Phase 2 study of dual VEGF/HER2 blockade with pazopanib + lapatinib in patients with first-line HER2 positive advanced or metastatic (adv/met) breast cancer.

Abstract

#4114 Background: 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. These data provide the rationale for simultaneous blockade of both pathways. Pazopanib (P) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit. Lapatinib (Tykerb®) (L) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2). This study (VEG20007) evaluated 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 met disease and had measurable disease per RECIST. Pts were enrolled in one of 2 cohorts. In cohort 1 (C1), pts were randomized to P 400 mg/d + L 1000 mg/d or L alone (1500 mg/d). Enrollment to cohort 2 (C2) began after completion of enrollment to C1. In C2 pts received the combination at doses of P 800 mg/d and L 1500 mg/d. 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 of C1 was progressive disease rate (PDR) at wk 12 in HER2 FISH+ pts. The primary endpoint of C2 is week 12 response rate in HER2 FISH+ pts.
 Results: 140 pts were included in the randomized cohort analysis which was previously reported [J Clin Onc 26:2008 (May 20 suppl; abstr 1016)]. Enrollment in C2 has been completed; 40 pts (36 confirmed FISH+) have been enrolled. A preliminary safety analysis has been performed. The most common adverse events of any grade were diarrhea, nausea, fatigue, hypertension, and rash. The most common laboratory abnormalities were ALT and AST increase. Efficacy data will be analyzed when the last pt has completed the week 12 assessment.
 Conclusion: This is the first Phase II trial to evaluate the combination of 2 oral targeted agents in first-line Her2+ adv/met breast cancer. The lower dose combination demonstrated improved response rate compared to L monotherapy. Previously unreported efficacy and safety data from the higher dose cohort will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4114.

A Phase II Study of Pazopanib in Patients with Recurrent or Metastatic Invasive Breast Carcinoma: A Trial of the Princess Margaret Hospital Phase II Consortium

“…Pazopanib and lapatinib (an oral inhibitor of epidermal growth factor receptor and HER-2) have been combined for dual signaling pathway blockade in HER-2 ϩ advanced breast cancer or MBC patients [36,37].…”

“…The future of therapy in breast cancer may include combinations of targeted agents based on multiple biological pathway activation, redundancy in pathways, and crosstalk between pathways. Pazopanib and lapatinib (an oral inhibitor of epidermal growth factor receptor and HER-2) have been combined for dual signaling pathway blockade in HER-2 ϩ advanced breast cancer or MBC patients [36,37]. In a randomized phase II study, patients received daily treatment with pazopanib, at 400 mg, plus lapatinib (1,000 mg) (n ϭ 69) or lapatinib (1,500 mg) alone (n ϭ 72).…”

Targeting Signaling Pathways in Inflammatory Breast Cancer

“…Tie2 kinase, a receptor of angiopoietins, has an important function in tumor growth, survival, and metastasis. A Phase 1b/2 study of rebastinib (DCC-2036), a selective and potent inhibitor of Tie2, in combination with paclitaxel in patients with advanced or metastatic solid tumors, including IBC, is ongoing (ClinicalTrials.gov Identifier: NCT03601897; An Open-Label, Multicenter, Phase 1b/2 Study of Rebastinib (DCC-2036) in Combination With Paclitaxel to Assess Safety, Tolerability, and Pharmacokinetics in Patients With Advanced or Metastatic Solid Tumors; Table 1) [115].…”

Targeting Signal Transduction Pathways in Metastatic Breast Cancer: A Comprehensive Review

“…A recent phase III trial (EGF104900) showed a significantly longer PFS time with the combination of lapatinib and trastuzumab than with lapatinib alone (12 weeks versus 8.1 weeks; p ϭ .008; hazard ratio [HR], 0.73) in patients with heavily pretreated, HER-2 ϩ MBC progressing on trastuzumab [59]. A summary of key lapatinib combination trials is presented in Table 3 [59,80,[82][83][84].…”