A phase II study of the efficacy and safety of AMG 102 in patients with metastatic renal cell carcinoma

• DOI: 10.1111/j.1464-410x.2010.09947.x
• Publication Date: 2010-12-13T13:04:16Z
• Authors: Patrick Schöffski; Jorge A. Garcia; Walter M. Stadler; Thierry Gil; Eric Jonasch; Scott T. Tagawa; Melanie Smitt; Xinqun Yang; Kelly S. Oliner; Abraham Anderson; Min Zhu; Fairooz Kabbinavar
• Keywords: Adult; Male; Infusions; renal cell carcinoma; Antineoplastic Agents -- administration & dosage -- adverse effects -- therapeutic use; papillary renal cell carcinoma; Antineoplastic Agents; clear cell renal cell carcinoma; Antibodies, Monoclonal, Humanized; Antibodies; Dose-Response Relationship; 03 medical and health sciences; 0302 clinical medicine; Hepatocyte Growth Factor -- blood; Kidney Neoplasms -- drug therapy -- mortality -- secondary; 80 and over; Biomarkers, Tumor; Humans; Infusions, Intravenous; Tumor Markers; Carcinoma, Renal Cell; c-Met; Aged; Aged, 80 and over; AMG 102; Dose-Response Relationship, Drug; Biological -- blood; Hepatocyte Growth Factor; Carcinoma; Antibodies, Monoclonal; Middle Aged; Survival Analysis; Kidney Neoplasms; 3. Good health; Renal Cell -- drug therapy -- mortality -- secondary; Cancérologie; hepatocyte growth factor; Treatment Outcome; Monoclonal -- administration & dosage -- adverse effects -- therapeutic use; Female; Drug; Intravenous

Study Type – Therapy (case series)Level of Evidence 4What’s known on the subject? and What does the study add?It is now recognized that all patients with mRCC will eventually become resistant to VEGF inhibition. Although existing level 1 evidence supports the use of second‐line therapy, the oral mTOR inhibitor Everolimus, recent data also indicates that sequential VEGF inhibition is an appropriate therapeutic manoeuver in this cohort of patients. Targeting the alternative signaling pathway of Hepatocyte growth factor/c‐met can lead to anti‐tumour activity in RCC. AMG‐102 is a fully human monoclonal antibody to HGF/SF that prevents HGF/SF from binding to c‐Met and blocks signaling pathways that drive tumour‐cell proliferation, migration, invasion and survival.It emphasizes the need to continue exploring new therapeutic targets in RCC.OBJECTIVE• To evaluate the efficacy and safety of single‐agent AMG 102, an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF), in renal cell carcinoma (RCC).PATIENTS AND METHODS• This open‐label phase II study included patients ≥18 years old with histologically confirmed, advanced or metastatic RCC (mRCC) and Eastern Cooperative Oncology Group performance status 0 to 2. AMG 102 was administered i.v. at 10 or 20 mg/kg once every 2 weeks.• A two‐stage design was used at each dose level and the primary endpoint was objective best confirmed response (by Response Evaluation Criteria in Solid Tumours) at any time.RESULTS• Sixty‐one patients with mRCC enrolled and received AMG 102 (40 at 10 mg/kg; 21 at 20 mg/kg). Overall, 70.5% were men, median age was 59 years (range, 39 to 84 years), and 92% had received previous anti‐vascular endothelial growth factor therapy. RCC histologies were: clear cell (75.4%), papillary (11.5%), chromophobe (4.9%) and unclassified (8.2%).• One confirmed partial response occurred at 10 mg/kg, maintained for over 2.5 years; 26 patients (43%) had stable disease, 10 (16%) for ≥32 weeks. The median profression‐free survival was 3.7 months at 10 mg/kg and 2.0 months at 20 mg/kg. The commonest adverse events were oedema (45.9%), fatigue (37.7%) and nausea (27.9%). Grade 3 or 4 adverse events occurred in 33% of patients, the most common being oedema (9.8%).• Baseline levels of plasma HGF/SF and soluble c‐Met as well as archival‐tumour c‐Met did not correlate with measures of efficacy.CONCLUSION• Single‐agent AMG 102 was tolerable, but it is unclear if AMG 102 was growth inhibitory in this population of patients with mRCC.