Perspectives on Systemic Therapy for Breast Cancer - Episode 2
Adam M. Brufsky, MD, PhD, FACP: Are you going to use this now? Is this something different than what you’ve done before? Francisco, are you going to use LHRH, letrozole, and ribociclib?
Francisco Esteva, MD, PhD: I think I would mostly use LHRH with tamoxifen and ribociclib. The combination of an LHRH agonist plus an aromatase inhibitor is, in my opinion, a little bit more toxic than LHRH plus tamoxifen. If you add ribociclib, the results are excellent. So, I think it’s another option for our patients.
Adam M. Brufsky, MD, PhD, FACP: Komal, do you do the same thing, or different?
Komal Jhaveri, MD, FACP: Yes.
Adam M. Brufsky, MD, PhD, FACP: You’re going to use this. Is it something different than you’ve done before or is it the same?
Komal Jhaveri, MD, FACP: No, I think we’ve been all using it in our practice. This is just confirming the data in a very nice way in a phase III setting with such a large population. But yes, it gives you an option if you’re not tolerating the AI plus LHRH. Especially in these younger women, you can use tamoxifen as the backbone if that is what you prefer or vice versa.
Lee Schwartzberg, MD, FACP: I would start with the AI because, in the metastatic setting, I want the best response rate. If you look at the subgroup analysis, they were very small groups. The tamoxifen’s hazard ratio was a little less good than the AI’s was.
Hope S. Rugo, MD: I think it depends on if it’s a de novo metastatic situation or not.
Adam M. Brufsky, MD, PhD, FACP: Right, that’s a very good point.
Hope S. Rugo, MD: In that situation, it may be a little bit harder to give the AI and ovarian suppression right off the bat, but most of our patients have already been exposed to endocrine therapy at one time or another and so we tend to use AIs. But again, I think that has to be individualized. We had a patient who had DCIS and her next presentation was metastatic disease. In that situation, she did better with tamoxifen up front. But mostly, I would like people to be on their first-line therapy for as long as possible, and that’s going to be using an AI.
Adam M. Brufsky, MD, PhD, FACP: Just a few more things and we’ll move on. The first thing is that this is done with ribociclib. I’m assuming that Novartis may ask for label expansion for this indication. Will that drive you to use ribociclib in this setting or do you think it’s a class effect across all the CDK4/6 inhibitors?
Hope S. Rugo, MD: It’s a class effect, but when we’re trying to decide how to use different agents, you have to use the studies that are done. That’s the only way for us to choose. Otherwise, it’s, “OK, it’s Monday. I’m going to use this drug.”
Adam M. Brufsky, MD, PhD, FACP: Which is what a lot of us may do.
Hope S. Rugo, MD: Yes.
Lee Schwartzberg, MD, FACP: Well, we extrapolate when we need to, but when we don’t need to we have the data here.
Adam M. Brufsky, MD, PhD, FACP: We have the data, right. This is the option that has the data.
Komal Jhaveri, MD, FACP: Yes, I think we all got comfortable using palbociclib. That was the first kid on the block when it came to CDK4/6 inhibitors, and I think we all continue to use that a lot more in practice. I do. But this would perhaps be the first kid on the block for premenopausal women, so I think if we had to go and be a purist and use the label for that, we would use ribociclib in premenopausal women.
Adam M. Brufsky, MD, PhD, FACP: That’s reasonable. Francisco, are you on board with that, too?
Francisco Esteva, MD, PhD: Yes.
Adam M. Brufsky, MD, PhD, FACP: What do you think of the issue of ribociclib versus palbociclib? We’ll get to abemaciclib in a minute.
Hope S. Rugo, MD: I think that there are some benefits in terms of being able to dose reduce by having the same drug and not having to get a new authorization and change over, which is a real pain. Now, I don’t dose reduce a lot. I find the major reason for dose reducing is fatigue in older women. I think that is an advantage, primarily with ribociclib more than the other 2 agents. The EKGs and worrying about other drugs are bigger issues for older women than younger women.
Komal Jhaveri, MD, FACP: I agree.
Hope S. Rugo, MD: I think one might try to parse out your decisions based on that.
Adam M. Brufsky, MD, PhD, FACP: That’s a good point. Antidepressants are the big one for me. I’m a medical oncologist. Yes, we’re all psychiatrists to some degree and we all will try an antidepressant, but I don’t want to be sitting there messing with my patient’s antidepressant. If someone calls me up and says that you can’t use ribociclib because they’re on one…
Hope S. Rugo, MD: You can’t give this drug, right.
Lee Schwartzberg, MD, FACP: Right. We have enough trouble with tamoxifen and that.
Adam M. Brufsky, MD, PhD, FACP: Right. I don’t want to go through that again. That’s the only thing that bothers me about this. That brings us to a little bit of a different story. What is the quality of life? Sara Tolaney presented data on MONALEESA-2. Does anybody have a comment on those data?
Komal Jhaveri, MD, FACP: Yes. I think we all try to in metastatic disease.
Adam M. Brufsky, MD, PhD, FACP: MONALEESA-2, just to explain to the audience, what was that?
Komal Jhaveri, MD, FACP: MONALEESA-2 was looking at ribociclib with letrozole in postmenopausal women in the first-line setting, and the regimen has been approved for that indication. That’s what we have been using in addition to the PALOMA-2 data we have with palbociclib. I think it was good to see that not only do we have an impact on progression-free survival in these trials, but we also have an impact on the quality of life of these patients, which is very, very important in the metastatic and palliative setting. The other interesting thing that those data showed was that there was a significant reduction in pain scores by 8 weeks with these women. So, I think that is very comforting to hear for our patients in the palliative setting.
Adam M. Brufsky, MD, PhD, FACP: Yes, I think the really cool thing about these drugs that I’m starting to realize—we see it in the trials, we are seeing it clinically, and I’m curious about people’s impressions of this—is that the response rates are kind of like chemotherapy.
Lee Schwartzberg, MD, FACP: They’re better.
Adam M. Brufsky, MD, PhD, FACP: They’re better, in some cases.
Lee Schwartzberg, MD, FACP: They’re better than chemotherapy.
Adam M. Brufsky, MD, PhD, FACP: They’re even better. I think we’re talking about, especially when we talk about neoadjuvant therapy in a few minutes, people who you would have thought about giving chemotherapy to up front in the neoadjuvant setting or even in the metastatic setting. You’ve got to reduce their pain, you’ve got to get a rapid response. And it turns out these drugs probably have the same degree of response rates, don’t they?
Hope S. Rugo, MD: It’s a little slower.
Lee Schwartzberg, MD, FACP: It’s a little slower, but the percentages are as good.
Francisco Esteva, MD, PhD: In ER—positive patients, these are the most effective therapies. A combination of an AI plus ribociclib or any of the other CDK4/6 inhibitors, in my opinion, is the most effective. What we saw is on top of that; it improves the quality of life of the patient. So, that’s the best we can expect in a patient with metastatic disease.
Hope S. Rugo, MD: Yes, I agree.
Francisco Esteva, MD, PhD: I was very pleased to see that, because even some patients with metastatic disease don’t have any symptoms. You give chemotherapy and their quality of life, of course, is worse, even though the scans look better. So, the fact that the quality of life was improved with ribociclib and letrozole was very reassuring compared with letrozole alone in patients with metastases who may or may not have symptoms.
Lee Schwartzberg, MD, FACP: This is a really important point. You can’t make an asymptomatic patient better. In this case, you’re giving an additional drug and the quality of life improved, just like it did with letrozole, because the patients had their symptoms controlled. Now we can feel really comfortable. We have an effective therapy, it has mild to moderate toxicity, and most of the moderate toxicity is lab toxicity. It doesn’t matter to the patient.
Adam M. Brufsky, MD, PhD, FACP: Right, neutrophil counts go down.
Lee Schwartzberg, MD, FACP: Except for fatigue.
Adam M. Brufsky, MD, PhD, FACP: Fatigue is bigger than we think. Fatigue is definitely bigger.
Hope S. Rugo, MD: Fatigue is a big issue for older patients.
Francisco Esteva, MD, PhD: In my experience, ribociclib is extremely well tolerated.
Hope S. Rugo, MD: It’s interesting because the FDA analysis that looked at older women in all 3 combined trials in the first-line setting definitely showed it. It’s interesting for me to look at that. Overall, the toxicity was about the same. But if you looked at grade 3/4 toxicity, it was higher. Now, the numbers are small, but it’s higher. They looked at patients over 60, 65, or 70 years old, etc, and really focused on patients over the age of 70 who we would all agree are older, but not elderly.
Adam M. Brufsky, MD, PhD, FACP: That depends.
Francisco Esteva, MD, PhD: The efficacy was the same.
Hope S. Rugo, MD: We’ve looked at it in the palbociclib group. It’s been looked at in the ribociclib group and a little, not quite as much, in abemaciclib. But I’m sure it will be the combined analysis that gives us a whole lot more power. What was interesting to me was that the number of dose reductions and dose discontinuations were higher in older women, too. And so that goes along with the fact that we have to be sensitive to the fact that older patients are going to be more sensitive to serious toxicity, and I think fatigue is the biggest one that I see.
Adam M. Brufsky, MD, PhD, FACP: In my practice, fatigue is now probably more around 10%. It’s reported at around 5%, or something like that. I think it’s double that.
Lee Schwartzberg, MD, FACP: You’re talking about grade 3?
Adam M. Brufsky, MD, PhD, FACP: Grade 3, yes.
Lee Schwartzberg, MD, FACP: That would indicate dose reduction.
Hope S. Rugo, MD: It’s really in older patients. I have a patient where I keep giving her a month off here and there because she just says, “I’m so tired.”
Adam M. Brufsky, MD, PhD, FACP: We’ll talk about abemaciclib in a minute, but do you think it’s specific to the drug? Do you see less fatigue with ribociclib than palbociclib or is it about the same?
Francisco Esteva, MD, PhD: It’s hard to tell. It’s hard to say.
Komal Jhaveri, MD, FACP: I think it’s about the same.
Hope S. Rugo, MD: They didn’t look at that separately within this analysis that Singh presented from the FDA, so it’s hard to know. I doubt, given the small numbers, you’d really be able to tell any difference.
Francisco Esteva, MD, PhD: As Hope mentioned earlier, the dose reduction is much easier with ribociclib. To go from 600 mg to 400 mg to 200 mg, you use the same dose in 3 pills, 2, then 1. I have a few patients on the MONALEESA-2 study who are even now on 200 mg with stable disease going on 3 or 3-and-a-half years. So, when you go to those levels, the disease still remains stable. It’s very well tolerated.
Adam M. Brufsky, MD, PhD, FACP: We’re all starting to see these long-term patients. Now that the drugs have been on the market for a couple of years—3, 4 years out now—they’re doing really well.
Hope S. Rugo, MD: I have a patient who’s been on for almost 5 years...
Adam M. Brufsky, MD, PhD, FACP: She’s on the trial.
Hope S. Rugo, MD: She’s on PALOMA-2.
Komal Jhaveri, MD, FACP: I wonder if we’re going to start doing what some people do with everolimus, where they start with a lower dose and then go up with the dose as patients tolerate it. Regarding the data for dose reduction not impacting the efficacy, where PALOMA-3 has been published already, I wonder if that could be something one could look at, especially in the older women.
Francisco Esteva, MD, PhD: That’s not to extrapolate, because you see the response so early. If you start with a lower dose, I don’t know about that.
Hope S. Rugo, MD: The toxicities from the drugs include fatigue. In my experience, even though people haven’t shown any change in the percentages of toxicity in long-term follow-up with CDK4/6 inhibitors overall, diarrhea, which we’ll talk about soon, is early. I think the fatigue is a late toxicity. It’s a long-term therapy toxicity. Unlike everolimus, where we worry about that initial toxicity, we now can control the stomatitis, but I think that there’s no real reason to start lower. I agree with you in that I don’t think we can extrapolate well.
Lee Schwartzberg, MD, FACP: I agree. Start at the full dose.
Komal Jhaveri, MD, FACP: Right.
Transcript Edited for Clarity