Journal Article

DKFZ-2023-00835

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Circulating tumor DNA analysis of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor treated with avapritinib or regorafenib.

Serrano, C. ; Bauer, S.DKFZ* ; Gómez-Peregrina, D. ; Kang, Y.-K. ; Jones, R. L. ; Rutkowski, P. ; Mir, O. ; Heinrich, M. C. ; Tap, W. D. ; Newberry, K. ; Grassian, A. ; Shi, H. ; Bialick, S. ; Schöffski, P. ; Pantaleo, M. A. ; von Mehren, M. ; Trent, J. C. ; George, S.

2023
Elsevier Amsterdam [u.a.

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Please use a persistent id in citations: doi:10.1016/j.annonc.2023.04.006

Abstract: The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that are indicated for avapritinib treatment. Here, ctDNA sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine-kinase inhibitor (TKI) resistance and to determine its clinical validity and utility.VOYAGER (N=476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and 1 or 2 additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end-of-treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes.386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib, and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib.CtDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.

Keyword(s): Avapritinib ; GIST ; KIT ; PDGFRA ; ctDNA ; regorafenib

Note: 2023 Jul;34(7):615-625

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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