A report of cardiac events in a phase II clinical study using trastuzumab combined with pertuzumab in HER2-positive metastatic breast cancer (MBC)

Abstract

1028 Background: T and P are humanized recombinant monoclonal antibodies (MoAB) that target different epitopes of HER2 extracellular domain. P blocks HER2’s ability to heterodimerize with other HER/ErbB receptors. Methods: This Ph II trial evaluates the efficacy and safety of T with P in patients (pts) with HER2+ (FISH +) MBC who had progressive disease (PD) on T-based therapy. Eligible pts must have had = 3 T-based regimens, normal (nl) left ventricular ejection fraction (EF=55%) and without significant cardiac history. Pts received IV T (6mg/kg) and P (420 mg) every 3 weeks (wks). EKG plus echocardiogram (ECHO) or cardiac MRI and tumor response were assessed every 3 and 6 wks, respectively. Results: Eleven pts received 39 (1 to 13) cycles, 1 pt achieved a partial response (PR) and 3 pts had stable disease. A total of 68 ECHOs and 8 cardiac MRIs were performed. Left ventricular systolic dysfunction (LVSD) with nl EKG was seen in 5 pts; Grade (Gr) 1 (n = 2) (EF 50–55%), Gr 2 (n = 2) (EF 40–50%) and Gr 3 (n = 1) (EF20–40%). Gr 2–3 events were associated with global hypokinesis. Gr 3 event was associated with symptomatic CHF. All 5 pts had received 240mg/m2 cumulative dose of doxorubicin, 2 pts (Gr 2–3) received chest wall radiation, and 1 pt (Gr 1) had HTN. Two pts with Gr 1–2 LVSD had a history of reduced EF during prior T-based treatment, which reversed to nl upon stopping T. Reduced EF appeared within 1–2 cycles, which returned to nl in 3 pts within 1wk to 3 months (mo) post discontinuing T/P. One pt had persistent Gr 2 LVSD 3 mo after the initial event. The pt with Gr 3 LVSD had extensive chest wall disease and died of PD and possibly CHF 2 mo after treatment termination. Conclusions: We observed Gr 1–3 LVSD in patients with HER2+ MBC who received dual MoAB treatment directed at HER2, in which very strict cardiac surveillance guidelines were required. One of 11 pts achieved PR and 1 pt had symptomatic CHF thus far. It is unknown whether the other events would have become symptomatic if treatment had continued. Further evaluation of the efficacy of combination T with P is required to define the overall risk and benefit. No significant financial relationships to disclose.