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CDK4/6 Inhibitors: Managing Toxicity in HR+ mBC

Insights From: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center
Published: Wednesday, Oct 25, 2017



Transcript:

Hope S. Rugo, MD: It’s very important for clinicians and the non-MD clinicians to understand the toxicities involved with using the 2 approved CDK4/6 inhibitors as first-line therapy in combination with letrozole for patients with metastatic hormone receptor-positive breast cancer, because with education and understanding the toxicity, you can really avoid any serious problems. So, I think it’s really important that we all know that neutropenia is the most common toxicity from both agents, palbociclib and ribociclib. The neutropenia is usually self-limited. It occurs during the therapy or after the therapy. It can occur. It usually occurs more frequently in the first couple of cycles.

And then for whatever reason, serious neutropenia is less common further into the course of treatment, I think mainly because if a patient has had grade 4 neutropenia several times, they’re usually dose reduced. And so, then you stop seeing it, actually. It’s not cumulative that neutropenia, so you basically see neutropenia on and off during the course of therapy if you’ve had it from the beginning. So, the neutropenia is actually quite predictable for patients. For example, on day 28 when we check the blood counts, if a patient has grade 3 neutropenia—so a neutrophil count of 700 or 800 repeatedly—what I’ll usually do is have them come in on day 32 instead of day 28, so they don’t have to come in twice and we don’t have to delay. That makes it a lot easier for the patient.

Neutropenia is the most common toxicity. Grade 3/4 neutropenia is seen quite commonly, and we don’t see an increase in febrile neutropenia, so that’s very important. Clinicians, when they’re first starting to use the CDK4/6 inhibitors, often will believe that they should treat the neutropenia in a similar way to the way we treat chemotherapy-induced neutropenia where you give growth factors. In this situation, because we don’t see a lot of mucosal damage and it’s very self-limited, we just don’t see an increase in febrile neutropenia. So, growth factors are not indicated for the treatment of CDK4/6-limited neutropenia like this that’s uncomplicated.

The other toxicities are also important to know about. We see grade 1 stomatitis in some patients, so they’ll have a single aphthous-like mouth sore, and it may happen with 1 cycle and not again. It may happen every third cycle, every fourth cycle. We don’t really know why. I’ve actually used a steroid dental paste, Kenalog, very successfully. Patients get a little tingling, they use the steroid dental paste, mouth sore goes away very rapidly, and it doesn’t bother them. For some patients, it’s so mild that it doesn’t even affect them. They don’t worry about it. They don’t use anything. So, that’s one thing to warn patients about just so they know.

Another toxicity that’s quite common is fatigue. Some patients notice more fatigue than others, and it probably is more common in patients who are more heavily pretreated and are older patients, where fatigue is already a bigger issue. If the fatigue is bothering the activities of daily living for a patient, you can dose reduce and then dose escalate again if they’re much better. But I found that dose reducing can really help with management of that fatigue. A small number of patients will get GI complaints, a little bit increase in loose stools. It’s not serious. You don’t have a grade 3 diarrhea, for example. It’s very mild. Nausea is really uncommon. I don’t really see nausea from these medications ever. Rash is also extremely uncommon. I really haven’t seen rash from the drugs either.

One thing I make a point to tell my patients about is alopecia. Grade 1/2 alopecia was seen in about one-third of patients who received palbociclib and ribociclib. Mostly it’s grade 1 with a little thinning of the hair. That’s more than what you would see with an aromatase inhibitor, for example. But occasionally, patients have enough hair loss where they want to wear a head covering like a wig. So, I do tell them that this can happen. I’ve actually used minoxidil successfully in patients who had significant hair loss. They use the minoxidil and they have significant filling in of their hair. And one of our colleagues who’s in dermatology has been looking at this at Memorial Sloan Kettering Cancer Center and also has said that a lot of times patients’ hair loss related to these oral medications can be alleviated with the use of these oral drugs like minoxidil. So, that’s importunate as well.

Ribociclib has a couple of toxicities that are quite mild, but it’s important to know about them. And they’re really issues early on in the course of therapy like the neutropenia is, and that is a prolongation of the QTc interval. We don’t believe that QTc interval is prolonged with palbociclib, although you still want to avoid concomitant administration with agents that cause significant problems with QTc. But for ribociclib, there does appear to be an issue, so you want to screen initially, look for the QTc, and not give it to patients who already have a long QTc. You want to avoid concomitant administration of QTc prolonging agents. And then the label requests that you check an EKG day 14 or day 15 in cycle 1, as well as at baseline, and then at day 28 to make sure you aren’t prolonging the QTc interval. If you are, you should stop the drug and dose reduce or discontinue the drug depending on the seriousness of the toxicity.

Of note, in the study that evaluated ribociclib in the first-line setting, MONALEESA, the risk of QTc prolongation was quite small, so it was very, very rare. And there is an ongoing study called COMPLEEMENT that is looking at QTc to get a better idea of what the real-world aspect of this is. Liver function tests, the AST and ALT, can be increased with ribociclib, and those are also followed in the first 2 months more closely than over time. And dose reduction improves the situation. If you have an increase in bilirubin, which is extraordinarily rare, the label asks that you stop the drug.

Transcript Edited for Clarity 
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Transcript:

Hope S. Rugo, MD: It’s very important for clinicians and the non-MD clinicians to understand the toxicities involved with using the 2 approved CDK4/6 inhibitors as first-line therapy in combination with letrozole for patients with metastatic hormone receptor-positive breast cancer, because with education and understanding the toxicity, you can really avoid any serious problems. So, I think it’s really important that we all know that neutropenia is the most common toxicity from both agents, palbociclib and ribociclib. The neutropenia is usually self-limited. It occurs during the therapy or after the therapy. It can occur. It usually occurs more frequently in the first couple of cycles.

And then for whatever reason, serious neutropenia is less common further into the course of treatment, I think mainly because if a patient has had grade 4 neutropenia several times, they’re usually dose reduced. And so, then you stop seeing it, actually. It’s not cumulative that neutropenia, so you basically see neutropenia on and off during the course of therapy if you’ve had it from the beginning. So, the neutropenia is actually quite predictable for patients. For example, on day 28 when we check the blood counts, if a patient has grade 3 neutropenia—so a neutrophil count of 700 or 800 repeatedly—what I’ll usually do is have them come in on day 32 instead of day 28, so they don’t have to come in twice and we don’t have to delay. That makes it a lot easier for the patient.

Neutropenia is the most common toxicity. Grade 3/4 neutropenia is seen quite commonly, and we don’t see an increase in febrile neutropenia, so that’s very important. Clinicians, when they’re first starting to use the CDK4/6 inhibitors, often will believe that they should treat the neutropenia in a similar way to the way we treat chemotherapy-induced neutropenia where you give growth factors. In this situation, because we don’t see a lot of mucosal damage and it’s very self-limited, we just don’t see an increase in febrile neutropenia. So, growth factors are not indicated for the treatment of CDK4/6-limited neutropenia like this that’s uncomplicated.

The other toxicities are also important to know about. We see grade 1 stomatitis in some patients, so they’ll have a single aphthous-like mouth sore, and it may happen with 1 cycle and not again. It may happen every third cycle, every fourth cycle. We don’t really know why. I’ve actually used a steroid dental paste, Kenalog, very successfully. Patients get a little tingling, they use the steroid dental paste, mouth sore goes away very rapidly, and it doesn’t bother them. For some patients, it’s so mild that it doesn’t even affect them. They don’t worry about it. They don’t use anything. So, that’s one thing to warn patients about just so they know.

Another toxicity that’s quite common is fatigue. Some patients notice more fatigue than others, and it probably is more common in patients who are more heavily pretreated and are older patients, where fatigue is already a bigger issue. If the fatigue is bothering the activities of daily living for a patient, you can dose reduce and then dose escalate again if they’re much better. But I found that dose reducing can really help with management of that fatigue. A small number of patients will get GI complaints, a little bit increase in loose stools. It’s not serious. You don’t have a grade 3 diarrhea, for example. It’s very mild. Nausea is really uncommon. I don’t really see nausea from these medications ever. Rash is also extremely uncommon. I really haven’t seen rash from the drugs either.

One thing I make a point to tell my patients about is alopecia. Grade 1/2 alopecia was seen in about one-third of patients who received palbociclib and ribociclib. Mostly it’s grade 1 with a little thinning of the hair. That’s more than what you would see with an aromatase inhibitor, for example. But occasionally, patients have enough hair loss where they want to wear a head covering like a wig. So, I do tell them that this can happen. I’ve actually used minoxidil successfully in patients who had significant hair loss. They use the minoxidil and they have significant filling in of their hair. And one of our colleagues who’s in dermatology has been looking at this at Memorial Sloan Kettering Cancer Center and also has said that a lot of times patients’ hair loss related to these oral medications can be alleviated with the use of these oral drugs like minoxidil. So, that’s importunate as well.

Ribociclib has a couple of toxicities that are quite mild, but it’s important to know about them. And they’re really issues early on in the course of therapy like the neutropenia is, and that is a prolongation of the QTc interval. We don’t believe that QTc interval is prolonged with palbociclib, although you still want to avoid concomitant administration with agents that cause significant problems with QTc. But for ribociclib, there does appear to be an issue, so you want to screen initially, look for the QTc, and not give it to patients who already have a long QTc. You want to avoid concomitant administration of QTc prolonging agents. And then the label requests that you check an EKG day 14 or day 15 in cycle 1, as well as at baseline, and then at day 28 to make sure you aren’t prolonging the QTc interval. If you are, you should stop the drug and dose reduce or discontinue the drug depending on the seriousness of the toxicity.

Of note, in the study that evaluated ribociclib in the first-line setting, MONALEESA, the risk of QTc prolongation was quite small, so it was very, very rare. And there is an ongoing study called COMPLEEMENT that is looking at QTc to get a better idea of what the real-world aspect of this is. Liver function tests, the AST and ALT, can be increased with ribociclib, and those are also followed in the first 2 months more closely than over time. And dose reduction improves the situation. If you have an increase in bilirubin, which is extraordinarily rare, the label asks that you stop the drug.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
34th Annual Miami Breast Cancer Conference® Clinical Case Vignette Series™May 25, 20182.0
Community Practice Connections™: CDK4/6 Inhibitors With the Experts: The Role of Emerging Agents for the Management of Metastatic Breast CancerMay 30, 20182.0
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