Abstract
BackgroundIn the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. In this retrospective, exploratory analysis of the GRID trial, we investigated whether a more comprehensive KIT mutation analysis could identify mutations that impact treatment outcome with regorafenib and a regorafenib-induced mutation pattern.MethodsArchived tumor samples, collected at any time prior to enrollment in GRID, were analyzed by Sanger sequencing (n = 102) and next-generation sequencing (FoundationONE; n = 47). Plasma samples collected at baseline were analyzed by BEAMing (n = 163) and SafeSEQ (n = 96).ResultsIn archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). At baseline, 81% of samples (78/96) had KIT mutations by SafeSEQ, including the M541L polymorphism (sole event in 6 patients). Coexisting mutations in other oncogenes were rare, as were mutations in PDGFR, KRAS, and BRAF. Regorafenib showed PFS benefit across all primary and secondary KIT mutational subgroups examined. Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment.ConclusionThese data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.
Highlights
The majority of gastrointestinal stromal tumors (GISTs; 70–80%) have mutations in the KIT receptor tyrosine kinase gene resulting in constitutive ligand-independent activationRidgefield, CT, USA of KIT intracellular signaling [1, 2]
The results presented here confirm the well-established observation that the majority of GISTs harbor KIT mutations, and the rapid translation of these mutational data into effective targeted kinase inhibitor therapies has borne out their importance in GIST pathogenesis [2, 29]
Being the second-most frequently mutated oncogene in GIST, mutations in PDGFR were rare in this study, which could be due to the fact that PDGFRA- mutated GISTs tend to have a lower risk of recurrence [30]
Summary
The majority of gastrointestinal stromal tumors (GISTs; 70–80%) have mutations in the KIT receptor tyrosine kinase gene resulting in constitutive ligand-independent activationRidgefield, CT, USA of KIT intracellular signaling [1, 2]. In the phase 3 GRID trial, regorafenib improved progression-free survival (PFS) independent of KIT mutations in exons 9 and 11. Results In archived tumor samples, 67% (68/102) had a KIT mutation; 61% (62/102) had primary KIT mutations (exons 9 and 11) and 12% (12/102) had secondary mutations (exons 13, 14, 17, and 18). Available patient-matched samples taken at baseline and end of treatment (n = 41; SafeSEQ), revealed heterogeneous KIT mutational changes with no specific mutation pattern emerging upon regorafenib treatment. Conclusion These data support the results of the GRID trial, and suggest that patients may benefit from regorafenib in the presence of KIT mutations and without the selection of particular mutation patterns that confer resistance.
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