Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 1016
© 2008 American Society of Clinical Oncology

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Abstract

Randomized study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer

University of California Los Angeles, Los Angeles, CA; GlaxoSmithKline, Philadelphia, PA

1016

Background: Preclinical evidence indicates a direct molecular link between HER2 amplification and up-regulation of VEGF in HER2+ breast cancer. Concurrent over-expression of HER2 and VEGF is associated with a poorer clinical outcome than over-expression of either alone. Together these data provide the rationale for clinical translation of simultaneous blockade of both pathways. Pazopanib (P) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit. Lapatinib (L) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2). This study (VEG20007) evaluates the efficacy and safety of dual pathway inhibition in patients (pts) with HER2+ adv/met breast cancer. Methods: Eligible pts received no prior chemotherapy or HER2-directed therapy for adv/met disease and had measurable disease per RECIST. Pts were randomized to receive P 400 mg/d + L 1,000 mg/d or L alone (1,500 mg/d) for 12 weeks. Following disease assessment at week (wk) 12, pts with an objective response could continue on study treatment following re-consent; those with stable disease could continue only where trastuzumab was unavailable. The primary endpoint was progressive disease rate (PDR) at wk 12 in HER2 FISH+ pts. A pre-specified interim analysis (IA) was performed when 62 of 140 pts reached wk 12. Results: 32 PL and 30 L pts were included in the IA (73% stage IV, 27% stage III). Pts in the PL arm had a shorter time since initial diagnosis (227 vs. 380 days); baseline characteristics were otherwise well balanced. Efficacy data (by independent review) at wk 12 were available in 69% (PL) and 77% (L) of pts: PDR was 19% (PL) vs. 27% (L); response rate was 44% (PL) vs. 30% (L). Reduction in target lesions occurred in 73% (PL) vs. 43% (L) of pts. The most common adverse events (PL vs. L) were diarrhea (63 vs. 57%), rash (22 vs. 20%) and nausea (22 vs. 17%). AST (63 vs. 33%) and bilirubin (39 vs. 21%) increases were more common on PL. Asymptomatic decline in left ventricular ejection fraction led to discontinuation of 1 pt on PL. Conclusions: This is the first phase II trial to evaluate the combination of 2 oral targeted agents in first-line HER2+ adv/met breast cancer. Preliminary data demonstrate the activity and tolerability of PL. The final analysis will be presented.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech BioOncology, GlaxoSmithKline GlaxoSmithKline

Abstract presentation from the 2008 ASCO Annual Meeting