Sara M. Tolaney, MD, MPH
CDK4/6 inhibitors have drastically changed practice in the treatment of patients with HR-positive breast cancer; however, their rise has left physicians with a new challenge: deciding which patients derive the most benefit from which treatment approach, said Sara M. Tolaney, MD, MPH.
East, Tolaney, professor of Medicine, Harvard Medical School, medical oncologist, Dana-Farber Cancer Institute, discussed developments in the treatment paradigms for patients with HR-positive or HER2-positive breast cancer.
OncLive: Please provide an overview of your presentation at the conference.
: Over the last few decades, we've seen a lot of changes in the management of metastatic HR-positive disease. This is particularly the case over the last decade, when we saw the introduction of mTOR inhibitors. More recently, over the last 3 years, we had approval of 3 different CDK4/6 inhibitors. I touched upon data looking at CDK4/6 inhibitors in both the upfront setting and then in the second-line setting with fulvestrant. I also discussed the use of CDK4/6 inhibition as monotherapy with data looking at abemaciclib alone, with efficacy in the refractory setting.
With all of these new therapies, how do you determine which agent is best for which patient population?
This is where we are struggling. We don't know how to decide which patients need a CDK4/6 inhibitor or which patients could get away with endocrine therapy alone. We also don't know what to do after progression on a CDK4/6 inhibitor.
There are some clinical parameters that look intriguing. For example, there was a pooled analysis of the MONARCH 2 and 3 studies. These were the trials that explored the addition of abemaciclib to endocrine therapy. Interestingly, they found that high-risk patients—patients who had liver metastases or who had short treatment-free intervals—derived significant benefit from the addition of abemaciclib. This helps us better understand that patients who have visceral or high-risk disease are getting a lot of benefit from these agents. This has changed how we practice because these are patients we used to just give chemotherapy to.
What are the unmet needs in ER-positive disease?
One is that we don't know what to do with someone who progresses on a CDK4/6 inhibitor. There is a lot of work that's been done to try to understand the resistance mechanisms. Thus far, the data seem to be that there are multiple ways you could become resistant. You could become resistant to the endocrine therapy or the CDK4/6 inhibitor. The way you become resistant to the CDK4/6 inhibitor might be through multiple different mechanisms like cyclin E amplification or FGFR
amplification. It's going to be complicated and more work certainly needs to be done there.
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