Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results
Résumé
Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.