Camizestrant in Combination with Three Globally Approved CDK4/6 Inhibitors in Women with ER+, HER2- Advanced Breast
Richard D Baird1, Begoña Bermejo de Las Heras2, Manuel Ruiz-Borrego3
1Cancer Research UK, Cambridge Centre, Cambridge, United Kingdom.
Purpose:
This trial investigated the safety and tolerability of camizestrant with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in women with estrogen receptor-positive, HER2- advanced breast cancer.
Patients And Methods:
SERENA-1 (NCT03616587) is a phase I, multipart, open-label study in women with refractory estrogen receptor-positive, HER2- advanced breast cancer. Patients received oral once-daily camizestrant 75 or 150 mg plus abemaciclib; camizestrant 75, 150, or 300 mg plus palbociclib; or camizestrant 75 mg plus ribociclib 400 or 600 mg. Safety/tolerability, pharmacokinetics, efficacy, and impact on estrogen receptor 1 mutation ctDNA were assessed.
Results:
By September 16, 2024 (data cutoff), 53 patients had received camizestrant plus abemaciclib, 78 camizestrant plus palbociclib, and 60 camizestrant plus ribociclib. Patients had a median of 2 (range, 0-7) prior regimens for advanced disease; 83% had received a prior CDK4/6i and 59% prior fulvestrant. The most common treatment-emergent adverse events for camizestrant 75 mg (phase III dose) plus each CDK4/6i were diarrhea [with abemaciclib (87.5%)] and neutropenia [with palbociclib (80%) and ribociclib (32.1% for 400 mg and 53.1% for 600 mg)]. The median camizestrant tmax was ∼4 hours postdose across combinations, with an estimated half-life of 9.5 to 17 hours. No clinically meaningful drug-drug interactions were evident. In this heavily pretreated population, CBR24 was 49.5% and the median progression-free survival was 7.4 months (95% confidence interval, 5.3-9.3), with antitumor activity across all combinations, including patients previously treated with CDK4/6i and/or fulvestrant, with or without estrogen receptor 1 mutation.
Conclusions:
Camizestrant is well tolerated, with antitumor activity in combination with CDK4/6i. These results support the evaluation of camizestrant 75 mg plus standard CDK4/6i doses in phase III trials.
Insights
Camizestrant combined with CDK4/6 inhibitors shows good tolerability and anti-tumor activity in advanced breast cancer. These findings support further evaluation of this combination in Phase 3 trials.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Advanced breast cancer treatment often involves endocrine therapy and targeted agents.
- Estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer is a common subtype.
- CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy are standard treatments for advanced ER+/HER2- breast cancer.
Purpose of the Study:
- To assess the safety and tolerability of camizestrant when combined with various CDK4/6 inhibitors.
- To evaluate the pharmacokinetic profile of camizestrant in combination regimens.
- To explore the anti-tumor activity and impact on ESR1 mutations (ESR1m) of circulating tumor DNA (ctDNA) with camizestrant plus CDK4/6i.
Main Methods:
- SERENA-1 (NCT03616587) is a Phase 1, open-label study involving women with refractory ER+, HER2- advanced breast cancer.
- Patients received oral camizestrant (75 or 150 mg) with abemaciclib, or camizestrant (75-300 mg) with palbociclib, or camizestrant (75 mg) with ribociclib.
- Safety, tolerability, pharmacokinetics, efficacy, and ESR1m ctDNA levels were monitored.
Main Results:
- 53 patients received camizestrant with abemaciclib, 78 with palbociclib, and 60 with ribociclib.
- Common adverse events included diarrhea (with abemaciclib) and neutropenia (with palbociclib and ribociclib).
- Clinical benefit rate (CBR24) was 49.5% and median progression-free survival (PFS) was 7.4 months, with observed anti-tumor activity across all combinations.
Conclusions:
- Camizestrant is well-tolerated when combined with CDK4/6 inhibitors in patients with advanced breast cancer.
- The combination demonstrates anti-tumor activity, even in heavily pre-treated populations.
- Results support the investigation of camizestrant 75 mg plus standard CDK4/6i doses in Phase 3 trials.
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