Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer

Cancers

WilliamE. Gooding¹  James Ohr²  Autumn Gaither-Davis²  JenniferR. Grandis³  Umamaheswar Duvvuri⁴  RobertL. Ferris⁴  Seungwon Kim⁴  JonasT. Johnson⁴  JulieE. Bauman⁵  John Winslow⁶  Gerald Wallweber⁶  AdamC. Soloff⁷  LauraP. Stabile⁷ 

[1] Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA;Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA;Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, San Francisco, CA 94115, USA;Division of Head and Neck Surgery, Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA;Division of Hematology/Oncology, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA;Monogram Biosciences Inc., South San Francisco, CA 94080, USA;UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA;

关键词: HNSCC;    cetuximab;    ficlatuzumab;    EGFR;    HGF;    cMet;   

DOI  :  10.3390/cancers12061537

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown