GIST Mutations: Treatment Decision Factors

Andrew Wagner, MD: Shreyas, given the different biology of the different mutations, should all patients be started on imatinib if they developed metastatic disease? How does mutation status influence your treatment decisions?

Shreyaskumar Patel, MD: This is why the guidelines clearly recommended that mutational analysis is highly recommended at the time of the first diagnosis. It’s important to at least find the subsets that should not be starting imatinib. The vast majority of them are sensitive to imatinib. Imatinib is the default first-line therapy in the metastatic disease setting. But the few exceptions where that would not be the right choice would be the PDGFR ADA42B–mutant location that you already briefly alluded to.

There is a phenotype that goes with it. It’s a very large gastric tumor that frequently looks indolent. But if it’s a 30-cm tumor, people tend to get nervous about it. The tendency tends to be this has to be high-risk, and I’m going to give this patient the imatinib in the adjuvant setting or even when there is metastatic disease. But that’s 1 subset that is resistant to imatinib.

The other subset that we must pay attention to is the so-called wild type, the non-KIT, non-PDGFR mutant subset. Especially the SDH-mutant subset that you talked about, where there is limited evidence that imatinib would be off any significant benefit. There are some of these subsets where we have to be careful. This is where having mutational analysis at the first point of entry can certainly guide therapy with regard to the best kinase inhibitor for that patient.

Andrew Wagner, MD: Great. Shreyas, that does remind me: I mentioned that there were 4 major classes of mutations in GIST [gastrointestinal stromal tumor]. There are a couple of other mutations that I neglected to discuss, so let me mention those and get your thoughts about whether they should be true. The other 2 that I would highlight are mutations in BRAF, notably the V600E mutation that’s also common in melanoma, and mutations in NF1, frequently in patients who have underlying neurofibromatosis type 1. Those are both rare tumors associated with the small bowel usually. But should these be treated with imatinib?

Shreyaskumar Patel, MD: The right answer, I guess, is that there are very, very, very limited data on that. I wish there was good evidence to support the answer 1 way or another. There are anecdotal responses to BRAF inhibitors in the BRAF-mutant GIST. There we have an out if you will. There was knowledge that one could certainly consider trying a BRAF inhibitor. But all of us who have treated this disease know that at some point in time, a tumor develops a resistance and you’re running out of options. In which case a trial of the standard kinase inhibitors becomes the default choice. Not because it’s the right 1, but that’s the only viable choice.

For the NF1 subset, the biology tends to be variable. That’s the subset that we would usually routinely not treat. But you would need to make sure that this decision is individualized. These are patients who may have a variable rate of progression. In a given patient where the rate of progression is relatively rapid—and these are qualitative terms, and we all realize that—if the tumor is progressing at an every-3-month interval, it’s hard to justify continued close observation. In that setting, by default we run through the commercially available and approved agents to treat these tumors.

Andrew Wagner, MD: Is there any role for conventional chemotherapy in the treatment of GIST?

Shreyaskumar Patel, MD: This has been tried. I think back to the early to mid-1990s with presented posters and published that the standard chemotherapy just does not have activity in this disease. In fact, we would always joke in the conference rooms where we are designing clinical trials for a new drug, that if you want to make a new drug succeed in soft-tissue sarcomas, exclude GI [gastrointestinal] leiomyosarcomas.

If you want to break that drug you include those tumors. Historically, when we used to call these GI leiomyosarcomas, none of the standard chemotherapeutic agents that we think have some activity in soft-tissue sarcomas works for this disease. That’s 1 blanket statement or emphatic statement that can be made, that standard sarcoma chemotherapy has no role in the treatment of gastrointestinal stromal tumors.

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.