Abstract S1-4: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study of AMG 479 With Exemestane (E) or Fulvestrant (F) in Postmenopausal Women With Hormone-Receptor Positive (HR+) Metastatic (M) or Locally Advanced (LA) Breast Cancer (BC)

Abstract Background: AMG 479 is an investigational, fully human monoclonal antibody targeting the type 1 insulin-like growth factor receptor (IGF1R) that blocks binding of IGF-1 and IGF-2. Preclinical data suggest that inhibition of estrogen receptor (ER) and IGF1R signaling in ER+ BC can result in greater suppression of cell proliferation than achieved by blocking either pathway alone. Inhibition of the IGF1R-signaling pathway might enhance sensitivity of 2nd-line hormonal therapy in BC patients (pts). We conducted a 2-arm, double blind, placebo-controlled, randomized study evaluating the addition of AMG 479 to either E or F in M or LA BC pts who had progressed on prior endocrine therapy. Patients: Eligibility included: HR+ incurable M or LA BC; progression while receiving prior endocrine therapy for MBC or LA or within 12 months of completing adjuvant hormonal therapy; post menopausal; adequate glycemic control. HER2+ tumor status allowed. Study Design: Pts were randomly allocated 2:1 to either AMG 479 or placebo; E or F was per investigator. Pts received AMG 479 12 mg/kg IV or placebo Q2W + either E 25 mg QD PO or F 500 mg IM on day 1, 250 mg IM day 15 and 29, and Q4W thereafter. Eligible pts who progressed on the placebo arm could proceed on open-label AMG 479. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. MRI or CT scans were done every 8 weeks and bone scans every 12 weeks (for pts with bone involvement at screening). Endpoints: The primary endpoint was progression-free survival (PFS), as measured by modified RECIST v1.0 per investigator review. Results: 156 pts were randomized between March 2008 and July 2009. Median age, 61 (range 36-88) years; M vs LA BC, 154 (99%) vs 2 (1%). 127 pts (81%) had discontinued treatment as of May 2010. See table for efficacy. For pts receiving AMG 479 or placebo, the incidence of grade ≥3 AE was 42% and 24% and for serious AE, 25% and 18%. The most common grade ≥3 AEs (AMG 479/placebo) were: hyperglycemia (6%/0%), neutropenia (6%/2%), thrombocytopenia (4%/0%), asthenia (4%/2%), and increased AST (4%/0%). There were 5 grade 5 AEs; none were treatment related: 4 in the AMG 479 arm (2 PD, 1 sub occlusive syndrome [progression], and 1 pulmonary embolism [post-operative setting]) and 1 in the placebo arm (alteration of general status). 8% of pts in the AMG 479 arm vs 12% in the placebo arm had AEs that led to discontinuation of any study treatment. Conclusion: The combination of AMG 479 + E or F did not result in an improvement in PFS in this population of pts with HR+ M or LA BC. There were no unanticipated safety findings. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-4.

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