Andrew Wagner, MD: Sharesh, you just had a great segue to a very important question: If indeed in the fourth-line setting we’re seeing efficacy similar to what we were seeing in second-line sunitinib, what is the role of, or what is the potential role for ripretinib in earlier line treatment? How is that being studied?
Shreyaskumar, Patel, MD: Yes, it is being studied. But let me back up a step. I think you very nicely outlined the mechanism of action. From my standpoint—and I’ll see what your thoughts are—1 of the most interesting aspects of ripretinib, long before we saw some encouraging clinical data, was indeed its mechanism of action. That is, this switch-pocket inhibition, to very much simplify it, tells me that if it’s going to minimize or delay the conformational changes in the kinase and delay the development of secondary resistance, the drug may very much have a role in earlier-line settings.
From a mechanistic standpoint, it kind of made sense. The PFS [progression-free survival] data in the fourth-line setting certainly support that notion. The final part of that equation is that we’ve already outlined that sunitinib, while a very important addition to the therapeutic armamentarium and has been a part of standard of care, is probably going to remain a standard of care. But I think things can be made better.
A better therapeutic index, with improvement in patient-related outcomes, would certainly be a very helpful addition to the current therapeutic armamentarium. For all these reasons, theoretically it absolutely makes sense that ripretinib gets tested in the earlier-line setting. As you outlined, there is the INTRIGUE trial going on. It’s a randomized phase 3 trial comparing ripretinib with sunitinib in the second-line setting. The trial is ongoing.
We await the results of that trial. The hope clearly is that despite the comparison to an active control—and here is where the glitch comes around—in the soft tissue sarcoma space we’ve seen plenty of trials with active treatment controls fail and some of them succeed. The INTRIGUE trial that will randomly compare ripretinib with sunitinib in the second-line setting will truly answer the question as to the value of the mechanism of action as it relates to delaying the secondary resistance development.
Then frankly there is the patient’s quality of life—how long they will continue therapy, and that sort of stuff. If we go back to the INVICTUS trial, a testament to the tolerability of the drug is still a relatively low discontinuation rate and relatively low and manageable dose interruptions and dose adjustments. These are the parameters that clearly tell us how well the drug is tolerated. Not just the classic phrase, “The drug is well tolerated.” But those are the actual parameters that reinforce that.
Transcript edited for clarity.
Andrew Wagner, MD, reports the following disclosures: Consulting with Deciphera, Daiichi-Sankyo, NanoCarrier. He also reports research funding to his institution with Daiichi-Sankyo, Eli Lilly, Karyopharm, Plexxikon, Aadi Biosciences.