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. 2020 Jun 11;12(6):1537.
doi: 10.3390/cancers12061537.

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

Julie E Bauman  1 , James Ohr  2 , William E Gooding  3 , Robert L Ferris  4   5 , Umamaheswar Duvvuri  4   5 , Seungwon Kim  4 , Jonas T Johnson  4 , Adam C Soloff  5   6 , Gerald Wallweber  7 , John Winslow  7 , Autumn Gaither-Davis  2 , Jennifer R Grandis  8 , Laura P Stabile  5   9
Affiliations

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

Julie E Bauman et al. Cancers (Basel). .

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.

Keywords: EGFR; HGF; HNSCC; cMet; cetuximab; ficlatuzumab.

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Conflict of interest statement

Gerald Wallweber and John Winslow are employees of Monogram Biosciences/Laboratory Corporation of America Holdings. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Dose tier escalation rules and treatment schema. (B) Waterfall plot showing percent change in tumor burden by patient and by ficlatuzumab dose. Twelve patients were treated—three at 10 mg/kg (black bars) and nine at 20 mg/kg (gray bars) ficlatuzumab. (C) Representative lung CT images (top) and clinical photographs (bottom) of patient #4 at baseline and after two treatment cycles. (D) Kaplan–Meir curves (solid lines) with 95% CIs (dotted lines) showing PFS (left panel) and OS (right panel) in months. Time to progression and death were measured from first day of on-protocol treatment.
Figure 2
Figure 2
(A) Correlations between tumor cMet, HGF and cMet–HGF complex measured by VeraTag assays. (B) Correlations between cMet, EGFR (H1T) and EGFR homodimers (H11D) and the cMet–HGF complex and EGFR (H1T). Spearman correlation coefficients and p values are shown.
Figure 3
Figure 3
Immunophenotyping of peripheral blood mononucleocytes (PBMCs) identifies unique immune profiles in PD and PR subjects. (A) PBMCs from responders (n = 2) or rapid progressors (n = 2) were assessed by spectral cytometry (21 color) and analyzed using Rphenograph in Cytofkit for unbiased population discovery. Combined analysis of responding and progressing patient subsets at baseline, at response, and at progression illustrated as a t-SNE plot. (B) Heatmap depicting antigen expression of selected phenotypic markers corresponding to cell subsets in Rphenograph t-SNE (A). (C) Heatmap illustrating the proportion of cell subsets expressed within responders or progressors (n = 2 per group per timepoint) during baseline, response (after two treatment cycles), and progression. t-SNE density plots illustrating the increased proportion of cell subsets corresponding to Rphenograph for (D) rapid progressors and (E) responders. (F) Spearman correlations among all evaluable subjects between the change in percentage of total CD3+ T cells or CD3+CD8+ T cells with progression-free survival or overall survival, as indicated.
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