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|Ref Type||Journal Article|
|Authors||Bauman JE, Ohr J, Gooding WE, Ferris RL, Duvvuri U, Kim S, Johnson JT, Soloff AC, Wallweber G, Winslow J, Gaither-Davis A, Grandis JR, Stabile LP|
|Title||Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer.|
|Date||2020 Jun 11|
|Abstract Text||Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Ficlatuzumab||AV-299|SCH900105||HGF Antibody 4||Ficlatuzumab (AV-299) is a monoclonal antibody that targets HGF and inhibits c-MET/HGF signaling, potentially resulting in decreased tumor growth (PMID: 23493885, PMID: 29346833, PMID: 32545260).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||head and neck cancer||not applicable||Cetuximab + Ficlatuzumab||Phase I||Actionable||In a Phase I trial, the combination of Erbitux (cetuximab) and Ficlatuzumab (AV-299) was tolerated and resulted in an overall response rate of 17% (2/12), a median progression-free survival (PFS) of 5.4 months, and an overall survival (OS) of 8.9 months in patients with advanced head and neck squamous cell carcinoma, baseline plasma scMet levels negatively correlated with PFS (HR = 1.92, p = 0.048), while tumor cMet or Hgf levels did not correlate with PFS or OS (PMID: 32545260; NCT02277197).||32545260|