KIT resistance mutations identified by circulating tumor DNA and treatment outcomes in advanced gastrointestinal stromal tumor.

• DOI: 10.1200/jco.2022.40.16_suppl.11514
• Publication Date: 2022-06-06T17:43:03Z
• Authors: Steven Bialick; Brandon Edward Rose; Andrea P. Espejo-...; Priscila Barreto ...; Philippos Apolina...; Leticia Campoverde; Leylah Drusbosky; Junaid Arshad; Cesar Serrano; Suzanne George; Sebastian Bauer; Neha Goel; Shree Venkat; Aditi Dhir; Emily Jonczak; Gina Z. D'Amato; Jonathan C. Trent
• Keywords: PDGFRA; Imatinib Mesylate

11514 Background: Tyrosine kinase inhibitors (TKIs) are the cornerstone treatment for advanced GIST via pharmacologic targeting of driver oncogenes such as KIT. Detection KIT alterations through tissue-based next-generation sequencing (NGS) is common, but circulating tumor DNA (ctDNA)-based NGS a less invasive alternative to identify and resistance mutations in GIST. Patients (pts) with KIT-mutant benefit from first-line (1L) imatinib; however, may confer imatinib-resistance differential sensitivity subsequent TKIs. We sought analyze ctDNA pts determine whether certain were associated superior outcomes particular TKIs second-line beyond (2L+). Methods: Under an approved institutional review board protocol, retrospective analysis was performed available results (Guardant360; Redwood City, CA) (N = 104) who progressed on 1L imatinib between 2017-21. Using R statistical programming, we identified primary 64) known exons 13 25) 17 35). studied median time failure (mTTF), defined start end (months) due progressive disease or toxicity, each 2L+ drug. Kaplan-Meier methods, calculated Cox proportional-hazard ratios (HR) confidence intervals (CI) p-values significance. Results: 49% male (median age 66; range, 31-94). Driver detected 80% 83), including KIT, NF1, PDGFRA BRAF. Of those alteration, 12 (19%) had exon 9 52 (81%) 11 mutations. observed 25; V654), 14 2; T670), 45; D816, D820, N822, Y823). Pts received therapy avapritinib, dose-escalated imatinib, nilotinib, pazopanib, ponatinib, regorafenib, ripretinib, sunitinib. mTTF V654 treated sunitinib, 800mg, other 10.8, 7.5, 3.7 months, respectively. TTF sunitinib vs drugs showed HR 0.51 (CI 0.33-0.8), p 0.003. (non-V654) 4.6, 1.2, 6.3 Comparison regorafenib not statistically significant. Conclusions: noninvasive tool detecting setting Regorafenib mutations, possibly their own activity against alterations. ctDNA-guided warrants evaluation prospective clinical trial.