Treatment Options After Relapse

Andrew Wagner, MD: Sharesh, a number of other tyrosine kinase inhibitors had been used either in clinical studies or more anecdotally for management of refractory GIST [gastrointestinal stromal tumors]. Depending on when the other drugs were developed, some of these were in the second- or third-line setting or certainly in the fourth-line setting. I was wondering if you could comment a little bit on what's been described as well as your own experience with the use of these medicines. This would include dasatinib, nilotinib, pazopanib, and sorafenib as examples.

Shreyaskumar, Patel, MD: Sure. I think it would be most appropriate to start this answer by clarifying it to the audience that the standard of care as long as possible in the second line and beyond line settings should be a clinical trial if available. That sort of admits to what we have already talked about, the limitations of the currently available agents, despite their approval and regulatory availability.

When clinical trials are not available, or a given patient is not eligible, or they cannot make it to a place where the trial is available, it has been an important and acknowledged fact that keeping these patients on a kinase inhibitor is always helpful as opposed to leaving them off a kinase inhibitor. I have frequently tried to explain it to patients and even our oncology colleagues that while it's totally unconventional for us to go back to the same chemotherapy, after chemotherapy hasn't worked for a given tumor pick one.

This is one where rechallenges with some of the same agents has been standard of care or has been the practice. And sometimes rather than rechallenging with the same agents we would use an analog if you will. So imatinib analog is nilotinib. We have had dasatinib as an SRC inhibitor available. Sorafenib and pazopanib as VEGF inhibitors. There are single arm trials or retrospective series of experiences that have been presented and even published with all of these agents. In the interest of time if I can summarize and lump all of them together, I think a fair statement is that dasatinib, nilotinib, sorafenib, pazopanib, these agents when tried in the fourth and beyond line setting if you will, probably helped maybe 1 out of 5 patients for maybe an average of I would say median of about 2 to 3 months.

As you pointed out earlier, we all have anecdotes who benefited a lot longer and there are ones who don't benefit at all. These drugs were felt to have some proof of principle activity and I think mechanistically it's not too hard to understand because some of the cells that are still addicted to the same kinase pathways. And inhibiting that certainly helps the tumor. It may progress, as I use a car analogy at 30 to 40 miles an hour, as opposed to off a kinase inhibitor that you might have made more but 50, 60 miles an hour.

And that faster rate of progression causes more symptoms, and difficulty in management, and quality of life. I think these agents have had some activity but clearly not enough for them to go to an indication or a registrational trial. The toxicity profile of all of these agents run through the same issues that the second- and third-line therapy go through. In fact, in some ways worse because typically the tumor bulk is more. And there are more abdominal and tumor related symptoms.

The response rates with this are typically relatively low, under the 10 % cut off number, if you will. And between the low response rate, relatively modest clinical benefit rate, none of these would be considered standard of care. Which again weighs into the fact that we needed newer agents that we have now blessed to have, that can certainly help us treat a patient for a little longer.

Andrew Wagner, MD: Yeah, absolutely agree and would add as you mentioned earlier the availability of clinical trials for eligible patients as well is a great approach to trying to find newer therapies for individual patients but as well as to move the field forward and learn more about how we can treat this disease.

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.