A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

Hamilton, E.; Oliveira, M.; Turner, N.; Garcia-Corbacho, J.; Hernando, C.; Ciruelos, EM.; Kabos, P.; Ruiz-Borrego, M.; Armstrong, A.; Patel, MR.; Vaklavas, C.; Twelves, C.; Boni, V.; Incorvati, J.; Brier, T.; Gibbons, L.; Klinowska, T.; Lindemann, JPO.; Morrow, CJ.; Sykes, A.; Baird, RD.

A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

All Authors

Hamilton, E.

Oliveira, M.

Turner, N.

Garcia-Corbacho, J.

Hernando, C.

Ciruelos, EM.

Kabos, P.

Ruiz-Borrego, M.

Armstrong, A.

Patel, MR.

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LTHT Author

Twelves, Chris

LTHT Department

Oncology

Publication Date

2024

Item Type

Journal Article
Clinical Trial, Phase I
Multicenter Study

Abstract

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged >=18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses <=150 mg. Median tmax was achieved ~2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).