Abstract
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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a morbid and lethal malignancy associated with chronic tobacco exposure or oropharyngeal infection with oncogenic human papillomavirus (HPV) [1]
Despite aberrant epidermal growth factor receptor (EGFR) signaling in the majority of head and neck squamous cell carcinoma (HNSCC) cases, the modest clinical activity of cetuximab has been disappointing and de novo or acquired resistance is inevitable [7]
Despite aberrant EGFR signaling in the majority of HNSCC cases, the modest clinical activity of Despite aberrant EGFR signaling in the majority of HNSCC cases, the modest clinical activity of cetuximab has been disappointing and either primary or acquired resistance is inevitable
Summary
Head and neck squamous cell carcinoma (HNSCC) is a morbid and lethal malignancy associated with chronic tobacco exposure or oropharyngeal infection with oncogenic human papillomavirus (HPV) [1]. Recurrence or metastasis following curative-intent therapy represents the major cause of death. Options for palliative management include the cytotoxic chemotherapies platinum, 5-fluorouracil, and taxanes; the anti-epidermal growth factor receptor (EGFR) human-murine IgG1 monoclonal antibody (mAb) cetuximab; and the immune checkpoint inhibitors targeting the programmed death-1 (PD1) receptor, pembrolizumab and nivolumab [2,3,4]. Despite aberrant EGFR signaling in the majority of HNSCC cases, the modest clinical activity of cetuximab has been disappointing and de novo or acquired resistance is inevitable [7]. A likely resistance mechanism to anti-EGFR therapy is compensatory activation of alternate RTKs. The MET oncogene encodes cMet, an RTK bound exclusively by the ligand, hepatocyte growth factor (HGF). Overexpression of cMet transforms normal epithelial cells and enhances motility, invasion, and metastasis [11]. Overexpression of cMet transforms normal epithelial cells and enhances motility, invasion, and metastasis [11]. cMet and/or HGF are overexpressed in approximately
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