Biomarker subanalysis of the phase III study of regorafenib vs placebo in TKI-refractory metastatic GIST

Detection of oncogenic kinase mutations in circulating plasma DNA and correlation with clinical benefit

Researchers using a tool called BEAMing technology, which can detect cancer-driving gene mutations in patients’ blood samples, were able to identify oncogenic mutations associated with distinct responses to therapies used to treat patients with metastatic gastrointestinal stromal tumours (GIST), according to data presented at the AACR Annual Meeting 2013, held in Washington D.C., April 6-10.

GRID (GIST–Regorafenib In Progressive Disease) is a phase III study for patients with advanced GIST following failure of imatinib and sunitinib who were randomized to receive either the multikinase inhibitor regorafenib or placebo. Regorafenib demonstrated a highly significant improvement in progression-free survival compared with placebo (HR 0.27, p<0.0001).
A preplanned retrospective biomarker analysis was conducted to assess GIST genotypes in GRID patients and to explore the possible impact of different driver oncogene mutations on clinical outcomes.

Dr George Demetri, director of the Ludwig Centre at Dana-Farber Cancer Institute and Harvard Medical School in Boston and colleagues conducted this exploratory analysis on patients in the GRID study to assess GIST genotypes. They isolated DNA from archival tumour tissue, which was then analysed for mutations in two genes, KIT and PDGFRA, which generate the cancer-driving proteins that are the targets of imatinib, sunitinib and regorafenib. The researchers believed that primary mutations would be detectable using traditional analysis, but that those mutations that developed after treatment with imatinib and sunitinib would not be detectable. They then took blood samples drawn at study entry after failure of both imatinib and sunitinib, and analysed them for mutations via BEAMing technology.

Mutations in the KIT gene were detected in 60% of the blood samples compared with 65% of the tumour tissue samples. However, when focusing their analysis on secondary KIT mutations, which are the mutations that drive resistance to targeted therapies like imatinib and sunitinib, the researchers found mutations in 48% of blood samples compared with only 12% of tissue samples. In addition, nearly half of the plasma samples in which secondary KIT mutations were identified harboured multiple secondary mutations, consistent with the results of previous studies on fresh tumour biopsies taken following resistance to both imatinib and sunitinib. Regorafenib was clinically active compared with placebo in all KIT mutational subgroups evaluated, including in patients with secondary KIT mutations.

According to Dr Demetri, these results show a clear association between the presence of different cancer-driving gene mutations in patients’ blood samples and clinical outcomes.
The researchers concluded that in GIST patients from the GRID trial, driver oncogenic mutations and secondary oncogenic mutations leading to imatinib and sunitinib resistance are readily detectable via BEAMing of circulating DNA from plasma. BEAMing may provide a real-time assessment of tumour genotype in GIST and other cancers using blood-derived circulating DNA that may be more comprehensive than tumour sampling. GIST patients with a wide spectrum of primary and secondary mutations in oncogenic kinases benefit from treatment with regorafenib.