Using CDK4/6 Inhibitors After HR+ mBC Disease Progression

Andrew D. Seidman, MD: I want to reinvent this case for Nick. Let’s say that this same patient who progressed in her fourth year of adjuvant AI [aromatase inhibitor] and got 2½ years of benefit from fulvestrant and ribociclib had a wild type PIK3CA in lung and bone at the time of progression, so she’s not mutated. Nick, take us through your algorithm in terms of how you’re thinking about therapy. Let’s say she’s not in visceral crisis and she’s had 2½ years on fulvestrant CDK4/6 inhibitor. What’s on the menu?

Nicholas McAndrew, MD, MSCE: In a case like this, the factors that make me decide which way I want to take this patient in terms of the next lines of therapy are the specifics of the case, what the actual disease progression is looking like, and whether the patient’s performance status is significantly hindered. As you mentioned, she’s not in visceral crisis, so that’s reassuring at least.

There are number of different questions. We have different degrees of answered and unanswered questions. One of the most common questions that comes up in my clinic from my patients is, “Can I return to a CDK4/6 inhibitor? Should we switch the CDK4/6 inhibitor?” We have limited data, and we’re awaiting results from the randomized maintained trial looking at patients who had progressed on palbociclib or ribociclib plus an aromatase inhibitor. Those patients are being randomized to either fulvestrant or fulvestrant plus ribociclib. That will be a very helpful study in helping us understand if there’s a role for just switching the endocrine therapy partner but continuing some form of a CDK4/6 inhibitor as an immediate next line of therapy.

We don’t have any prospective data in this, but there was a retrospective analysis of 4 different centers performed by Seth Wander et al and presented at 2019 ASCO [American Society of Clinical Oncology] Annual Meeting. There were about 58 patients in this retrospective analysis who had received either a single agent or combination of abemaciclib and had progressed on that. They had then received either 1 non-CDK4/6 inhibitor-containing therapy in between resuming CDK4/6 or had gone on to another CDK4/6. About one-third of patients had early progressive disease. However, one-third of patients did have a significant clinical benefit in greater than 6 months. Then about 17 of the patients had been continuing on the CDK4/6 inhibitor at the time of analysis. There seems to be, at least in some retrospective data, some benefit of continuing or switching a CDK4/6 inhibitor. But until we have some randomized data helping us understand the true benefit of this, I tend to prefer other regimens, especially a regimen that would contain an mTOR inhibitor, such as an everolimus.

That would then bring us to some of the studies that have shown benefit with the use of everolimus plus exemestane. Certainly, the BOLERO-2 trial showed patients who had progressed on a nonsteroidal aromatase inhibitor. There was improved median progression-free survival with the combination of exemestane plus everolimus, which is what helped this combination gain approval by the FDA.

Of course, there have been other retrospective studies that are more modern, including the EVERMET trial. EVERMET was a retrospective study that looked at patients with both prior CDK inhibition and without CDK inhibition, and then also in the first-line setting who had received the combination of everolimus and exemestane. It showed that median progression-free survival was worse in patients who had received a prior CDK4/6 inhibitor, which isn’t surprising. But I don’t think this would steer me away from recommending this regimen in such a case. My general practice is to extinguish all targeted therapy options prior to moving on to chemotherapy.

Andrew D. Seidman, MD: I’m going to go off-script for a second and ask you each to give me a 15-second answer. Do any of you find a place for tamoxifen in such a patient as a consideration for third-line endocrine therapy? Dejan, why don’t you start?

Dejan Juric, MD: Not in the second line. The treatment paradigm for me is very simple in the second-line setting for CDK. I use fulvestrant-alpelisib for patients with PIK3CA mutations regardless of prior use of fulvestrant. Wenow have 2 data sets that show that prior fulvestrant doesn’t really matter. For patients who are a wild type, I use fulvestrant-everolimus based on PrECOG data, regardless of whether they had prior fulvestrant. I will use tamoxifen. Interestingly, tamoxifen has activity against some ESR1 mutants. I’d consider it in the third-line setting in patients who are really doing well, have low disease burden, and are progressing under second-line therapy but could benefit from some additional hormonal blockade and are not candidates for clinical trials for whatever reason.

Andrew D. Seidman, MD: Hope, in half that amount of time—15 seconds—is there a place for tamoxifen in the third-line endocrine setting for any of your patients?

Hope S. Rugo, MD: Yes, I think so. We have data with tamoxifen and everolimus. If a patient has received fulvestrant without a partner and doesn’t have a PIK3CA mutation, I could see giving tamoxifen; especially in patients with the ESR1 mutations with everolimus, based on the first data we saw. I have a patient who missed the CDK4/6 inhibitors, and she responded to tamoxifen and CDK4/6 inhibitor with PCR [polymerase chain reaction] in liver for 2 years. It definitely still works in the endocrine-sensitive population.

Andrew D. Seidman, MD: Nick, you’ve heard of tamoxifen. I know you’re a young oncologist. Have you used it in the third-line metastatic setting, or is it just not sexy enough?

Nicholas McAndrew, MD, MSCE: I feel bad for tamoxifen. It gets forgotten about in the age of glitzy combination regimens of targeted molecular therapy and other more recent endocrine therapy partners. But yes, I would certainly consider going back to tamoxifen or trying tamoxifen, especially in patients who have demonstrated at least in the first-line setting significant endocrine therapy sensitivity. But I agree that I’d extinguish all other combinations of molecular therapy partners and clinical trial options, including single-agent endocrine therapy trials that are looking at some of these newer agents, including oral SERDs [selective estrogen receptor degraders] and some of the PROTAC [proteolysis-targeting chimera] inhibitors. There’s certainly need for more endocrine therapy partner choices, and we should be trying to enroll patients in trials to help us understand the benefit of that. I would go back to tamoxifen, which I certainly have heard of.

Transcript Edited for Clarity