Background: Epidermal growth factor receptor inhibitors (EGFR-Is) may alleviate neuropathic pain (NP).1 The proof-of-concept study NoTOPain demonstrated a clinical signal of efficacy for the treatment of NP with the intravenous EGFR-I cetuximab.2 Here, we report the exploratory biomarker analysis from this study.
Methods: Fourteen patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerve (CPN) or complex regional pain syndrome (CRPS) were treated within the NoTOPain study, an investigator-initiated proof-of-concept study using a randomized, double-blind, placebo-controlled, single dose, cross-over design. Single doses of the mAB cetuximab and placebo were administered iv in a cross-over fashion, followed by a single dose of open-label cetuximab.
Responders for the biomarker analysis were defined as patients with a ≥ 50% pain reduction on a 10-point NRS on any day between days 2 and 15 following blinded cetuximab. Pretreatment levels of 52 plasma proteins were analyzed with ELISAs and multiplexed immunoassays. Difference in mean biomarker levels between responders and non-responders was compared with t-tests, unadjusted for multiplicity.
Results:  Two participants with insufficient baseline pain scores (<4) were omitted from the final analysis. In the different NP entities, four of six patients with CRPS and three of six patients with CPN were considered clinical responders. Selected markers appear to be of particular interest in the context of EGFR-I and NP.

Table 1

Difference in baseline biomarker levels according to response to blinded cetuximab.  BDNF=Brain-Derived Neurotrophic Factor; MDC=Macrophage-Derived Chemokine; MIP-1 beta= Macrophage Inflammatory Protein-1 beta; MMP-9=Matrix Metalloproteinase-9; NRG2= Neuregulin-2; SCF= Ligand for the receptor-type protein-tyrosine kinase KIT/Stem Cell Factor
Conclusion:  Identification of predictive biomarkers for cetuximab in the treatment of neuropathic pain could be feasible and should be explored further.

References.
1.	Br J Anaesth. 2015 doi: 10.1093/bja/aev326.
2.	Pain Med. 2019 doi: 10.1093/pm/pnz101.

POTENTIAL PREDICTIVE BIOMARKERS FOR CETUXIMAB IN THE TREATMENT OF NEUROPATHIC PAIN -EXPLORATORY BIOMARKER ANALYSIS FROM THE NOTOPAIN TRIAL-