Occurrence and Management of Selpercatinib- and Pralsetinib-Related AEs in Patients with RET Fusion-Positive mNSCLC
The panel reviews LIBRETTO-001 and ARROW safety data on selpercatinib and pralsetinib in RET fusion-positive mNSCLC, and share their clinical experience in adverse event (AE) management in patients who are receiving one of these therapies.
Joel Neal, MD, PhD: Lauren, you said that most patients don't come in wanting chemotherapy. I'm like, yes, patients never come in wanting chemotherapy, or any other treatment for lung cancer, right? So being patient and mapping out that road trip and saying not only what's the fastest way to get there but what's the easiest way to get there. And the TKIs with high response rates, once we settle into tolerability, often in oral therapy is much easier with much less frequent side effects and less leashing to our oncology offices, which is the best gift we can give. We don't want to give chemotherapy or treatments either if we don't have to. Adverse events, Lauren, have you had experience with selpercatinib and management of the adverse events and get into dose reductions in your experience?
Lauren Welch, MSN, NP-C, AOCNP: I fortunately had selpercatinib in Phase 1 and so I had a number of patients who did extremely well. Even during dose escalation, it was very encouraging to see responses in the, I would say amazing tolerability. Very comparable to how well tolerated some of the, how well tolerated third generation EGFR inhibitors can be. When we think about it in the adjuvant setting for EGFR, something that's going to be tolerable and be compatible with quality of life, certainly we saw that with selpercatinib. So, my patients who, I still have patients, I'm seeing one tomorrow who was on the initial Phase 1 trial still doing well, really with no evidence of disease, and that just speaks to the tolerability. The big side effects that you may encounter, diarrhea certainly, but rates much lower than the mobocertinib that we just talked about. The diarrhea is generally manageable. Dry mouth, which often we don't mention because we're like, “Oh, it's just dry mouth,” but it can be pretty profound. I've actually had patients request dose holds and reductions because of dry mouth. Those are the big ones. And then the hypertension is something else that I've had to address with patients. Those are the biggest ones. Diarrhea, we have played with the dosing some. I have one patient that doses, alternates dosing, I think 120 and 160 if I'm thinking of it correctly, alternates every other day and that has worked well for her as well as some prophylactic loperamide. And then it's standard management for hypertension. It's rare that I've have to actually dose modify for that, more just make sure I've got the right antihypertensives onboard.
Joel Neal, MD, PhD: Yeah, I've also observed some LFT abnormalities, although not usually serious or life-threatening. Sometimes when they get high enough, we think about dose reductions for. And occasionally rarely there's the QT prolongation, so always worth doing a little bit of early cardiac monitoring every few weeks. In my experience usually those QT prolongations either happen or they don't for a given patient, so as long as they don't start a new therapy, it's good.
Joel Neal, MD, PhD: Zosia, do you have experience with pralsetinib and the adverse events? Any distinguishing things we should keep in mind compared to selpercatinib?
Zosia Piotrowska, MD: No, I think we do have experience with it. We also participated in some of the early trials. I think overall very, very well tolerated drug, similar to selpercatinib. I think distinguishing features, one, not a side effect but just a practical issue, pralsetinib is dosed once daily as opposed to b.i.d. dosing with selpercatinib, and that's not a huge difference but something to keep in mind. I think in terms of toxicities, they're generally similar to what we discussed with selpercatinib. I think that you can see a little bit of myelosuppression, specifically decreased white blood cell, lymphopenia, with this drug, so that's something to keep an eye on. But overall, many of the others, hypertension can be seen. The liver function tests can be seen. I don't think we see quite as much QTc prolongation with pralsetinib as we do with selpercatinib. But with both agents you can see ILD or pneumonitis, rarely, but something that's important to keep an eye on. So, I think overall, both of these drugs really are just very well tolerated, and patients generally feel incredibly well on them. And again, as you mentioned, Joel, they also tend for the majority of patients to work very well and they're a great treatment option, although I also recently just had a case of a patient who unfortunately had a quite suboptimal response, and just a good reminder of how difficult that is when we have so much hope when patients don't have the amazing responses we're used to seeing with these agents.
Joel Neal, MD, PhD: Yeah, I think it's, by analogy to the ALK inhibitors, I think it's really neat to have two drugs that are both well tolerated and really highly active and a slightly different side effect profile. So as an alternative to dose reduction or discontinuation of these drugs, I think trying the other drug in the class would make a lot of sense for certain side effects the patients have. So, this patient started pralsetinib 400 mg daily. Had very well tolerated overall grade 1 constipation. Feels like it's always either diarrhea or constipation as a guarantee. And when you look at some of the adverse events charts for many of these drugs, both of them appear, so they can all happen. And then patient had a great partial response on imaging. Lauren, how many patients have you seen that required kind of dose interruptions, discontinuations, dose reductions on pralsetinib? Do you have experience with pralsetinib as well?
Lauren Welch, MSN, NP-C, AOCNP: I do. And I would say with both, patients that have actually needed dose holds and dose reductions has been the exception. Most of these patients have been able to keep on full dose.
Joel Neal, MD, PhD: And I know that we have a clinical trial now open for patients who have acquired resistance to these, we'll call them the first generation, extremely targeted RET inhibitors. There were a bunch of less targeted, multi-targeted kinase RET inhibitors that had lower response rates and not as well-tolerated. But we'll learn more hopefully about acquired resistance to these drugs and overcoming those common pathways too. So, I think a lot more exciting research to be done.
