/476 (81%). detected 333 (86%), 250 18 showing least one (75%) PDGFRA (5%) variant, respectively. 71% (exon 11, 56%; exon 9, 14%; 13, 1%) secondary 55% pts. Activation loop (AL, exons 17 18) more commonly affected (44%) than ATP-binding pocket (ABP, 13 14; 23%). Among tumors, multiple within individual tumors (mean, 2.56; range, 1-14). Notably, 17% had > 3 6.07; 4 14). Median PFS OS shorter for whose positive V654A T670I (ABP hot spots) when vs. regorafenib: mPFS, 1.9 mo 7.4 mo; log-rank p <.001; mOS, 8.3 11.7 log rank =.0651. mPFS mutation if concurrently V654A/T670I absent avapritinib, no difference OS: 4.7 6.7 =.03; 19.2 NR; =.628. longer ABP compared those present (5.6 <.001). There differences considering AL (3.8 3.9 =.622) avapritinib. Regorafenib showed similar activity regardless mutational status location mutation. Conclusions: Hybrid capture-based detects majority TKI-resistant GIST, including heterogeneity mutations. This study first show that correlates Identification (exon13/14) negatively activity.