Patients with gastrointestinal stromal tumors (GISTs) who have KIT mutations may benefit from regorafenib treatment without the selection of particular mutation patterns that confer resistance to treatment, according to results of a new study published in Gastric Cancer.

However, the authors stressed that the study “was not powered to address biomarker-related questions” and that the results are “exploratory and hypothesis-generating.”

A multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial called GRID showed that regorafenib treatment improved progression-free survival in patients with GIST regardless of KIT mutations.


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In the present study, a team of researchers led by Michael Teufel, PhD, executive director of translational medicine and clinical pharmacology at Boehringer Ingelheim, conducted a retrospective, exploratory analysis of the GRID trial to clarify the impact of different KIT mutations on treatment outcomes.

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They analyzed the sequences of archived tumor samples collected before enrollment in GRID, with 102 samples undergoing Sanger sequencing and 42 samples undergoing next-generation sequencing. They also analyzed plasma samples collected at baseline.

The results showed that 68 of the 102 (67%) tumor samples had a KIT mutation. Of those, 62 had primary mutations in exons 9 and 11, and 12 had secondary mutations in exons 13, 14, 17, and 18.

Of the plasma samples, 81% had KIT mutations at baseline, which included the M541L polymorphism. Mutations in other oncogenes or in the PDGFR, KRAS, or BRAF genes were rare. Patients with both primary and secondary KIT mutations benefited from regorafenib in terms of progression-free survival.

When the researchers analyzed patient-matched samples taken at baseline and at the end of the treatment period, they found that there were heterogeneous KIT mutational changes but no specific mutation pattern following treatment.

“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,” the researchers concluded.

References

Jeffers M, Kappeler C, Kuss I, et al. Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial. Gastric Cancer. Published online January 20, 2022. doi:10.1007/s10120-021-01274-6

Study of regorafenib as a 3rd-line or beyond treatment for gastrointestinal stromal tumors (GIST) (GRID). ClinicalTrials.gov. January 7, 2011. Updated January 29, 2021. Accessed February 3, 2022.