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.

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).

BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.