Safety of pertuzumab plus trastuzumab in a phase II trial of patients with HER2-overexpressing metastatic breast cancer which had progressed during trastuzumab therapy

BACKGROUND: Pertuzumab (P) is a humanized MAb, the first of a new class of HER dimerization inhibitors (HDI), that binds to HER2 blocking HER2 homodimerization as well as heterodimerization between HER2 and other HER receptors, targeting multiple HER pathways. In contrast, trastuzumab (Herceptin®, H) binds to the juxta-membrane epitope preventing both HER2 signal transduction and shedding of the extracellular domain of the receptor. Xenograft studies suggest that the complementary mechanisms of action of P&T could lead to increased efficacy when combined. An understanding of the adverse event (AE) profile of this combination, particularly cardiac, is of importance. METHODS: Pts with measurable, centrally tested HER2-overexpressing metastatic breast cancer (MBC) who had received ≤3 prior lines of therapy (including adjuvant therapy), who had progressed during H as most recent treatment, with a baseline left ventricular ejection fraction (LVEF) ≥55% without decline to <50% during prior H treatment, were eligible for this single-arm, two-stage trial. Consenting patients receive H at 2 mg/kg qw (4 mg/kg loading dose [LD]) or 6 mg/kg q3w (8 mg/kg LD) plus P at 420 mg q3w (840 mg LD) starting within 9 weeks of the last dose of H. LVEF is assessed regularly in all pts. RESULTS: By end-April 2007, 42 pts had received ≥1 dose of therapy and 33 had ≥1 tumor evaluation while on treatment. Activity in these 33 pts was: CR 1 (3%); PR 5 (15%); SD ≥6 months 7 (21%); SD <6 months 10 (30%); PD 10 (30%). Of 42 pts evaluable for safety, 34 had ≥1 AE. Frequent AEs (>10%) included: diarrhea (57%), nausea/vomiting (33%), fatigue (31%), rash (28%), muscle spasms (17%), cough (14%), headache (12%), dyspnea (12%), nasopharyngitis (12%). Over 80% of these AEs were grade 1 or 2. Five pts had an AE ≥grade 3, including diarrhea (n=1), rash (n=1), and deep vein thrombosis (n=1); only diarrhea was considered treatment related (the rash was attributed to CT contrast medium). 64.3% of pts had received prior anthracycline. One pt experienced the protocol-defined AE of fall in LVEF of ≥10% to <50%; this pt remained asymptomatic and was withdrawn from the study for PD. DISCUSSION: The combination of P&H is active and well tolerated in HER2-positive MBC patients who had progressed during prior H therapy. AEs have been generally grade 1 or 2 and no patient has been withdrawn because of treatment-related AEs. Updated safety data will be presented at the meeting. Further studies on pts with either MBC or early breast cancer are planned.