Article

A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma

Center for Neuro-Oncology, Dana Farber/Brigham and Women's Cancer Center, Shields Warren 430 D, Boston, MA 02115, USA.
Neuro-Oncology (Impact Factor: 5.29). 02/2011; 13(4):437-46. DOI: 10.1093/neuonc/noq198
Source: PubMed

ABSTRACT This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and ≤3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria. Of the 61 patients who enrolled, 60 received AMG 102. Twenty-nine patients (48%) had previously received bevacizumab. There were no objective responses per central assessment, but 1 patient had an objective response per investigator assessment. Median overall survival (95% CI) in the 10- and 20-mg/kg cohorts was 6.5 months (4.1-9.8) and 5.4 months (3.4-11.4), respectively, and progression-free survival (PFS) per central assessment was 4.1 weeks (4.0-4.1) and 4.3 weeks (4.1-8.1), respectively. PFS was similar among patients who had previously received bevacizumab compared with bevacizumab-naive patients. The most common adverse events were fatigue (38%), headache (33%), and peripheral edema (23%). AMG 102 serum concentrations increased approximately dose-proportionally with 2-fold accumulation at steady state. Plasma total HGF/SF and soluble c-Met concentrations increased 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM.

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    • "Inhibition of MET, a frequently overexpressed receptor in GBMs, is also currently under evaluation in clinical trials [40]. Unfortunately, a phase II trial using an anti-MET antibody , AMG102, demonstrated no significant antitumor activity in patients with recurrent GBMs [41]. Overall, these therapeutic approaches have yielded at best marginally positive results and TMZ, the hallmark chemotherapeutic agent routinely used to treat GBMs, remains the primary therapeutic alternative. "
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    • "Selectivity is not an issue for antibodies toward HGF (Wen et al., 2011) and MET (Jin et al., 2008), which are also under clinical investigation. Although a monomeric MET antibody showed promising results in NSCLC in combination with an EGFR inhibitor (Jin et al., 2008), the HGF antibody AMG-102 did not show efficacy in a glioblastoma trial (Wen et al., 2011). Earlier studies showed that AMG-102 led to increased HGF levels, this effect was explained by stabilization of HGF by the antibody and thereby not be used as a biomarker for tumor response (Gordon et al., 2010). "
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