CDK4/6 Inhibitors & Endocrine Therapy: Treatment Resistance

Sara M. Tolaney, MD, MPH:There has been a lot of interest in trying to better understand why patients may develop resistance to CDK4/6 inhibition, and there’s actually been a lot of work that has been done looking at this. What’s really been found is that it’s not just 1 mechanism; there are several different ways that patients can develop resistance. Sometimes the resistance develops not really to the CDK4/6 inhibitor but rather to the endocrine therapy that’s being given in combination with it. Some data have found that patients can developESR1mutations, which are a mechanism of resistance, for example, to aromatase inhibition.

Other trials have shownHER2mutation as a potential resistance mechanism to the endocrine therapy. And then there are data suggesting a myriad of different ways that patients may be acquiring CDK4/6 resistance. Some of these include loss of Rb [retinoblastoma protein], amplification of FGFR [fibroblast growth factor receptor], amplification of cyclin E. And so, there are lots of potential pathways for resistance, and I think this really begs the question of, what’s the optimal strategy to treat a patient with at the time of progression on a CDK4/6 inhibitor?

There are lots of trials that are ongoing, trying to address the question of whether or not we should continue a CDK/6 inhibitor beyond progression and just switch the endocrine therapy partner. For example, there’s a trial that’s looking at patients who have progressed on a CDK4/6 inhibitor with an aromatase inhibitor and then randomizes them to receive fulvestrant alone or fulvestrant with palbociclib; or actually fulvestrant with palbociclib and avelumab. So that’s 3 different arms that it’s looking at. I think these types of studies are going to help us better understand if there’s utility to continuation. My guess is that it’s really going to be very dependent on individual patients, because it seems that there isn’t just 1 mechanism of resistance. And so, for example, a patient who’s developing resistance to the endocrine therapy may do very well with swapping the endocrine agent and continuing CDK4/6 inhibition. But if you have a patient who has biallelic loss of RB, they’re very unlikely to derive benefit from continuation of CDK4/6 inhibition. And so I do wonder if, in the future, this will be a personalized treatment decision based on genomic alterations.

At this time, we don’t know whether or not there is benefit to continuation of CDK4/6 inhibition beyond progression. And so I will say that outside a clinical trial setting, I am not routinely continuing CDK4/6 inhibition beyond progression. I think what we are still struggling with, however, is the optimal approach in terms of what treatment to give these patients.

There are several trials exploring this question, but in general I think the standard treatment approaches would either be using exemestane with everolimus based on the BOLERO-2 data, or potentially using fulvestrant in combination with everolimus based on the PrECOG study. For example, for a patient who had received an aromatase inhibitor with a CDK4/6 inhibitor at the time of progression, I’m often thinking of using a fulvestrant-based regimen—either fulvestrant alone or fulvestrant with everolimus.

We now have data from SOLAR-1 looking at alpelisib in patients withPIK3CAmutations showing a very impressive benefit in progression-free survival from 5.7 to 11 months. I think, given this, for a patient who has aPIK3CAmutation, if they’ve progressed on first-line aromatase inhibition with CKD4/6 inhibition, then it would be very reasonable to give that patient fulvestrant with alpelisib.

So I do think there are lots of different choices. However, I do think data are quite limited because we really don’t have very much data regarding outcomes in patients who’ve already progressed on a CDK4/6 inhibitor, including data from SOLAR-1, which had very few patients who had prior CDK4/6 inhibition.

For a patient who’s progressed on a CDK4/6 inhibitor with endocrine therapy, I don’t think there is 1 right choice. You know, I think it will depend on so many factors, in terms of what prior therapy they got on the first-line setting and what their sensitivity was to that treatment. If it’s a patient who’s had very prolonged benefit to endocrine therapy and CDK4/6 inhibition, I would like to expose them to another endocrine agent. At that point, you’re looking at either exemestane and everolimus or fulvestrant, or fulvestrant and everolimus. I think your other choice is really to move to chemotherapy. And so again, I think it is just so dependent on how that patient has done, and what their current situation is that’s going to allow you to make those decisions.

In the future, I’m hopeful that a better understanding of a patient’s genomics will also help you choose the right treatment approach. I do think considering clinical trials for those patients who have progressed on CDK4/6 inhibition is very critical because it is really looking to help us answer the questions of whether or not continuing CDK4/6 inhibition will be beneficial or whether or not different combination therapies will be beneficial. There are trials looking at, for example, Aurora kinase inhibition at post-CDK4/6 progression, and trials looking at FGFR inhibition. And so we really are trying to look at whether or not hitting particular mechanisms of resistance will help those patients do better.

For CDK4/6 inhibition, I really think that the field has dramatically changed over the last few years. We’ve seen the approval of 3 different CDK4/6 inhibitors, which result in statistically significant improvements in progression-free survival. And now we even see benefit in terms of overall survival in the second-line setting for patients with endocrine-sensitive disease. I’m looking forward to seeing if there’s going to be a survival benefit from use of CDK4/6 inhibition in the first-line setting, and I think those data should be available shortly.

I’m also very curious to know whether or not continuation of CDK4/6 inhibition beyond progression will be efficacious. We’re hoping to see data from trials looking at that, also in the near future.

And I think better having a better understanding of mechanisms of resistance to CDK4/6 inhibitors are going to help us better develop treatments that are targeted to patients with specific tumor alterations that hopefully will allow patients to do better in the long run.

Transcript edited for clarity.

Case: A 58-Year-Old Woman With Metastatic ER+ Ductal Carcinoma

• 58-year-old woman with estrogen-receptor-positive (ER+), progesterone-receptor-negative (PR-), HER2-negative (HER2-) invasive ductal carcinoma (IDC) of L breast; she completed adjuvant anastrozole for 5 years
• Now, 13 months later, she presents with 4 small (<1.0 cm) asymptomatic lesions in the left lung and mediastinal and hilar lymphadenopathy.
• Mediastinoscopy was performed and confirmed ER+ PR- Her2- carcinoma
• ECOG PS: 0
• The patient was started on abemaciclib + fulvestrant