Global Perspective: CDK4/6 Inhibitors in HR+ Breast Cancer - Episode 10

Abemaciclib Monotherapy's Role in HR+ Breast Cancer

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Matthew P. Goetz, MD: Abemaciclib is unique among the CDK4/6 inhibitors because it has an FDA approval as monotherapy as well as in combination with endocrine therapy. As we look back at the preclinical data, it’s fairly clear that combining endocrine therapy along with a CDK4/6 inhibitor leads to synergistic effects. There is some theoretical concern that if one targets the CDK4/6 cyclin D1 access without targeting the estrogen receptor [ER], targeting the estrogen receptor will have effects on transcriptional targets other than cyclin D. Of course, these are things such as the classic ER target genes, epiregulin, or the progesterone receptor. This is probably why the data suggest that, at least preclinically, the combination is actually the best.

What about in the clinical setting? The data with abemaciclib are unique because the drug showed single-agent activity with response rates that approached 20%, which was actually quite interesting, again suggesting that abemaciclib may be having effects more than just on targeting the estrogen receptor. In the future, there will be clinical trials that are actually looking specifically at this question: What is the best approach between abemaciclib monotherapy versus the combination?

Joyce A. O’Shaughnessy, MD: The MONARCH 1 single-arm phase II trial of abemaciclib was a large phase II trial of about 130 patients who had a median of 2 prior chemotherapy regimens in the metastatic setting and 2 prior endocrine therapies as well. It was a somewhat heavily pretreated population who had never had a CDK4/6 inhibitor, and they received single-agent abemaciclib at a higher dose, 200 mg bid [twice a day]. This trial showed a 19.7% response rate, a clinical benefit rate of 42%, and median progression-free survival of 6 months. And then, the final survival data were updated at ASCO with a median survival in this heavily pretreated population of 22 months, which is quite impressive when we think back to our chemotherapy studies in the later-line population. So these were encouraging but single-arm data.

Really, I think this is going to be useful for a small subset of patients who have been living a long time and are well beyond their opportunity to receive first- or second-line CDK4/6 inhibitor therapy with an aromatase inhibitor or fulvestrant. They’ve had those, they’ve become endocrine therapy refractory, and they’ve been treated with chemotherapy, but they haven’t had a CDK4/6 inhibitor. We really have level 1 evidence that abemaciclib would be an excellent option for those patients. But as more and more patients get CDK4/6 inhibitors in the first- and second-line settings, particularly the first-line setting, the question then becomes, Is there no cross-resistance? Can patients be treated with chemotherapy and endocrine agents, and later on in their natural history—having had a CDK4/6 inhibitor first line—can they respond later line?

We don’t have any data on that yet, so we really can’t use that right now in clinical practice, but that’s a very important question. We really look forward to ongoing trials reporting whether utilizing a CDK4/6 inhibitor after previous progression on a CDK4/6 inhibitor therapy will be beneficial. There’s some limited utility right now for the MONARCH 1 data in those patients who have never had a CDK4/6 inhibitor.

Stephen Johnston, MA, PhD, FRCP: The role of CDK4/6 inhibitors in randomized trials has often been to look in the first- or second-line setting. But many of the patients who we treat in the clinic might have already had exposure to endocrine therapies for a number of years, maybe 2 or 3 lines of treatment. The question has been, Would these CDK4/6 inhibitors be effective then as a later-line option, either as monotherapy or indeed in combination? Having data that show the drug can have efficacy as a monotherapy in a later line of treatment not only speaks to the fact that these are effective anticancer agents but also gives another nonchemotherapy option for those patients at a later stage. I think that’s an important consideration, and the durability of the responses and the length of progression-free survival in the MONARCH 1 phase II study are impressive for an agent in a later line of treatment.

Transcript Edited for Clarity