Addition of abemaciclib to endocrine therapy extends invasive DFS in breast cancer subset
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The addition of abemaciclib to endocrine therapy significantly extended invasive DFS.
The invasive DFS was extended for patients with high-risk hormone receptor-positive, HER2-negative breast cancer, according to findings presented during ESMO Virtual Congress 2020.
Results of the open-label, phase 3 monarchE study also showed the combination had a safety profile consistent with that previously observed with abemaciclib (Verzenio, Eli Lilly), researchers noted.
“Many patients diagnosed with hormone receptor-positive, HER2-negative breast cancer will not experience recurrence with standard-of-care therapies. However, we know that up to 20% may develop recurrence or distant relapse within the first 2 years, and the risk for recurrence is much greater for those who have certain high-risk clinical or pathological features based upon grade, node and size,” Stephen R.D. Johnston, MA, PhD, FRCP, professor of breast cancer medicine and consultant medical oncologist at Royal Marsden Hospital NHS Foundation Trust in the U.K., said during a press conference. “This is especially so within the first few years on adjuvant endocrine therapy. Thus, novel treatments are urgently needed to overcome resistance and prevent these early recurrences and distant metastases.”
Abemaciclib — an oral, continually dosed cyclin-dependent kinase (CDK) 4/6 inhibitor — is approved for use by patients with advanced breast cancer or with hormone receptor-positive, HER2-negative breast cancer in combination with endocrine therapy based upon data from the MONARCH 2 and MONARCH 3 trials.
In the international monarchE study, Johnston and colleagues assessed abemaciclib in the adjuvant setting among 5,637 men and women with hormone receptor-positive HER2-negative early-stage breast cancer at high risk for relapse.
Researchers defined high risk as having more than four involved lymph nodes or one to three involved lymph nodes with a tumor more than 5 cm in size, histologic grade 3 or high proliferation.
Between July 2017 and August 2019, the investigators randomly assigned patients to either 150 mg abemaciclib twice daily for 2 years plus endocrine therapy or endocrine therapy alone.
Invasive DFS served as the primary endpoint, and distant RFS, OS and safety served as secondary endpoints.
At the time of data cutoff, 323 invasive DFS events had occurred, including 136 events with abemaciclib and 187 events with endocrine therapy alone (2-year invasive DFS rates, 92.2% vs. 88.7%). This corresponded to a 25% reduced risk for invasive disease with the addition of abemaciclib to endocrine therapy (HR = 0.74; 95% CI, 0.59-0.93).
“The data beyond the 2-year cutoff are immature at this point, but the study is ongoing and further follow-up will be important to see the ongoing magnitude of the early separation of the curves between the treatment arms,” Johnston added.
Investigators observed similar results for distant RFS, with 106 events in the abemaciclib group vs. 152 events in the endocrine therapy-alone group (2-year distant RFS rates, 93.6% vs. 90.6%). This corresponded to a 28.3% reduced risk for metastatic disease (HR = 0.71; 95% CI, 0.55-0.92) and an absolute difference of 3.3%.
Johnston noted that the majority of decreases in distant recurrence occurred in bone and the liver.
The safety of the abemaciclib regimen appeared consistent with the known profile of abemaciclib. Diarrhea was the most common adverse event.
“These patients who are at high risk for developing early recurrence, despite the standard-of-care treatment that we are administering, are now actually having sites of metastases prevented through treatment in the early phase of this study due to the addition of [abemaciclib],” Johnston said. “Importantly, the results that indicate a prevention of early recurrence and a reduction of metastases suggest an impact on endocrine resistance in subclinical metastatic disease that may be present in these high-risk patients and attests to the efficacy of [abemaciclib] in having an impact in the early-stage setting.”
Perspective
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Charles L. Shapiro, MD, FASCO
The findings from the monarchE trial are a great result, albeit with short-term follow-up.
However, several points deserve mention. It is highly likely that the majority of these high-risk patients received adjuvant chemotherapy and radiation. Will the benefits translate to lower-risk populations, representing the majority of women with breast cancer, for whom adjuvant chemotherapy has no benefit based on genomic assays?
Another large trial, the PALLAS trial, of similar design but with palbociclib [Ibrance, Pfizer], did not meet its primary endpoint. Were the negative results from the PALLAS trial perhaps due to a lower-risk study population, or are there truly differences in therapeutic efficacy among CDK4/6 inhibitors?
Nonetheless, the monarchE study will likely change practice for high-risk women, especially those receiving adjuvant chemotherapy and radiation.
Reference:
Mayer EL, et al. Ann Oncol. 2020;doi:10.1093/annonc/mdx362.064.
Perspective
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Giuseppe Curigliano, MD, PhD
The important question in the adjuvant setting is, for which patients do we need to escalate or de-escalate treatment? The patient population of the monarchE study is at high risk for relapse. The researchers have shown that abemaciclib in combination with endocrine therapy will decrease invasive DFS. This is an important trial that will change clinical practice.
It is very important to understand that in a high-risk population, we give chemotherapy and afterward offer treatment with endocrine therapy for 5 years to 10 years. With abemaciclib, there was a decrease in invasive DFS events and a decrease in metastatic events, which is very important. We now need longer follow-up to understand the impact on survival, and we also need longer safety data.
This is important research, targeting a high-risk population in which we have the opportunity to reduce the number of invasive DFS and metastatic events. However, we need more research to help us understand if a certain population of patients can be spared chemotherapy. Future research should compare endocrine therapy plus CDK 4/6 inhibitors vs. chemotherapy in a select population.
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Johnston SRD, et al. Abstract LBA5_PR. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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