A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor-Positive Advanced or Recurrent Endometrial
Angela K Green1,2, Qin Zhou3, Alexia Iasonos3
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Inhibition of the cyclin D-cyclin-dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor-independent cyclin D1-CDK4/6 activation. We hypothesized that the addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant would be an effective therapeutic strategy in patients with advanced or recurrent endometrial cancer.
Patients And Methods:
In this phase II study, patients with advanced or recurrent endometrial cancer received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included estrogen receptor or progesterone receptor expression ≥1% by IHC, measurable disease, ≤2 prior lines of chemotherapy, and ≤1 prior lines of hormonal therapy. The primary endpoint was the objective response rate by RECIST v1.1.
Results:
Twenty-seven patients initiated therapy, and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number-low/no specific molecular profile tumors, 1 response (9%) was in a microsatellite instability-high tumor, and no responses were observed in copy number-high/TP53abnormal tumors. The objective response rate was 44% (90% confidence interval, 27.0%-62.1%). The median duration of response was 15.6 months. The median progression-free survival was 9.0 months (90% confidence interval, 1.8-20.4). The most common grade ≥3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified.
Conclusions:
The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent endometrial cancer; a randomized trial is planned. See related commentary by Garg and Oza, p. 2073.
Insights
The combination of abemaciclib and fulvestrant shows promise for treating advanced or recurrent endometrial cancer, achieving a 44% objective response rate. This combination therapy offers durable responses and warrants further investigation in a randomized trial.
Area of Science:
- Oncology
- Pharmacology
Background:
- Endocrine monotherapy for advanced endometrial cancer has suboptimal response rates, potentially due to genomic alterations activating the cyclin D-CDK4/6 pathway.
- The cyclin D-cyclin-dependent kinase (CDK)4/6-INK4-retinoblastoma pathway is a target for overcoming treatment resistance.
Purpose of the Study:
- To evaluate the efficacy and safety of combining abemaciclib, a CDK4/6 inhibitor, with fulvestrant in patients with advanced or recurrent endometrial cancer.
Main Methods:
- A phase II study involving patients with advanced or recurrent endometrial cancer.
- Patients received oral abemaciclib and intramuscular fulvestrant.
- The primary endpoint was the objective response rate (ORR) assessed by RECIST v1.1.
Main Results:
- The ORR was 44% in 25 evaluable patients.
- Responses were observed predominantly in tumors with specific molecular profiles (copy number-low/no specific molecular profile).
- Median duration of response was 15.6 months; median progression-free survival was 9.0 months. Common adverse events included neutropenia and anemia.
Conclusions:
- The combination of abemaciclib and fulvestrant demonstrates promising activity and durable responses in advanced or recurrent endometrial cancer.
- Further evaluation in a randomized trial is planned.
- No new safety concerns were identified.
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