HR+/HER2- Metastatic Breast Cancer: Real-World Data on CDK4/6 Inhibitors


A brief review of molecular testing’s role in HR+/HER2- metastatic breast cancer and how certain driver mutations can impact care.


Massimo Cristofanilli, MD, FACS: One major area of interest with regard to the drug development process, with consideration of real-world data, is to produce real-world evidence. This is something that the FDA has put a lot of effort into in the last few years. Because these drugs, particularly CDK4/6, became available to the community after the approval in the last 7 years, it’s possible to generate real-world evidence. In fact, the use of this drug in the community is associated with benefit sometimes and overall survival benefit. The major question is always how to gather and where to obtain this information from real-world data. We know that electronic medical records are great resources of data, but many times it’s difficult to collect and analyze these data because they’re unstructured. There are different types of real-world data that we can obtain from electronic medical records. One is chart reviews from single-institution studies, retrospective analysis, and trying to identify the major end points that we’re interested in. One without controversy is overall survival. It’s very difficult to delineate the accurate time of progression and recurrence.

There have been retrospective reviews with regard to oncologist practices treating patients with CDK4/6 inhibitors. They’ve shown that in the first and second line, when used according to the FDA label—for example, palbociclib…in the first line and fulvestrant in the second line—you see an improvement or delay in treatment recurrence. In particular, there are a significant number of patients who remain on treatment for 1, 2, or 3 years. There’s a possibility to identify patients to are long-term survivors. This is obviously 1 type of study that’s never a control group because irrespective of nature use and structure a data.

With regard to the structure of data, we know for example that the database is 1 of the major sources of reliable, structured data. The data collected, according to specific protocol, is able to identify patients in postmenopausal range. For example, patients that have been treated with androgen therapy with a comparable median age and progressive site of recurrence. In this context, if you have a large number of patients eligible who’ve already completed androgen therapy, you can identify patients who’ve been selected with combination treatment as a single agent. This has been done, and there has been a clear demonstration as presented by Dr [Hope] Rugo…. They showed that when you study a large database of patients, you identify these patients treated with palbociclib and AI [aromatase inhibitor] in the community. Compared with single agent, there’s improvement in overall survival and progression-free survival when it’s possible to calculate based on careful annotation.

There are other studies. We’ve been looking at different questions. One question, for example, is the sequence of CDK4/6. In a retrospective database, you can identify patients who have been started with CDK4/6 [inhibitors] and what happened afterward. We know the survival of this patient is dependent on a series of treatments, so it appears that patients who go from 1 CDK4/6 [inhibitor] to another can probably do better, especially if they benefit from the first-line CDK4/6. That’s something we’ll see more in the community, a change in the androgen agent and maintaining the CDK4/6 [inhibitor] or switching to another. Of course, when you look at retrospective data, these are mostly hypothesis generating, but clinical studies will be presented. In fact, this is probably 1 of the best treatment strategies. When you go from a CDK4/6 inhibitor combination to non–CDK4/6 inhibitor, retrospective data seem to suggest that there’s less of benefit for this population. This group of patients seems to be doing a little worse. Of course, these are not supported by molecular data with retrospective studies, but they are intriguing data to be better evaluated in prospective analyses.

The other question that was raised many times is, what’s the value or the benefit of CDK4/6 [inhibitors] in patients who have germline mutation? We just mentioned that some of the recent FDA approvals for patients with BRCA2 germline mutation may include ER [estrogen receptor]–positive disease. From retrospective analysis it has been identified that a small population of patients who had a germline mutation appear to have less benefit. The only difference, in this case, was that the time for the next therapy … the progression-free survival, seems to be shorter when you have a germline mutation and have been treated with CDK4/6. These are more important data because they not only support CDK4/6 inhibitor combination early on, but it can also improve survival in the community, which suggests that there are some other questions. It may not be as prospective in many clinical trials because there were a variety of patients in the practice in different settings. But using these data, we can answer some important questions about patients with germline mutation.

Transcript edited for clarity.

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