CDK4/6 inhibitor abemaciclib boosts PFS in first-line treatment of advanced breast cancer
Adding the CDK4/6 inhibitor abemaciclib to endocrine therapy improves progression-free survival (PFS) in first-line treatment of hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer, according to results of the phase III MONARCH 3 study presented at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid, Spain. [ESMO 2017, abstract 236O_PR]
“This is the third study demonstrating that the combination of endocrine therapy with a CDK4/6 inhibitor is better than endocrine therapy alone, coming after the PALOMA-2 trial [with palbociclib] and MONALEESA-2 trial [with ribociclib],” said lead author Dr Angelo Di Leo of the Hospital of Prato, Istituto Toscano Tumori, Prato, Italy. [N Engl J Med 2016;375:1925-1936; N Engl J Med 2016;375:1738-1748]
“While most women in our study had substantial benefit from the addition of abemaciclib, we found that endocrine therapy alone may be sufficient in those with good prognosis,” he added.
In the MONARCH 3 study, 493 postmenopausal women with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer were randomized to receive letrozole 2.5 mg QD in combination with abemaciclib 150 mg BID or placebo.
“The study met its primary endpoint of investigator-assessed PFS after a median follow-up of 17.8 months. Median PFS was not reached in the abemaciclib arm vs 14.7 months in the placebo arm [hazard ratio (HR), 0.543; p=0.000021],” reported Di Leo. “The PFS benefit with abemaciclib was observed across all preplanned subgroups and confirmed by blinded independent central review [HR, 0.508; p=0.00102].”
Adding abemaciclib to letrozole also improved objective response rate (48.2 percent vs 34.5 percent for endocrine therapy alone; p=0.002). The overall survival (OS) data were immature for analysis.
Abemaciclib was generally well-tolerated in the study. Dose reduction (43.4 vs 6.2 percent) and treatment discontinuation (19.6 vs 2.5 percent) due to adverse events (AEs) were more frequently reported in patients receiving abemaciclib plus letrozole vs letrozole alone. Compared with letrozole alone, more patients receiving the combination had grade 3/4 diarrhoea, neutropenia, anaemia and leukopenia.
“In an exploratory PFS analysis of patients who had received prior endocrine therapy, the benefit of adding abemaciclib to letrozole was more pronounced in those who had a treatment-free interval [TFI] of <36 months [HR, 0.48] than those with a TFI of ≥36 months [HR, 0.83]. In addition, we found that the benefit of abemaciclib was less pronounced in patients with bone-only disease,” noted Di Leo. “These observations suggest that patients with indicators of poor prognosis had substantial benefit from the addition of abemaciclib. In contrast, endocrine therapy alone may be an appropriate initial therapy in patients with a long TFI or bone-only disease, which comprised one-third of the studied population in MONARCH 3.”
“The findings of this study are practice changing. The magnitude of PFS improvement with CDK4/6 inhibitors [palbociclib, ribociclib and abemaciclib] in combination with an aromatase inhibitor was observed across studies, suggesting that the benefit may be a class effect,” said discussant Professor Nicholas Turner of the Institute of Cancer Research, London, UK. “However, all three studies of CDK4/6 inhibitors in first-line treatment of locally advanced or metastatic breast cancer are substantially underpowered for OS.”