BCC 2021 | Safety outcomes in the Phase III monarchE trial of abemaciclib + ET in HR+, HER2- breast cancer
Hope Rugo, MD, FASCO, University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, shares the safety outcome data from the Phase III monarchE trial (NCT03155997) of abemaciclib in combination with endocrine therapy in hormone receptor-positive, HER2-negative, high risk, early breast cancer. Primary trial analyses showed that the addition of abemaciclib to endocrine therapy in the adjuvant setting significantly improved invasive disease-free survival rates compared to endocrine therapy alone. Safety analyses found that 17.2% of patients discontinued abemaciclib due to adverse events, most of which occurred in the earliest months of treatment. Most adverse events were low grade and manageable with dose adjustments. The trial is ongoing and safety data collection continues. This interview took place during the 17th St. Gallen International Breast Cancer Conference.
Transcript (edited for clarity)
We looked, actually at monarchE and keeping in mind that 25% of patients have finished the two year prescribed course of therapy, to just try and get a better understanding of the safety evaluations for patients. And there were still, just to keep in mind that after the data cutoff, almost 1700 patients on each arm of the study, of endocrine therapy alone or abemaciclib and endocrine therapy. And what we found was actually quite interesting...
We looked, actually at monarchE and keeping in mind that 25% of patients have finished the two year prescribed course of therapy, to just try and get a better understanding of the safety evaluations for patients. And there were still, just to keep in mind that after the data cutoff, almost 1700 patients on each arm of the study, of endocrine therapy alone or abemaciclib and endocrine therapy. And what we found was actually quite interesting.
So the first thing we found was that discontinuations due to adverse events were highest in the earliest months. And it’s really quite striking after the first three months that discontinuation really drops off. In contrast to the PALLAS study, only 17% of patients discontinued abemaciclib due to adverse events. And the reasons for this are complex. Part of that is that you can dose adjust, you can hold drug, reduce the dose and manage the most common reason for discontinuation, which was diarrhea at 5%, quite easily in essentially all of the patients I treated on the study and clearly based on numbers, the majority of patients. Neutropenia was only a discontinuation reason in 0.9% and fatigue after adjuvant therapy just under 2%. So it’s actually quite interesting to see. And I think that when you’re looking at neutropenia as your primary toxicity, then the issue is really protocol mandated holds, dose reductions and discontinuations due to ongoing neutropenia. And you just don’t have that with diarrhea, so it’s a little bit easier to manage.
The other thing that was interesting was that most of the discontinuations that occurred were due to low grade adverse events that were not protocol mandated for monarchE. And this really has to do with educating both the providers and the patients about dose reducing and holding, and that you can manage this toxicity, it’s not just going to continue for two years. And that really helps to keep people on treatment.
And then we looked actually at how well we could manage diarrhea. The median time to onset was about eight days, which is of course explains why the early discontinuations. And grade two and three events occurred mainly in the first three months and they were very short lived, so you stop the drug, diarrhea goes away. And patients received antidiarrheal drugs but what’s interesting is that the dose reductions and holds only occurred in about a fifth of the patients. So I think that, we really need to continue to help people understand how to manage this diarrhea rate, which is really quite straight forward and easy once you understand.
The other thing we looked at was other relevant adverse events. And there was some concern in the metastatic setting about liver enzyme elevation, but it’s actually, they were all reversible, it’s extremely low percentages and you could count less than 10 patients that had clinically significant elevations in liver enzymes.
We looked at specific rare toxicities, including venous thromboembolic events. And I was particularly interested in this because tamoxifen was allowed in monarchE. And what we found was that there was a little bit increase in the rate of venous thromboembolic events in patients taking tamoxifen versus aromatase inhibitors. And this is actually, if you look at any grade, it was 1.7% for AIs and 4.1% for tamoxifen, so it is clearly increased. And of course, looking at those two groups, there was no difference in the endocrine therapy alone arm, about 0.5% of patients in the study discontinued due to venous thromboembolic events. But this really helps us a lot, it tells us that, tamoxifen might not be the choice of partner in the adjuvant setting when you’re using abemaciclib. And I think it also tells us something about the metastatic setting as well. And in fact, recently a patient I started on tamoxifen and abemaciclib in the metastatic setting, I started on low dose anticoagulation and just warned her.
Then interstitial lung disease is the last toxicity to manage. We know this occurs with a whole host of drugs that we use and CDK4/6 inhibitors. Thankfully any grade was only 2.9%. It’s often hard to adjudicate because of radiation therapy that may increase the risk of pneumonitis, but grade three or greater only occurred in 0.4% and 0.1% in endocrine therapy alone. So the added number of pneumonitis overall, ILD as a whole class, was 0.3%. So that’s actually very helpful to know. So overall it seems to be a very well tolerated drug and understanding the toxicities really helps us perspectively manage these in our patients, educate patients and prevent significant toxicity as well as discontinuation of drug.
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