Randomized, phase II study of ficlatuzumab with or without cetuximab in patients (pts) with cetuximab-resistant, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)

Abstract

Background: 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 tumorintrinsic 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/MHNSCC (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%. SerumVeristrat, a proteomic classifier predictive of differential treatment benefit fromanti‐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 armfollows the hypothesis that continued anti‐EGFR blockade may overcome reciprocal compensation between the EGFR and cMet pathways. Trial design: This is a multicenter phase II trial with a randomized, non‐comparative, 2‐ armdesign (ArmA: ficlatuzumab and Arm B: ficlatuzumab+ cetuximab) in pts with R/ MHNSCC after failure of cetuximab. Key eligibility criteria include: R/MHNSCC; cetuximab resistance (recurrence during or within 6 mos of cetuximab‐radiation or palliative cetuximab); ECOG0‐1; 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.