Efficacy, safety and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in HER2+ metastatic breast cancer patients previously treated with trastuzumab.
Authors: Baselga J , Imadalou K , Paton V , Gray D , Swain S 
Published: December 2010

Abstract
Abstract #3138
Pertuzumab (P), a humanized monoclonal antibody, is a first-in-class HER heterodimer inhibitor that binds to the HER2 dimerization domain, inhibiting the interaction of HER2 with other HER family members. Xenograft studies demonstrated a synergistic effect of P with trastuzumab (T) in combating HER2-amplified breast cancer, and two clinical P+T PhII studies were undertaken in HER2+ MBC.&#x2028; The first Ph II study evaluated the efficacy and safety of P+T in HER2+ MBC patients (pts) who progressed during prior T therapy (Gelmon et al, ASCO 2008).&#x2028; Pts received T at either 4mg/kg loading dose (LD) followed by 2mg/kg qw or 8mg/kg LD followed by 6mg/kg q3w and P 840mg LD followed by 420mg q3w; 21/66 pts remain on therapy. Of the 16/66 pts (24%) who responded to therapy, there were 5 CRs, 11 PRs, and an additional 17 pts with SD for ≥6mos, for a total of 33/66 (50%) receiving clinical benefit. Most frequent events include diarrhea (64%), fatigue (33%), nausea (27%) and rash (26%). Three pts experienced Gr3 AEs that resolved for therapy to continue, and no Gr4 AEs were noted. There were no symptomatic declines in left ventricular ejection fraction (LVEF). No pts withdrew for treatment or cardiac-related AEs.&#x2028; The second Ph II study evaluated P+T in HER2+ MBC previously treated with T (Portera et al, Clin Can Res 2008). Pts in this study progressed on T-based regimens and had a baseline LVEF ≥55%. Pts received T 8mg/kg LD followed by 6mg/kg q3w and P 840mg LD followed by 420mg q3w. Of the 11 pts, 2 (18%) achieved PR and 3 pts had SD ≥18wks. Gr1-3 left ventricular systolic dysfunction (LVSD) was seen in 5/11 (45%) pts; 1 had symptomatic CHF. All 5 pts had previously received at least 240 mg/m2 doxorubicin, and LVSD resolved in 3/5 (60%) pts following therapy. Other AEs were mild- moderate and were not treatment limiting.&#x2028; These studies have shown that the combination of P+T is well tolerated and active in HER2+ MBC pts who have progressed on T-based therapies. No dose limiting toxicities have been identified to date, and further data as well as biomarker analyses are ongoing.&#x2028; This is a promising biologic combination therapy targeting HER2 disease that shows activity while avoiding typical chemotherapy side effects.&#x2028; Additional studies examining this combination include the currently enrolling Ph III Cleopatra study (Clinical Evaluation of P and T), a 1st line HER2+ MBC trial that will randomize 800 pts to docetaxel (D) & T +/- P. The primary endpoint compares progression-free survival (PFS) between pts based on tumor assessments by independent review facility (IRF). Pts will receive D 75mg/m2 q3w, T 8mg/kg LD followed by 6mg/kg q3w, and P 840mg LD followed by 420mg q3w or placebo. Extensive biomarker data will be collected to test markers that may correlate with treatment success.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3138.