Relief of Neuropathic Pain Through Epidermal Growth Factor Receptor Inhibition: A Randomized Proof-of-Concept Trial

Abstract

Objective Case reports and a case series have described relief of neuropathic pain (NP) after treatment with epidermal growth factor receptor inhibitors (EGFR-Is). These observations are supported by preclinical findings. The aim of this trial was to explore a potential clinical signal supporting the therapeutic efficacy of EGFR-Is in NP. Methods In a proof-of-concept trial using a randomized, double-blind, placebo-controlled design, 14 patients with severe, chronic, therapy-resistant NP due to compressed peripheral nerves or complex regional pain syndrome were randomized to receive a single infusion of the EGFR-I cetuximab and placebo in crossover design, followed by a single open-label cetuximab infusion. Results The mean reduction in daily average pain scores three to seven days after single-blinded cetuximab infusion was 1.73 points (90% confidence interval [CI] = 0.80 to 2.66), conferring a 1.22-point greater reduction than placebo (90% CI = –0.10 to 2.54). Exploratory analyses suggested that pain reduction might be greater in the 14 days after treatment with blinded cetuximab than after placebo. The proportion of patients who reported ≥50% reduction in average pain three to seven days after cetuximab was 36% (14% after placebo), and comparison of overall pain reduction suggests a trend in favor of cetuximab. Skin rash (grade 1–2) was the most frequent side effect (12/14, 86%). Conclusions This small proof-of-concept evaluation of an EGFR-I against NP did not provide statistical evidence of efficacy. However, substantial reductions in pain were reported, and confidence intervals do not rule out a clinically meaningful treatment effect. Evaluation of EGFR-I against NP therefore warrants further investigation.

A pharmacological interactome platform for discovery of pain mechanisms and targets

“…An intriguing theme emerging from these distinct interactomes is the prominence of epidermal growth factor receptor (EGFR) ligands as possible mediators of interactions between diseased tissue and mouse and human nociceptors. This finding is consistent with recent preclinical and clinical findings suggesting efficacy of blocking EGFR signaling for chronic pain (Kersten et al, 2013;Kersten et al, 2015;Martin et al, 2017;Kersten et al, 2019).…”

“…Animal pain models suggest that EGFR activation by epiregulin encoded by the EREG gene promotes inflammatory and neuropathic pain and that EGFR signaling is critical for pain promoting effects of opioids (Martin et al, 2017;Puig et al, 2020). Finally, several clinical trials have been done with EGFR inhibitors for neuropathic pain and some of these have been positive (Kersten et al, 2013;Kersten et al, 2015;Kersten et al, 2019). Our results point to a diversity of EGFR ligands that are upregulated in painful tissues such as joints of people with rheumatoid arthritis and in pancreatic cancer.…”

“…For instance, EREG-mediated EGFR activation causes pain sensitization through PI3K/AKT/mTOR pathways in inflammatory pain models (Martin et al, 2017) and EGFR inhibition reduces opioid tolerance and hyperalgesia (Puig et al, 2020). Moreover, EGFR inhibitors have recently been used successfully for the treatment of neuropathic pain in patients (Kersten et al, 2015;Kersten et al, 2019). RA treatment has been transformed by the use of TNFa targeting biologics, but chronic pain remains a persistent problem for RA patients (Catrina et al, 2017;Krock et al, 2018).…”

Differential effects of epidermal growth factor receptor inhibitors in a single patient with neuropathic pain

“…Based on this, we performed a randomised, placebo-controlled double-blind proof-of-concept trial of cetuximab in patients with severe, treatment-refractory NP due to non-malignant compressed peripheral nerves (n=7) or complex regional pain syndrome (n=7). 22 This so-called NoTOPain trial (NoTOPain: Novel Treatment Option for neuropathic Pain) reported relatively high response rates among treatment-resistant patients and the magnitude of pain relief seen in those patients who benefited was encouraging. 22 Eight of the trial patients chose to continue with oral EGFR-Is after study completion.…”

“…22 This so-called NoTOPain trial (NoTOPain: Novel Treatment Option for neuropathic Pain) reported relatively high response rates among treatment-resistant patients and the magnitude of pain relief seen in those patients who benefited was encouraging. 22 Eight of the trial patients chose to continue with oral EGFR-Is after study completion. The current case report describes the clinical course of one of the trial participants during and for 48 months after the NoTOPain trial.…”