In a study that evaluated, for the first time, the clinical validity and potential clinical utility of circulating tumour DNA (ctDNA) determination in a large cohort of patients with metastatic gastrointestinal stromal tumour (GIST) with plasma samples collected prospectively in the VOYAGER study, the researchers documented the landscape of KIT and PDGFRA mutations in metastatic, imatinib-resistant GIST. The selective pressure exerted with prior treatment lines promotes a shift toward increased resistant subpopulations in the KIT activation loop. Individual mutations in KIT/PDGFRA determine tyrosine kinase inhibitor (TKI) sensitivity and resistance in metastatic GIST. ctDNA-detected KIT/PDGFRA mutations in imatinib-resistant GIST prognosticate third- or fourth-line TKI treatment outcomes.
Consideration of ctDNA to monitor disease progression and provide more personalised treatment options in patients with GIST should continue to be explored according to Dr. César Serrano of the Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitario Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus in Barcelona, Spain, and colleagues who published the findings on 25 April 2023 in the Annals of Oncology.
The authors wrote in the background that GIST constitutes a paradigm to address the clinical impact of ctDNA determination. The majority of GISTs are driven by gain-of-function mutations in genes encoding KIT (approximately 70%) or PDGFRA (approximately 15%) receptor tyrosine kinases. Targeted inhibition of these receptors with first-line imatinib achieves major responses and durable clinical benefit.
KIT oncogenic signalling remains the primary oncogenic driver after imatinib failure, as emergence of secondary mutations in KIT is the primary cause of imatinib resistance in approximately 90% of KIT-mutated GISTs. Previous tumour tissue-based series showed these mutations cluster in the ATP-binding pocket (encoded by exons 13 and 14) and the activation loop (encoded by exons 17 and 18).
The current treatment paradigm of imatinib-resistant metastatic GIST does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutated GISTs that are indicated for avapritinib treatment.
Several studies have attempted to provide evidence to support use of ctDNA determination to guide therapeutic decisions. The rarity of this disease together with the heterogeneity of technologies used in previous studies have limited the understanding of GIST progression and the development of ctDNA analysis technology as a clinical tool.
In this work, the researchers evaluated prospectively collected ctDNA molecular data from the phase III VOYAGER study to understand the evolving landscape of TKI progression and expand on the potential clinical utility of ctDNA determination in patients with advanced GIST who experienced progression after 2 or 3 lines of treatment.
The VOYAGER compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutated GIST previously treated with imatinib and 1 or 2 additional TKIs. 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.
A total, 386 of 476 patients with KIT/PDGFRA-mutated tumours underwent baseline 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 (80.4%) and ATP-binding pocket (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-binding pocket mutations negatively prognosticated avapritinib activity, with a median progression-free survival (PFS) of 1.9 versus 5.6 months for regorafenib. Median PFS for regorafenib did not vary regardless of the presence or absence of ATP-binding pocket or activation loop mutations and was greater than median PFS with avapritinib in this population. Secondary KIT ATP-binding pocket pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib.
The authors wrote that this analysis of the mutational spectrum of acquired resistance as demonstrated by ctDNA reinforces the critical role of KIT oncogenic signalling and provides the basis for future drug development in GIST after progression to various lines of treatment.
It also demonstrates that ctDNA assessment might predict TKI activity in metastatic GIST in the third- and fourth-line setting. Although the VOYAGER study did not yield significant differences in median PFS between avapritinib and regorafenib, ctDNA determination revealed the detection of ATP-binding pocket mutations in plasma was a strong negative prognostic marker of avapritinib activity. Patients with GIST harbouring activation loop mutations in the absence of ATP-binding pocket achieved equal benefit from avapritinib and regorafenib. This, in turn, is consistent with the known mechanism of action of avapritinib, its superior efficacy in patients with tumours harbouring the PDGFRA D842V mutation, and the enrichment of KIT exon 13 V654A subpopulations observed at the time of progression.
This project was funded in part by the Fero Foundation and the Asociación Española Contra el Cáncer. The study was funded by Blueprint Medicines Corporation.
Reference
Serrano C, Bauer S, Gómez-Peregrina D, et al. 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. Annals of Oncology; Published online 25 April 2023. DOI: https://doi.org/10.1016/j.annonc.2023.04.006