ScholarWorks@성균관대학교

초록

BackgroundAdding the pan-Akt serine/threonine kinase (AKT) inhibitor capivasertib to first-line paclitaxel in metastatic triple-negative breast cancer (TNBC) led to significantly longer progression-free survival (PFS) and overall survival (OS) versus placebo–paclitaxel in the phase II PAKT trial. CAPItello-290 was designed to further assess capivasertib–paclitaxel, including in patients with PIK3CA/AKT1/PTEN-altered tumours.Patients and methodsPatients with previously untreated metastatic TNBC were randomised 1 : 1 to paclitaxel 80 mg/m2 [day 1, weeks 1-3 (4-week cycle)] plus capivasertib 400 mg or placebo twice daily (days 2-5, weeks 1-3). PIK3CA/AKT1/PTEN alterations were analysed by retrospective central molecular testing. Dual primary endpoints were OS in the overall population and in patients with PIK3CA/AKT1/PTEN-altered tumours; investigator-assessed PFS was a key secondary endpoint.ResultsFrom July 2019 to February 2022, 812 patients were randomised; 30.7% of patients had PIK3CA/AKT1/PTEN tumour alterations. At final analysis [data cut-off (DCO) 18 March 2024], the median OS for the overall population was 17.7 and 18.0 months with capivasertib–paclitaxel and placebo–paclitaxel, respectively [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.78-1.08, P = 0.3239] and for patients with PIK3CA/AKT1/PTEN-altered tumours, it was 20.4 months in both arms (HR 1.05, 95% CI 0.77-1.43, P = 0.7602). At PFS DCO (25 May 2022), the median PFS in the overall population numerically favoured capivasertib–paclitaxel (5.6 versus 5.1 months placebo–paclitaxel; HR 0.72, 95% CI 0.61-0.84); this was also the case in patients with PIK3CA/AKT1/PTEN-altered tumours (7.5 versus 5.6 months placebo–paclitaxel; HR 0.70, 95% CI 0.52-0.95). The most frequent adverse event (AE) of grade ≥3 was diarrhoea [12.7% versus 0.7% placebo–paclitaxel (overall population)]. Capivasertib was discontinued due to AEs in 8.5% of patients (4.9% placebo–paclitaxel; overall population); AEs led to death in 4.2% of all patients.ConclusionsCapivasertib–paclitaxel did not meet the prespecified boundary for improving OS in either population; PFS numerically favoured the combination, especially in PIK3CA/AKT1/PTEN-altered tumours. The safety of capivasertib–paclitaxel was generally manageable and consistent with prior studies.

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