Targeted MET Inhibition in Castration-Resistant Prostate Cancer: A Randomized Phase 2 Study and Biomarker Analysis With Rilotumumab Plus Mitoxantrone and Prednisone.

Division of Hematology /Oncology, University of California - San Francisco.
Clinical Cancer Research (Impact Factor: 8.72). 11/2012; 19(1). DOI: 10.1158/1078-0432.CCR-12-2605
Source: PubMed


To evaluate the efficacy, safety, biomarkers, and pharmacokinetics of rilotumumab, a fully human, monoclonal antibody against hepatocyte growth factor (HGF)/scatter factor, combined with mitoxantrone and prednisone (MP) in patients with castration-resistant prostate cancer (CRPC).

Experimental design:
This double-blinded phase II study randomized (1:1:1) patients with progressive, taxane-refractory CRPC to receive MP (12 mg/m(2) i.v. day 1, 5 mg twice a day orally days 1-21, respectively) plus 15 mg/kg rilotumumab, 7.5 mg/kg rilotumumab, or placebo (i.v. day 1) every 3 weeks. The primary endpoint was overall survival (OS).

One hundred and forty-four patients were randomized. Median OS was 12.2 versus 11.1 months [HR, 1.10; 80% confidence interval (CI), 0.82-1.48] in the combined rilotumumab versus control arms. Median progression-free survival was 3.0 versus 2.9 months (HR, 1.02; 80% CI, 0.79-1.31). Treatment appeared well tolerated with peripheral edema (24% vs. 8%) being more common with rilotumumab. A trend toward unfavorable OS was observed in patients with high tumor MET expression regardless of treatment. Soluble MET levels increased in all treatment arms. Total HGF levels increased in the rilotumumab arms. Rilotumumab showed linear pharmacokinetics when co-administered with MP.

Rilotumumab plus MP had manageable toxicities and showed no efficacy improvements in this estimation study. High tumor MET expression may identify patients with CRPC with poorer prognosis.

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Available from: Rui Tang, Dec 12, 2015
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    • "Susceptibility to pre-analytical variables such as sample type, tissue fixation and processing and the subjectivity of interpretation can be liabilities for IHC. These considerations coupled with the detrimental outcomes seen in patients with low levels of MET expression treated with MET-targeted drugs will demand stringent quality control with respect to the performance and interpretation of IHC in GEC [47, 48, 62]. IHC assays to determine HER2 status in GEC have been in clinical practice as companion diagnostic assays for around three years and have taught us about the benefits and challenges of such an approach. "
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    • "In contrast BMS-777607, another MET inhibitor, did not significantly affect the proliferation of PCa cells but inhibited their invasiveness and migration [18]. In the clinic, a number of agents that selectively target MET have failed to show a substantive clinical benefit in patients with CRPC [19,20]. "
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