344P - Pharmacokinetics (PK) of Pertuzumab (P) With Trastuzumab (T) and Docetaxel (D) in HER2-Positive First-Line Metastatic Breast Cancer (MBC): Results From the Phase III Trial Cleopatra

Abstract

ABSTRACT Introduction P is a humanized mAb that inhibits heterodimerization of HER2. P and T bind distinct HER2 epitopes, and due to their complementary mechanisms of action they provide a more comprehensive blockade of HER2 signaling. Based on preclinical efficacy models, a steady-state trough P concentration (Ctrough) of 20 ug/ml was selected as target in pts. CLEOPATRA is a Phase III study comparing P + T + D vs placebo (Pla) + T + D in HER2-positive 1L MBC (Baselga NEJM 2012). The objectives of the substudy reported here are to characterize the P PK in the presence of T and D, and to explore potential drug - drug interactions. Methods P/Pla (840 mg loading, 420 mg maintenance) was administered on Day 1 of each cycle; T (8 mg/kg loading, 6 mg/kg maintenance) was administered on Day 2 of Cycle 1 and on Day 1 of each cycle onward following P; D (75 mg/m2, escalation to 100 mg/m2 if tolerated) was administered on Day 2 of Cycle 1 following T and on Day 1 of each cycle onward following T. All drugs were given q3w iv. Blood samples for P were collected before and after infusion at Cycles 1, 3, 6, 9, 12, 15, 18, and at treatment discontinuation. Samples for T were collected before and after infusion at Cycles 1 and 3. Samples for D were collected at Cycle 1 at 8 serial time points during and following the infusion over a 24 h period to allow calculation of Cmax, CL, Vss, t1/2, AUC0–t, and AUC0-inf. Results 37 pts (17 Pla arm, 20 P arm) were available for PK evaluation. Serum P Ctrough exceeded the target of 20 ug/ml in >90% of pts and there was no impact of T and D on P PK, compared with historical data. Mean serum T Cmax and Cmin at Cycles 1 and 3 were similar in both arms. Ratios of geometric LS means of P + T + D/Pla + T + D x100 for serum T were: Cycle 1 Cmax 90.3; Cycle 3 Cmin 95.9; Cycle 3 Cmax 81.0. D PK parameters were similar in both arms. Ratios of geometric LS means of P + T + D/Pla + T + D x100 for plasma D were: AUC0–t 104.9, AUC0-inf 101.4, Cmax 92.5. Conclusion P PK parameters were consistent with previous studies, and co-administration of T and D appears not to influence P PK in HER2-positive MBC. There was no evidence of drug - drug interactions between P and T, or between P and D, which have different clearance pathways. Disclosure J. Cortes: I am an advisory board member for Roche, Celgene and Novartis. I have received research funding from Roche, Celgene, Cephalon and Ferrer. S. Swain: Advisory Board for Genentech/Roche for EMILIA study and Avastin - uncompensated. Research funding: Genentech/Roche. T. Patel: I have an advisory board membership for Genentech/Roche to disclose and are a speaker for Genentech/Roche. I have received research funding from Genentech/Roche. N. Masuda: I have honoraria to disclose received from Chugai Pharmaceutical Co., Ltd. V. McNally: I am a Roche employee and hold Roche shares. J. Visich: I am an employee of Genentech. J. Baselga: Dr Baselga reports the following relationships with relation to the topic of this abstract: Roche, Sanofi Aventis, Consulting/Scientific Advisory Board. Roche, Sanofi Aventis, Honoraria for speaking engagements. All other authors have declared no conflicts of interest.