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Rugo Relays Next Wave of Developments in HR+ Breast Cancer

Caroline Seymour
Published: Tuesday, Oct 30, 2018

One of the important things in these studies is the need for very long-term follow-up. Even with stage I breast cancer, we’re seeing 14% of patients with recurrent disease after 5 years of adjuvant endocrine therapy and [risk of recurrence] up to 20 years. That can rise to 50% in patients who have higher-risk multi-node breast cancer. Could we use CDK4/6 inhibitors to “nip the disease in the bud,” so you don’t have dormancy and late recurrences? That will be fascinating to see as we look at these trials over time. It’s also going to be important to evaluate quality of life and make sure that we’re not making everybody exhausted for all those years. Identifying the patients who are most likely to benefit will be critical.

The NATALEE trial, which is supposed to open later this year, will use 3 years of a CDK4/6 inhibitor; this is the adjuvant trial with ribociclib. Three years is a long time, so it will be interesting to see what the compliance is with longer durations. We’ve found that even 2 years is a long time in the adjuvant setting, although many people with high-risk disease will stick with it.

What other pathway blockades are being investigated?

Along with CDK4/6 inhibitors, there’s a great desire to look at other pathways to block. There are many different studies ongoing looking at HDAC inhibitors, early-phase trials of FGFR inhibitors, and other agents of great interest. IPATunity 130 is a trial with the AKT inhibitor ipatasertib in both ER-positive and triple-negative breast cancer. The trial is targeting patients whose tumors have disordered AKT-PI3K or PTEN tumor suppressor gene.

Next on the block is PI3K. We know up to 50% of our patients with ER-positive breast cancer will, at some point, have mutations in PI3K. An alpha-specific inhibitor, alpelisib (BYL719), has the greatest promise of any of the PI3K inhibitors that we’ve studied so far, including the pan-PI3K inhibitors. The beta-sparing PI3K inhibitor taselisib (GDC-0032) had very minimal activity and a lot of toxicity. Alpelisib [is associated with] skin rash and hyperglycemia, as well as weight loss that we have seen with the more focused PI3K inhibitors. However, it doesn’t have some of the other toxicities that make [those more focused PI3K inhibitors] tough, like colitis, psychiatric issues and liver function test abnormalities.

A news release suggested that the primary endpoint of improved PFS was met in the SOLAR-1 trial, which randomized patients in the second-line setting to fulvestrant and placebo or alpelisib. We need to see those data presented at the 2018 ESMO Congress, but I’m very excited that these data will lead to the first approved PI3K inhibitor in treating PI3K-mutant metastatic breast cancer.*

That may lead us to understand how we’re going to use targeted agents. If the cancer has a PI3K mutation, maybe the patient should get that drug before a CDK4/6 inhibitor. Maybe we’ll learn that in the setting of further studies with oral selective ER down regulators, where there are many drugs in clinical trials.

*This interview was conducted prior to the 2018 ESMO Congress, where data from the SOLAR-1 trial were released.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?May 31, 20191.5
Community Practice Connections™: A Better Way to Stop Pain: Paths Toward Responsible Postsurgical Pain Management for Patients With Breast CancerMay 31, 20191.5
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