Unmet Needs in GIST: Toxicity Management

Shreyaskumar Patel, MD: That’s a nice summary, Andy. For the sake of discussion, would it be fair to then use the buzzword unmet need in this patient population? My definition of unmet need is that unless we have cured everybody with zero toxicity and the drug is completely free, there is always going to be some unmet need. Not to get that theoretical, but do you think it’s fair to say that the likelihood of response is relatively low? The clinical benefit rate reflected in progression-free survival is obviously decent, better than placebo, which is why the drugs got approved. But it is still limited.

This certainly comes at a price in terms of some of the toxicities you already described. It’s important to point out to the audience that part of the problem is that some of these toxicities overlap with the symptoms of bulky tumor. It’s not just the drug. It is the drug plus tumor that makes it difficult for patients to tolerate some of these second- and third-line agents for a more prolonged period of time. Which is what leads to some active research to find newer agents with a better therapeutic index.

Andrew Wagner, MD: Yeah, I absolutely agree. I would add though that aggressive management of toxicity with these drugs is critical. It often can make these drugs more tolerable, as can dose reductions for these medicines. Patients often do quite well with lower-than-labeled doses of these medicines. We try to get patients to labeled dose, but if they can’t tolerate it, then dose reduction is still an effective strategy for many patients.

As you described, we want to cure patients. The reality is that right now we can’t in the metastatic setting. Instead, we need to balance the control of the disease with the toxicity of the medications. There is absolutely a need for additional treatment strategies; there’s no question about it. To be more effective, more durable, and less toxic. But I also don’t want patients necessarily to be scared by us discussing the toxicities.

Many patients are able to tolerate these medicines and have prolonged periods of disease control with them. The numbers you quoted were absolutely accurate, but they’re the medians. Which means that half the patients are doing better than what we described. The progression of imatinib, sunitinib, and regorafenib is a very effective and tolerable strategy for the majority of patients. But there is absolutely no question that we need better drugs for all the reasons we just described.

I would also add that the other areas of clear unmet need until recently were…the VEGFR-mutant tumors, for which imatinib, sunitinib, and regorafenib do not seem to have any activity. We’ll come back to that shortly. Certainly for the SDH-mutant, GIST [gastrointestinal stromal tumors] too, although the VEGF receptor antagonists do seem to provide some benefit, we need better strategies for managing that subtype of GIST as well.

Shreyaskumar Patel, MD: You brought up a very important point of proactive management of adverse effects and toxicities, dose interruptions, dose reductions—that sort of stuff. That leads me to make 1 final point before we move on to the next topic. The recommended doses in the package label tend to be different than what we—the folks who treat these tumors day in and day out—use. This may be a point of education for the broader community listening in: 4 weeks on, 2 weeks off or 3 weeks on, 1 week off for sunitinib and regorafenib, respectively, frequently leads to a higher toxicity profile.

That is, 50 mg of sunitinib is poorly tolerated compared with a 37.5 mg daily dose. For regorafenib, 160 mg versus 120 mg. And from a pharmacological standpoint, a continuous dosing schedule may well be more effective in the long run, rather than the postdosing schedules. We all recognize and understand what the label indicates, but the standard practice among all of us who treat these tumors all the time is to indeed use sunitinib at 37.5 mg continuously daily and regorafenib possibly at 120 mg daily orally. That would certainly improve tolerance and not give breaks where the tumor has a chance to repopulate.

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.