Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial

Abstract

Background In 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. Methods Archived 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). 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). 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. 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. The study was not powered to address biomarker-related questions, and the results are exploratory and hypothesis-generating.

Role and Significance of c-KIT Receptor Tyrosine Kinase in Cancer: A Review

“…This has led to the approval of other TK inhibitors, such as sunitinib and regorafenib, with activity against secondary c- kit mutations [ 169 ]. Among these, there are agents such as sunitinib, which elicits longer progression-free survival and overall survival in patients that harbor exon 13 or 14 secondary c- kit mutations compared to those with exon 17 or 18 secondary c- kit mutations [ 167 , 168 ], and regorafenib, which has equal efficacy in tumors with secondary exon 13/14 or exon 17/18 mutations, or combinations thereof [ 170 ]. Ripretinib, a novel type II switch control kinase inhibitor, is a broad-spectrum inhibitor of secondary drug resistance mutations, including activation loop mutations targeted by type I inhibitors [ 171 ].…”

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

“… 102 , 113 Sunitinib is more effective for patients with exon 13/14 secondary c-kit mutations compared to those with exon 17/18 secondary c-kit mutations, 108 , 111 while regorafenib is an effective choice for patients whose tumors harbor secondary exon 13/14 or exon 17/18 mutations. 114 …”

“…102,113 Sunitinib is more effective for patients with exon 13/14 secondary c-kit mutations compared to those with exon 17/18 secondary c-kit mutations, 108,111 while regorafenib is an effective choice for patients whose tumors harbor secondary exon 13/14 or exon 17/18 mutations. 114 Another TKI that was approved by the US FDA in 2020, based on the positive results obtained from the INVICTUS trial, is ripretinib. It was recommended for advanced or metastatic GIST patients who were resistant to three or more kinase inhibitors including imatinib.…”