Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.

At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.

“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

The efficacy of abemaciclib was consistently seen across all subgroups.

“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.

The study was stopped for efficacy at the interim analysis.

Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.

Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).

They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.

In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).

In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.

The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.

“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.

“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.

Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.

op@frontlinemedcom.com

MONARCH 3: Abemaciclib plus AI boosts PFS in HR+/HER2- breast cancer