The research was presented Sept. 19 at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology.
The monarchE trial compared 2 years of abemaciclib plus endocrine therapy vs endocrine therapy alone among 5,600 patients and found that the combination was associated with a 25% relative risk reduction in the primary endpoint – invasive disease-free survival (P =.0096; HR, 0.75; 95% CI, 0.60 - 0.93)
At 2 years, the rate of invasive disease-free survival was 92.2% in the abemaciclib arm vs 88.7% in the group that took endocrine therapy alone.
“This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer,” said lead investigator Stephen Johnston, MD, PhD, from the Royal Marsden Hospital NHS Foundation Trust in London, UK, in a meeting press release.
He told Medscape Medical News that the high-risk patients in their study “are predicted to relapse quite quickly” as a result of having a degree of endocrine resistance, “and by intervening early we are stopping these recurrences within the first 2 years.”
He continued: “The key issue ... is whether you need 2 years of treatment or perhaps even longer. One other trial is looking at 3 years with another drug, and we’ll just have to await further follow-up of the data to see if the [monarchE] curves continue to separate while on treatment.”
According to Giuseppe Curigliano, MD, PhD, head of the Division of Early Drug Development at the European Institute of Oncology, Milan, Italy, “This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2-negative early breast cancer, the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy.”
Curigliano, who was not involved with the study, further commented during a meeting press conference that a randomized trial will be needed to answer a new important question: Can these high-risk patients treated with a CDK4/6 inhibitor be spared chemotherapy?
Investigator Johnston pointed out that many patients diagnosed with HR+, HER2 breast cancer will not experience recurrence with standard-of-care therapies.
But he also explained “that up to 20% may develop recurrence or distant relapse in the first 10 years” and that the risk of recurrence is “much greater” for patients who have high-risk clinical or pathological features, “especially during the first few years on their adjuvant endocrine therapy.”
Study details
Abemaciclib was approved by the US Food and Drug Administration in 2017 and is approved in combination with the endocrine therapy fulvestrant for the treatment of HR+, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.
The approval was, in part, based on data from the MONARCH-2 trial, which showed consistent overall survival benefits with the combination.
MonarchE, on the other hand, examined the impact of abemaciclib in the first-line adjuvant setting, enrolling patients with HR+, HER2-negative, node-positive early breast cancer who had a tumor size of ≥5 cm, histologic grade 3 disease, and/or Ki67 index of ≥20%.
They were randomly assigned in a 1:1 fashion to abemaciclib 150 mg twice daily for up to 2 years plus standard of care endocrine therapy or standard of care endocrine therapy alone.
The choice of endocrine therapy was left to the physician and was continued for 5-10 years, as clinically indicated.
The trial included 5,637 patients. An efficacy interim analysis was planned for when 75% of the estimated invasive disease-free survival events had occurred, which equated to 323 events in the intention-to-treat population.
This occurred after approximately 15.5 months of follow-up in each arm, when 12.5% of patients had completed the 2-year treatment period, leaving 70% still in treatment.
The intention-to-treat population included 2,808 patients from the abemaciclib plus endocrine therapy group and 2,829 in the group taking endocrine therapy alone.
The two groups were well balanced in terms of their baseline characteristics. The vast majority (approximately 85%) of patients were younger than 65 years, and 56.5% were postmenopausal.
Also, 37% had previously received neoadjuvant chemotherapy, and approximately 58% had adjuvant chemotherapy.
Distant relapse-free survival was significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a 2-year rate of 93.6% and 90.3%, respectively.
Johnston highlighted that not only was the number of patients with distant recurrences reduced with the combination therapy, at 92 vs 142 with endocrine therapy alone, but also the reductions were in key locations.
The number of patients with recurrences in the bone were 32 with abemaciclib and 81 with endocrine therapy alone; 29 patients with abemaciclib and 42 with endocrine therapy alone had recurrences in the liver.
The results show that the most frequent adverse events in the abemaciclib arm were diarrhea (82%), neutropenia (45%), and fatigue (38%), whereas arthralgia (31%), hot flush (21%), and fatigue (15%) were seen most often in the control group.
Venous thromboembolic events were recorded in 2.3% of patients in the abemaciclib group versus 0.5% of those on endocrine therapy alone; interstitial lung disease was seen in 2.7% and 1.2%, respectively.
Despite the protocol allowing dose reductions from 150 mg to 100 mg twice daily if required, 463 (16.6%) patients discontinued abemaciclib as a result of adverse events. Of those, 306 continued on endocrine therapy.
“Adherence to treatment will be an important issue to be considered in the real-life population of patients when this treatment is approved and used in clinical practice,” Johnston said.
Nevertheless, diarrhea frequency and severity decreased significantly over time, and only 4.8% of the abemaciclib group discontinued use as a result of this adverse event.