Key Takeaways From ESMO: CDK4/6 Inhibitors for Metastatic HR+/HER2-Breast Cancer
PracticeUpdate: How are CDK 4/6 inhibitors currently used in hormone receptor-positive breast cancer?
Dr. Schwartzberg: Since the introduction several years ago of the class of agents called CDK4/6 inhibitors for hormone receptor-positive, HER2-negative breast cancer in the metastatic setting, the treatment of these patients has been profoundly changed for the better. We now know that by giving one of these three drugs that are on the market, palbociclib, ribociclib, or abemaciclib, that we can get improvement in progression-free survival when adding these drugs to endocrine therapy, typically either an aromatase inhibitor or fulvestrant, a selective estrogen receptor, a down-regulator.
And this combination therapy has rapidly become the standard of care, typically in patients with first-line, hormone receptor-positive metastatic breast cancer, but it has also shown efficacy in later lines of therapy if patients were previously treated.
PracticeUpdate: What are some of the key questions that remain about this class of drugs that were addressed at this year's ESMO?
Dr. Schwartzberg: There are many things to still be learned about CDK4/6 inhibitors. And in some cases they prolong the overall survival. We've seen that with studies previously reported for ribociclib and for abemaciclib. But we still have some issues, particularly now focusing on quality of life. We have a wonderful group of agents that improve progression-free survival and overall survival. Do they do that at the expense of patients' quality of life?
One of the studies done at ESMO 2020 was a pooled analysis of the MONALEESA trials, the MONALEESA-2, -3, and -7, which looked at patients with hormone receptor-positive metastatic breast cancer, to look at their quality of life in that trial. And what they found using a particular tool, the time to deterioration in global health score, was [that it was] better with ribociclib, the CDK4/6 used in that particular group of studies, compared to the control arm. That's a typical measure that we look at in patients with metastatic breast cancer, because ultimately, typically when their disease progresses, their quality of life deteriorates. So a standard measure is the time to deterioration.
And it was actually better with ribociclib, even before progression for patients that were on therapy. And of course, they were on therapy for a longer period of time when they received ribociclib as well. They also looked at the global quality of life and that was retained with ribociclib. And they looked at certain sub-scores within the tools that they looked at. For example, they looked at pain. And the time to deterioration of greater than 10% in pain for these patients with advanced breast cancer was better for the patients in these studies who received ribociclib plus endocrine therapy compared to endocrine therapy alone.
And the global health scores were improved and maintained regardless of patient factors. In other words, whether or not they were younger or older, or had poorer or better ECOG status, they did better with ribociclib. We can be reassured from this type of study that patients who are getting a drug that improves their progression-free survival, and hopefully their overall survival, also maintains or improves their quality of life.
PracticeUpdate: What other trials on CDK4/6 inhibitors are practice-informing?
Dr. Schwartzberg: Another trial that was presented in an oral session on CDK4/6 inhibitors in advanced breast cancer was the next MONARCH trial. This was an earlier trial that compared abemaciclib, one of the CDK4/6 inhibitors, either given with tamoxifen, or compared to monotherapy with abemaciclib at the 150 mg dose, or the 200 mg dose, which is the monotherapy dose with prophylactic loperamide. And what they found was the overall survival was higher for the patients who received abemaciclib plus tamoxifen, compared to abemaciclib 200 mg as monotherapy. It was 24 months for these patients, and this was a group of patients that were previously treated with one or two rounds of chemotherapy in the metastatic setting. There really wasn't any difference in the progression-free survival between the arms.
I think this is interesting because some of these patients had received prior tamoxifen and in the forest plot, sub-group analysis showed that patients benefited from abemaciclib plus tamoxifen whether or not they had had prior tamoxifen in the advanced setting. This kind of study reinforces the combination therapy approach for our patients using a CDK4/6 plus endocrine therapy, even if they've had endocrine therapy in the past, either in the adjuvant or in the advanced setting. I really think the data supports that blocking both pathways, the endocrine pathway and the CDK4/6, blocking cell cycle signaling, is a great strategy to keep patients with hormone receptor-positive, HER2-negative breast cancer, before chemotherapy, on an endocrine-based treatment which is well tolerated.
PracticeUpdate: What kind of data do we have comparing the different CDK 4/6 inhibitors?
Dr. Schwartzberg: We don't have direct comparisons of the different CDK4/6 inhibitors in clinical trials. So we have to use other data sources to determine whether or not there are differences between these drugs both in efficacy and toxicity. My colleagues and I did a study using real-world data, using a claims database and using electronic health record database, and we compared ribociclib with palbociclib with regard to toxicity, specifically neutropenia. And what we found from this database, from patients that were treated in the world real-world setting in the United States in 2017 and 2018, [was] that patients who received palbociclib had a higher rate of neutropenia and hospitalizations due to neutropenia compared to ribociclib.
We also saw that drug discontinuations were higher with palbociclib compared to ribociclib. The rates of grade 3 and 4 neutropenia were higher for palbociclib compared to ribociclib. And the duration of neutropenia was longer for palbociclib compared to ribociclib. So in terms of this most prevalent toxicity of both of these drugs, it did appear to be more neutropenic-related toxicity from palbociclib, compared to ribociclib in the real-world setting.
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