Managing Toxicities of ROS1 Inhibitors in Non-Small Cell Lung Cancer (NSCLC) – Dr. Estela Rodriguez

Understanding ROS1 NSCLC and Crizotinib's Historical Role Hello and welcome back to the ones that have been here with us before and thank you to the ones that are joining us today for the first time on our Oncology Brothers podcast. I'm Rahul Gosain and I'm here with Rohit, my older brother and your Co host. We're both practicing community medical oncologist and with our discussions here, we hope to bridge the gap between academic research and community practice. We're back with our Talk Check series where our goal is to move beyond the approval and focus on what really matters in our clinic day in, day out, which is managing the side effects, optimizing the dose and keeping our patients safely on therapies for as long as possible. Today we're tackling Ross 1 fusion positive non small cell lung cancer and here we have a few Tkis that are available for this rare subset. But understanding how to handle these adverse events for these Ross One inhibitors is critical to walk us through these side effects and touch on clinical paroles around the management. We're honored to have doctor Estella Rodriguez, a thoracic medical oncologist from Sylvester Comprehensive Cancer Center. Estella, thank you so much for joining us. Speaker 2 Thank you for the invitation. Honor to be here. Speaker 3 Estella, great to have you back again. Before we dive into the discussion talking about non small cell lung cancer, making sure that we are doing comprehensive NGS on solid and liquid tissue is extremely critical. So the focus on today's discussion is Ross One Tkis where we are targeting Ross 1 fusion protein. The first option that we are going to be talking about is krosotinib, which now gets barely used especially when we have more effective options. Though this will help us to reiterate the at least the side effect profile from class effect standpoint that is fatigue, diarrhea, edema, Estella. Could you please go over crosotnib and if you have utilized what sort of side effect profile have you seen and important clinical pearls around this agent? Speaker 2 So it's been a long time since I used croissantinib, but there are people in practice who had a patient on croissantinib that did extraordinarily well who's still on treatment. It is a drug that was a dirty TKI because it can cause many side effects, It can target many things. It's not the best Ross inhibitor. So I wouldn't use it today for a patient, especially young patients, because it doesn't protect people in the brain for the side effects that we understood. We will counsel people that they will have visual changes so that they shouldn't be driving at night. They will get these floaters. All of these pills can cause pneumonitis, chyotoxicity. Acute is prolongation. You need to do an EKG and evaluate liver function. So we rarely use that. But it was an important treatment at the beginning of all of this because it targeted ALK and it targeted Ross and it really was an option for these patients. Speaker 1 Even in my practice, I've never used quizatinib and that is because now we have better treatment options and be it for ALK inhibitor and TRAK inhibitor or Roswyn inhibitors. Navigating Repotrectinib's Dizziness and Dose Reduction Strategies OK. So jumping from a drug that is not readily used to one that is more commonly used here, Rapotrectinib, a second generation Roswan TTI inhibitor, not only do we have better overall response when compared to your first generation Tkis, but we also have good CNS responsive disease with this, right? We've covered this briefly in our entrect discussion post ASCO as well, Estella. With repotrectinib, we have to worry about dizziness, balance issues, peripheral edema, and we also have to keep LFTS in mind. Can you touch on the side effects here? What to look out for in any clinical pearls around this? Speaker 2 So this is a treatment that patients need to understand what's going to happen. I had patients, especially younger patients that never had CNS, dizziness and that could be very disturbing. People feel they're going to fall over, they can't really function. And that's why the drug has a ramped up dose from a lower dose to a higher dose to get the brain and the nervous system ready for this drug. And that helps. But what has helped me a lot is to counsel patients or what to expect, follow them closely, especially during those first three months and also do those reductions. So we're very comfortable doing those reductions for these patients. You can start at the 160 BID, that's a therapeutic dose, but you can go to 120 and even 80 and have wonderful responses and still have that efficacy in the brain. They have data for patients when those reductions really maintaining that response. So I think not being afraid to find the dose that is going to allow those patients to stay on treatment longer because these are more effective agents and they can work at lower doses. But again, following liver abnormalities for these patients, understanding the CNS effect and it's kind of hard because we worry about brain mass. So is this dizziness? Does it require another MRI? Most of the time it doesn't because if you hold the dose you quickly understand that it's the drug and it's not that he sees, so you don't have to rush to do an. Speaker 3 MRI, I want to reiterate something that you stated, Stella, that is you have to educate the patient so they're well aware of the side effect profile they are going to encounter. And when comparing our second generation Ross One Tkis that is repotectinib to our first generation crizotinib and entrectinib, one has to acknowledge that second generation Tkis are designed to overcome these acquired resistant mutations. As a result, they're all more potent agents. With regards to dosing, as you stated, starting out with 160 milligrams daily for 14 days and then transitioning to 160 milligrams twice a day. Estella, with regards to the side effects that one is facing, you mentioned that 120 milligrams as well as 80 milligrams. Do you skip and maybe start at the same dose if the patients are doing well or go with the dose reduction? When you're doing this dose reduction, do you start them again on a loading or rather low dose that is Q day and then transition to BID? Speaker 2 So it depends, we all learn, every patient's different when the side effects happen, but for the most part, holding the dose and going to the lower dose is what's worked for me. If you were bid, start going to once a day and then if you're still encounter side effects, do the dose reduction. So the same way that we go up on steps, I try to lower this on steps. But I think the big message here, and I have patients that they already know how to do this because this dizziness can come without knowing. They know that it's OK to hold it and nothing bad is going to happen and then you're going to be able to go up again. Once you have encountered significant side effects. Even in the clinical trial, once you dose reduce, you stay at the lower dose. I try to do that for patients, especially if they have brain mass. Speaker 3 Thanks as to something that we have seen with other Tkis, especially with the second generation is also skeletal fractures and hyperuricemia. Key Clinical Pearls for Entrectinib and Taletrectinib Management Any role of prophylactically getting them started on bone strengthening agents or even for hyperuricemia? Allopurinol. Speaker 2 So these are some of the side effects that if you're not aware of them, you're not even looking. So I don't do uric acid all the time, but this is a time that I have done that. And if someone who's elderly has renal insufficiency, I have thought of allopurinol those it's not really on the label. You have to customize it to the patient. If you have a patient that already has severe super osis elderly patient, I think prevention, it goes a long way. These are rare complications, but if you could prevent them, obviously you wouldn't see them monitoring patients as I think dizziness takes the precedence because it's what patients feel differently first. But these other things you have to monitor in your routine checkups. Speaker 1 And what again, some of these are class effects, we'll touch on entrecten up in a second, but we see that CNS side effects here as well. And actually even with entrectenib, we tend to see more fractures and hyperuricemia. So some of this ends up being more of a class effect with these Ross One inhibitors. Actually, this is a good segue to entrectenib, which is approved in 2019. I've used entrectinib for a breast cancer and track positive patient and very similar side effects. The patient described that walking around as if I'm drunk. So that's CNS, dizziness, confusion, something to keep in mind. But with entrectinib, we also have to keep GI side effects and let's not forget fatigue. Estella, any clinical pearls around managing these side effects with entrectinib? Speaker 2 I think again, I, I, we really encourage people to do an EKG at baseline. So you cannot understand if this patient will be a risk for Q2 prolongation. And we are lucky enough to have a pharmacist to review medications, but you cannot count on a pharmacist to make sure you don't have other drugs that could cause trouble for patients. The CNS side effects are there because he has that ENTRAC component. However, this drug is not as good for patients because of the IT doesn't do a good job of preventing resistant mutations and the CNS responses are not the same. Speaker 3 Thanks Estella for covering that. I'm back to reiterate the dosing here for entrectonib. The starting dose is 600 milligrams daily and if one is going through some side effects then reducing it to 400 milligrams or 200 milligrams. Though there are some class related side effects that one can see that is CNS dizziness which we have covered, important to check that QTC intervals. As a result, initial EKG is important and then tracking it for future and dose interactions. Again, skeletal fractures and vision changes just like rhizotinib here. Now moving along into our next Ross One TCAP which was recently approved in June 2025 is talatrectinib, another second generation TKI, similar side effect profile that is tying into CNS side effects. But along with that, something similar that we've seen with intrectinib QTC prolongation along with fractures, ILD and patotoxicity. Stella thoughts on side effect profile here and any clinical pearls optimizing this therapy? Speaker 2 When CNS dizziness is listed, this drug doesn't have a pronounced effect. You can start at the full dose. It has an amazing intracranial response and a very impressive response rate, but you still have some of the same class effects that you have to monitor. And every so often we have people that have significant nausea and vomiting with these drugs. I mean, they're oral Tkis. It's kind of everybody digests things differently. So I do want to send patients with antiemetics. I want to counsel them about that as a possibility. Even diarrhea, we discussed with them the hyper yourascemia is something that you have to incorporate if we have more drugs than patients in some of these practices for Ros 1. So you don't really probably have formulated what orders set to have for these patients, but know that Xenia will be something to follow, especially because these patients can do really well for many years. These side effects stay with them for a long time. So for them to stay on drug that is efficacious, you have to find the dose for each patient that is the best for them and then you have to find the cadence of when you're going to see them. So I will say for most of these drugs, as we're making adjustments, we are going to see patients sometimes weekly, monthly. And then for the first three months, there's a lot of follow up. And then after that we have found the dose that works for that patient, that they tolerate, that we don't have unforeseen side effects and then we can see patients less often. But I will say those first three months, these are not Tkis that you just write them and I'll see you in three months. These are Tkis that you need to talk to the patients, manage them, make adjustments, and once you get to that steady dose, you'll be able to stay with the patient and not see them as often. Speaker 1 You know the dose thing you said full dose here for your telotrectinib is 600 milligrams and then we can we reduce this further to 400 milligrams and then down to 200 milligrams. Estella, one thing that you touched on was the second generation TK is are more potent what you brought this up as well. So we're not using prezoptinib or and trectanib that frequently. So we're often relying on talotrectanib or repotrectanib. Well, another class effect that we run into in our clinic ends up being peripheral edema. Any clinical pros around this? Is this more responsive to our diuretics or do you again step down on the dose there? Speaker 2 That's another side effect. People's vascular system is different one person to the next. So in some people at the same dose, nothing happens and in other people is very significant. We have tried compression stockings and diuretics, but to really reduce swelling you have to use very high doses of diuretics. And if you're wearing it about hyperurosemia, you have to kind of measure these things and monitor them closely. I have not seen a lot of significant dizziness yet for both of these drugs in my practice. I also find that in younger people this is seen less often than in some of the older patients. Speaker 1 Estella, for telotrectinib, you brought up full dosing which ends up being starting at 600 milligrams daily, but this can be reduced down to 400 and then to 200 milligrams daily if need be. Strategies for Progression and Empowering Patients with Education And as we're nearing, and can we touch on a few important points here, We're talking about dose reduction, but what if a patient cannot tolerate even that lower dose in that settings? Estella, do you try another second generation TKI or completely forgo this and move on to chemotherapy? Speaker 2 No, I have switched people because in these trials there is a group of patients that have prior Ross TKI inhibitors. Many of them, especially the talent traction of data is mostly Asian population. So many of them were, but there were patients on other agents. So there is some salvage with another drug that can be a little bit different. If you have time and there's not visceral crisis, I have gone to another TKI. This is a actionable mutation. Chemotherapy is only going to take you that far. If you had someone that have visceral crisis and you didn't feel comfortable because of pneumonitis, chemotherapy could be a bridge. These patients do respond to Pemitrex and platinum based chemotherapy as well. Speaker 1 And Estella, before we close like we tend to do for our EGFR inhibitors, if the disease was to progress on single agent, we often add chemotherapy but continue with that EGFR inhibitor. What about Ross One inhibitors? If the disease was to progress on these agents, do you add chemotherapy and continue with this Ross 1 inhibitor? Speaker 2 So that's a great one because most of these trials were tested on people who progress and we switched to another TKI and they got months and years of the next agent. So finding a clinical trial and finding the next best agent and we have trials for the next generation of active Ross inhibitors out there. So finding a trial for this young patient is probably the best course. Do we drop the TKI and add chemo? That's going to be the rare case that we couldn't find another option. I think that we have other things that we can do if they have CNS metastasis and they tolerate the treatment agent well. I have continued the TKI with the chemotherapy because it really penetrates the brain better. Speaker 1 Absolutely. Speaker 3 Clinical trials is always the right answer and also during these talks, one thing that is apparent and something that you also mentioned, Estella is keeping our patients educated on what to expect and having those frequent check insurance, which makes a world of difference. Estella, thanks so much for all these practical takeaways. I'm hoping this will get us all a little more comfortable out in community when utilizing Ross 1 Tkis for our patients. For our listeners, let us go or a quick recap from today's discussion. Today in our Toxic series with Doctor Estella Rodriguez, a thoracic medical oncologist, we discussed class effects and some unique side effects we need to keep on our radar. When utilizing Ross 1 Tkis. In Ross 1 fusion positive non small cell lung cancer within Trectonib, keeping fatigue, edema, and CNS side effects along with some other rare side effects such as increased risk of bone fractures is critical. Speaker 1 Than for our second generation Rossmann Tkis, which are now the preferred treatment options, we touched on repotrectinib, where again we have to keep CNS side effects such as dizziness or balance issues in mind when it comes to talatrectinib. Besides your common class effects, keep an eye out for more liver toxicities with this one Off front, patient education on what to expect can go a long way. Thanks for joining us. Be sure to check out our other talk check episodes, conference highlights, and treatment algorithms. We are the oncology brothers.