First-line abemaciclib supported for HR+HER2– advanced breast cancer
medwireNews: Results from the MONARCH 3 study give support to first-line use of the oral selective CDK4/6 inhibitor abemaciclib, taken alongside nonsteroidal aromatase inhibitor (AI) therapy, in patients with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.
“The conclusions of our study are that abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior [to] a nonsteroidal aromatase inhibitor alone in terms of progression-free survival (PFS), but also in terms of the objective response rate (ORR), as the initial treatment of HER2-negative, endocrine-sensitive advanced breast cancer in postmenopausal patients,” said Angelo Di Leo, from Hospital of Prato, Istituto Toscano Tumori in Italy.
The findings were reported at the ESMO 2017 Congress, held in Madrid, Spain.
At interim analysis, after 189 events, the primary endpoint of median PFS was unreached for the 328 patients who were randomly assigned to receive abemaciclib 150 mg twice daily, plus anastrazole 1 mg/day or letrozole 2.5 mg/day, until disease progression. This compared with a median PFS of 14.7 months for the 165 patients who were given placebo plus an AI, giving a significant hazard ratio (HR) of 0.543.
The secondary endpoint of overall survival is yet immature but the ORR was significant in favor of abemaciclib therapy for both the total population (48.2 vs 34.5%) and the subgroup of patients with measurable disease at baseline (59.2 vs 43.8%).
Preplanned subgroup analysis of PFS indicated that most groups of patients derived significant benefit from abemaciclib.
“However, we observe that the patients deriving the largest benefit from abemaciclib are those that have adverse prognostic factors,” the presenter said.
Exploratory analysis suggested that patients with a treatment-free interval of less than 36 months had greater benefit from abemaciclib therapy compared with placebo than did those with a longer interval (HR=0.48 and 0.83, respectively). This was also the case for patients with disease that spread beyond the bones (HR=0.51 vs 0.58 for bone-only disease) and those with liver metastases (HR=0.47 vs 0.57 for no liver metastases).
This suggests that “patients with indicators of poor prognosis had substantial benefit from the addition of abemaciclib, while in patients with a long treatment-free interval or bone-only disease, single-agent endocrine therapy may be an appropriate initial therapy,” Di Leo explained.
Although abemaciclib therapy was “generally well tolerated” and patients could be given the treatment continuously, grade 3 and 4 adverse events were reported in 38.4% and 6.4% of patients, respectively. Most notably these included grade 3 neutropenia (19.6 vs 0.6% with placebo), albeit with just one episode of neutropenic fever, diarrhea (9.5 vs 1.2%), and leukopenia (7.3 vs 0.0%).
Abemaciclib is significantly more potent against CDK4 than CDK6 and this may explain the reduced rate of neutropenia, compared with other CDK4/6 inhibitors, but the higher rate of diarrhea, Di Leo commented at a press conference. “It is quite clear that the safety profiles of these compounds [are] not overlapping,” he said.
The presenter added: “Diarrhea typically occurred early and was managed with dose adjustment and antidiarrheal medication.”
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