The evidence supporting this protocol is provided by two phase III multicentre international randomised trials.rrr
MONARCH 3r,r
MONARCH 3 involved 493 patients with hormone receptor positive, HER2 mutation negative, advanced (inoperable) or metastatic breast cancer, comparing first line abemaciclib in combination with a non-steroidal aromatase inhibitor (either letrozole or anastrozole) versus non-steroidal aromatase inhibitor and placebo.
Between November 2014 and November 2015, 328 patients were randomised to receive standard dose non-steroidal aromatase inhibitor plus abemaciclib 150 mg orally twice daily in 28 day cycles (with continuous abemaciclib dosing). 165 patients were randomised to receive standard dose non-steroidal aromatase inhibitor plus matching placebo. The primary end point was progression free survival (PFS), and secondary end points were objective response rates (ORR) and safety.
MONARCH 2r,r
MONARCH 2 involved patients with hormone receptor positive, HER2 mutation negative, advanced (inoperable) or metastatic breast cancer, who had progressed within 12 months of treatment whilst receiving either adjuvant or neoadjuvant hormone therapy; or progressed on first line palliative hormone therapy.
Between August 2014 and December 2015, 446 patients were randomised to receive fulvestrant 500 mg IM on day 1 and 15 of the first cycle and on day 1 of subsequent cycles plus abemaciclib 150 mg orally twice daily in 28 days cycles (with continuous abemaciclib dosing). 223 patients were randomised to receive fulvestrant plus matching placebo. The primary endpoint was PFS, and secondary endpoints were overall survival, ORR, duration of clinical benefit, quality of life and safety.
Efficacy
MONARCH 3r
After a median follow-up of 8.1 years, median PFS was 29.0 months in the abemaciclib arm and 14.8 months in the placebo arm (HR 0.535; 95% CI, 0.429-0.668; P<0.0001). The results for OS were not statistically significant. There were 198 OS events (60.4%) in the abemaciclib group versus 116 (70.3%) in the placebo group (HR 0.804; 95% CI, 0.637-1.015; P=0.0664). Median OS was 66.8 months vs 53.7 months in the abemaciclib vs placebo groups.
Progression free survivalr
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Overall survivalr
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MONARCH 2rr
Median follow up was 19.5 months. PFS in the abemaciclib and fulvestrant arm was 16.4 months, compared to 9.3 in the placebo controlled fulvestrant arm (HR=0.55, 95% CI, 0.45- 0.68, p<0.001). Sub group analysis showed benefit across all subgroups favouring the abemaciclib combination. ORR was 35.2% in the abemaciclib arm, versus 16.1% in the control arm.
Progression free survival (A) investigator assessed and (B) independent central reviewr
© J Clin Oncol 2017
A final pre-specified overall survival analysis was done at a median follow up time of approximately 6.6 years (data presented in abstract form). The median OS was 45.8 months in the abemaciclib arm and 37.2 months in the placebo arm (HR=0.784; 95% CI, 0.644-0.955). The survival benefit was more pronounced in subgroups associated with a poorer prognosis such as visceral disease (HR: 0.643; 95% CI, 0.499-0.829), primary resistance to endocrine therapy (HR=0.634; 95% CI, 0.436-0.922) or negative progesterone receptor status (HR=0.623; 95% CI, 0.405-0.959).
Toxicity
MONARCH 3r
8 deaths occurred in the abemaciclib arm as a result of therapy, versus 2 in the control arm. Diarrhoea was the most common toxicity in the abemaciclib arm. Median onset was day 8 of cycle one. Most patients did not require dose adjustments as a result of diarrhoea. Other frequent grade 3 and 4 adverse events were neutropaenia and leukopaenia. Of note, 4.9% developed thromboembolic events in the abemaciclib arm, compared to 0.6% in the control arm.
Dose reductions as a result of toxicity occurred in 43.4% of patients in the abemaciclib arm versus 6.2% in the control arm. Interruption of dosing occurred in 56.3% of patients in the abemaciclib arm versus 19.3% in the placebo control arm. 19.6% of patients on abemaciclib discontinued therapy as a result of adverse events, compared to 2.5% in the control arm.
Treatment-emergent adverse events from MONARCH 3r
© J Clin Oncol 2017
MONARCH 2r
There were 9 deaths in the abemaciclib arm and 2 deaths in the control arm that were attributable to therapy. The most common side effects were diarrhoea, neutropaenia, nausea, fatigue and abdominal pain. Thromboembolic events were observed in 2% of patients on abemaciclib, compared with 0.4% in the control arm.
Dose interruptions occurred in 51.9% of patients on abemaciclib, versus 11.7% in the control arm. Dose reductions occurred in 42.9% of patients receiving abemaciclib, versus 1.3% receiving the control. Abemaciclib was discontinued in 15.9% of patients secondary to adverse events, versus 3.1% in the control arm.
Treatment-emergent adverse events from MONARCH 2r
© J Clin Oncol 2017