New Frontiers in Breast Cancer: Updates and Advances in Treatment - Episode 5

Adjuvant Abemaciclib in Early Breast Cancer: The monarchE Trial


Shared insight on the monarchE trial, which studied adjuvant abemaciclib in patients with HR+, HER2- high-risk early breast cancer.


Joyce A. O’Shaughnessy, MD: I wanted to summarize the adjuvant abemaciclib data because this was approved in October of 2021, so pretty new for patients at high risk in the adjuvant setting. Two years of adjuvant abemaciclib, hormone receptor [HR]-positive, HER-2 negative patients based on the monarchE data; this is a very important trial. These patients have high risk; in cohort 1, it was patients with 4 or more lymph nodes positive, or 1 to 3 lymph nodes positive, and either grade 3 and/or T3 or T4 disease. So big cancers, grade 3, 1 to 3 nodes, or anybody with 4 or more nodes who’s HR-positive, HER2-negative. There was a smaller cohort 2, a bit over 500 patients, 1 to 3 lymph nodes positive, and they did not have grade 3 disease or T3/T4 disease, but they had a centrally confirmed high Ki-67, 20% or more. And 95% of them had chemotherapy. They had their endocrine therapy, they were randomized to 2 years of abemaciclib, 150 mg twice a day, continuously, no break, versus just endocrine therapy alone. It was not placebo-controlled, with the primary end point of invasive disease-free survival.

This is the intent-to-treat population with the invasive disease-free survival, and this is at the additional follow-up 1 period that was requested by the FDA prior to approval. This is with 27 months median follow-up, and we’re looking at 3-year invasive disease-free survival. At that time in the intent to treat, we see a 5.4% absolute improvement in invasive disease-free survival, and the hazard ratio is 0.69, so a 31% reduction in the risk of a recurrence in the first 3 years. This is a very high-risk population to be having that number of recurrences despite chemotherapy and optimal endocrine therapy. We’re still having an unacceptably high degree of recurrences in this population. The distant relapse-free survival was also significant, it was a 4.2% absolute improvement in preventing distant recurrences, 0.68 was the hazard ratio.

Now, the FDA chose to approve abemaciclib in cohort 1, the 4 more nodes, or 1 to 3 nodes with grade 3 disease and/or T3/T4 disease, plus a high Ki-67, because those patients had a 7.1% improvement in invasive disease-free survival. The trend is there for survival with a hazard ratio of 0.76 in that cohort 1 population with a high Ki-67. That meant a lot to the FDA to see that trend toward survival this early. However, ASCO [American Society of Clinical Oncology] and NCCN [National Comprehensive Cancer Network] guidelines have chosen to endorse adjuvant abemaciclib for the intent-to-treat population, both cohort 1 and cohort 2. In my experience, that’s generally covered by insurers, what’s on the NCCN and ASCO guidelines, the intent-to-treat population. That’s what been on my mind. I know a high-risk patient when I see one. I think, does she meet the monarchE criteria?

Now I’m going to take Sarah’s hint and say, she also needs germline BRCA testing. If there’s high enough risk that I’m thinking about monarchE, I need to be thinking about germline BRCA testing as well. I am utilizing this quite a bit. I’m not going outside of the NCCN and ASCO guidelines. For example, if I had a patient with 3 positive nodes and she’s grade 2, and T2, but she’s not T3, not grade 3, she is cohort 2, but her Ki-67 isn’t 20% or higher. Let’s say she’s 10%, she’s on the lower side, but she’s high risk, I haven’t been using the abemaciclib for her. Sarah, how about you? What are you doing? We have definite risk, but we’ve got more indolent biology. What are you doing with those kinds of patients?

Sara A. Hurvitz, MD: It’s tough, Joyce. We’re all waiting to see longer-term follow-up because it may be that these slower-growing tumors recur later, and doing the abemaciclib may be improving outcomes, even if we’re not seeing that substantial benefit. We know those patients with high Ki-67 have a high risk, a worse outcome, at least in the short term. But we know that hormone receptor breast cancers come back even 20 years later, and what we do early may impact the risk of having disease recur years later. It’s a bit of a conundrum. I saw a patient yesterday who had 14 positive lymph nodes after standard neoadjuvant chemotherapy, ACT [doxorubicin, cyclophosphamide, paclitaxel]; a very young woman and didn’t have a BRCA mutation to go after, and the Ki-67 was 10% to 15% by several pathologists. I can’t believe that she wouldn’t benefit from abemaciclib, and maybe abemaciclib is delaying the development of metastatic cancer, and it’s inevitable anyway. But I don’t have that pessimistic viewpoint. I feel compelled to give her the benefit of the doubt and treat with abemaciclib.

Joyce A. O’Shaughnessy, MD: In monarchE, if you look at the 4 or more nodes, and they can be a heavy nodal burden, but as you say, they can be lobular and don’t have to be that highly proliferative. But 55% of the 4 or more lymph nodes positive were not high Ki-67, and the 4 or more nodes are eligible. The FDA said plus high Ki-67, but ASCO and NCCN said go by the intent to treat in those patients. I am treating because the hazard ratio is 0.6 in the 4 to 9 nodes, 55% of them were Ki-67 low. It’s a big benefit, as you point out. Furthermore, if we look at the low Ki-67, your point’s well taken. The hazard ratio is about 0.7, a 30% reduction in the lower Ki-67, less than 20%. There is a nice reduction in the risk of recurrence. Ki-67 is prognostic, it’s not predictive of benefit. I’m going by the intent-to-treat population definition right now, but we’re going to have more data that will come out over time. As we get more follow-up, and as you said Sarah, about what we do early on greatly influencing what happens later, I think we may even want to enlarge it to everybody with substantial risk.

Transcript edited for clarity.