Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for R/M HNSCC but only a minority benefits. c-Met and EGFR signaling converge at the PI3K/Akt and MAPK nodes. Preclinical evidence shows that c-Met can drive tumor-intrinsic resistance to EGFR inhibition. Ficlatuzumab is an IgG1 mAb against HGF, the sole ligand for cMet. We recently completed a phase Ib study evaluating ficlatuzumab and cetuximab in pts with cetuximab-resistant, R/M HNSCC (Bauman JE et al, ASCO 2017). Twelve pts were treated; 11 were platinum-refractory. Grade 3 adverse events included edema, hypoalbuminemia, infection, and thromboembolism. No DLTs were seen. Median progression-free survival (PFS) at the recommended phase II dose (RP2D) was 6.0 mos (90% CI = 2 mos – not reached). Confirmed overall response rate (ORR) was 17% (90% CI = 0-28%). Clinical benefit rate was 67%. Serum Veristrat, a proteomic classifier predictive of differential treatment benefit from anti-EGFR therapy, did not correlate with PFS. We designed a randomized phase II trial evaluating ficlatuzumab with or without cetuximab in patients with cetuximab-resistant, R/M HNSCC. The combination arm follows the hypothesis that continued anti-EGFR blockade may overcome reciprocal compensation between the EGFR and cMet pathways.
This is a multicenter phase II trial with a randomized, non-comparative, 2-arm design (Arm A: ficlatuzumab and Arm B: ficlatuzumab + cetuximab) in pts with R/M HNSCC after failure of cetuximab. Key eligibility criteria include: R/M HNSCC; cetuximab resistance (recurrence during or within 6 mos of cetuximab-radiation or palliative cetuximab); ECOG 0-1; mandatory baseline research biopsy. The primary objective is to assess the efficacy of ficlatuzumab, with or without cetuximab, as measured by PFS. To test the hypothesis that either regimen improves historical PFS from 2 months to 3.33 months requires 66 eligible patients. Key secondary endpoints are ORR and survival. Biomarkers to be correlated with efficacy include tumor HGF/cMet dimers, phosphoproteins, and immunoscores and serum Veristrat. Two of 66 patients have enrolled.
Clinical trial identification
Legal entity responsible for the study
University of Arizona Cancer Center.
University of Arizona Cancer Center; Aveo.
The author has declared no conflicts of interest.