Cetuximab in combination with methotrexate (MTX) as 1st-line treatment in recurrent or metastatic (R/M) SCCHN, a phase Ib – randomized phase II study versus single agent MTX
First-line palliative treatment in R/M SCCHN consists of the combination of cetuximab with cisplatin and 5-FU with a median progression free survival (PFS) and overall survival (OS) of 5.5 and 10.1 months, respectively, at the expense of substantial toxicity. Single agent MTX has minimal side effects, but response rate, gain in PFS and OS are limited. We hypothesized that adding cetuximab to MTX could improve PFS without adding major toxicities. Because this combination had not been tested before, we first performed a phase Ib study followed by a randomized phase II study.
In the phase Ib study, patients (pts) with previously untreated R/M SCCHN were treated with weekly MTX 40 mg/m2 and cetuximab 250 mg/m2, after a loading dose of cetuximab 400 mg/m2. The primary objectives of the phase Ib study were feasibility and safety of the combination of cetuximab and MTX. In the phase II study pts were randomized to either MTX or the combination (1:2). The primary objective of the phase II study was to detect an increase in median PFS from 3 to 5 months with combination vs single agent MTX. Secondary endpoints were toxicity and OS.
Six pts were included in the phase Ib study. No dose limiting toxicities were observed, median PFS was 24.4 weeks (range 7.1-55.0). In the phase II study 45 pts were included; 15 pts received MTX (73% male, median age 64 years (range 50-77)) and 30 pts cetuximab and MTX (77% male, median age 69 years (range 46-80)). In the phase II study median PFS was significantly different: 8.0 weeks (range 3.0-39.0) in the MTX arm and 17.0 weeks (range 3.9-76.6+) in the combination arm (p=.009). Nine pts in the combination arm experienced a serious adverse event (SAE), 3 were possible treatment-related (pneumonia, pneumonitis and hypersensitivity reaction) compared with 5 pts with an SAE in the MTX group, all unrelated. OS and detailed toxicity results will be presented later.
The combination of cetuximab and MTX in pts with R/M SCCHN is feasible. This randomised phase II study met its primary endpoint: a significantly longer PFS in the cetuximab and MTX combination arm, while toxicity was acceptable.