Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain

Abstract

Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance. Significance: Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST. This article is highlighted in the In This Issue feature, p. 1

Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward

“… 22 In recent preclinical work, a novel human GIST cell line with a knocked-in D842V mutation was highly resistant to ripretinib, thus arguing against ripretinib activity in these patients. 17 This data points in the same direction regarding its homologous KIT exon 18 D816V mutation. Finally, although ripretinib was granted for the treatment of all GIST molecular subtypes, only seven GIST WT patients were randomized to ripretinib, and therefore ripretinib activity in this setting remains unknown.…”

“…KIT and PDGFRA primary and secondary genotypes have consistently predicted the activity of the different TKIs investigated in GIST. 10 , 14 , 16 , 17 The innovative dual mechanism of action of ripretinib allows the effective inhibition of a broad range of KIT and PDGFRA mutations through promoting the shift toward the inactive conformation of the kinases. Although ripretinib has shown to be effective against all KIT and PDGFRA mutants tested in a wide range of cellular models, it is necessary to see if this holds true in correlative studies from the two clinical trials.…”

“…For instance, there are several reports supporting the survival benefit of maintaining TKI treatment after progression. 17 , 36 Imatinib re-challenge could be an option as well. 35 Other considerations could be: include shorter washing times from prior treatments (i.e.…”

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

“…However, as expected, the onset of resistance may occur over time also for D842Vmutant GIST [28]. In fact, a recent study by Bauer et al provided the first evidence of secondary resistance mutations through sequencing of tumor tissue and plasma biopsies in six out of seven patients receiving avapritinib, suggesting that understanding the emer-gence of resistance represents an unmet need in this setting [28].…”

Individualized Management of Blood Concentration in Patients with Gastrointestinal Stromal Tumors

“…KIT/PDGFRA wildtype GIST and PDGFRA D842V do not respond to IM or other TKIs, but PDGFRA D842V most may respond to avapritinib. 80 SDH-deficient also had no response to IM and limited response to SU or regorafenib. NF1 mutation also have little response to TKIs.…”