Adding the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy significantly reduces the risk of early recurrence in high-risk hormone receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, suggests a preplanned interim analysis of a phase 3 trial.
The research was presented September 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 5600 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+, HER-2 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.”
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 two 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 5637 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 two-year treatment period, leaving 70% still in treatment.
The intention-to-treat population included 2808 patients from the abemaciclib plus endocrine therapy group and 2829 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 age 65 years, and 56.5% were postmenopausal.
Also, 37% had previously received neoadjuvant chemotherapy and approximately 58% adjuvant chemotherapy.
Distant relapse-free survival was also significantly reduced with abemaciclib plus endocrine therapy vs endocrine therapy alone, at a hazard ratio of 0.72 (P = .0085), and a two-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.
A venous thromboembolic event was 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.
George W. Sledge Jr, MD, professor of medicine (oncology) at Stanford University Medical Center, Palo Alto, California, was the invited discussant after the presentation.
He said that “positive trails raise as many questions as they answer, and monarchE is no exception.”
For example, there is the conundrum posed by the negative results of the very similar PALLAS trial, which looked at the addition of palbociclib to adjuvant endocrine therapy for HR+, HER2-negative early breast cancer, and was also presented at the ESMO meeting.
Returning to monarchE, Sledge asked what the ultimate increase in invasive disease- and distant relapse-free survival will be with the drug combination, noting that the trial has “very, very short follow-up.”
“Second, will the improvements seen in disease-free survival lead to what we really care about: improved overall survival? Again, time will tell, but healthcare systems and patients care deeply about the answer to this question.”
Sledge continued: “How about late recurrence? Do CDK4/6 inhibitors kill off dormant or slow-growing micro-mets that lead to recurrences 5 or more years out?”
He also asked what the optimum duration therapy would be: “Is it more than we need, or not enough?”
Sledge wondered whether it is possible to determine who benefits “and why the drug fails some patients.”
Finally, Sledge said, “These drugs are expensive…2 years of adjuvant therapy is simply out of reach for the majority of patients around the globe who might be candidates for adjuvant CDK4/6 inhibitor therapy.”
And he observed an important truism: “A patient cannot benefit from a drug she cannot take.”
The study was funded by Eli Lilly and Company. Johnston, Sledge, and Curigliano have financial ties to Eli Lilly and multiple other drug companies.
ESMO Virtual Congress 2020: Abstract LBA5_PR. Presented September 19, 2020.
J Clin Oncol. Published online September 19, 2020. Full text
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