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Rationale for Targeting KIT in Advanced SM

Insights From: Hervé Dombret, MD, Institut Universitaire d’Hématologie; Richard M. Stone, MD, Dana-Farber Cancer Institute; Cem Akin, MD, University of Michigan
Published Online: Tuesday, May 16, 2017



Transcript:

Cem Akin, MD:
There is an unmet need for treatment of advanced mastocytosis, and that’s because of the toxicities associated with cladribine and interferon-alpha and the inability of imatinib to inhibit the D816V mutation seen in the majority of patients with advanced varieties. So, that brings us to the question of, what would be the most appropriate target to cure this disease? The obvious answer is an inhibitor that works against the D816V mutation. The research has focused on tyrosine kinase inhibitors with specific abilities to inhibit the D816V KIT mutation.

One such inhibitor is midostaurin, or PKC412. This is a multi-targeted kinase inhibitor. It is not specific for KIT or even tyrosine kinase; it inhibits a variety of other kinases. But it also inhibits D816V and wild-type nonmutated KIT versions. Because of that reason, there has been a lot of interest in trying this medication in mastocytosis. There are other candidate drugs that work more specifically against the D816V mutation that are in early stage clinical trials, but midostaurin appears to be the most advanced along the clinical trial and the approval process. At this point, it has not been approved by the FDA yet. It is currently under review.

Richard M. Stone, MD: The reason why midostaurin was tested was based on work done in the laboratory, actually by Dr. Gary Gilliland years ago—who’s now head of the cancer center at Fred Hutchinson—who’s looking for tyrosine kinase mutations and drugs that could inhibit them. Midostaurin was shown to inhibit the D816V or cells that were transformed by the D816V c-KIT mutation, as well as a lot of other tyrosine kinases, like FLT3. So, it was known to be a D816V inhibitor. Now, imatinib is a tyrosine kinase inhibitor—inhibits ABL—and was thought to maybe be a KIT inhibitor, but it wasn’t very effective in systemic mastocytosis because it’s not a very good KIT inhibitor.

Some of the second-generation ABL inhibitors, namely dasatinib, are KIT inhibitors as well. Dasatinib does have a role in some patients with systemic mastocytosis, but it’s not very effective. So, if you were looking for an effective D816V inhibitor, midostaurin was a logical choice.

Transcript Edited for Clarity
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Transcript:

Cem Akin, MD:
There is an unmet need for treatment of advanced mastocytosis, and that’s because of the toxicities associated with cladribine and interferon-alpha and the inability of imatinib to inhibit the D816V mutation seen in the majority of patients with advanced varieties. So, that brings us to the question of, what would be the most appropriate target to cure this disease? The obvious answer is an inhibitor that works against the D816V mutation. The research has focused on tyrosine kinase inhibitors with specific abilities to inhibit the D816V KIT mutation.

One such inhibitor is midostaurin, or PKC412. This is a multi-targeted kinase inhibitor. It is not specific for KIT or even tyrosine kinase; it inhibits a variety of other kinases. But it also inhibits D816V and wild-type nonmutated KIT versions. Because of that reason, there has been a lot of interest in trying this medication in mastocytosis. There are other candidate drugs that work more specifically against the D816V mutation that are in early stage clinical trials, but midostaurin appears to be the most advanced along the clinical trial and the approval process. At this point, it has not been approved by the FDA yet. It is currently under review.

Richard M. Stone, MD: The reason why midostaurin was tested was based on work done in the laboratory, actually by Dr. Gary Gilliland years ago—who’s now head of the cancer center at Fred Hutchinson—who’s looking for tyrosine kinase mutations and drugs that could inhibit them. Midostaurin was shown to inhibit the D816V or cells that were transformed by the D816V c-KIT mutation, as well as a lot of other tyrosine kinases, like FLT3. So, it was known to be a D816V inhibitor. Now, imatinib is a tyrosine kinase inhibitor—inhibits ABL—and was thought to maybe be a KIT inhibitor, but it wasn’t very effective in systemic mastocytosis because it’s not a very good KIT inhibitor.

Some of the second-generation ABL inhibitors, namely dasatinib, are KIT inhibitors as well. Dasatinib does have a role in some patients with systemic mastocytosis, but it’s not very effective. So, if you were looking for an effective D816V inhibitor, midostaurin was a logical choice.

Transcript Edited for Clarity
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