Real-World Use of CDK4/6 Inhibition in HR+/HER2- Breast Cancer

Transcript:

Hope S. Rugo, MD, FASCO: There are a few other comments to discuss here, and that maybe will inform us a little bit. When we look at real-world data, we talked about the patient population at clinical trial, which is always going to be contrived. There’s no way around it, but we’ve also seen now that the inclusion criteria for different trials have a huge impact on the outcome. You really are treating a different patient population with a different biology of tumor in many situations, so there’s now quite a lot of real-world data on CDK4/6 inhibitors. Then there’s also some data about routine clinical practice, people who manage adverse effects, etc. Aditya, can you tell us a little bit about the data that exists on this?

Aditya Bardia, MD, MPH: We have real-world data from various databases, and we have data related to palbociclib as well as ribociclib; I’ll start with palbociclib first. At [the] ASCO [American Society of Clinical Oncology annual meeting] we had an update by Dr Rugo looking at overall survival with first-line palbociclib plus endocrine therapy. If you look at the results, they are quite similar to the other clinical trials with ribociclib and even abemaciclib in the sense that you see an improvement in overall survival. Patients who received palbociclib had an overall survival of 53.4 months as compared with 40 months with standard endocrine therapy, and this corresponded to a hazard ratio of 0.76. Now this is real-world data, so we must be careful in terms of interpreting it. It was not a randomized trial but at least there’s evidence that it improved overall survival. There was another real-world data set called the POLARIS trial [NCT03280303], which looked at palbociclib and the choice of AI [aromatase inhibitor] vs fulvestrant and the management of adverse effects. Essentially, many patients got AI, but some got fulvestrant as well in the first-line setting. Patients who received fulvestrant plus albociclib had better overall survival, as compared with those who got AI plus palbociclib, and this could be based on therapy selection. Again, it’s not a randomized trial, but this does have implications because there are ongoing studies looking at AI plus CDK4/6 vs oral SERDs [selective estrogen receptor degraders] plus CDK4/6. In terms of management of adverse effects, in general the common adverse effects we’re seeing are neutropenia as well as some degree of alopecia and fatigue. With data from real-world data sets demonstrating that patients who got ribociclib had an improvement in overall survival as compared to those who didn’t get it, again substantiates data from the MONALEESA series, so no surprises there. We also have real-world evidence regarding PI3 kinase inhibitors and essentially similar data that patients who receive PI3 kinase inhibitors, regardless of the subsets, there’s an improvement in progression-free survival. In a patient with PIK3CA mutant hormone receptor-positive breast cancer in the second-line and beyond setting, the use of alpelisib, the PI3 kinase inhibitor should be considered.

Hope S. Rugo, MD, FASCO: Following up on that, there was some interesting data at ASCO looking at genetic factors of response and resistance to CDK4/6 inhibitors, and then in the update of SOLAR-1 [NCT02437318] and BYLieve [NCT03056755], the investigators also looked at those particular biomarkers. What did you think aboutthat? I mean, is this something that’s going to make it to the clinic? Are we going to be able to tell something more about how to properly treat patients from that?

Aditya Bardia, MD, MPH: I think from a clinical decision-making perspective no, from a clinical research perspective, yes. There was a study which looked at biomarkers predicting resistance to CDK4/6 inhibitors. They called the data set [the Guardant360] breast cancer data set and looked at different pathways. The bottom line was if you have loss of RB [retinoblastoma], that could confer resistance of CDK4/6, which makes sense because CDK4/6 inhibitors require the RB pathways to be intact. If there’s little loss of RB, the E2F would allow the cell cycle to move forward, and CDK4/6 inhibitors would not be that effective. The other interesting thing from that data set was MYC amplifications and upregulation of MYC appears to also confer resistance to CDK4/6 inhibitors. I think this is hypothesis generating, requires validation in other data sets, but in my mind, it’s not practice changing. We should not be looking at these biomarkers. The only biomarker we should look at is the presence of ER. As long as there’s ER, we should consider the use of CDK4/6 inhibitors in the first-line setting.

Hope S. Rugo, MD, FASCO: I think that’s a really good point. MYC actually is emerging as a resistance factor, not just in early-stage triple-negative breast cancer where my colleague Andrei Goga, [MD, PhD,] has described that, but also was a resistance factor in the SOLAR-1 data that [Dejan] Jurik, [MD,] presented at ASCO this year looking at the patients who had MYC amplifications. It was really a poor outcome, whereas all the other mutations didn’t make much of a difference, so that was a small data set, but very interesting that MYC may play a role if we could ever figure out how to downregulate. It is still an undruggable target. Mark, are there any other resistance factors that you would keep in mind or think about?

Mark Pegram, MD: For CDK4/6 inhibitors there’s some literature on FGF [fibroblast growth factor] receptor alteration in resistant patients and, consequently, there are some ongoing clinical trials looking at FGF receptor inhibitors for that purpose. There’s some interesting tantalizing data that just came out recently looking at subcellular distribution of the drugs after they get into the intercellular space in tumor cells, and that can be altered, and if you can force the drugs into the right compartment, they can have restored activity, according to this hypothesis. That was very intriguing; it might be very hard to test with clinical specimens, but the science and the biology looked really interesting, and I had never thought of that as a mechanism before for drug resistance. The biggest disappointment has been the serious biomarker campaigns that have already happened both in the PALOMA series and in the MONALEESA series of trials. There was a very rigorous biomarker series of experiments done with both those rich data sets and the striking thing is that everything they looked at they all seemed to benefit from CDK4/6 inhibition. They really were not clinically useful biomarkers for clinical decision-making; it’s hard to find a group that doesn’t benefit from this group of agents, so it’s really striking.

Transcript edited for clarity.