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Tripathy Discusses Developments in HR+ Breast Cancer

Caroline Seymour
Published: Tuesday, Aug 14, 2018

The [data on the] intermediate-risk group was presented at the 2018 ASCO Annual Meeting, and results confirmed that there was no benefit of chemotherapy in that intermediate-score group. There was a caveat in that patients who were younger, under the age of 50, and had the higher range of intermediate scores from 16 to 25 appeared to benefit [from chemotherapy]. [These patients showed] anywhere from a 6% to 8% reduction in recurrence risk. For those patients, chemotherapy could be discussed.

When you're looking at subsets, it's very hard to make clear and firm conclusions. The bottom line is we believe that intermediate-score patients can be treated with endocrine therapy alone, perhaps with the exception of the younger patient within the high range of intermediate scores. 

What are your thoughts on the frontline approval of abemaciclib (Verzenio) with an AI?

  Abemaciclib is an interesting drug. It may be a little bit different from the other CDK4/6 inhibitors, such as ribociclib and palbociclib (Ibrance). It is as effective as the other drugs both in the first- or second-line settings. The first trial to come out with abemaciclib was as a single agent, not with endocrine therapy, for patients who had already progressed on multiple therapies. It showed effectiveness. It was a single-arm study, but compelling enough with the absence of other nonchemotherapeutic drugs. That was one of the labels for its original indication.

Shortly after that, the second-line therapy came out [as a result of the] MONARCH 2 study, which looked at fulvestrant with or without abemaciclib. Again, it showed the same degree of benefit—roughly a doubling of PFS.

The most recent one was an AI with or without abemaciclib. That also showed a significant benefit. It has a slightly different profile for toxicity. [It shows] a little more in the way of gastrointestinal toxicity and a little less in the way of hematologic toxicity. It distinguishes itself in that it shows activity in later lines of therapy as well. There is a lot yet to learn about the different CDK4/6 inhibitors. They all have benefit now in the first- and second-line settings.

We need to learn more about whether there are predictors for patients who perhaps don't benefit. Thus far, all of the subsets look like they benefit. There may be some biological subsets that may point us in certain directions. At the 2018 AACR Annual Meeting, there was some indication that patients with cyclin E overexpression don't do as well. We have some data from our institution that low-molecular weight cyclin E may spell resistance to not only CDK4/6 inhibitors but with endocrine therapy. The loss of the retinoblastoma protein may also be one.

It's something that seems to evolve over the course of therapy based on some of the initial studies. We may get to the point where we can be a little more discriminating as to who we think should be on these drugs, [and] more importantly, learn about the mechanisms of resistance to develop therapeutic approaches [that circumvent] the development of resistance. 

Could CDK inhibitors in combination with checkpoint blockade and targeting the PI3K pathway be a strategy?

Yes. There is a huge interest in combining CDK4/6 inhibitors with other biological therapies. There was an interesting study called the neoMONARCH study, in which patients received neoadjuvant abemaciclib and endocrine therapy. The biopsies that were done after patients had been on therapy for some time showed the development of an immune infiltrate with T cells in the tumor. That has raised the interest in immunotherapy combinations because HR-positive cancers don't have much response to checkpoint inhibitors and other immune therapies.

It's possible that CDK4/6 inhibitors may, through mechanisms that aren't clear yet, bring this about. There has also been interest in combining CDK4/6 inhibitors with other targeted therapies, such as signal transduction inhibitors like PI3K inhibitors. Those trials are underway. The data show that you can safely give these drugs. We're going to need later-phase trials to sort out the benefits from those and many other combinations that are underway.  

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Online CME Activities
TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
Community Practice Connections: Oncology Best Practice™ Targeting Cell Cycle Progression: The Latest Advances on CDK4/6 Inhibition in Metastatic Breast CancerOct 31, 20181.0
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