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
Por:
Hamilton E, Oliveira M, Turner N, García-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
Publicada:
1 ago 2024
Ahead of Print:
1 jul 2024
Resumen:
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 t(max) was achieved similar to 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).
Filiaciones:
Hamilton E:
Sarah Cannon Research Institute, Nashville, USA
Oliveira M:
Medical Oncology Department, Vall d'Hebron University Hospital and Breast Cancer Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
Turner N:
Breast Cancer Now, Toby Robins Research Centre, Institute of Cancer Research, London, UK
García-Corbacho J:
ICMHO Clinical Trials Unit, Hospital Clinic, Barcelona
Hernando C:
Department of Medical Oncology, Hospital Clinico Universitario de Valencia, Biomedical Research Institute (INCLIVA), Valencia
Ciruelos EM:
Medical Oncology Department, 12 de Octubre University Hospital, Madrid, Spain
Kabos P:
Division of Medical Oncology, University of Colorado, Denver, USA
Ruiz-Borrego M:
Department of Medical Oncology, H U Virgen del Rocio, Seville, Spain
Armstrong A:
The Christie NHS Foundation Trust and the University of Manchester, Manchester, UK
Patel MR:
Florida Cancer Specialists/Sarah Cannon Research Institute/Sarasota Memorial Hospital, Sarasota
Vaklavas C:
Huntsman Cancer Institute, University of Utah, Salt Lake City, USA
Twelves C:
Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, UK
Boni V:
START Madrid, CIOCC, Madrid, Spain
Incorvati J:
Fox Chase Cancer Center, East Norriton-Hospital Outpatient Center, Philadelphia, USA
Brier T:
Research and Early Development, Oncology R&D, AstraZeneca, Cambridge
Gibbons L:
Research and Early Development, Oncology R&D, AstraZeneca, Cambridge
Klinowska T:
Late Development, Oncology R&D, AstraZeneca, Cambridge
Lindemann JPO:
Research and Early Development, Oncology R&D, AstraZeneca, Cambridge
Morrow CJ:
Research and Early Development, Oncology R&D, AstraZeneca, Cambridge
Sykes A:
Research and Early Development, Oncology R&D, AstraZeneca, Cambridge
Baird RD:
Cancer Research UK, Cambridge Centre, Cambridge, UK
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