Updated findings of the MONARCH 3 trial of abemaciclib added to a nonsteroidal aromatase inhibitor presented at ESMO 2022 revealed prolonged overall survival in hormone receptor-positive, HER2-negative breast cancer.
Abemaciclib (Verzenio) plus a nonsteroidal aromatase inhibitor (NSAI) led to an increase in the median overall survival (OS) in patients with hormone receptor-(HR) positive, HER2-negative early breast cancer, both in the intention-to-treat (ITT) population and subgroup of patients with visceral disease (sVD), according to the MONARCH 3 trial (NCT02246621).1
Findings from the second interim prespecified overall survival analysis of MONARCH-3 were presented at the ESMO 2022 Congress by Matthew Goetz, MD, chair of the Breast Cancer Disease-Oriented Group and co-leader of the Women's Cancer Center at the Mayo Clinic in Rochester, Minnesota.
Results of this analysis showed there to be an increase in the median OS by over 12 months with the addition of abemaciclib to NSAI. However, neither the ITT or sVD populations met the threshold for formal statistical significance.
“At this second interim analysis, a numerically favorable overall survival difference was observed in both the intent-to-treat population, as well as this subgroup of patients with visceral disease. Although neither group met the threshold for stopping or for statistical significance due to the alpha spending procedure, in the intent-to-treat population, this was a greater than 12 month difference, and in the visceral disease population, this was greater than 16 months. Consistent overall survival differences were observed across the pre-specified subgroups, abemaciclib delayed subsequent receipt of chemotherapy, and we saw no new safety signals,” said Goetz in a presentation of the data at the ESMO 2022 Congress.
Abemaciclib is an oral, potent, cyclin dependent kinase 4 and 6 (CDK4, CDK6) inhibitor. The inhibitor is the first and only one of its kind to be approved in advanced breast cancer and in combination with endocrine therapy for the adjuvant treatment of high-risk, HR-positive, HER2-negative early breast cancer.
Previously, MONARCH 2 led to the approval of abemaciclib in combination with fulvestrant (Faslodex) in patients with HR-positive, HER2-negative advanced breast cancer who progressed on prior endocrine therapy. A significant improvement in OS for the combination was demonstrated in the trial, leading to the start of the MONARCH 3 trial.
In the randomized, double-blind, placebo-controlled, phase 3 MONARCH-3 trial, the combination of abemaciclib and an NSAI was examined in postmenopausal women with HR-positive, HER2-negative metastatic or locally advanced breast cancer.2
Enrollment was open to female patients aged 18 years and older with HR-positive, HER2-negative breast cancer with locoregionally recurrent disease that could not be fixed by resection or radiation therapy with curative intent or metastatic disease. Other requirements were to be postmenopausal, either measurable disease or nonmeasurable bone-only disease, an ECOG performance status of 0 to 1, adequate organ function, and the ability to swallow capsules. Additionally, patients must have discontinued previous localized radiotherapy.
The primary end point of the study was investigator-assessed progression-free survival (PFS) with secondary end points including OS, percentage of patients with complete response, partial response, or stable disease, duration or response, pharmacokinetics, and safety.
A total of 493 patients were randomized 2:1 to receive either 150 mg of abemaciclib twice a day plus 1 mg of anastrozole or 2.5 mg of letrozole daily (n = 328), or placebo plus the same dosages of anastrozole or letrozole (n = 165).
Findings showed that with a median follow-up of 26.7 months, PFS for those receiving abemaciclib plus NSAI was 28.2 months vs 14.8 months with placebo plus NSAI (HR, 0.540; 95% CI, 0.418-0.698; P =.000021). At this time, OS was immature with 29.5% observed between each arm of the study.
At the time of this second interim analysis with a data cutoff of July 2, 2021, the median OS for the ITT population was 67.1 months for those receiving abemaciclib plus NSAI vs 54.5 months for those administered placebo plus NSAI (HR, 0.754; 95 CI, 0.584-0.974; P =.0301).
In the ITT population and with a median follow-up of 5.8 years, the median PFS for those in the abemaciclib plus NSAI arm was 29.0 months vs 14.8 in the placebo plus NSAI arm (HR, 0.518; 95% CI, 0.415-0.648; P <.0001). There are also more patients remaining progression-free at 5 years in the abemaciclib plus NSAI arm at 26.7% vs those in the placebo plus NSAI arm at 9.6%.
The chemotherapy-free survival for patients in the ITT population was also higher with abemaciclib plus NSAI at 46.7 months vs 30.6 months for placebo plus NSAI (HR, 0.636; 95% CI, 0.505-0.801).
For the subgroup of patients with sVD in the second interim analysis, the median OS was 65.1 months with abemaciclib plus NSAI vs 48.8 months with placebo plus NSAI (HR, 0.708; 95 CI, 0.508-0.985; P =.0392). Although statistical significance was not reached, these data are still maturing favorably with a 16.3 month difference in median OS (HR, 0.708; 95% CI, 0.508-0.985).
Regarding safety, no new safety signals were observed with long-term use of abemaciclib. A total of 323 patients (98.8%) in the abemaciclib plus NSAI arm had at least 1 treatment emergent adverse event (TEAE) of any grade vs 152 patients (94.4%) who were given placebo plus NSAI. The most common any grade TEAEs for those given abemaciclib were diarrhea (83.2%), neutropenia (46.8%), and fatigue (44.3%). The most common grade 3 and greater TEAEs in this arm were neutropenia (27.2%), diarrhea (9.8%), and anemia (8.9%).
Overall, these updated findings showed there to be a longer OS observed in both the ITT and sVD populations and safety data were consistent with the known profile of abemaciclib.
“The final OS analysis is planned after at least 315 events in the ITT and at least 189 events in the visceral disease subgroup. We anticipate that the final overall survival data should be read out in 2023,” added Goetz in the presentation.