Managing Toxicities of CDK4/6 Inhibitors in Hormone Positive Breast Cancer - Dr. Stephanie Graff

Understanding CDK4/6 Inhibitors and Ribociclib Fundamentals Rohed, today we have 4 CDK 46 inhibitors that we tend to use commonly in our clinical practice, 3 in the world of breast cancer and one trilocyclub for small cell lung cancer. Today on our podcast Oncology Brothers, we're going to focus on the ones that we use in the world of breast cancer. Hello everyone, thanks for joining us. I'm Rahul Gosain here with your Co host and my brother Rohit Gosain. Speaker 2 Here we continue our toxic series, a deeper dive into the side effects of CDK 46 inhibitor and how to manage these to ensure our patients can stay on these medications safely. We will focus on three agents, ribocyclib, abemaciclib and palbociclib. We are excited to have our oncology big sister, the one who got us started, Doctor Stephanie Graf of medical breast oncologist from Brown University Health. Stephanie, thanks so much for joining us. Thank. Speaker 3 You so much for having me. Speaker 1 Stephanie, welcome. When talking about CDK 46 inhibitors, they were initially approved for hormone receptor positive metastatic breast cancer and in this settings we have all three Ribo, palbo, abama, but more mature data is stronger for ribocyclib and abemaciclib. Because of this the practice has changed. A lot of us are not using polycyclib heavily unless knowledge with combinations like an Novelocity. But more recently, based off Natalie trial and Monarchy trial, we've seen that ribocyclib and abemaciclib have made their way in early breast cancer and adjuvant settings with ribocyclib having a broader inclusion criteria. OK. So can we start here with ribo, the approved starting dose is 400 milligrams in adjuvant settings and 600 milligrams in metastatic settings. With ribocyclib, we have to be careful with QTC. So we monitor Ek, GS LFT, you have to be very careful with monitoring that. But we still have to keep neutropenia on our radar as that is more of a class effect with CDK 46 inhibitors. Navigating Ribociclib Treatment with Patient Preferences Stephanie, when you're talking through these options with your patients and when it comes to ribocyclib, what should be on our radar and any clinical pros on how to manage these? Speaker 3 Yeah. So when I talk to a patient about RIBO CICLIB versus abemaciclib in the adjuvant setting, first, I talked to patients about them early. I mentioned that this is probably going to be a part of the patient's treatment plan at our first consultation often before surgery because I know that the patient has a larger tumor, is node positive, has a high grade tumor, has that profile with a little bit lower ERA, little bit lower PR. That makes me think that their oncotypes going to come back sky high. I'll mention I think that you're probably going to end up on this other pill as well because I think that so often patients with hormone receptor positive disease think that they have good breast cancer. For anyone listening on the podcast, I'm using air quotes around the word good because I hate that. And so that I think helps patients kind of prepare that this is coming. And then in terms of choosing between RIBO CICLIB and Abema CICLIB, I go by the trials. There is a slightly wider group of patients that are eligible for Ribo CICLIB than ABEMA CICLIB. I try not to color outside of the lines and give ABEMA CICLIB to the lower risk patients. I engage the patient in shared decision making. I have the I have patients who don't want to take riboseclib because they don't want a risk of liver toxicity. I have patients who had terrible diarrhea with their chemotherapy and the idea of that being a side effect with ABEMA is quite concerning for them. Alternatively, they have chronic Constipation and they're like, give me the ABEMA. And so it goes sort of every which way. We do have a press release that tells us that Abema Siclib is going to be showing us overall survival data in no time at all here at the upcoming ESMO meeting. And we'll watch to see the impact of that data and how it influences these conversations. We're also going to be getting longer term follow up on Natalie ribosiclib. But I think that what we've seen is that those curves for Natalie, although that trial accrued at a later time point has separated at a similar pace and rate as the ABEMA data. You know, we can't really do cross trial comparison. There was a lower risk population of patients, so is the impact a little bit smaller? Yes, but that's probably representative of the patient populations. I think ultimately I feel very comfortable with both drugs and it really just comes down to what group of side effects that patient wants to feel. Managing Ribociclib QTC, Dosing, and Patient Support Thanks for unpacking that. Stephanie, With regards to riboseclib QTC being something that we have to worry about, could you do EKG at baseline and then two weeks and then start of cycle 2 and then forgo after that? Speaker 3 Yeah. So when Natalie was released and the package insert got updated, regulators dropped that two week EKG from the package inserts. Now the recommendation is a baseline EKG and then EKG at a month. I typically just do 2 OK GS. I do a careful review of their meds because I think the biggest predictor is drug interactions, and I tell patients I'm prescribing ribociclib that QT prolongation is a side effect, and the biggest predictor of that is them taking something that causes QT prolongation. Even some holistic therapies can do that, things like grapefruit juice and St. John's Wart. I encourage them that any time they start a new medicine, they need to call and let me know so that we can watch when we're managing things like nausea. We need to be thoughtful about what nausea medicine. If we have to reach for things like ondansotron to manage Zofran, we have to go back to checking Ekgs because it can prolong QT interval. Speaker 1 Stephanie, talking about that, 600 milligrams is what we have for metastatic settings and 400 milligrams and adjuvant settings. Is the QTC dose dependent? And what about the LFTS? Speaker 3 Yeah, we certainly saw a lower rate of QT prolongation in Natalie, which leads you to think that the QT may be dose dependent. I think that the incidence of QT prolongation was so low that it's hard to say. I don't have the statistics to tell me that it's truly a dose dependent phenomenon. The fact that we saw much lower rates of QT prolongation at the 400 milligram dose compared to the 600 milligram dose, I would say, yes, there's some dose dependency. Speaker 2 And tying in with the dose aspect as well, what we saw from Phase 2 Emily trial is that which showed in metastatic setting 400 milligrams of RIBO was non inferior to 600 milligrams. Stephanie, in your practice, is there a subset of patients that you feel comfortable starting at 400 milligrams rather than higher dose and then down titrating if they're having side effects? Speaker 3 So Amily, the end point of Amily was the sort of AES, not clinical benefit. We've seen data that with both drugs that it patients who have dose reductions because of side effects do not have an inferior outcome. If you have an AE and you need a dose reduction, delay, hold or modification of any sort, you don't have an inferior long term outcome compared to patients who do not. That is very reassuring. Patients feel good knowing that they don't have to endure their terrible diarrhea because they think it's going to give them the best outcome and that's just not OK. We should be dose reducing those patients. We have seen data that the lower dose patients have less side effects, but we haven't yet seen the head to head comparison that's starting at that lower dose and titrating up results in the same long term outcome. And at least academically, I can argue that if your largest cyto reduction comes with that first dose or patients that are having toxicity are metabolically processing the drug differently and maybe more effectively in a way that's giving them that toxicity. And therefore are the patients that need to have that lower dose. The patients that need the higher dose are having a window of, I don't want to call it sub therapeutic, but less than dosing. I still tend to start at the starting dose and I just keep the threshold low and honest about dose reduction. Mask, which is the multi National Association has a oral chemotherapy program that you can actually call patients. It's called the Oral Agent teaching tool and you can download it. I'm going to ask patients this 12 question toolkit and what they recommend and what they validated in some studies with different cancer centers globally. When we call patients every week for the first month and then twice a month for month 2 and month 3, which honestly, I think with drugs like CDK for six inhibitors, which are pretty well tolerated, may even be more than we need to just do those 12 questions, which are things like are you taking it? Do you feel OK? What kind of side effects are you having? Patients not only have better side effect management, but they have better adherence, they have less anxiety, they feel more empowered in their care. They have a reduction in their sorry, they have an improvement in their overall quality of life. And so I think that there's ways for all of us in practice to utilize our care team, our nurses, our chemo teach teams, our pharmacists, our nurse practitioners to be connecting with our patients in a structured way that are on these oral agents without necessarily dragging them into clinic or having them have a physician visit every time that makes sure we're appropriately addressing all their symptoms and side effects they're experiencing. Comprehensive Management of Abemaciclib's Key Side Effects Absolutely. Again, a few things to reiterate here. It is reassuring that if we're those producing for side effects, we're not compromising outcomes and then again, relying on our other team partners, nurses, nurse practitioners, nurse navigators to make sure we're getting our patients through these medications safely. And again, in my clinical practice between RIBO or ABEMA, I'd find that RIBO is better tolerated because of the diarrhea that comes along with ABAMA. And this ends up being a big quality of life issue for our patients. That said, ABAMA perhaps might be a little more active agent and we've seen some data with switch therapy or a hint of activity with intracranial disease. With ABAMA, we have to keep diarrhea in mind. We have to keep that increased risk of VTE in mind and again, neutropenia when it comes to abema. Stephanie, can you touch on some of the side effects that you worry about and how do you manage them? Speaker 3 With abemaciclib are side effects that really are concerning are diarrhea. Obviously with everyone talks about it, we also worry about side effects like abdominal pain, decreased appetite. I think that in some ways those are actually mediated by the diarrhea itself. We can see things like fatigue. I do think that the fatigue can be a function of the the diarrhea and dehydration, but it can also just be being on a CDK 46 inhibitor and is sensitive to dose modification. Cytopenias, neutropenia, lymphopenia can happen. Thrombocytopenia and anemia are a little bit less common but can also still happen. We still can see elevated liver function studies with abemaciclib less common than we see obviously with ribociclib where it's a bigger concern, but still a potential risk and side effect that we need to monitor for. Last but not least, the rare side effects that are serious and we worry about a small risk of BTE venous thermal embolism and a small risk of interstitial pneumonitis. The risk of both of those quite low. But again, always something to sort of mention to your patients if they're having new signs or symptoms that would be concerning for that. They need to make sure that they're seeking emergency care, alerting your office depending on the particular sign or symptom. Speaker 2 We'll dive into the ILD pneumonitis story shortly. And this is rather a class effect which can be seen with riboabema as well as Palbo. Sticking to the topic of diarrhea here, Stephanie, I know I'm sounding like a broken record here, but back to the dosing question. As we saw with ribocyclib, if we reduce the dose, what we see is better side effect profile. Now tying that with abemaciclib for adjuvant settings, we often start with 150 milligrams BID, but any consideration for starting at 100 milligrams BID and then uptight rating if they're tolerating the therapy well And any role of prophylactic Imodium or do you have it at standby and start that at the first episode when patients are experiencing diarrhea? Speaker 3 Yeah. So I start everyone on the starting dose and then titrate down after having symptoms and side effects. I do prescribe Imodium with the initial prescription so that patients have it at home. I don't necessarily have them take it prophylactically, but I am very clear that I expect them to have diarrhea and I expect them to take Imodium when they have diarrhea, not think that the diarrhea is somehow OK. The rate in monarchy of any grade diarrhea was 83%. The chances that your patient has no diarrhea at all is really low. So I I just tell patients, you know how your first sign of diarrhea take an Imodium. And if that doesn't make it stop, that's the point that I want you to be letting the office know because if it persists, we may need to think about giving you extra fluids, checking your potassium, upgrading you from Imodium to Lomotil, taking a treatment break and lowering your dose. Obviously, we don't go from one episode of diarrhea to all of that, but by emphasizing with the patient that it can escalate relatively quickly. And I don't want to know on day 5 of 14 loose stools a day that this has been going on. And, and we've all had that experience for our patients. Like I didn't want to bother you. It's that they don't call and they show up hypotensive or with a really low potassium or some other symptom that you're like, Oh my gosh. Speaker 2 Thanks for covering that, Stephanie. Diarrhea is something that impacts the quality of life significantly. It is important for us to educate our patients around this and telling them that reach out to us as we have multiple supportive medications like as you stated, Imodium or Lomotil that can help them significantly in these settings. Palbociclib Management and Holistic Patient Support OK. Now moving along to our last CDK 46 inhibitor, palbosyclib. I was using this heavily in my practice prior to the OS data. Now things have changed where the reliance is more on ribosyclib and bemosyclib with AI, but palbosyclib is still available within Naval, which is pick 3 California inhibitor. Rahul, this is another topic that we need to cover in our tox check discussion. That is pick three CA inhibitor. Yep. OK, coming back to palbociclib, Stephanie, neutropenia, fatigue and another one that we were talking about the class side effect is ILD or pneumonitis. When it comes to palbociclib, how do you manage some of these side effects? Speaker 3 Yeah. So when I prescribe any of the CDK 46 inhibitors, I do tell patients that ILD pneumonitis is a potential side effect, that it's rare. I tell them the constellation symptoms that I would expect ILD pneumonitis to present with and tell them that those are things I would want to hear about even if it's happening months after they've developed. For me. Pablo, Ciclib is a medicine that I'm prescribing in the metastatic setting. If or when I'm prescribing it, as you alluded to, it is a prescription that I'm using less frequently than Ribo and Abema at this point. But with any of the CDK 46 inhibitors, we sometimes get ACT scan and see some haziness and then be stuck wondering, oh goodness, what is this in? In which case we lean just like in the setting of pembro, we lean a little bit on the clinical contacts that the patient is in, our pulmonary colleagues for things like good sputum samples, the patient's symptoms, the nature of their disease, to make our decisions on whether we think that that's a post viral symptom, disease progression or truly a drug effect. For the most part, I would say that it's clear clinically what's happening to your patients. You either can clearly elicit a history of an infectious sign or symptom and diagnose that, or you have other evidence of disease progression that makes you suspicious that what you're seeing is lung based disease or you're stuck thinking it's your CDK 46 inhibitor. The management of ILD pneumonitis is the same as any other pneumonitis. I would treat it with high dose steroids and hold the drug. It is not a side effect that I have re challenged with ACDK 46 inhibitor. It has given me pause on whether to use other therapeutics that are associated with ILD. Patients with pre-existing ILD were excluded from trials in the Destiny family of trials, which is obviously what you're all nodding and thinking about. But trustezumabdroxtican is such an effective therapy that in a patient that's had a full recovery and now has clear lungs and otherwise has metastatic disease, I think I turn to that shared decision making and careful lung follow up for a patient that I would choose to treat with a different therapy, not another CDK 46 inhibitor and a history of a pneumonitis event. Back to side effects of Palbo have really been the cytopenias more profound than with the other two CDK 46 inhibitors that has led to really broad sweeping dose reduction. The number of patients that I was able to maintain on 125 of Palbo was quite low. Most of my patients ended up with the dose reduction relatively early in their disease course due to persistent cytopenias. I don't know if that's why we ended up seeing less of the other side effects like transaminitis because they were never on the high dose elbow for long. But otherwise, patients, once you found the right dose for their marrow to stay happy, tended to do quite well on PAL though, and I think that's still true. Just like with the other two CDK 46 inhibitors, I still tend to start at that 125 dose and just monitor their CBC quite carefully. Speaker 1 Again, going back to ILD for a second here, you touched on immunotherapy, something that we're using heavily, CDK 46 inhibitors, TDXD, of course, the mortality associated. So we have to put our internist hats and rely on our pulmonologist, Stephanie. I know we're well over time here, but before we close any other supportive care strategy that should be on our radar when using CDK 46 inhibitors or treating breast cancer patients in general. Speaker 3 I think it's important that we take time to listen and believe the things our patients are telling us. Often our patients tell us they're fatigued or tired and they use different sorts of language to communicate that it's easy for us to think, yeah, I'm tired too and not really cure that for what it is, which is sometimes a grade three side effect. Sometimes patients are minimizing other symptoms like decreased appetite, repairing these medicines with aromatase inhibitors or fulvestrant. So patients could be having hot flashes, joint pain, and especially in the metastatic setting where they might have Bony metastasis. Ignore some of the side effects because we're busy and the patient in front of us may not be making a big deal out of them, but it's important to take that next step and ask us follow up questions. As we all know, the tips and tricks to manage the hot flashes, joint stiffness and fatigue responds well to just modification of the CDK 46 inhibitor. It's just important that we take the time to hear our patients when they're saying those things. Speaker 1 Absolutely. I have two little ones at home. So we tell listening is important, not hearing. Stephanie, thank you so much for sharing your experience and thoughts around these available treatment options. This kind of discussion is what we hope helps our colleagues keep their patients on life prolonging therapies on for extended period of time safely. For our listeners, let's do a quick recap from today's talk check discussion today with doctor Stephanie Graf. We touched on the side effects and their management for three CDK 46 inhibitors that we have available for breast cancer. Palbocyclib main concern is neutropenia, so monitoring that CBC is crucial. For ribocyclib, we touched on monitoring LFTS and EKG for us. For Abema, managing that diarrhea and being mindful of that increased risk of VTE is critical. Speaker 2 And remember the starting dose of Ribocyclopin adjuvant settings is 400 milligrams Q day for three weeks and then one week off for a total of three years time. And Abemaciclopin adjuvant setting is 150 milligrams BID for two years. Thanks so much for joining us. Check out our other talks, check episodes, treatment algorithms and challenging K series. We are the unclogy brothers.