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CDK4/6 Inhibitors: Treating Beyond Progression

Panelists: Joyce O Shaughnessy, MD, Baylor University Medical Center; Kevin Kalinsky, MD, MS NewYork-Presbyterian Hospital; Elizabeth Mittendorf Dana-Farber; Ruth O Regan, MD, University of Wisconsin Carbone Cancer Center; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Tuesday, Apr 09, 2019



Transcript: 

Joyce O’Shaughnessy, MD:
So then comes a thorny question. A patient has done well. Let’s say they’ve responded and now they’re progressing. Again, let’s consider the evolving practice patterns and discuss how you’re deciding what to recommend for patients. Of course, we’re looking forward, hopefully, to having alpelisib around too. So that will be a plus. How about you, Kevin? What are you doing now for post-CDK [cyclin-dependent kinase] therapy?

Kevin Kalinsky, MD, MS: In general, I try to keep patients on hormonal therapy, or hormonal therapy in combination with an mTOR inhibitor for as long as I can before going to chemotherapy. I think some of the concerns had been that maybe the biology of the cancer would change and that patients would need to go to chemotherapy quicker. But you know we have data that demonstrate that’s not the case, right? The median time to chemotherapy was still good with the combination. So I tend to do that unless the patient is really becoming symptomatic, in which case then they’ll need to go on to chemotherapy.

Joyce O’Shaughnessy, MD: Yes. And regarding the mTOR inhibitors, with everolimus you’ve had good….

Kevin Kalinsky, MD, MS: Yes. If a patient, for instance, is getting an aromatase inhibitor plus a CDK4/6 inhibitor, I tend to go to something like fulvestrant. Based upon the PrECOG data, I tend to go to fulvestrant plus Afinitor. If I could get it paid for by the insurance company, then that’s what I tend to do. I don’t know if you guys have a similar approach?

Ruth O'Regan, MD: Well, I would put the patient on your trial….

Kevin Kalinsky, MD, MS: Right.

Ruth O'Regan, MD: I can talk about what I would do if I know drug trials.

Kevin Kalinsky, MD, MS: Right. Thank you. So we have a study that is trying to answer the question about whether there’s a role for continuation of CDK4/6 inhibition. You know, this is something that is commonly coming up in terms of sequencing. We have a study where patients are getting any aromatase inhibitor plus any CDK4/6 inhibitor, and then they’re randomized to fulvestrant plus ribociclib versus fulvestrant plus placebo.

Erica Mayer, MD, MPH, has a similar study that has patients getting fulvestrant plus PALBO [palbociclib] versus fulvestrant, plus fulvestrant/PALBO [palbociclib] and a checkpoint inhibitor. So these are randomized studies that are ongoing that hopefully will yield some answers in terms of whether there’s a role for continuation of CDK4/6 inhibition.

Joyce O’Shaughnessy, MD: Right. But outside of a clinical trial, at this time, we probably wouldn’t continue the CDK4/6 inhibitor, right?

Kevin Kalinsky, MD, MS: No, I think in the absence of data….

Joyce O’Shaughnessy, MD: Yes.

Ruth O'Regan, MD: I think so too. And I think the decision point is determining just what goes with single-agent endocrine therapy at that point, if they’ve done very well with the CDK inhibitor and endocrine therapy combination. Or would you do like Kevin suggested: Use everolimus in that scenario? I think they’re all questions that we don’t know the answer to, and it’s great that we have some trials addressing this. There isn’t good preclinical data saying you should switch the CDK inhibitor. There’s certainly the similar resistant lines that seem panresistant. So I don’t think the data really support doing it off study, although it is being done, I’m sure.                

Hope S. Rugo, MD: I’m of course hopeful that we’ll have the alpha-specific PI3 kinase inhibitor, alpelisib, available before too long, sometime this year, based on SOLAR-1. Then I would generally check for a PI3 kinase mutation at some point during that therapy that they’re on with the CDK4/6 inhibitor; or with a tumor biopsy obtained on progression, and you can get the results back fairly quickly now. Then I would treat patients with a PI3 kinase mutation with alpelisib and fulvestrant, and then, with the other patients, potentially use everolimus like you do, or a clinical trial.

We have a trial right now, the BYLieve study, that’s looking at patients who’ve had a prior CDK4/6 inhibitor, have a PI3 kinase mutation, and can go on a single arm with alpelisib and hormone therapy.

Joyce O’Shaughnessy, MD: That’ll be great because we really need that. We need to know what the data with alpelisib and endocrine therapy are at the time of progression on the CDK.

Ruth O'Regan, MD: After the CDK.

Joyce O’Shaughnessy, MD: Right, because there’s only a small percentage of those in the SOLAR-1 study.

Ruth O'Regan, MD: Tiny.

Joyce O’Shaughnessy, MD: Tiny. It looked just as good, but it was so tiny we need more data. So that’s great. That’ll be really good.

Ruth O'Regan, MD: I think some of the preclinical models have shown that PI3 kinase is activated in these CDK inhibitor-resistant cell lines, so I think it’s a perfect rationale to look at that.

Hope S. Rugo, MD: Do you try and biopsy patients when they progress? It’s just a question because you’re mentioning that activation.

Ruth O'Regan, MD: Yes. I do think that these patients need to have other biopsies. What I tend to do is wait until I think they’re endocrine resistant. This is kind of defined loosely: Progression within 6 months of their last therapy. I think that’s where you’re going to get most of your answers.
 
I think what’s very exciting is the liquid biopsy technology, which hopefully would allow us to actually be able to look at the cancers in real time. And I think in context of some other signs of breast cancer, which we’ll talk about later on, you do see some actionable mutations in ER [estrogen receptor]-positive breast cancer. So I’d be interested to hear when other people send those assays or rebiopsy.

Kevin Kalinsky, MD, MS: Yes, I also increasingly am utilizing cell-free DNA, really just in the context of clinical decisions, because we have actionable clinical trials. So if somebody has a PI3K mutation, we have a study that patients would go on; or an ESR1 mutation for oral SERD [selective estrogen receptor degrader]. So it’s because we have something at our institution that’s actionable.

Joyce O’Shaughnessy, MD: And the HER2 [human epidermal growth factor receptor 2] mutations I think, too. Not on the NCCN [National Comprehensive Cancer Network] guidelines yet, with regard to fulvestrant and neratinib, but there are some increasing data coming out for HER2 mutations, which we do see. We do see this in both lobulars and ductal. So I think we’re still learning about the mechanisms of resistance to the CDK4/6 inhibitors. And the alpelisib, initially, will be for the PIK3CA-mutant population. But of course, there are other ways to activate the PI3 kinase pathway too, and perhaps it’ll be useful across the board in CDK4/6 inhibitor-resistant patients. But we’re going to need more data on that.


Transcript Edited for Clarity

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Transcript: 

Joyce O’Shaughnessy, MD:
So then comes a thorny question. A patient has done well. Let’s say they’ve responded and now they’re progressing. Again, let’s consider the evolving practice patterns and discuss how you’re deciding what to recommend for patients. Of course, we’re looking forward, hopefully, to having alpelisib around too. So that will be a plus. How about you, Kevin? What are you doing now for post-CDK [cyclin-dependent kinase] therapy?

Kevin Kalinsky, MD, MS: In general, I try to keep patients on hormonal therapy, or hormonal therapy in combination with an mTOR inhibitor for as long as I can before going to chemotherapy. I think some of the concerns had been that maybe the biology of the cancer would change and that patients would need to go to chemotherapy quicker. But you know we have data that demonstrate that’s not the case, right? The median time to chemotherapy was still good with the combination. So I tend to do that unless the patient is really becoming symptomatic, in which case then they’ll need to go on to chemotherapy.

Joyce O’Shaughnessy, MD: Yes. And regarding the mTOR inhibitors, with everolimus you’ve had good….

Kevin Kalinsky, MD, MS: Yes. If a patient, for instance, is getting an aromatase inhibitor plus a CDK4/6 inhibitor, I tend to go to something like fulvestrant. Based upon the PrECOG data, I tend to go to fulvestrant plus Afinitor. If I could get it paid for by the insurance company, then that’s what I tend to do. I don’t know if you guys have a similar approach?

Ruth O'Regan, MD: Well, I would put the patient on your trial….

Kevin Kalinsky, MD, MS: Right.

Ruth O'Regan, MD: I can talk about what I would do if I know drug trials.

Kevin Kalinsky, MD, MS: Right. Thank you. So we have a study that is trying to answer the question about whether there’s a role for continuation of CDK4/6 inhibition. You know, this is something that is commonly coming up in terms of sequencing. We have a study where patients are getting any aromatase inhibitor plus any CDK4/6 inhibitor, and then they’re randomized to fulvestrant plus ribociclib versus fulvestrant plus placebo.

Erica Mayer, MD, MPH, has a similar study that has patients getting fulvestrant plus PALBO [palbociclib] versus fulvestrant, plus fulvestrant/PALBO [palbociclib] and a checkpoint inhibitor. So these are randomized studies that are ongoing that hopefully will yield some answers in terms of whether there’s a role for continuation of CDK4/6 inhibition.

Joyce O’Shaughnessy, MD: Right. But outside of a clinical trial, at this time, we probably wouldn’t continue the CDK4/6 inhibitor, right?

Kevin Kalinsky, MD, MS: No, I think in the absence of data….

Joyce O’Shaughnessy, MD: Yes.

Ruth O'Regan, MD: I think so too. And I think the decision point is determining just what goes with single-agent endocrine therapy at that point, if they’ve done very well with the CDK inhibitor and endocrine therapy combination. Or would you do like Kevin suggested: Use everolimus in that scenario? I think they’re all questions that we don’t know the answer to, and it’s great that we have some trials addressing this. There isn’t good preclinical data saying you should switch the CDK inhibitor. There’s certainly the similar resistant lines that seem panresistant. So I don’t think the data really support doing it off study, although it is being done, I’m sure.                

Hope S. Rugo, MD: I’m of course hopeful that we’ll have the alpha-specific PI3 kinase inhibitor, alpelisib, available before too long, sometime this year, based on SOLAR-1. Then I would generally check for a PI3 kinase mutation at some point during that therapy that they’re on with the CDK4/6 inhibitor; or with a tumor biopsy obtained on progression, and you can get the results back fairly quickly now. Then I would treat patients with a PI3 kinase mutation with alpelisib and fulvestrant, and then, with the other patients, potentially use everolimus like you do, or a clinical trial.

We have a trial right now, the BYLieve study, that’s looking at patients who’ve had a prior CDK4/6 inhibitor, have a PI3 kinase mutation, and can go on a single arm with alpelisib and hormone therapy.

Joyce O’Shaughnessy, MD: That’ll be great because we really need that. We need to know what the data with alpelisib and endocrine therapy are at the time of progression on the CDK.

Ruth O'Regan, MD: After the CDK.

Joyce O’Shaughnessy, MD: Right, because there’s only a small percentage of those in the SOLAR-1 study.

Ruth O'Regan, MD: Tiny.

Joyce O’Shaughnessy, MD: Tiny. It looked just as good, but it was so tiny we need more data. So that’s great. That’ll be really good.

Ruth O'Regan, MD: I think some of the preclinical models have shown that PI3 kinase is activated in these CDK inhibitor-resistant cell lines, so I think it’s a perfect rationale to look at that.

Hope S. Rugo, MD: Do you try and biopsy patients when they progress? It’s just a question because you’re mentioning that activation.

Ruth O'Regan, MD: Yes. I do think that these patients need to have other biopsies. What I tend to do is wait until I think they’re endocrine resistant. This is kind of defined loosely: Progression within 6 months of their last therapy. I think that’s where you’re going to get most of your answers.
 
I think what’s very exciting is the liquid biopsy technology, which hopefully would allow us to actually be able to look at the cancers in real time. And I think in context of some other signs of breast cancer, which we’ll talk about later on, you do see some actionable mutations in ER [estrogen receptor]-positive breast cancer. So I’d be interested to hear when other people send those assays or rebiopsy.

Kevin Kalinsky, MD, MS: Yes, I also increasingly am utilizing cell-free DNA, really just in the context of clinical decisions, because we have actionable clinical trials. So if somebody has a PI3K mutation, we have a study that patients would go on; or an ESR1 mutation for oral SERD [selective estrogen receptor degrader]. So it’s because we have something at our institution that’s actionable.

Joyce O’Shaughnessy, MD: And the HER2 [human epidermal growth factor receptor 2] mutations I think, too. Not on the NCCN [National Comprehensive Cancer Network] guidelines yet, with regard to fulvestrant and neratinib, but there are some increasing data coming out for HER2 mutations, which we do see. We do see this in both lobulars and ductal. So I think we’re still learning about the mechanisms of resistance to the CDK4/6 inhibitors. And the alpelisib, initially, will be for the PIK3CA-mutant population. But of course, there are other ways to activate the PI3 kinase pathway too, and perhaps it’ll be useful across the board in CDK4/6 inhibitor-resistant patients. But we’re going to need more data on that.


Transcript Edited for Clarity
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