Post-Conference Perspectives: Advanced Gastrointestinal Stromal Tumors - Episode 3
Jean-Yves Blay, MD, PhD: Ripretinib is in new class of tyrosine kinase inhibitors [TKIs], very different from the classical tyrosine kinase inhibitors used for the treatment of GISTs [gastrointestinal stromal tumors]: imatinib, sunitinib, and regorafenib. What it does actually is block the kinase in an inactive form by binding to the activated form of the kinase much more efficiently than the first generation of tyrosine kinase inhibitors. And the reason for that is that all the resistance mutations, which are actually the major problem for patients with advanced GISTs that drive the secondary resistance progression and intimately death of the patients, are being blocked by this new tyrosine kinase inhibitor.
This is probably why we have such a dramatic impact on both progression-free survival and also overall survival in this study. This is clearly a new class of tyrosine kinase inhibitor, which is completely changing the landscape, because in the past we were trying to cope with a secondary resistance by using drugs that were targeting specific secondary resistance imitation. Here we are targeting more, so this is a much more efficient TKI for this purpose.
The safety profile of ripretinib was very much in concordance with what has been observed in the phase I setting. There are actually very limited adverse effects for ripretinib. We observed fatigue and alopecia, which is observed more frequently than with the other tyrosine kinase inhibitors of this class for KIT. I think in about 20% of the patients experienced grade 1, grade 2 adverse events. There were also some gastrointestinal effects, which were generally mild. There were no cognitive effects as observed with other inhibitors of this class of certain series of patients; again, very consistent with what was observed in the phase I setting.
We have a tyrosine kinase inhibitor of a new generation, which has a safety profile that is very much favorable, and actually probably very superior to the second generation of TKIs that we had in the past: sunitinib, regorafenib, sorafenib, and pazopanib, which were used so for the treatment of GIST. Here we are speaking of a drug that is easy to handle for the patient.
The practical implication of a broad-spectrum tyrosine kinase inhibitor for KIT and PDGFR receptor alpha actually results from the nature of resistance, which is being observed in patients receiving first-generation TKIs. What is happening for this patient is that accrual resistance emerged. Here you have a patient with several sites of metastases, several metastases. And most of the time progression happens in 1 of few sites. This is sometimes referred to as focal progression. And what is happening in this site is that actually some clones equipped with specific resistant mutations do progress, subsequently, or the site may progress. But what is important here is the heterogeneity of the landscape of mutation.
Patients may have mutations including resistant protein in different metastases with different types of resistant mutations. How do we target that? Previously, we used sunitinib and regorafenib, which are active against subsets of these resistant mutations, and target better for instance exon 11, exon 17, and exon 18 mutations for 1 and exon 13 and exon 14 for the other. That may be an issue when you have a patient who is affected with multiple types of mutation in different metastases.
Actually, this is something that is being observed. If you look at circulating tumor DNA, where you do not capture the single mutation in the specific site where you biopsy it but outside it. With a tyrosine kinase inhibitor of this generation such as ripretinib, we are able to target all resistant mutations. We don’t have to face this problem. We have partial omni-focal resistance. Then we use the treatment to target all resistant mutations with KIT and PDGF receptor alpha as well. That’s very much an advantage that is probably 1 of the explanations of the major benefit b
Transcript Edited for Clarity