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

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Division of Hematology/Oncology, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA
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Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
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Division of Head and Neck Surgery, Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA
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Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Monogram Biosciences Inc., South San Francisco, CA 94080, USA
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Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, San Francisco, CA 94115, USA
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Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(6), 1537; https://doi.org/10.3390/cancers12061537
Received: 21 May 2020 / Revised: 3 June 2020 / Accepted: 8 June 2020 / Published: 11 June 2020
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. View Full-Text
Keywords: HNSCC; cetuximab; ficlatuzumab; EGFR; HGF; cMet HNSCC; cetuximab; ficlatuzumab; EGFR; HGF; cMet
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Bauman, J.E.; Ohr, J.; Gooding, W.E.; Ferris, R.L.; Duvvuri, U.; Kim, S.; Johnson, J.T.; Soloff, A.C.; Wallweber, G.; Winslow, J.; Gaither-Davis, A.; Grandis, J.R.; Stabile, L.P. Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer. Cancers 2020, 12, 1537.

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