Adam M. Brufsky, MD, PhD, FACP: Let’s move on to the third agent. Unfortunately, when we think of the third one, we think of diarrhea. How does abemaciclib play into all of this? Does someone want to start with this? Komal, do you use abemaciclib in your practice?
Komal Jhaveri, MD, FACP: I’ve used abemaciclib mostly on clinical trials. I think it just got approved, so I really haven’t used that as a standard-of-care CDK4/6 inhibitor in my patients yet. But yes, when we think about abemaciclib, we think about palbociclib and ribociclib together in terms of their toxicity profile, and we feel like the toxicity profile of abemaciclib is given its activity beyond specifically the CDK4/6 alone and the other CDK kinases. This is why we probably see the differential toxicity of diarrhea in abemaciclib compared with ribociclib and palbociclib, where we see neutropenia as the predominant side effect profile. But as we’ve discussed earlier already, I think, across the board, these CDK4/6 inhibitors have similar hazard ratios whether they’ve been used in the first-line setting or in the second-line setting, in this case with MONARCH-2 in the second line and with MONARCH 3 in the first line. I think it’s a class effect with a little difference in toxicities. That’s how I see them.
Lee Schwartzberg, MD, FACP: Preclinically, they do look different.
Adam M. Brufsky, MD, PhD, FACP: I think abemaciclib has a much lower IC50 than the other 2, right?
Lee Schwartzberg, MD, FACP: Right. And it has a larger kinome, so it really does attack. But so far, that has not translated into the clinical setting, with the exception of the single-agent approach. Now, you could say that was the clinical trial. There is activity as a single agent. We don’t have too many patients who haven’t had a CDK inhibitor, but occasionally you have a patient who you’ve treated previously with endocrine therapies who’s on chemotherapy now. I have tried abemaciclib on those patients, and I’ve seen some good results.
Adam M. Brufsky, MD, PhD, FACP: In people who have had a CDK4/6 inhibitor or who have not?
Lee Schwartzberg, MD, FACP: No, who have not.
Adam M. Brufsky, MD, PhD, FACP: Remember, the label very importantly says nothing about CDK4/6. It just says failure of an endocrine therapy.
Hope S. Rugo, MD: Actually, we have a few people who are now on abemaciclib, although it’s a little too early because it just got approved. For people who didn’t get it and are now laid out or who had a prior CDK4/6 inhibitor, now you can try abemaciclib. It’s just very important to educate people about diarrhea. It’s more like pertuzumab and not as much like neratinib in that you don’t have to start prophylactically. But they better have it in their pocket because it’s early. It happens right away, and then people have on-and-off sensitivity to food and things over time. I thought it was interesting. There are a lot of studies going on looking at palbociclib after palbociclib or abemaciclib after palbociclib.
Adam M. Brufsky, MD, PhD, FACP: There are 3 trials.
Hope S. Rugo, MD: That’s a lot. I think that people are really interested in seeing what happens and if extending the therapy after progression will be useful.
Francisco Esteva, MD, PhD: Extending therapy may be a little bit different for palbociclib and ribociclib as opposed to abemaciclib, which may be a little different.
Hope S. Rugo, MD: It may be.
Francisco Esteva, MD, PhD: It reminds me of anastrozole and letrozole versus exemestane. It may be that abemaciclib is a little bit different and may produce different efficacy as opposed to ribociclib and palbociclib, which look more similar.
Adam M. Brufsky, MD, PhD, FACP: The question is, I’ll give this to you, what is the mechanism of CDK4/6 resistance? Is there CDK4/6 resistance? As someone who spent 15 years studying HER2 resistance, is there CDK4/6 resistance?
Hope S. Rugo, MD: Yes, there is.
Lee Schwartzberg, MD, FACP: There is.
Francisco Esteva, MD, PhD: Of course, yes.
Adam M. Brufsky, MD, PhD, FACP: Clinically?
Hope S. Rugo, MD: There is, clinically. I just saw a patient, and she has de novo metastatic disease in the peritoneum, lobules, and her ER is 100%. So, she got letrozole and palbociclib, and in 3 months she can’t eat, she’s admitted, and she’s put on TPN (total parenteral nutrition). She’s sick as a dog.
Adam M. Brufsky, MD, PhD, FACP: TPN, yes, that’s bad.
Hope S. Rugo, MD: She would have been dead. She couldn’t take anything in her mouth early after diagnosis. So, they sent off genomic sequencing, and she has an Rb mutation.
Adam M. Brufsky, MD, PhD, FACP: Really?
Hope S. Rugo, MD: Yes. This is rare, but these are up-front resistances to CDK inhibition. It can’t work.
Adam M. Brufsky, MD, PhD, FACP: But I thought in the PALOMA-2 or PALOMA-1 trial, Rb had nothing to do with it when you look at the subgroup analysis.
Hope S. Rugo, MD: No, because it’s really uncommon. That’s the thing.
Adam M. Brufsky, MD, PhD, FACP: OK, fair enough.
Hope S. Rugo, MD: Actually, they have data at UCLA that suggest in these patients who have loss of Rb, as you would expect, that mechanistically it can’t work.
Lee Schwartzberg, MD, FACP: That’s primary resistance versus acquired.
Adam M. Brufsky, MD, PhD, FACP: This is why those CDK4/6 inhibitor beyond-progression trials are going to be very important. If there is benefit, just like there was with trastuzumab 20 years ago or 10 years ago, it will be more expensive, but it will at least, hopefully, get to that scientific question one way or the other.
Francisco Esteva, MD, PhD: We’re doing a study like that where, for patients who develop progressive disease on palbociclib or ribociclib with an AI [aromatase inhibitor], we continue ribociclib with fulvestrant compared to fulvestrant alone.
Adam M. Brufsky, MD, PhD, FACP: Right, that’s Kevin Kalinsky’s trial at Columbia.
Francisco Esteva, MD, PhD: Yes, at Columbia, at NYU—several institutions are doing this trial.
Adam M. Brufsky, MD, PhD, FACP: We can call it the “NEW YORK” trial, since it’s New York institutions.
Hope S. Rugo, MD: Then there’s a palbociclib trial.
Francisco Esteva, MD, PhD: This is a relatively small trial.
Adam M. Brufsky, MD, PhD, FACP: It’s 150 patients, I think.
Francisco Esteva, MD, PhD: But I think it’s a really important question. As you said, I’m sure there is resistance, but can we overcome that resistance by switching the hormone therapy like we’ve done with Herceptin (trastuzumab)? We don’t know that.
Hope S. Rugo, MD: I still think it’s a really fascinating thing to add additional targeted agents that may be able to overcome resistance. There are trials looking at a combined mTOR and PI3 kinase inhibitor, gedatolisib, that are added on for the patients who previously had a CDK4/6 inhibitor, and you keep the CDK4/6 inhibitor. There were fascinating data presented at San Antonio with this FGFR receptor amplification that is associated with resistance to CDK4/6 inhibitors, and there’s a trial going on that we’ll be participating in, when it gets out of phase I, looking at an FGFR inhibitor.
Adam M. Brufsky, MD, PhD, FACP: We’ve been burnt before in the FGFR space.
Lee Schwartzberg, MD, FACP: This is different.
Adam M. Brufsky, MD, PhD, FACP: How is it different than lucitanib? We’ve all been burnt by lucitanib.
Hope S. Rugo, MD: It’s less toxic, and it doesn’t have VEGF activity.
Adam M. Brufsky, MD, PhD, FACP: Looking at the lucitanib trial, it was FGF, progressive metastatic disease that’s hormone receptor—positive, no CDK4/6…
Hope S. Rugo, MD: There were no CDK inhibitors.
Adam M. Brufsky, MD, PhD, FACP: There weren’t then, but it didn’t work. It was a bust. So, how is this different?
Komal Jhaveri, MD, FACP: It was a dirty FGFR inhibitor. Lucitanib was not really a selective FGFR inhibitor, and I think the problem with the FGFR pathway is 2-fold. One is the right drug targeting the right target. So, lucitanib targets more of the VEGF and the PDGF more than the FGF, which is what we saw with the toxicity profile of hypertension predominantly with the VEGF inhibitors.
Adam M. Brufsky, MD, PhD, FACP: I’m just being provocative.
Komal Jhaveri, MD, FACP: So, the JNJ compound that Hope is talking about with fulvestrant and palbociclib in the phase I setting, which we’ll be participating in as well, is a selective FGFR inhibitor. A similar compound is the Debio compound, which is also a selective FGFR inhibitor.
Adam M. Brufsky, MD, PhD, FACP: Fair enough.
Lee Schwartzberg, MD, FACP: I think there’s life in FGFR inhibitors.
Transcript Edited for Clarity