Donald W. Northfelt, MD, MS, FACP, discusses the progress made with CDK4/6 inhibitors in the treatment of patients with ER-expressing breast cancer and pivotal trials that have moved the needle forward.
CDK4/6 inhibitors have clinically significant value in the treatment of patients with metastatic estrogen receptor (ER)–positive breast cancer, according to Donald W. Northfelt, MD, MS, who added that lessons learned from the phase 3 monarchE (NCT03155997) and RxPONDER (NCT012720337) trials have shed necessary light on which patients will benefit most from certain adjuvant approaches.
Data from monarchE showed that the CDK4/6 inhibitor abemaciclib (Verzenio), when paired with standard adjuvant endocrine therapy, led to a significant improvement in invasive disease-free survival (iDFS; HR, 0.713; 95% CI, 0.58-0.87; P = .0009) and distant recurrence-free survival (HR, 0.687; 95% CI, 0.55-0.86; P = .0009) vs endocrine therapy alone in patients with high-risk, ER-positive disease.1
“Specific criteria were used in the study to define women as high risk, so it’s important to look at those criteria to know that you’re identifying someone who truly falls within that group and that the addition of abemaciclib [will be] beneficial,” noted Northfelt.
Additionally, data from a prespecified interim analysis of RxPONDER showed that although the addition of chemotherapy to endocrine therapy resulted in an improved 5-year iDFS of 94.2% vs 89.0% with endocrine therapy alone in premenopausal patients, these rates were 91.6% vs 91.9%, respectively, in postmenopausal women with an Oncotype recurrence score between 0 and 25 (adjusted HR, 0.97; 95% CI, 0.78-1.22; P = .82).2
“The RxPONDER results demonstrated that within an intermediate range of Oncotype DX recurrence score, there was no added value with adjuvant chemotherapy,” added Northfelt. “This information can be used to spare a significant number of women from the harm of chemotherapy with the confidence that their antiestrogen-driven therapy will be sufficient to protect them from relapse.”
In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on breast cancer, Northfelt, a professor of medicine and associate medical director of the breast clinic at the Mayo Clinic in Arizona, discussed the progress made with CDK4/6 inhibitors in the treatment of patients with ER-expressing breast cancer and pivotal trials that have moved the needle forward.
Northfelt: The information that came from the European Breast Cancer Conference in 2020 and from the 2020 San Antonio Breast Cancer Symposium [SABCS] was related to the addition of abemaciclib to conventional adjuvant antiestrogen treatment to reduce the risk of relapse. The monarchE study identified what they consider to be “highrisk patients,” women whose cancers had characteristics that placed them at very high risk for early relapse of their cancer after initial definitive local therapy. Those women were randomly assigned to receive either a conventional adjuvant antiestrogen therapy or conventional adjuvant antiestrogen therapy combined with abemaciclib.
The investigators reported a striking reduction in risk for relapse among women who received abemaciclib in addition to their adjuvant antiestrogen [treatment]. It’s anticipated that this is going to be a practice-changing observation. This [indication] has not yet gained FDA approval, but abemaciclib is available by prescription because it’s been approved for the treatment of [patients with] metastatic breast cancer. [This treatment], at least theoretically, is available to women by prescription, [although] there may be insurance barriers to receiving it for adjuvant treatment prior to FDA approval. It’s anticipated that this approval will be forthcoming in the near future. That usually triggers an agreement on the part of insurance companies to pay for the treatment.
In terms of the monarchE study, the update at SABCS was simply to lengthen the timeline from the initial report that was made at the European Breast Cancer Conference. Investigators acknowledged that their initial report was after a very short follow-up time, and they wanted to provide longer follow-up. The reporting interval went from 15 months to 19 months. It wasn’t a very long additional interval that they reported, but the impact of abemaciclib was striking enough on the outcomes of these high-risk patients that they felt justified, and the organizers of SABCS felt justified, in having [the trial] presented again.
[Those 2 studies] were done in [patients with] metastatic disease. Their purpose was to compare conventional palliative antiestrogen treatment with the combination of conventional antiestrogen treatment plus abemaciclib, or plus ribociclib [Kisqali]. In those studies, it was shown that the addition of a CDK4/6 inhibitor dramatically lengthened the duration of disease control achieved by palliative antiestrogen therapy. Updates of these studies have been reported, further burnishing the reputation of these drugs to improve progression-free survival. [Moreover,] an overall survival advantage [has been demonstrated] with the addition of ribociclib. These findings just served to cement the use of CDK4/6 inhibitors in managing women with metastatic breast cancer.
Comparative studies have not been done to determine whether one CDK4/6 inhibitor is necessarily better than another, so all the comparisons [that have been made] are cross-study comparisons; this is generally frowned upon when we’re trying to apply evidence to our practice. What has happened, as a consequence, is that the selection of CDK4/6 inhibitors is based more on what anticipated toxicities might be rather than on any perceived difference in efficacy.
We know, for example, that palbociclib [Ibrance] tends to cause cytopenias, primarily. We know that abemaciclib [also] causes some cytopenias, but in particular, it causes diarrhea in many women. Additionally, ribociclib has concern associated with it [because of its] potential to provoke arrhythmias. If I were particularly concerned about a patient’s blood cell counts, I’d probably avoid palbociclib. If I were particularly concerned about the potential for diarrhea in a patient, I would probably avoid abemaciclib. If I were particularly concerned about cardiac arrhythmias, I’d probably avoid ribociclib.
This is not unfamiliar to medical oncologists looking for the sweet spot, which is to get the best efficacy but, at the same time, the least toxicity. We are very familiar with doing this dance with various chemotherapies and other strategies that we use.
In in the 21st century, we are primarily using genomic analyses to make determinations about the value of chemotherapy as an adjuvant or neoadjuvant strategy in [patients with] localized breast cancer. When we encountered a patient with resectable breast cancer but who happened to have lymph node involvement, the old practice was to simply count the number of lymph nodes and use that to judge the degree of risk or concern that we had for the patient; we would then make a chemotherapy prescription based on that [information]. That strategy could have been applied in the 19th century because they knew how to count lymph nodes then, as well. However, with the dawn of the 21st century, and the advances made in genomic analysis, it became possible for several platforms to be developed in which genomic analyses could more precisely indicate the biologic nature of the cancer.
These analyses have been refined with statistical techniques to allow us to make predictions about the effectiveness of chemotherapy for a given genomic profile. I would say that many people in practice who are of my generation remember always using anatomic features of the disease, such as the size of the primary cancer in the breast and number of lymph nodes involved in the axilla, as the primary means to identify those who would theoretically benefit from postoperative chemotherapy to reduce risk of relapse. However, there is a big change occurring in the field, where the use of genomic analyses is increasingly being applied to make these determinations, and it’s becoming somewhat less relevant to use the old-time anatomic considerations.
Now, an effort has been made to bridge the gap by creating calculations in which the clinical features and the anatomic features are blended with the genomic information to derive a more precise estimate of risk for relapse and a more meaningful prediction about the benefit of chemotherapy. I’m sympathetic to those efforts to blend the old with the new, but I also have a sense that we understand more powerfully the biology of the cancer when we rely on the genomic analyses to guide us. None of these approaches are perfect. We still end up giving chemotherapy to women who may not require it, and we still may not give chemotherapy to some women who would benefit from it, regardless of which of these strategies we apply. In the future, it’s going to be more of a molecular decision-making, and less of an anatomic decision-making, process that we undertake.
For this analysis, patients with axillary lymph node involvement were randomly assigned to receive either chemotherapy or not, when their genomic analysis, the Oncotype DX analysis, was within a certain sort of intermediate range. This intermediate range of risk, designated by the Oncotype DX analysis, [is one] in which clinicians were still anxious about whether we were learning enough to make a firm decision for or against adjuvant chemotherapy. What that analysis showed was that for women in that intermediate range of Oncotype DX scores, there was no added value in providing adjuvant chemotherapy. [It also showed] that adjuvant anti- estrogen therapy was sufficient to protect those women in that intermediate score range so that the addition of chemotherapy was a “Why bother?” We would be sparing a large fraction of women from the harm of adjuvant chemotherapy, when the genomic analysis showed that it was not going to be beneficial to them.
When I’m talking to patients, I try to emphasize that I don’t believe this is a negative; it’s a positive. I say, “What we learned from the genomic analysis was that your cancer will be controlled and that your risk of relapse will be lowered sufficiently with adjuvant antiestrogen therapy. In other words, there’s no added benefit from chemotherapy and we know that there’s the potential for harm, so let’s skip it.” Most women are very pleased to hear that kind of message.