Abemaciclib demonstrated unexpected single-agent activity in patients with hormone receptor (HR)-positive metastatic breast cancer and a clinical benefit rate exceeding 70% in combination with fulvestrant.
Amita Patnaik, MD
The cyclin-dependent kinase (CDK)-4/6 inhibitor abemaciclib demonstrated unexpected single-agent activity in patients with hormone receptor (HR)-positive metastatic breast cancer and a clinical benefit rate exceeding 70% in combination with fulvestrant, two small clinical trials showed.
In the single-agent evaluation, a fourth of patients with heavily pretreated disease had objective responses to abemaciclib. Clinically significant tumor shrinkage was observed in patients who had received as many as nine prior regimens.
The combination of the CDK4/6 inhibitor and fulvestrant led to stable disease in 13 of 18 patients, three of whom had unconfirmed partial responses, Amita Patnaik, MD, reported at the 2014 Annual Meeting of ASCO in Chicago.
“We were surprised, actually,” said Patnaik, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio. “We did not expect to see this kind of response in such a heavily treated patient population. Although it appears to be fairly active as a single agent, we need to see all of the data. Evaluation of the drug with fulvestrant or an aromatase inhibitor will continue.”
The estrogen receptor interacts with cyclin-D1, a key molecule in the CDK4/6 pathway. Abemaciclib is a cell-cycle inhibitor that blocks both CDK4 and CDK6. In preclinical studies, the agent demonstrated dose-dependent G1 cell-cycle arrest in human breast tumors. Phase I clinical investigation demonstrated the safety and preliminary evidence of clinical activity in breast cancer.
The results provided the impetus for continued evaluation of abemaciclib by itself and in combination with the estrogen-receptor inhibitor, fulvestrant, in women with metastatic HR-positive breast cancer.
The single-agent study involved 47 patients, who were part of a larger dose-escalation trial of patients with various types of advanced solid tumors. The trial permitted enrollment of patients who had HR-positive, negative, or unknown status, and 36 (76.6%) of the women had confirmed HR-positive tumors. The results showed that nine patients, had complete responses, 14 had stable disease ≥24 weeks, and 10 had stable disease <24 weeks. The subgroup of patients with confirmed ER-positive tumors included all nine of the patients who had partial responses, 13 of 14 patients with stable disease ≥24 weeks, and 7 of 10 patients with stable disease <24 weeks.
Analysis of 13 patients who had ≥30% decreases in tumor volume showed that eight had received six or more prior regimens. Only one patient had received as few as two prior regimens.
The clinical benefit rate (objective response plus stable disease ≥24 weeks) was 61.1%, and the median progression-free survival (PFS) was 8.8 months. In contrast, patients with HR-negative tumors had a clinical benefit rate of 11.1% and a median PFS of 1.1 months.
The most frequently observed adverse events (all grades) possibly related to treatment were diarrhea (32 of 47), nausea (27), fatigue (20), decreased neutrophil count (19), vomiting (19), thrombocytopenia (18), and leukopenia (13).
Studies conducted thus far have shown that HR-positive tumor status is the more useful biomarker to select patients with tumors likely to benefit from treatment, Patnaik noted. Given that observation, postmenopausal patients with metastatic HR-positive breast cancer were enrolled into a study of combined hormonal manipulation with abemaciclib and fulvestrant. Patnaik presented results for 18 patients who had a median age of 56.5. Ten patients had measurable disease and eight had nonmeasurable disease. The patients had a treatment history that included a median of four prior systemic regimens. All but one patient had undergone surgery, and 15 of 18 had been treated with radiotherapy.
The results showed that six of 10 patients with measurable disease attained stable disease, as did seven of eight patients with nonmeasurable disease status. Four patients had progressive disease as best response, three with measurable disease, and one without. Overall, 13 of 18 patients obtained clinical benefit from treatment with abemaciclib and fulvestrant.
Nine of the 10 patients with measurable disease could be assessed for tumor response. Seven of the nine had some degree of tumor shrinkage, including three patients whose reductions in tumor size qualified as partial responses.
The most common adverse events were diarrhea (11 of 18 patients), fatigue (10), nausea (eight), decreased neutrophil count (seven), vomiting (six), leucopenia (six), anorexia (five), abdominal pain (four), and dehydration (three).
No grade 4 adverse events were reported. The most common grade 3 adverse events were decreased neutrophil count (six patients) and leukopenia (four).