Case Studies in Thyroid Cancer - Episode 19

Pralsetinib: MOA and ARROW Trial Data

Lori Wirth, MD, discusses the mechanism of action of pralsetinib and key data from the phase 1/2 ARROW clinical trial.

Lori Wirth, MD: We must talk about pralsetinib. In terms of the mechanism of action, you could draw a very similar cartoon as you did for selpercatinib. Both drugs were designed with similar ideas in mind, to be potent and specific RET inhibitors and to have as little off-target kinase inhibition as possible and to block that oncogenic signaling when RET is fused or mutated in medullary thyroid cancer. Pralsetinib as well was designed to inhibit RET fusions as well as all the known RET mutations, including RET V804. The ARROW trial was a phase 1/2 trial investigating pralsetinib and in RET-mutant MTC [medullary thyroid cancer], and the study design is shown here. There were cohorts of patients with non–small cell lung cancer, as well as previously treated RET-mutant medullary thyroid cancer, RET-mutant MTC without prior systemic therapy, and other RET-altered patients.

So far, we’ve seen data presented in 55 patients with MTC who had received prior vandetanib and or cabozantinib and 29 patients that were cabozantinib and vandetanib naïve. In terms of the overall response rate, in the patients who had received prior therapy, we’re seeing a 60% overall response rate, and in the patients who are treatment naïve, we’re seeing a 66% response rate. Also, we’re seeing complete responses as well with pralsetinib, particularly in the patients who were treatment naïve, along with good long median durations of response that haven’t been reached at the time of last follow-up.

Overall, the adverse-effect profile with pralsetinib is similarly fairly good, with most treatment-related adverse events being grade 1 or 2. When we drill down and look at the grade 3 and grade 4 adverse events, we see some hypertension, patients with fatigue, as well as dyspnea. There is some bone marrow suppression with pralsetinib. You can see some neutropenia, anemia, lymphocytopenia, and a little thrombocytopenia as well. Marcia, how do you anticipate these data from pralsetinib impacting on your practice? You have 2 FDA-approved RET-specific inhibitors.

Marcia Brose, MD: They’ll have the same impact. It will have similar impact to the selpercatinib data. We do not have head-to-head comparison, and there have been a couple of situations where I’ve had a patient who wasn’t doing well on 1, and I switched to the other and they did better. It might be good to have both because the issues that patients may get may be specific to 1 agent or the other, possibly a hypersensitivity reaction. They’re both going to have a major impact on patients who have RET-positive medullary thyroid cancer because they’ll have these nice long periods where they’ll get good responses and have a real quality of life. That will do well for them for probably more than a year, maybe even 2 or 3 or more. It’s going to have a huge impact. I’ll say that, and we don’t have a head-to-head, but the numbers do seem a little better sometimes for the selpercatinib. I sometimes pick that 1 first, but that’s not necessarily data driven; that’s just what I’ve been doing.

Some people have said pralsetinib is once a day. I don’t really think once vs twice a day matters much in my patient population; therefore, I don’t find that as big a determinant as to which I’ll use. I’ve had a more issues with the pralsetinib and the bone marrow suppression, with anemia and things like that. I’ve had some patients who had that problem. Interestingly, it happened up front and then with dose reductions got better. Pralsetinib can still be used, but that’s something I didn’t see so much in the other. I’d sum it up that both are just great wins for our patients.

Lori Wirth, MD:I agree on the comment that they’re both great wins for sure. There were a couple of case reports of patients with MTC who developed tumor lysis syndrome. Andrew, is that something that you worry about? Or have you modified what you do with these patients because of those reports of tumor lysis syndrome?

Andrew Gianoukakis, MD: Clearly, we need to be on the lookout for tumor lysis syndrome. Depending on the tumor burden and the response we’re getting, those are likely to be risk factors for developing tumor lysis syndrome. Fortunately, it seems to be rare, but it should be something that we consider. If it happens, it’s likely to happen early. If we’re on the lookout, we can avoid morbidity associated with it by not missing it. One thing I wanted to ask in terms of the combination of the 2 drugs: was it the selpercatinib that allowed for prior pralsetinib use, or was it the reverse? Will we see those data? There won’t be a direct comparison, but there may be second-line RET-specific inhibitor data? Selpercatinib allowed for pralsetinib.

Lori Wirth, MD: There aren’t data that have been published, but my guess is that because the mechanism of action is so similar, we see patients with beautiful responses who can eventually progress and develop acquired resistance. We’re learning more about what the mechanisms of acquired resistance are. For example, we’ve identified in some patients an acquired RET-solvent front mutation at codon G810. That solvent front mutation should block the activity of both pralsetinib and selpercatinib. In patients who progress, respond, and then eventually progress on 1 drug or the other, my guess is that there’s not going to be too much activity. But as Marcia mentioned, sometimes there are drug tolerability issues and we can see responses if a patient, say, develops hypersensitivity on 1 drug and can be switched to the other drug and still achieve some good activity.

This transcript has been edited for clarity.