WO2020115108A1

WO2020115108A1 - Egfr inhibitors and their use in the treatment of neuroathic pain

Info

Publication number: WO2020115108A1
Application number: PCT/EP2019/083620
Authority: WO
Inventors: Marte Gronlie Cameron; Svein MJALAND; Christian KERSTEN
Original assignee: Sørlandet Sykehus Hf
Priority date: 2018-12-06
Filing date: 2019-12-04
Publication date: 2020-06-11

Abstract

The present invention concerns biomarkers which aid in the stratification of patients afflicted with neuropathic pain and in vitro methods to determine the abundance of said biomarkers to predict the likelihood of response to a neuropathic pain treatment with an EGFR inhibitor of a patient inflited with neuropathic pain. The invention further pertains to EGFR inhibitors for use in the treatment of neuropathic pain in patients which based on their biomarker status are likely to respond to such treatment. The invention further provides a method of treatment of patients afflicted with neuropathic pain which are likely to respond to a treatment with an EGFR inhibitor.

Description

EGFR inhibitors and their use in the treatment of neuroathic pain

FIELD OF THE INVENTION

The present invention concerns an in vitro method to predict the likelihood that a patient suffering from neuropathic pain will respond to a neuropathic pain treatment with EGFR inhibitors. The invention also concerns the use of EGFR inhibitors in individuals inflicted with neuropathic pain who are likely to respond to a treatment with said EGFR inhibitors.

BACKGROUND

Neuropathic pain (NP) is a clinical description of a pain state resulting from damage to the somatosensory nervous system. Clinical features are variable, but often characterized by spontaneous continuous and/or lancinating pain associated with tingling, burning sensations and amplified pain responses. Chronic neuropathic pain is associated with worse health outcomes than non-neuopathic pain and is widely accepted as being more difficult to treat, even with the most effective available medications which frequently have unacceptable side effects. Neuropathic pain reflects a range of different underlying pathophysiologies including post-herpetic neuralgia, diabetic and chemotherapy induced neuropathy, cancer related neuropathic pain and failed back surgery syndrome. Radicular back pain due to compressed nerves (CN) and complex regional pain syndrome (CRPS) are two types of neuropathic pain that are particularly difficult to treat. The prevalence of moderate to severe chronic neuropathic pain in the Western world is estimated to be 5% and the global burden is escalating rapidly due to the aging population and rising incidence of diseases that cause nerve damage.

Chronic pain has recently been associated with mutations in both the EGFR gene and in the EREG gene which encodes an EGFR ligand. In addition, reduction of nocifensive behavior after treatment with EGFR inhibitors has been demonstrated in rodent models of neuropathic pain. These pathophysiological findings point to the EGFR as a plausible target for treatment of neuropathic pain. There are at least eighteen published cases of neuropathic pain in which the administration of four different EGFR inhibitors which included cetuximab, panitumumab, erlotinib and gefitinib resulted in markedly improved pain control (BMJ Case Rep. 2012;2012; Journal of Pain. 2013;4 (2013) 3-7; Br J Anaesth. 2015;1 15(5):761 -7). Patients in these studies had a variety of underlying disorders including malignancy and benign conditions such as CN (n=5) and CRPS (n=1 ). The use of anti-EGFR antibodies in the treatment of neurological conditions such as e.g. neuropathic pain is also disclosed in WO2013/005108 A1. WO2014/095088 A1 discloses a method of treating patients inflicted with neuropathic pain in which pain is associated with pain nerve fibres type A, B, or C, or myelinated fibers by inhibiting at least one biological function of EGFR. The above results, however, do not allow to predict if a patient will respond to a neuropathic pain treatment with an EGFR inhibitor. Thus, there is currently no treatment option available which employs an evidence-based approach to chronic pain management that reflects mechanistic understanding. Instead, clinical practice in the management of neuropathic pain remains empirical and often unsatisfactory for patients, whose individual response to treatment cannot be predicted. The lack of evidenced-based treatment options for neuropathic pain therefore represents a critical unmet medical need and novel therapeutic options should be sought. It is thus an objective of the present invention to provide novel treatment options which aid in the stratification of patients with neuropathic pain to identify those patients that are likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that patients suffering from neuropathic pain are likely to respond to a neuropathic pain treatment with an EGFR inhibitor if the abundance of at least one biomarker selected from the group comprising BDNF, MDC, MIP1_beta_MMP9, NRG2, or SCF in a sample from said patient is equal to, or below a given threshold value for at least one of BDNF, MDC, MMP9, or NRG2, or equal to or above a given threshold value for at least one of MIP1_beta, or SCF.

Accordingly, the present invention provides in a first embodiment for an in vitro method for predicting the likelihood that the patient suffering from neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor wherein the method comprises determining in a sample obtained from said patient the abundance of at least one biomarker selected from the group comprising BDNF, MDC, MIP1_beta; MMP9, NRG2 and SCF, , wherein the abundance of said at least one biomarker above or below the threshold value for said at least one biomarker in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

According to one embodiment, the biomarker abundance is determined at baseline prior to treatment with an EGFR inhibitor.

In one embodiment, the abundance of the at least one biomarker in the patient sample is determined using a bead-based essay or by ELISA. According to one embodiment, the at least one biomarker abundance of BDNF below or equal to its threshold value of 3ng/ml BDNF in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

According to one embodiment, the at least one biomarker abundance of MDC below or equal to its threshold value of 300pg/ml MDC in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

According to one embodiment, the at least one biomarker abundance of MMP9 below or equal to its threshold value of 200ng/ml MMP9 in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

In one embodiment the at least one biomarker abundance below or equal to its threshold value of 8ng/ml NRG2 in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

In one embodiment, wherein the at least one biomarker MIP1_beta equal to or above its threshold value of 1 10pg/ml MIP1_beta in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

According to one embodiment, the at least one biomarker SCF equal to or above its threshold value of 21 Opg/ml SCF in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

In one embodiment, the inventive method comprises determining the abundance of at least two biomarkers in said patient sample, wherein the at least two biomarkers include NRG2.

According to one embodiment, the inventive method comprises determining the abundance of two biomarkers which includes NRG2 and the abundance of one further biomarker selected from BDNF, MDC, MIDP1_beta, MMP9, or SCF.

According to one embodiment, the biomarker abundance of NRG2 and SCF is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of SCF equal to or greater than its threshold value of 210 pg/ml SCF in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

According to one embodiment, the biomarker abundance of NRG2 and MDC is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of MDC below or equal to its threshold value of 300pg/ml MDC in said patient sample indicates that said patient is likely to respond a neuropathic pain treatment with an EGFR inhibitor.

According to one embodiment, the inventive biomarker abundance of NRG2 and MIP1_beta is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of MIP1_beta equal to or greater than its threshold value of 1 10pg/ml MIP1_beta in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according the invention is to be administered by means of infusion, or an oral EGFR inhibitor.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention which is to be administered by means of infusuion is one of panitumumab, cetuximab, necitumumab, or matuzumab.

According to one embodiment, the oral EGFR inhibitor for use in the treatment of neuropathic pain according to the invention is one of afatinib, gefinitib, erlotinib, lapatinib, neratinib, vandetanib, dacomitinib, rocilentinib, olmutinib, osimertinib, nazaternib, avinitib, PF-06747775, or ASP8273.

According to one embodiment, the patient in the inventive in vitro method is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

In one embodiment, the patient sample used in the inventive method is a blood or a plasma sample.

According to one embodiment, the patient in the inventive in vitro method is afflicted with one of non-compressive neuropathic pain, toxin-induced neuropathic pain, metabolic neuropathic pain, traumatic neuropathic pain, autoimmune-induced neuropathic pain, infection caused neuropathic pain, congential or hereditary neuropathic pain, complex regional pain syndrome (CRPS), or cancer-induced neuropathic pain.

In one embodiment, the present invention pertains to an EGFR inhibitorfor use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain and who is characterized by at least one biomarker threshold value for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient indicating that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml. According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain is used in a patient characterized by a biomarker threshold value of <8ng/ml NRG2 and <3ng/ml BDNF in a sample from said patient.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain is used in a patient characterized by a biomarker threshold value of <8ng/ml NRG2 and >200 pg/ml SCF in a sample from said patient

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain is used in a patient characterized by a biomarker threshold value of <8ng/ml NRG2 and <300pg/ml MDC in a sample from said patient.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain is used in a patient characterized by a biomarker threshold value of <8ng/ml NRG2 and >1 10pg/ml MIP1_beta in a sample from said patient.

According to one embodiment, the sample from said patient is a a blood or a plasma sample.

According to one embodiment, EGFR inhibitor for use in the treatment of neuropathic pain is used in a patient suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is cetuximab.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is panitumumab.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is matuzumab.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is necituzumab.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is an oral EGFR inhibitor.

According to one embodiment, the oral EGFR inhibitor for use in the treatment of neuropathic pain is afatinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, dacomitinib, rocilentinib, olmutinib, osimertinib, nazartinib, avitinib, PF-06747775.

In one embodiment, the present invention pertains to an oral EGFR inhibitor for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain wherein the patient is characterized by at least one biomarker threshold value for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml.

In one embodiment, the present invention pertains to an oral EGFR inhibitor for use in the treatment of neuropathic pain, wherein the patient is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

In one embodiment, the present invention pertains to an oral EGFR inhibitor for use in the treatment of neuropathic pain in a patient as disclosed above, wherein the biomarker values in the blood or plasma sample are determined at baseline prior to treatment with an oral EGFR inhibitor, wherein the oral EGFR inhibitor is selected from the group comprising afatinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, dacomitinib, neratinib, rocilentinib, olmutinib, osimertinib, nazartinib, PF-06747775.

In one embodiment, the present invention pertains to a method of treating a patient afflicted with neuropathic pain who is likely to respond to neuropathic pain treatment based on his biomarker status wherein the method comprises administering to said patient an EGFR inhibitor.

In one embodiment, the inventive method of treatment the patient’s biomarker status indicating that said patient is a likely candidate to respond to a neuropathic pain treatment with an EGFR inhibitor comprises determining the biomarker abundance of at least one of BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient and wherein the at least one biomarker threshold value of NRG2<8ng/ml in said patient sample indicates that the patient is likely to respond to said neuropathic pain treatment.

In one embodiment, the inventive method of treatment of neuropathic pain as disclosed above comprises determining a second biomarker value for one of the biomarkers selected from the group of BDNF, MDC, MIP1_beta_MMP9, and SCF.

In one embodiment, in the inventive method of treatment biomarker threshold values of <8ng/ml NRG2 and <3ng/ml BDNF in said patient sample indicate that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

In one embodiment, in the inventive method of treatment biomarker threshold values of <8ng/ml NRG2 and >200 pg/ml SCF in said patient sample indicate that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. In one embodiment, in the inventive method of treatment biomarker threshold values of <8ng/ml NRG2 and <200ng/ml MMP9 in said patient sample indicate that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

In one embodiment, in the inventive method of treatment biomarker threshold values of <8ng/ml NRG2 and >1 10pg/ml MIP1_beta in said patient sample indicate that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

According to one embodiment, the EGFR inhibitor to be adiminstered in the inventive method of treatment is an oral EGFR inhibitor, or may be an EGFR inhibitor which is administered by means of infusion.

According to one embodiment, the EGFR inhibitor to be administered in the inventive method of treatment is one of cetuximab, panitumumab, necitumumab, or matuzumab.

According to one embodiment, the EGFR inhibitor to be administered in the inventive method of treatment is one of afatinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, dacomitinib, neratinib, rocilentinib, olmutinib, osimertinib, nazartinib, PF-06747775.

In one embodiment, the patient to be treated according to the inventive method is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0- 10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

According to one embodiment, the patient to be treated with the inventive method is afflicted with analgesic treatment-refractory neuropathic pain.

According to one embodiment, in the neuropathic pain to be treated with the inventive method as disclosed above is one of non-compressive neuropathic pain, compressive neuropathic pain, toxic neuropathic pain, metabolic neuropathic pain, traumatic neuropathic pain, autoimmune neuropathic pain, neuropathic pain caused by infection, cancer treatment- induced neuropathic pain, congential or hereditary neuropathic pain and complex regional pain syndrome (CRPS).

According to one embodiment, the patient sample in the inventive method of treatment is a blood or plasma sample.

In one embodiment, the abundance of the at least one biomarker is determined at baseline prior to treatment with an EGFR inhibitor as disclosed above.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 : Trial Design. The trial was divided into 3 periods: Period 1 : Patient-reported pain assessments on days -7 to -3 leading up to the first blinded infusion established baseline pain levels. Patients received either one intravenous dose of blinded cetuximab or matching placebo. Treatment was followed by a fourteen day period of expected response in which primary outcome was assessed on days 4-8. This was followed by a fourteen-day wash-out period ending with establishement of the second baseline (on days -7 to -3) prior to period 2. Period 2: All patients crossed over to the alternate treatment, after which outcomes were assessed and a third baseline was established in a corresponding manner. Period 3: Twenty-eight days after the second blinded infusion, all patients received one dose of open-label cetuximab. The trial ended after a further 30 days of observations. Periods 1 and 2 provided data for the placebo-controlled assessment of effectiveness of cetuximab, whereas period 3 was intended to provide additional data for exploratory purposes.

FIGURE 2: Participant flow diagram. ITT = intention to treat; ^*Data sets of trial participants who exhibited insufficient pain scores (<4) prior to the blinded cetuximab infusion, precluding reliable testing of treatment effects, were omitted (CN; 003 and CRPS; 007) from selected exploratory analyses.

FIGURE 3: Baseline characteristics of the 14 evaluable patients. CN = compressed nerve;

CRPS = complex regional pain syndrome; FBSS = failed back surgery syndrome. ^#A Pain DETECT score > 18 is considered to confer a > 90% probability of NP. SD = standard deviation. " = 0-10 numeric rating scale.

FIGURE 4: Point estimates and 90% confidence intervals for pain reduction after cetuximab and placebo. # = Unadjusted mean average pain scores; ^* = Exploratory population excluding two patients (003; CN and 007; CRPS) who were retrospectively found to have insufficient baseline pain scores (<4) prior to blinded cetuximab in period 2; n = One patient (009; CN) chose not to receive the third trial infusion (open label cetuximab) due to lack of analgesia during the first two periods. One patient (015; CRPS) did not have the required baseline period as treatment was brought forward due to serious pain recurrence during wash-out.

FIGURE 5: Average pain responses: 4a: Percentage of patients reporting reduction in mean daily average pain scores on days 4-8 after each treatment, by percent. 4b: Daily average pain scores before and after treatment with blinded and open- label cetuximab and placebo. 4c: Daily average pain scores before and after treatment with blinded and open-label cetuximab and placebo for seven patients with compressed nerve (CN). 4d: Daily average pain scores before and after treatment with blinded and open-label cetuximab and placebo for seven patients with complex regional pain syndrome (CRPS).

FIGURE 6: Adverse events (AE) (according to CTCAE v.4.0) among the 15 included patients in the 28 days after each infusion. TRAE = treatment-related adverse events. ^*Cetuximab infusion (in period 1 ) was stopped due to an allergic reaction after <3% of the scheduled cetuximab dose had been delivered. The patient is reported separately in the table because he did not receive enough cetuximab to develop further adverse events. ^# One patient (CN; 009) chose not to receive the open-label cetuximab due to lack of pain relief after both blinded treatments. She did not report AEs in period 3.

DETAILED DESCRIPTION OF THE INVENTION

Although the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

Throughout this specification and the claims which follow, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step but not the exclusion of any other non-stated member, integer or step. The term "consist of" is a particular embodiment of the term "comprise", wherein any other non-stated member, integer or step is excluded. In the context of the present invention, the term "comprise" encompasses the term "consist of".

The terms "a" and "an" and "the" and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

The described objectives are solved by the present invention, preferably by the subject matter of the appended claims. More preferably, the present invention is solved according to a first embodiment by an in vitro method for predicting the likelihood that a patient suffering from neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor whereby the method comprises determining in a sample obtained from said patient the abundance of at least one biomarker selected from the group comprising BDNF, MDC, MIP1_beta; MMP9, NRG2 and SCF, wherein the at least one biomarker threshold value for said biomarkers in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. The term "EGFR inhibitor" as used for the present invention refers to a molecule having the ability to inhibit at least one biological function of the epidermal growth factor receptor (EGFR), or any of its sequence variants, deletion or insertion mutants as disclosed above. Accordingly, the term "inhibitor" is defined in the context of the biological role of EGFR.

For example, the inventive in vitro method is used to predict the likelihood that a patient afflicted with neuropathic pain will respond to a treatment with an EGFR inhibitor whereby the the biomarkers are selected from the group of BDNF, MDC, MIP1_beta; MMP9, NRG2 and SCF and wherein at leat one biomarker threshold value in the sample from the patient suffering from neuropathic pain indicates that the patient is likely to respond to the treatment with an EGFR inhibitor. In the inventive method as disclosed herein, the biomarker BDNF refers to brain derived neurotrophic factor (UniProtKB P23560), MDC refers to macrophage-derived cytokine, also referred to CCL22 (UniProtKB 000626), MIP1_beta refers to Macrophage Inflammatory Protein-1 beta, which may e.g. also be referred to as CCL4 (UniProtKB P13236), MMP9 refers to Matrix metallopeptidase 9 (UniProtKB P14780), NRG2 refers to pro- neuregulin-2 (UniProtKB 01451 1 ) and SCF refers to stem cell factor which may e.g. also be referred to as KIT-ligand, KL, or steel factor having the amino acid sequence as set forth in UniProtKB P21583.

The term “biomarker” as used with the inventive method refers to differentially expressed protein or any proteolytic fragment thereof of prognostic value, e.g. a protein or proteolytic fragment thereof may be less or more abundant in a patient sample from a subject or group of subjects characterized by a certain biological status, or medical condition compared to a control subject or group likely to respond to a medical treatment. The term “likelihood of response” or any grammatical equivalent thereof as used for the inventive in vitro method is meant to indicate the probability that a patient suffering from neuropathic pain will respond to the treatment with an EGFR inhibitor. For example, a patient is likely to respond if the likelihood of response is >50% and is unlikely to respond if the likelihood of response is <50%. The term EGFR as used herein refers to Epidermal Growth Factor Receptor having the amino acid sequence as set forth in UniprotKB P00533, or any sequence variant or mutant thereof such as e.g. G719C, G71 19S, G71 19A, V689M, N700D, E709K/Q, S720P; D761Y, T790M, L858R, L861 Q, Exon 19 deletion mutants, such as e.g. DE746-A750, DE746-T751 , DE746-A750 (ins RP), DE746-T751 (ins A/I), DE746-T751 (ins VA), DE746-S752 (ins A/V), DI.747-E749 (A750P), DI.747-A750 (ins P), DI.747-T751 , DI.747-T751 (ins P/S), DE747-S752, DI.747-752 (E746V), DI.747-752 (P753S), DE747-S752 (ins Q), DI.747-R753, DI.747-R753 (ins S), DS752- I759, or e.g. Exon 20 deletion or insertion mutants, such as e.g. A763_Y764insFQEA; D770_N771 insNPG, D770_N771 (ins SVQ), D770_N771 (ins G), N771 T V769L, S768I, T790M delE746_A750; L858R, N826S, A839T, K846R, L861 Q, G863D; V765A, T783A. Sequence variants may e.g. also include amino-acid encoding SNPs of the EGFR gene, e.g. rs2227983, or rs1 1569017. For example, if a patient afflicted neuropathic pain is found to be likely to respond to a treatment to an EGFR inhibitor according to the inventive in vitro method, the probability of response in said patient is >50%, >60%, >70%, >80%, >90%. In the inventive method the act of obtaining a sample from the patient afflicted with neuropathic pain does not form part of the present invention.

According to one embodiment, the at least one biomarker threshold is determined at baseline prior to the treatment with an EGFR inhibitor. For example, the abundance of the at least one biomarker may be determined 30 days, 25 days, 20 days, 14 days, or 7 days prior to an intended neuropathic pain treatment with an EGFR inhibitor and to determine whether the at least one biomarker abundance equals, or is above, or below a given biomarker threshold for a biomarker selected from the group of BDNF, MDC, MIP1_beta; MMP9, NRG2 and SCF.

According to one embodiment, the at least one biomarker abundance according to the inventive in vitro method may be determined using a bead-based assay, or by means of an ELISA Bead-based assays, for example, which can be used to quantitatively measure at least one, e.g. one, two, or three biomarkers selected from the group of BDNF, MDC, MIP1_beta; MMP9, NRG2 and SCF may include the Luminex® technology such as e.g. the Luminex® FlowMetrix® system as described in Clinical Chemistry 43:9 1749-1756 (1997), or e.g. as described in Methods 61 (2013) 23-29. For example, in one embodiment, fluorecence intensities as provided by the bead-based Luminex® assays may be used directly to determine the absolute concentration or abundance of the inventive biomarkers according to the method disclosed in Cytokine 71 (2015) 188-198. The inventive biomarkers may .e.g. also be detected and quantified using enzyme-linked immunosorbent assays (ELISA) as described in Methods in Enzymology Volume 1 18, 1986, Pages 742-766, or e.g. in Current Protocols in Immunology 2.1 .1 -2.1 .23, August 201 , or e.g. as disclosed in Sci Rep. 2015; 5: 17989. Commercially available ELISA kits may e.g. also be used to determine the abundance of the inventive at least one biomarker in a patient sample. Other methodologies known in the art for the detection of the above inventive biomarkers may be used, such as e.g. antibody arrays as described in PLoS One. 2013 Oct 8;8(10):e76795, or e.g. by means of automated microfluidic cartridge- based methods as decribed in Journal of Immunological Methods 451 (2017) 1-10.

The use of bead-based assays or ELISA may e.g. be desireable if a large number of samples needs to be processed and analyzed, as the assays are scaleable to a larger number of patient samples. Also, bead-based assyas and ELISA have proven to be reliable in the detection of blood- or plasma biomarkers. Commercial antibodies may be used in the inventive method to detect the biomarkers in a blood or plasma sample from a patient afflicted with neuropathic pain as disclosed herein.

According to one embodiment, the at least one biomarker threshold value of <3ng/ml BDNF in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of BDNF in the patient sample, whereby a BDNF concentration of about <3 ng/ml, or of about 1 -3 ng/ml, or of about 0.25 ng/ml, 0.5 ng/ml, 0.75ng/ml to less than about 2.0 ng/ml, 2.5 ng/ml, 2.75ng/ml BDNF, or from about 1 .25 ng/ml to about 2.25 ng/ml BDNF, orfrom about 1 ng /ml to about 2 ng/ml BDNF, orfrom about 2ng/ml to less than about 3ng/ml BDNF in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

According to one embodiment, the at least one biomarker threshold value of <300pg/ml MDC in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of BDNF in the patient sample, whereby a MDC concentration or abundance of about <300pg/ml, or of about 50, 75, 100pg/ml to about less or equal to 300 pg/ml, or of about 100, 125, 150 pg/ml to about less than or equal to 175pg/ml, 200pg/ml, 225pg/ml, 250pg/ml, 275 pg/ml MDC, or from about 175pg/ml, 200pg/ml, 225pg/ml, 250pg/ml to about less than or equal to 275pg/ml, 280pg/ml, 290pg/ml, 300pg/ml MDC in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

According to one embodiment, the at least one biomarker threshold value of <200ng/ml MMP9 in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of BDNF in the patient sample, whereby a MMP9 concentration or abundance of about <150ng/ml, 160ng/ml, 175ng/ml, 200ng/ml MMP9, or of about 50, 75, 100ng/ml to about less or equal to 125ng/ml, 150ng/ml, 160ng/ml, 175ng/ml, 200pg/ml, or of about 100ng/ml, 125ng/ml, 150ng/ml, 160ng/ml to about less than or equal to 175ng/ml, 180ng/ml, 190ng/ml, 200ng/ml MMP9 in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor. According to one embodiment, the at least one biomarker threshold value of <8ng/ml NRG2 in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of NRG2 in the patient sample, whereby a NRG2 concentration or abundance of about <2 ng/ml, 3ng/ml, 4ng/ml, 5ng/ml, 6ng/ml, 7ng/ml, 8ng/ml NRG2, or of about 0.25ng/ml, 0.5ng/ml, 0.75ng/ml, 1.0ng/ml, 1.25ng/ml, 1 .5ng/ml, 1 .75ng/ml, 2ng/ml, 2.5ng/ml, 3ng/ml to about less or equal to 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml NRG2, or of about 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml to about less or equal to 8ng/ml NRG2 in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

According to one embodiment, the at least one biomarker threshold value of >1 10pg/ml MIP1_beta in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of MIP1_beta in the patient sample, whereby a MIP1_beta concentration or abundance of e.g. about greater than or equal to 1 10pg/ml, 1 15pg/ml, 120pg/ml, 125pg/ml, 130pg/ml, 135pg/ml, 140pg/ml, 145pg/ml, 150pg/ml, 155pg/ml, 160pg/ml, 165pg/ml, 170pg/ml, 180pg/ml, 190pg/ml MIP1_beta, or e.g. of about 1 10pg/ml, 1 15pg/ml, 120pg/ml, 125pg/ml, 130pg/ml, 135pg/ml, 140pg/ml to about 145pg/ml, 150pg/ml, 155pg/ml, 160pg/ml, 165pg/ml, 170pg/ml, 180pg/ml, 190pg/ml MIP1_beta, or e.g. of about 145pg/ml, 150pg/ml, 155pg/ml, 160pg/ml to about 165pg/ml, 170pg/ml, 180pg/ml, 190pg/ml MIP1_beta in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

According to one embodiment, the at least one biomarker threshold value of >210pg/ml SCF in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of SCF in the patient sample, whereby a SCF concentration or abundance of e.g. about greater than or equal to 210pg/ml, 215pg/ml, 220pg/ml, 225pg/ml, 230pg/ml, 235pg/ml, 240pg/ml, 245pg/ml, 250pg/ml, 255pg/ml, 260pg/ml, 265pg/ml, 270pg/ml, 275pg/ml, 280pg/ml, 285pg/ml, 290pg/ml 295pg/ml, 300pg/ml SCF, or e.g. of about 210pg/ml, 215pg/ml, 220pg/ml, 225pg/ml, 230pg/ml, 235pg/ml, 240pg/ml, 245pg/ml, 250pg/ml, 255pg/ml, 260pg/ml to about 265pg/ml, 270pg/ml, 275pg/ml, 280pg/ml, 285pg/ml, 290pg/ml 295pg/ml, 300pg/ml SCF, or e.g. of about 210pg/ml to about 215pg/ml, 220pg/ml, 225pg/ml, 230pg/ml 235pg/ml, 240pg/ml, 245pg/ml, 250pg/ml, 255pg/ml, 260pg/ml SCF in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

According to one embodiment, the abundance of at least two inventive biomarkers in said patient sample is determined, wherein the at least two inventive biomarkers include NRG2.

According to one embodiment, the abundance of at least two inventive biomarkers is determined, wherein the inventive biomarkers include NRG2 and one further biomarker selected from BDNF, MDC, MIDP1_beta, MMP9, or SCF. For example, according to the inventive in vitro method, the concentration or abundance of NRG2 and BDNF, or e.g. of NRG2 and MDC, or of NRG2 and MIP1_beta, or of NRG2 and MMP 9, or of NRG2 and SCF in a patient sample is determined.

In one embodiment, the abundance of the inventive biomarkers NRG2 and SCF is determined and wherein a biomarker threshold value of <8ng/ml NRG2 and >210 pg/ml SCF in the patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, the abundance of the inventive biomarkers NRG2 and SCF in a patient sample may be determined using any of the detection methods disclosed above whereby biomarker threshold values of of <8ng/ml NRG2 and >210 pg/ml SCF indicate that the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. The term biomarker threshold value as used for the inventive method refers to a certain concentration of the at least one inventive biomarker, e.g. NRG2, BDNF, MDC, MIDP1_beta, MMP9, or SCF, which above or below a defined biomarker prognostic abundance or prognostic concentration in the patient sample indicates whether a patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor, whereby the inventive threshold values are as disclosed above. For example, the biomarker threshold value for the NRG2 concentration or abundance of about <2 ng/ml, 3ng/ml, 4ng/ml, 5ng/ml, 6ng/ml, 7ng/ml, 8ng/ml, or of about 0.25ng/ml, 0.5ng/ml, 0.75ng/ml, 1 .0ng/ml, 1 .25ng/ml, 1 .5ng/ml, 1 .75ng/ml, 2ng/ml, 2.5ng/ml, 3ng/ml to about less or equal to 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml NRG2, or of about 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml to about less or equal to 8ng/ml and the biomarker threshold value for the SCF abundance or concentration of about greater than or equal to 210pg/ml, 215pg/ml, 220pg/ml, 225pg/ml, 230pg/ml, 235pg/ml, 240pg/ml, 245pg/ml, 250pg/ml, 255pg/ml, 260pg/ml, 265pg/ml, 270pg/ml, 275pg/ml, 280pg/ml, 285pg/ml, 290pg/ml 295pg/ml, 300pg/ml SCF, or e.g. of about 210pg/ml, 215pg/ml, 220pg/ml, 225pg/ml, 230pg/ml, 235pg/ml, 240pg/ml, 245pg/ml, 250pg/ml, 255pg/ml, 260pg/ml to about 265pg/ml, 270pg/ml, 275pg/ml, 280pg/ml, 285pg/ml, 290pg/ml 295pg/ml,

300pg/ml SCF, or e.g. of about 210pg/ml to about 215pg/ml, 220pg/ml, 225pg/ml, 230pg/ml 235pg/ml, 240pg/ml, 245pg/ml, 250pg/ml, 255pg/ml, 260pg/ml in the patient sample indicates that the patient is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

In one embodiment, the abundance of the inventive biomarkers NRG2 and BDNF is determined and wherein an abundance of the inventive biomarker NRG2 below or equal to the biomarker threshold value of 8ng NRG2/ml and the abundance of the inventive biomarker BDNF is below or equal to the biomarker threshold value of 3ng BDNF/ml in the patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. The abundance or concentration of the at least one inventive biomarker may e.g. be determined as disclosed above by means of a bead-based assay or ELISA. If the abundance or concentration of the inventive biomarkers in the patient sample is above or below the respective biomarker threshold values the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, if the abundance of the inventive biomarkers NRG2 and BDNF in the patient sample as determined by the methods disclosed above, is less than 2 ng/ml, 3ng/ml, 4ng/ml, 5ng/ml, 6ng/ml, 7ng/ml, 8ng/ml, or of about 0.25ng/ml, 0.5ng/ml, 0.75ng/ml, 1 .0ng/ml, 1 .25ng/ml, 1.5ng/ml, 1.75ng/ml, 2ng/ml, 2.5ng/ml, 3ng/ml to about less or equal to 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml NRG2, or of about 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml to about less or equal to 8ng/ml NRG2 and the abundance or concentration of BDNF is e.g. less than 3ng/ml, or of about 1 -3 ng/ml, or of about 0.25 ng/ml, 0.5 ng/ml, 0.75ng/ml to less than about 2.0 ng/ml, 2.5 ng/ml, 2.75ng/ml BDNF, or from about 1.25 ng/ml to about 2.25 ng/ml BDNF, or from about 1 ng /ml to about 2 ng/ml BDNF, or from about 2ng/ml to less than about 3ng/ml BDNF this biomarker status indicates that a patient afflicted with neuropathic pain with an average pain intensity > 6 in a numericsal rating scale from 1 -10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT® score, is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

In one embodiment, the abundance of the inventive biomarkers NRG2 and MDC is determined and wherein an abundance of the inventive biomarker NRG2 below or equal to the biomarker threshold value of 8ng NRG2/ml and the abundance of the inventive biomarker MDC below or equal to the biomarker threshold value of <300pg MDC/ml in the patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. The abundance or concentration of the at least one inventive biomarker may e.g. be determined as disclosed above and if the abundance or concentration of the inventive biomarkers in the patient sample is above or below the respective biomarker threshold values for NRG2 and MDC the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, if the abundance or concentration of the inventive biomarkers NRG2 and MDC in the patient sample as determined by the methods disclosed above is less than 2 ng/ml, 3ng/ml, 4ng/ml, 5ng/ml, 6ng/ml, 7ng/ml, 8ng/ml, or of about 0.25ng/ml, 0.5ng/ml, 0.75ng/ml, 1.0ng/ml, 1.25ng/ml, 1 .5ng/ml, 1.75ng/ml, 2ng/ml, 2.5ng/ml, 3ng/ml to about less or equal to 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml NRG2, or of about 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml to about less or equal to 8ng/ml NRG2 and about <300pg/ml MDC indicating that the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment using an EGFR inhibitor. In one embodiment, the abundance or concentration of the inventive biomarkers NRG2 and MDC in the patient sample as determined by the methods disclosed above may be below or equal to the biomarker threshold value of 8ng/ml NRG2 and the abundance or concentration of MDC is less than or equal to about 50, 75, 10Opg/ml to less or equal to about 300 pg/ml, or of about 100, 125, 150 pg/ml to less than or equal to about 175pg/ml, 200pg/ml, 225pg/ml, 250pg/ml, 275 pg/ml MDC, or from about 175pg/ml, 200pg/ml, 225pg/ml, 250pg/ml to less than or equal to about 275pg/ml, 280pg/ml, 290pg/ml, 300pg/ml MDC indicating that the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

In one embodiment, the abundance of the inventive biomarkers NRG2 and MIP1_beta is determined and wherein an abundance of the inventive biomarker NRG2 below or equal to the biomarker threshold value of 8ng NRG2/ml and the abundance of the inventive biomarker MIP1_beta is greater than or equal to the biomarker threshold value of <1 10pg MIP1_beta /ml in the patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. The abundance or concentration of the at least one inventive biomarker may e.g. be determined as disclosed above and if the abundance or concentration of the inventive biomarkers in the patient sample is below or equal to the respective biomarker threshold value for NRG2 and greater than or equal to the respective threshold value for MIP1_beta the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, the concentration of the inventive biomarkers NRG2 and MIP1_beta in the patient sample as determined by the methods disclosed above of less than 2 ng/ml, 3ng/ml, 4ng/ml, 5ng/ml, 6ng/ml, 7ng/ml, 8ng/ml, or of about 0.25ng/ml, 0.5ng/ml, 0.75ng/ml, 1 .0ng/ml, 1.25ng/ml, 1.5ng/ml, 1.75ng/ml, 2ng/ml, 2.5ng/ml, 3ng/ml to about less or equal to 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml NRG2, or of about 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml to about less or equal to 8ng/ml NRG2 and a MIP1_beta concentration or abundance of e.g. about greater than or equal to 1 10pg/ml, 1 15pg/ml, 120pg/ml, 125pg/ml, 130pg/ml, 135pg/ml, 140pg/ml, 145pg/ml, 150pg/ml, 155pg/ml, 160pg/ml, 165pg/ml, 170pg/ml, 180pg/ml, 190pg/ml MIP1_beta, or e.g. of about 1 10pg/ml, 1 15pg/ml, 120pg/ml, 125pg/ml, 130pg/ml, 135pg/ml, 140pg/ml to about 145pg/ml, 150pg/ml, 155pg/ml, 160pg/ml, 165pg/ml, 170pg/ml, 180pg/ml, 190pg/ml MIP1_beta, or e.g. of about 145pg/ml, 150pg/ml, 155pg/ml, 160pg/ml to about 165pg/ml, 170pg/ml, 180pg/ml, 190pg/ml MIP1_beta indicates that the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment using an EGFR inhibitor.

In one embodiment, the abundance of the inventive biomarkers NRG2 and MMP9 is determined and wherein an abundance of the inventive biomarker NRG2 below or equal to the biomarker threshold value of 8ng NRG2/ml and the abundance of the inventive biomarker MMP9 below or equal to the biomarker threshold value of 210pg MMP9/ml in the patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. The abundance or concentration of the at least one inventive biomarker may e.g. be determined as disclosed above and if the abundance or concentration of the inventive biomarkers in the patient sample is below or equal to the respective biomarker threshold value for NRG2 and smaller than or equal to the respective threshold value for MMP9 the patient afflicted with neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, the concentration of the inventive biomarkers NRG2 and MIP1_beta in the patient sample as determined by the methods disclosed above of less than 2 ng/ml, 3ng/ml, 4ng/ml, 5ng/ml, 6ng/ml, 7ng/ml, 8ng/ml, or of about 0.25ng/ml, 0.5ng/ml, 0.75ng/ml, 1 .0ng/ml, 1.25ng/ml, 1 .5ng/ml, 1.75ng/ml, 2ng/ml, 2.5ng/ml, 3ng/ml to about less or equal to 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml NRG2, or of about 3.5ng/ml, 4ng/ml, 4.5ng/ml, 5ng/ml, 5.5ng/ml, 6ng/ml, 6.5ng/ml, 7ng/ml, 7.5ng/ml to about less or equal to 8ng/ml NRG2 and a MMP9 concentration or abundance of e.g. <200ng/ml MMP9, e.g. of about <150ng/ml, 160ng/ml, 175ng/ml, 200ng/ml MMP9, or of about 50, 75, 100ng/ml to about less or equal to 125ng/ml, 150ng/ml, 160ng/ml, 175ng/ml, 200pg/ml, or of about 100ng/ml, 125ng/ml, 150ng/ml, 160ng/ml to about less than or equal to 175ng/ml, 180ng/ml, 190ng/ml, 200ng/ml MMP9 in the patient sample indicates in the inventive method that the patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, according to the inventive in vitro method the patient sample may be subjected to or used in any of the assays as disclosed above to quantitatively determine the abundance of MMP9 and NRG2 in the patient sample.

According to one embodiment, the EGFR inihibitor used according to the invention as disclosed above is formulated is a liquid formulation which is to be administered by means of infusion. The term“infusion” as used for the EGFR inhibitors according to the invention refers to the delivery of the liquid EGFR formulation into a vein of an individual which may e.g. also be referred to as intravenous (i.v.) administration. Intravenous administration may e.g. be done by means of a central venous catheter, a peripheral line, a periphally inserted central catheter, or by means of an implantable port. The term infusion according to the invention may e.g. also include intra-muscular (i.m.), or subcutaneous (s.c.) administration of the EGFR inhibitors. The application of such infusion means to a patient afflicted with neuropathic pain does not form part of this invention and is done in accordance with standard of care procedures by nurses or physicans.

In one embodiment, the EGFR inhibitor according to the invention may e.g. be formulated for intramuscular, or subcutaneous injection. Subcutaneous injection of the EGFR inhibitor according to the invention may e.g. be done using bolus injectors, or injection pens. Corresponding liquid formulations of the EGFR inhibitor may e.g. also comprise soluble glycosaminoglycanases as e.g. disclosed in W02006/091871 A1 to facilitate the subcutaneous injection of a therapeucically effective dose of the EGFR for use in the treatment of neuropathic pain and to reduce the pain associated with such injection. For example, bolus injectors that may be used for the administration of the EGFR inhibitor according to the invention as disclosed above are described in WO2014/204894 A1 , or WO201 1/086505 A1 .

According to one embodiment, the EGFR inhibitor used according to the invention is an oral EGFR inhibitor. The term“oral EGFR inhibitor” according to the invention refers to EGFR inhibitors which have been formulated as an oral dosage form and which are administered to patients orally (“p.o.”). For example, the EGFR inhibitor for use according to the invention may be formulated into a tablet which comprises a therapeutically effective dose dose of the EGFR respective inhibitor. The tablet comprising the oral EGFR inhibitor according to the invention may e. g. be swallowed, chewed, or be formulated as a buccal or sublingual tablet, or may e.g. be formulated as a capsule, lozenge, pastille, pill, or powder. In one embodiment, the oral EGFR inhibitor according to the invention may be formulated as an oral emulsion, oral suspension, or syrup.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention and as disclosed above is panitumumab. Panitumumab may e.g. be administered to a patient afflicted with neuropathic pain by means of infusion at a concentration of about 6 mg/kg body weight over 60 minutes if less than 1000mg are to be administered to an individual afflicted with neuropathic pain, or e.g. over 90 minutes, if more than 1000mg of panitumumab are to be administered.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is cetuximab. Cetuximab may e.g. be administered to an individual afflicted with neuropathic pain by means of infusion at a concentration of 400mg/m² body surface over 120 minutes, whereby the body surface may e.g. be computed according to the Dubois method, in which the body surface area of a subject (m²) is calculated using the subject's body weight (wt) given in kg and the subject’s height given in cm: m²=(wt⁰⁴²⁵ x height^{0 725}) x 7,184x10^s.

According to one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is necitumumab. Necitumumab may e.g. be administered to an individual afflicted with neuropathic pain in a fixed dose of 800mg over 60 minutes.

For example, cetuximab may e.g. be administered to a patient characterized by analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire and wherein the patient is characterized by at least one biomarker abundance for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said biomarkers as disclosed above in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker includes NRG2 with an abundance of below or equal to its threshold value of 8ng/ml

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention may e.g. be matuzumab. For example, matuzumab may be administered by means of infusion in a fixed dosed of about 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, or be administered in a dose of about 5mg/kg body weight to about 20mg/kg body weight, or from about 7.5mg/kg body weight to about 17.5mg/kg body weight, or from about 10mg/kg body weight to about 15mg/kg body weight, or from about 12.5mg/kg body weight to about 25mg/kg body weight, or from about 2.5mg/kg body weight to about 5mg/kg body weight, 7.5mg/kg body weight, 10mg/kg body weight, 12.5mg/kg body weight, or e.g. at a concentration of 50 mg/m², 75mg/m², 100mg/m², 150mg/m², 200mg/m², 250mg/m², 300mg/m², 350mg/m², 400mg/m² body surface whereby the body surface may be calculated according to the Dubois method as disclosed above. Matutzumab may e.g. be administered over a period of time of about 20 minutes to about 120 minutes, e.g. 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 1 10 minutes.

For example matuzumab may be administered to a patient characterized by analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire and wherein the patient is characterized by at least one biomarker abundance for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said biomarkers as disclosed above in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker includes NRG2 with an abundance of below or equal to its threshold value of 8ng/ml

In one embodiment, the EGFR inhibitors as disclosed above that can be used in the treatment of neuropathic pain according to the invention may e.g. also include biosimilars of the respective antibodies, whereby the term“biosimilar” or“biosimilarity” has the meaning as set forth in 42 U.S.C. § 262 (2): The term "biosimilar" or "biosimilarity", in reference to a biological product means (A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and (B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

In one embodiment, the EGFR inhibitors as disclosed above for use according to the invention may e.g. be administered following a premedication of the individual afflicted with neuropathic pain with corticosteroids, synthetic glucocorticoids, antihistamines and non-steroidal anti inflammatory drugs to reduce infusion-related reactions.

According to one embodiment, the EGFR inhibitor for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention may be an oral EGFR inhibitor.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain as disclosed above is the oral EGFR inhibitor afatinib. Afatinib may e.g. be administred in the dosage form of tablets comprising 20mg, 30mg, or 40mg afatnib per unit dosage form.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor erlotinib. For example, erlotinib may be used in dosage forms of about 25mg, 75mg, 10Omg, 125mg, 150mg according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor gefitinib. For example, gefitinib may be used in its approved dosage form according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor lapatinib. For example, lapatinib may be used in its approved dosage form according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor neratinib. For example, neratinib may be used in its approved dosage form according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor vandetanib. For example, vandetanib may be used in its approved dosage form according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor dacomitinib. For example, dacomitinib may be used in the dosage form of a tablet according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor rociletinib. For example, rociletinib may be used in any suitable dosage form such as a tablet in a therapeutically effective amount according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor avitinib. For example, avitinib may be used in any suitable dosage form such as a tablet in a therapeutically effective amount according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor PF-06747775.. For example, PF-06747775 may be used in any suitable dosage form such as a tablet in a therapeutically effective amount according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

In one embodiment, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention as disclosed above is the oral EGFR inhibitor ASP8273. For example, ASP8273 may be used in any suitable dosage form such as a tablet in a therapeutically effective amount according to the invention in the treatment of neuropathic pain in patients that are characterized by a biomarker status as disclosed above indicating that such patients are likely to respond to such neuropathic pain tratement.

According to one embodiment, the EGFR inhibitors for use in the treatment of neuropathic pain according to the invention as disclosed above may be administered once at the beginning of the neuropathic pain treatment (day 1 ) to patients in a therapeutically effective amount who based on their biomarker status as disclosed above are likely to respond to a neuropathic pain treatment with an EGFR inhibitor. For example, the therapeutically active amount of an EGFR inhibitor as disclosed above that is administered to patients likely to respond to a neuropathic pain treatment with an EGFR inhibitor may correspond to the maximal tolerated dose of the EGFR inhibitor, or may be less than the maximal tolerated dose, or preferably may correspond to the dose indicated on the label of the EGFR inhibitor as disclosed above as approved by national and/or regional regulatory authorities.

According to one embodiment, the patient in the inventive in vitro method for predicting the likelihood that a patient suffering from neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^® questionnaire. The numerical rating scale which is used according to the invention ranges from 0 (zero) representing no pain to 10 (ten) representing extreme pain, which affected individuals may e.g. also refer to as“worst pain imaginable”. Other rating scales such as those described in J Clin Nurs. 2005 Aug;14(7):798- 804 may e.g. be used to assess the average pain intensity of the patient afflicted with neuropathic pain, however, if different rating scales are used it needs to be ensured that the average pain intensity as determined by the other rating scales corresponds to an average pain intensity of >6 of the numerical rating scale as disclosed above. For example, if the visual analog scale is used in the inventive in vitro method the average pain intensity should be at least that corresponding to a value of >6 in the numerical rating scale from 0-10. If for example a verbal rating scale is used the corresponding pain intensity according to the invention is at least moderate to severe pain corresponding to a value of 2-3 in the verbal rating scale. The term “Pain Detect® questionnaire” as used in the inventive method referes to a screening questionnaire as published in Current Medical Research and Opinion® Vol. 22, No. 10, 2006, 191 1-1920 and which can be used to detect neuropathic pain components in an individual. The PainDetect® questionnaire comprises seven questions that address the quality of neuropathic pain symptoms which e.g. address the graduation of pain, the pain course pattern and whether the pain is radiating into other regions of the body, each of which are awarded a graded score as shown below which in sum gives rise to the baseline score:

(taken from: Curr Med Res Opin 2006; 22(10))

Accordingly, patients that are characterized by an average pain intensity of >6 as determined by the numerical rating scale disclosed above and a baseline score greater or equal to 13/38 according to the PainDetect questionnaire as disclosed above, or e.g. by corresponding pain rating scales as disclosed above and who are characterized by a biomarker concentration in a sample from said patients according to the invention as disclosed above, are likely to respond to a neuropathic pain treatment with an EGFR inhibitor, whereby the EGFR inhibitor is selected from those EGFR hinbitors disclosed above.

In one embodiment, a patient characterized by e.g. at least one biomarker concentration of below or equal to, or above or equal to one of the biomarker threshold values of <3ng/ml BDNF, <300pg/ml MDC, <200ng/ml MMP9, <8ng/ml NRG2, >110pg/ml MIP1_beta, or ³210pg/ml SCF in a sample from said patient as disclosed above and whereby the patient has an average pain intensity of >6 as determined by the numerical rating scale disclosed above, or e.g. by corresponding pain rating scales as disclosed above and a baseline score of > 13/38 according to the PainDETECT^® questionnaire, is likely to respond to neuropathic pain treatment with an EGFR inhibitor according to the inventive method.

For example, in one embodiment, a patient characterized by two biomarker concentrations of below or equal to, or above or equal to one of the biomarker threshold values of <3ng/ml BDN F, <300pg/ml MDC, <200ng/ml MMP9, <8ng/ml NRG2, >1 10pg/ml MIP1_beta, or ³210pg/ml SCF in a sample from said patient as disclosed above, whereby the the biomarkers include NRG2 and whereby the patient has an average pain intensity of >6 as determined by the numerical rating scale disclosed above, or e.g. by corresponding pain rating scales as disclosed above and a baseline score of > 13/38 according to the PainDETECT^® questionnaire, is likely to respond to neuropathic pain treatment with an EGFR inhibitor according to the inventive method. For example, according to the inventive method, a patient characterized by a biomarker concentration below or equal to the biomarker threshold value of 8ng/ml NRG2 and a biomarker concentration of below or equal to the biomarker threshold value 300pg/ml MDC, or below or equal to the biomarker threshold value of 200ng/ml MMP9, or greater or equal to the biomarker threshold value of 1 10pg/ml MIP1_beta, or greater or equal to the biomarker threshold value of 210pg/ml SCF and the patient is characterized by an average pain intensity of >6 as determined by the numerical rating scale disclosed above, or e.g. by corresponding pain rating scales as disclosed above and a baseline score of > 13/38 according to the PainDETECT^® questionnaire, is likely to respond to neuropathic pain treatment with an EGFR inhibitor.

In one embodiment, the patient suffering from neuropathic pain who is determined to be likely to respond to a neuropathic pain treatment by the inventive method as disclosed above is afflicted with analgesic treatment-refractory neuropathic pain, whereby the term analgesic treatment-refractory neuropathic pain refers to a condition in which the treatment of the neuropathic pain using standard of care pain treatment options has failed. The term analgesic treatment-refractory neuropathic pain may e.g. also refer to neuropathic pain which could also not be effectively treated using adjuvant analgesics in combination with conventional analgesics. Typically, such treatments involve the administration of opioids in combination with adjuvant analgesics such as gabapentin, or pregabalin. Analgesic treatment-refractory also refers to situations in which the treatment with tricyclic antidepressants in combination with fluphenazine, gabapentin in combination with nortriptyline, or the combination of NMDA receptor blockers and analgesic drugs as not resulted in a reduction of the neuropathic pain to a tolerable degree (see also e.g. Cochrane Database Syst Rev. 2012 Jul 1 1 ;(7):CD008943).

According to one embodiment the patient sample according to the inventive method as disclosed above is or is derived from a blood or plasma sample. For example, the sample from said neuropathic pain patient may be a serum sample, or a blood plasma sample. Blood serum for use in the inventive method may e.g. be obtained by allowing a whole blood sample from said neuropathic pain patient to clot and removing the clot by centrifugation. Blood plasma from said neuropathic pain patient may e.g. be produced by treating a whole blood from said patient with an anticoagulant, e.g. by using collection tubes coated with an anti-coagulant such that the blood does not clot in the respective tube. Blood cells may then be removed by e.g. centrifugation and the resulting supernatant (plasma) may be carefully removed from the cell pellet and used in the inventive method to determine the concentration of the at least one biomarker as disclosed above by means of an ELISA, or bead-based assay as disclosed above.

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with compressive neuropathic pain. The condition compressive neuropathic pain according to the invention refers to a medical condition that is e.g. caused by direct pressure on a nerve.

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with toxin-induced neuropathic pain. As used according to the invention toxin-induced neuropathic pain refers to a neuropathy caused by drug ingestion, drug or chemical abuse, or industrial chemical exposure from the workplace or the environment.

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with traumatic neuropathic pain. As used according to the invention toxin-induced neuropathic pain refers to neuropathic pain caused by e.g. traumatic neuroma.

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with autoimmune neuropathic pain. As used according to the invention autoimmune neuropathic pain refers to neuropathic pain caused by e.g. autoimmune diseases, in which the immune system attacks the body’s own tissues, can lead to nerve damage, one example of autoimmune disease that may cause neuropathic pain is multiple sclerosis.

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with neuropathic pain which is caused by infection. For example, infections that may cause neuropathic pain are HIV infections, infection with syphilis, or shingles.

In one embodiment, a patient found to be likely to respond to a neuropathic pain treatment according to the inventive method as disclosed above is afflicted with congenital or hereditary neuropathic pain. Hereditary neuropathies that may cause neuropathic pain include for example Charcot-Marie-Tooth disease, one of the hereditary motor and sensory neuropathies, or Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with cancer-induced neuropathic pain. Cancer-induced neuropathic pain as used in the present invention can be disease-related or related to the acute or chronic effects of cancer treatment. For example, chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, dose-dependent complication of anticancer drugs such as e.g. platinums, taxanes, epothilones, or vinca alkaloids and which may occur in up to 90% of patients receiving chemotherapy. For example, oxaliplatin-induced neuropathy as a cause for cancer-induced neuropathic pain is associated with an acute phase of allodynia and pricking dysaesthesia affecting the hands and feet and also pharyngolaryngeal dysaesthesia with sensations of shortness of breath or swallowing difficulties induced by cold drinks.

In one embodiment, the patient which is found to be likely to respond to a neuropathic pain treatment using the inventive method as disclosed above is afflicted with complex regional pain syndrome (CRPS) which may also be referred to as morbus Sudeck. As used herein, CRPS describes a chronic (lasting greater than six months) pain condition that most often affects one limb (arm, leg, hand, or foot) usually after an injury. CRPS may be caused by damage to, or malfunction of, the peripheral and central nervous systems. CRPS is characterized by prolonged or excessive pain and changes in skin color, temperature, and/or swelling in the affected area.

In one embodiment, the present invention provides for an EGFR inhibitor for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, whereby said patient is characterized by a biomarker status of at least two biomarkers selected from the group of BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF, whereby the respective concentrations of the at least two biomarkers in a sample from said patient indicate that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor, if the respective biomarker concentrations in said patient sample for at least one of

(a) BDNF, MDC, MMP9 are below or equal to the respective biomarker threshold values for said biomarkers as disclosed above, or

(b) SCF, MIP1_beta are above or equal to the biomarker threshold values for said biomarkers as disclosed above, and wherein the at least two biomarkers include at least NRG2 and wherein the concentration for the at least one biomarker NRG2 is below or equal to the biomarker threshold value of 8ng/ml in said patient sample.

In one embodiment, the present invention provides for an EGFR inhibitor for use in the treatment of neuropathic pain in patients that are afflicted with analgesic treatment-refractory neuropathic pain that are likely to respond to a neuropathic pain treatment with an EGFR inhibitor based on the status of at least two biomarkers selected from NRG2, BDNF, SCF, MMP9, MIP1_beta and MDC, whereby the at least two biomarkers include NRG2. For example, the EGFR inhibitor for use in the treatment of neuropathic pain according to the invention may be used in patients in which the biomarker status for the at least two biomarkers BDNF and NRG2, MDC and NRG2, MMP9 and NRG2, MIP1_beta and NRG2, or SCF and NRG2 as determined in a sample from said patient indicate that said patient is likely to respond to the neuropathic pain treatment with an EGFR inhibitor. The respective biomarker threshold values for the inventive biomarkers may e.g. be determined as disclosed above by means of an ELISA, or by a bead-based assay, whereby the individual biomarker threshold values may e.g. be as disclosed above. Accordingly, the EGFR inhibitor for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention may e.g. be used in patients characterized by a biomarker status of <8ng/ml NRG2 and <3ng/ml BDNF, <8ng/ml NRG2 and <300pg/ml MDC, <8ng/ml NRG2 and <200ng/ml MMP9, <8ng/ml NRG2 and >200pg/ml SCF, <8ng/ml NRG2 and >1 10pg/ml MIP1_beta as determined in a sample from said patient and which indicates that said patient is likely to respond to said analgesic treatment-refractory neuropathic pain treatment with said EGFR inhibitor. The above biomarkers according to the invention may e.g. be determined separately by means of commercially available ELISA or bead-based assays, whereby the biomarker concentration or abundance may be determined in parallel, or separetly using a bead-based assay such as e.g. Luminex® xMAP. Depending on the number of samples to be analyzed a bead-based assay may be preferable as it allows the simultaneous detection of several analytes thereby reducing the amount of time required for an analysis. If the respective analyses of the biomarker abundance will be predominantly conducted in a clinical setting it may e.g. be preferable to use assay systems which are commonly used in clinical routine such that the analysis of the biomarker status of a patient afflicted with neuropathic pain as disclosed herein can be readily carried out without the need to send the patient samples to specialized laboratories which will results in lower costs. If required by national regulations the analysis may e.g. also be carried out in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. For example, bead-based assays such as the Luminex® xMAP may be used to determine at least two biomarkers simultaneously, e.g. two, three, four, five or all of the biomarkers disclosed above simultaneously. According to one embodiment, the sample from said patient patient afflicted with neuropathic pain according to the invention as disclosed above is a blood, serum or plasma sample. For example, depending on the assay used to detect the inventive biomarkers in the patient sample, serum, or plasma samples are preferred which may be obtained from a patient’s blood sample by standard precedures as described above.

In one embodiment, the EGFR for use in the treatment of analgesic treatment-refractory neuropathic pain is used in patients characterized by a biomarker status according to the invention as disclosed above and whereby the patient is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^® questionnaire. The average pain intensity according to the invention may e.g. be determined using the numerical rating scale, visual analog scale, or verbal rating scale as disclosed above and the PainDetect® questionnaire as described above.

According to one embodiment, the EGFR inhibitor for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above is selected from the group of anti-EGFR antibodies comprising cetuximab, panitumumab, matuzumab, or necitumumab. Each of the anti-EGFR antibodies is e.g. used at the respective approved dose as indicated on the label of the respective anti-EGFR antibodies, or e.g. as disclosed above.

In one embodiment, the present invention provides for cetuximab for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, wherein the patient is characterized by at least one biomarker selected from the group of BDNF, MDC, MIP1_beta_MMP9, NRG2 or SCF and wherein the concentration of said at least one biomarker is above, or below, or equal to a biomarker threshold value for the respective biomarker in a in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml. For example, cetuximab may be used according to the invention at a dose of 400mg/m² body surface on the first day of each treatment period, whereby the patients afflicted with analgesic treatment-refractory neuropathic pain are characterized by the biomarker status as disclosed above indicating that said patient is likely to respond to a neuropathic pain treatment with cetuximab. For example, cetuximab may be used in the treatment of analgesic treatment-refractory neuropathic pain if the biomarker concentrations of the biomarkers disclosed above in a sample from said patient fall within the biomarker thresholds of <8ng/ml NRG2 and <3ng/ml BDNF, <8ng/ml NRG2 and <300pg/ml MDC, <8ng/ml NRG2 and <200ng/ml MMP9, <8ng/ml NRG2 and >200pg/ml SCF, <8ng/ml NRG2 and >1 10pg/ml MIP1_beta, indicating that the patient is likely to respond to such treatment with cetuximab. In one embodiment, the present invention pertains to cetuximab for use in patients as disclosed above suffering from neuropathic pain, or analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^® questionnaire.

According to one embodiment, the concentration of the inventive at least one biomarker in a sample from said patient is determined at baseline prior to treatment with an EGFR inhibitor. For example, the patient sample from which the concentration of the inventive biomarkers may be determined may e.g. be obtained 14 days, 13 days, 12 days, 1 1 days, 10 days, 9 days 8 days, 7 days, 6 days, 5 days, 4 days, up to 1 , 2, 3 days prior to a treatment with the EGFR inhibitor cetuximab, or e.g. 21 days up to 14 days, 18 days up to 12 days, 14 days up to 10 days, 10 days up to 5 days, 5 days up to 1 day prior to treatment with cetuximab. The concentration of each of the inventive biomarkers may e.g. be determined as disclosed above by means of ELISA, or by bead-based assays which may be single-plexed, or multi-plexed assays.

In one embodiment, the invention pertains to cetuximab for use in a patient characterized by analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire and wherein the patient is characterized by at least one biomarker abundance for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said biomarkers as disclosed above in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker includes NRG2 with an abundance of below or equal to its threshold value of 8ng/ml.

In one embodiment, the present invention provides for panitumumab for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, wherein the patient is characterized by at least one biomarker selected from the group of BDNF, MDC, MIP1_beta_MMP9, NRG2 or SCF and wherein the concentration of said at least one biomarker is above, or below, or equal to a biomarker threshold value for the respective biomarker in a in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml. For example, panitumumab may be used according to the invention at a dose of 6mg/kg i.v. over 60 minutes if up to 1000mg are administered, or over 90 minutes if more than 1000mg are administered on the first day of each treatment period, whereby the patients afflicted with analgesic treatment-refractory neuropathic pain are characterized by the biomarker status as disclosed above indicating that said patient is likely to respond to a neuropathic pain treatment with panitumumab. For example, panitumumab may be used in the treatment of analgesic treatment-refractory neuropathic pain if the biomarker concentrations of the biomarkers disclosed above in a sample from said patient fall within the biomarker thresholds of <8ng/ml NRG2 and <3ng/ml BDNF, <8ng/ml NRG2 and <300pg/ml MDC, <8ng/ml NRG2 and <200ng/ml MMP9, <8ng/ml NRG2 and >200pg/ml SCF, <8ng/ml NRG2 and >1 10pg/ml MIP1_beta, indicating that the patient is likely to respond to such treatment with panitumumab.

In one embodiment, the present invention pertains to panitumumab for use in patients as disclosed above suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^®questionnaire.

According to one embodiment, the concentration of the inventive at least one biomarker in a sample from said patient is determined at baseline prior to treatment with an EGFR inhibitor. For example, the patient sample from which the concentration of the inventive biomarkers may be determined may e.g. be obtained 14 days, 13 days, 12 days, 1 1 days, 10 days, 9 days 8 days, 7 days, 6 days, 5 days, 4 days, up to 1 , 2, 3 days prior to a treatment with the EGFR inhibitor panitumumab, or e.g. 21 days up to 14 days, 18 days up to 12 days, 14 days up to 10 days, 10 days up to 5 days, 5 days up to 1 day prior to treatment with panitumumab. The concentration of each of the inventive biomarkers may e.g. be determined as disclosed above by means of ELISA, or by bead-based assays which may be single-plexed, or multi-plexed assays.

In one embodiment, the invention pertains to panitumumab for use in a patient characterized by analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire and wherein the patient is characterized by at least one biomarker abundance for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said biomarkers as disclosed above in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker includes NRG2 with an abundance of below or equal to its threshold value of 8ng/ml.

In one embodiment, the present invention provides for necitumumab for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, wherein the patient is characterized by at least one biomarker selected from the group of BDNF, MDC, MIP1_beta_MMP9, NRG2 or SCF and wherein the concentration of said at least one biomarker is above, or below, or equal to a biomarker threshold value for the respective biomarker in a in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml. For example, necitumumab may be used according to the invention at a dose of 800mg i.v. over 60 minutes on the first day of each treatment period, whereby the patients afflicted with analgesic treatment-refractory neuropathic pain are characterized by the biomarker status as disclosed above indicating that said patient is likely to respond to a neuropathic pain treatment with necitumumab. For example, necitumumab may be used in the treatment of analgesic treatment-refractory neuropathic pain if the biomarker concentrations of the biomarkers disclosed above in a sample from said patient fall within the biomarker thresholds of <8ng/ml NRG2 and <3ng/ml BDNF, <8ng/ml NRG2 and <300pg/ml MDC, <8ng/ml NRG2 and <200ng/ml MMP9, <8ng/ml NRG2 and >200pg/ml SCF, <8ng/ml NRG2 and >1 10pg/ml MIP1_beta, indicating that the patient is likely to respond to such treatment with necitumumab.

In one embodiment, the present invention pertains to necitumumab for use in patients as disclosed above suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^®questionnaire.

According to one embodiment, the concentration of the inventive at least one biomarker in a sample from said patient is determined at baseline prior to treatment with an EGFR inhibitor. For example, the patient sample from which the concentration of the inventive biomarkers may be determined may e.g. be obtained 14 days, 13 days, 12 days, 1 1 days, 10 days, 9 days 8 days, 7 days, 6 days, 5 days, 4 days, up to 1 , 2, 3 days prior to a treatment with the EGFR inhibitor necitumumab, or e.g. 21 days up to 14 days, 18 days up to 12 days, 14 days up to 10 days, 10 days up to 5 days, 5 days up to 1 day prior to treatment with necitumumab. The concentration of each of the inventive biomarkers may e.g. be determined as disclosed above by means of ELISA, or by bead-based assays which may be single-plexed, or multi-plexed assays.

In one embodiment, the invention pertains to necitumumab for use in a patient characterized by analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire and wherein the patient is characterized by at least one biomarker abundance for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said biomarkers as disclosed above in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker includes NRG2 with an abundance of below or equal to its threshold value of 8ng/ml.

In one exemplary embodiment, the present invention provides for matuzumab for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, wherein the patient is characterized by at least one biomarker selected from the group of BDNF, MDC, MIP1_beta_MMP9, NRG2 or SCF and wherein the concentration of said at least one biomarker is above, or below, or equal to a biomarker threshold value for the respective biomarker in a in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml. For example, matuzumab may be used according to the invention at a dose of 10Omg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, or e.g. at a dose of about 5mg/kg body weight to about 20mg/kg body weight, or from about 7.5mg/kg body weight to about 17.5mg/kg body weight, or from about 10mg/kg body weight to about 15mg/kg body weight, or from about 12.5mg/kg body weight to about 25mg/kg body weight, or from about 2.5mg/kg body weight to about 5mg/kg body weight, 7.5mg/kg body weight, 10mg/kg body weight, 12.5mg/kg body weight, or e.g. at a dose of 50 mg/m², 75mg/m², 100mg/m², 150mg/m², 200mg/m², 250mg/m², 300mg/m², 350mg/m², 400mg/m² body surface whereby the body surface may be calculated according to the Dubois method as disclosed above, whereby matutzumab may e.g. be administered over a period of time of about 20 minutes to about 120 minutes, e.g. 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 1 10 minutes on the first day of each treatment period, whereby the patients afflicted with analgesic treatment- refractory neuropathic pain are characterized by the biomarker status as disclosed above indicating that said patient is likely to respond to a neuropathic pain treatment with matuzumab. For example, matuzumab may be used in the treatment of analgesic treatment-refractory neuropathic pain if the biomarker concentrations of the biomarkers disclosed above in a sample from said patient fall within the biomarker thresholds of <8ng/ml NRG2 and <3ng/ml BDNF, <8ng/ml NRG2 and <300pg/ml MDC, <8ng/ml NRG2 and <200ng/ml MMP9, <8ng/ml NRG2 and >200pg/ml SCF, <8ng/ml NRG2 and >1 10pg/ml MIP1_beta, indicating that the patient is likely to respond to such treatment with matuzumab.

In one exemplary embodiment, the present invention pertains to matuzumab for use in patients as disclosed above suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^®questionnaire.

According to one embodiment, the concentration of the inventive at least one biomarker in a sample from said patient is determined at baseline prior to treatment with an EGFR inhibitor. For example, the patient sample from which the concentration of the inventive biomarkers may be determined may e.g. be obtained 14 days, 13 days, 12 days, 1 1 days, 10 days, 9 days 8 days, 7 days, 6 days, 5 days, 4 days, up to 1 , 2, 3 days prior to a treatment with the EGFR inhibitor matuzumab, or e.g. 21 days up to 14 days, 18 days up to 12 days, 14 days up to 10 days, 10 days up to 5 days, 5 days up to 1 day prior to treatment with matuzumab. The concentration of each of the inventive biomarkers may e.g. be determined as disclosed above by means of ELISA, or by bead-based assays which may be single-plexed, or multi-plexed assays.

In one embodiment, the invention pertains to matuzumab for use in a patient characterized by analgesic treatment-refractory neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire and wherein the patient is characterized by at least one biomarker abundance for BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said biomarkers as disclosed above in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker includes NRG2 with an abundance of below or equal to its threshold value of 8ng/ml.

According to one embodiment, the EGFR inhibitor for use in the treatment of of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above is an oral EGFR inhibitor. Oral EGFR inhibitors for use according to the invention in the treatment of analgesic treatment-refractory neuropathic pain are selected from the group comprising afatinib, erlotinib, gefinitib, lapatinib, neratinib, dacomitinib, rocilentinib, olmutinib, osimertinib, nazartinib, avitinib and PF-06747775. The oral EGFR inhibitors for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention may e.g. be used in their respective approved dosage forms and dosing

In one embodiment, the present invention provides for an oral EGFR inhibitor for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, wherein the patient is characterized by at least one biomarker selected from the group of BDNF, MDC, MIP1_beta_MMP9, NRG2 or SCF and wherein the concentration of said at least one biomarker is above, or below, or equal to a biomarker threshold value for the respective biomarker in a in a blood or plasma sample from said patient indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least one biomarker threshold value for NRG2 is <8ng/ml. For example, the oral EGFR inhibitor according to the invention may be used in the treatment of analgesic treatment-refractory neuropathic pain on the first day of each treatment period, whereby said patients are characterized by a biomarker status as disclosed above indicating that said patients are likely to respond to a neuropathic pain treatment with an oral EGFR inhibitor. For example, the oral EGFR inhibitors according to the invention and as disclosed above may be used in the treatment of analgesic treatment-refractory neuropathic pain if the biomarker concentrations of the biomarkers disclosed above in a sample from said patient fall within the biomarker thresholds of <8ng/ml NRG2 and <3ng/ml BDNF, <8ng/ml NRG2 and <300pg/ml MDC, <8ng/ml NRG2 and <200ng/ml MMP9, <8ng/ml NRG2 and >200pg/ml SCF, <8ng/ml NRG2 and >1 10pg/ml MIP1_beta, indicating that the patient is likely to respond to such treatment with an oral EGFR inhibitor.

In one embodiment, the present invention pertains to an oral EGFR inhibitor for use in patients as disclosed above suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT^®questionnaire.

According to one embodiment, the concentration of the inventive at least one biomarker in a sample from said patient is determined at baseline prior to treatment with an EGFR inhibitor. For example, the patient sample from which the concentration of the inventive biomarkers may be determined may e.g. be obtained 14 days, 13 days, 12 days, 1 1 days, 10 days, 9 days 8 days, 7 days, 6 days, 5 days, 4 days, up to 1 , 2, 3 days prior to a treatment with an oral EGFR inhibitor as disclosed above, or e.g. 21 days up to 14 days, 18 days up to 12 days, 14 days up to 10 days, 10 days up to 5 days, 5 days up to 1 day prior to treatment with an oral EGFR inhibitor. The concentration of each of the inventive biomarkers may e.g. be determined as disclosed above by means of ELISA, or by bead-based assays which may be single-plexed, or multi-plexed assays.

According to one embodiment, the oral EGFR inhibitor of the invention for use in the treatment of analgesic treatment-refractory neuropathic pain as disclosed above is selected from the group comprising afatinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, dacomitinib, rociletinib, olmutinib, osimertinib, nazartinib, PF-06747775.

According to one exemplary embodiment, afatinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at its recommended dose of 40mg once daily. Lower doses may e.g. be used in case of renal impairment of the neuropathic pain patient. According to one exemplary embodiment, erlotinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at its recommended dose of 100mg or 150mg once daily.

According to one exemplary embodiment, gefitinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at its recommended dose of 250mg once daily.

According to one exemplary embodiment, lapatinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at its recommended dose of 1250mg up to 1500mg.

According to one exemplary embodiment, neratinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at its recommended daily dose of 240mg.

According to one exemplary embodiment, dacomitinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at a dose of e.g. 45mg every 12 hours, or e.g. 45mg once daily, or e.g. 90mg once daily, or e.g. 60mg every 12hours, or e.g.120mg once daily.

According to one exemplary embodiment, rociletinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at a dose of e.g. 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 750mg, 800mg, 900mg, 1000mg once daily, or e.g. of 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg to 600mg, 750mg, 800mg 900 mg twice daily, or e.g. of 10Omg to 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg, 750mg, 800mg, 900mg twice daily.

According to one exemplary embodiment, olmutinib (Bl 1482694) for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at a dose of e.g. 800mg twice daily, or e.g. from about 500mg, 550mg, 600mg to about 650mg, 700mg, 750mg, 800mg, 900mg twice daily. According to one exemplary embodiment, osimertinib for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at a dose of e.g. 75mg, 10Omg, 150mg, 200mg to 250mg, 275mg, 300mg, 350mg, 400mg, 450mg, 500mg orally once daily, or e.g. at a dose of 75mg, 10Omg, 150mg, 200mg to 250mg orally twice daily.

According to one exemplary embodiment, PF-06747775 for use in the treatment of analgesic treatment-refractory neuropathic pain according to the invention as disclosed above may be used on the first day of each neuropathic pain treatment cycle at a dose of e.g. 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 200mg to 250mg, 275mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg orally once daily, or e.g. at a dose of 25mg, 50mg, 75mg, 100mg, 125mg,

150mg, 200mg, 250mg, 300mg orally twice daily.

WO 2020/115108 P18-264L PCT/EP2019/083620

EXAMPLES

The following examples are intended to further illustrate the invention. They are not intended to limit the subject matter or scope of the invention thereto.

EXAMPLE 1

Clinical trial

An investigator-initiated, randomized, placebo-controlled, single-dose, double-blind, cross over, phase II POC trial was carried out based on the scheme depicted in Figure 1.

Setting and Patients

The trial was conducted at a regional hospital (Center for Cancer Treatment, Kristiansand) in Norway. Patients were referred by physicians across Norway. Recruitment was facilitated by social media, newspapers and television.

Key eligibility criteria were age > 18 years and definite NP (either CN or CRPS), confirmed by Special Interest Group on Neuropathic Pain guidelines (26) in patients with CN and by “Budapest clinical diagnostic criteria” (Pain. 2010;150(2):268-74) in patients with CRPS. Neuropathic pain (NP) had to be characterized as chronic, irreversible, and treatment refractory, with a duration between six and 30 months. PainDETECT questionnaire Curr Med Res Opin. 2006;22(10):191 1-20 final score > 13/38 with average pain intensity > 6 (0-10 numeric rating scale [NRS]) over the last four weeks and a pattern indicating that the NP was constantly present were required for inclusion. Full eligibility criteria are available at ClinicalTrials.gov (NCT02490436).

Interventions

The trial was divided into 3 periods (see Figure 1 ).

• Period 1 : Patient-reported pain assessments on days -7 to -3 leading up to the first blinded infusion established baseline pain levels. Patients received either one intravenous dose of blinded cetuximab or matching placebo. Treatment was followed by a fourteen-day period of expected response in which primary outcome was assessed on days 4-8. This was followed by a fourteen-day wash-out period ending with establishement of the second baseline (on days -7 to -3) prior to period 2.

• Period 2: All patients crossed over to the alternate treatment, after which outcomes were assessed and a third baseline was established in a corresponding manner. • Period 3: Twenty-eight days after the second blinded infusion, all patients received one dose of open-label cetuximab. The trial ended after a further 30 days of observations.

Periods 1 and 2 provided data for the placebo-controlled assessment of effectiveness of cetuximab, whereas period 3 was intended to provide additional data for exploratory purposes.

Cetuximab and placebo were provided by Merck KGaA through Catalent Pharma Solutions, UK. The solutions were equivalent in terms of fluidic properties and appearance. A dedicated pharmacist was responsible for handling and storage of trial drugs. Cetuximab or placebo was administered on the first day (day 1 ) of each treatment period (see Figure 1 ) at a dose of 400 mg/m².

Standard supportive medications (dexamethasone, dexchlorpheniramine, methylprednisolone, paracetamol and tetracycline) were given with each of the three trial treatments to reduce the risk of infusion-related reactions and the development of acneiform rash. Patients were permitted to continue with both regular and breakthrough pain medications.

Outcomes

The primary objective of this POC trial was to investigate whether a clinically relevant signal supporting the potential therapeutic effectiveness of EGFR-inhibition in NP could be observed. To determine an appropriate sample size, calculations were made based on a primary outcome that would be applicable in a comparable hypothesis-testing trial. This primary outcome was defined as the difference in the mean of average daily NP scores on days 4-8 after treatment with cetuximab versus placebo, compared to baseline.

Secondary and exploratory objectives included assessment of pain and pain interference scores, rates of 30% and 50% reductions in average and worst pain scores, overall health satisfaction, time to improvement of NP, use of pain medication, differences in outcomes between the two pain entities, safety, the association of plasma-biomarkers to therapeutic effect and correlation of allodynia to reported pain.

Assessments

The primary outcome was tested using a 0-10 patient-reported NRS for average daily pain intensity. Secondary outcomes were assessed using the following patient-reported measures: Brief Pain Inventory 3-7 days prior to and 4-8 days following each infusion; health satisfaction seven days after each infusion, 2-hourly 0-10 NRS of“pain right now” for the first 24 hours after each infusion, and daily 0-10 NRS for worst and average pain, and pain medication diary daily throughout the trial.

Allodynia was assessed in the neuropathic pain patients by quantifying the mechanical pain threshold with Semmes-Weinstein nylon monofilaments. Blood for exploratory biomarker analysis was drawn at baseline, prior to each patient’s first treatment.

Adverse events (AEs) were recorded at each patient contact, according to Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0.

Randomization and masking

Randomization was managed by the Frontier Science Scotland (FSS), Amherst, MA, USA. Subjects were randomly assigned (permutated block system), in a non-stratified, 1 :1 ratio, to receive either cetuximab or placebo first. Following randomization, a unique patient identification (ID) was assigned. This ID, without treatment assignment information, was emailed to the trial nurse. The randomization system was also used to email the blinded treatment lot number to the pharmacist, using the unique patient ID. The pharmacist prepared the drug formulations and handed them over to the trial nurse. Patients, investigators, nurses and pharmacists were blinded to treatment assignment and contents of the infusions at all times.

Data management

The trial database was built using an open-source clinical trials management system. A trial nurse, the investigators, and FSS staff entered data into the electronic database. FSS performed periodic on-site monitoring and reviewed all CRF pages. An Independent Data Monitoring Committee (IDMC), comprising scientific, clinical and biostatistical experts with access to unblinded data, reviewed the trial in order to ensure validity and integrity of safety data so that patients were not exposed to undue risk.

Statistics

The purpose of a POC trial is to demonstrate the potential of a new concept rather than to deliver a formal statistical test of a hypothesis. Sample sizes for POC studies are therefore often pragmatic (32). However, for this trial, some formality was conferred by conjecturing a requirement to identify a difference of 2.5 points (equivalent to 1 .25 standard deviations) in the measured pain reduction between treatment and placebo. Assuming 90% power at 10% significance for a two-tailed test, the required sample size was 14 subjects. It was pre-specified that if a patient withdrew or was withdrawn from the trial before completion of primary outcome assessment, an additional patient would be randomized in order to obtain 14 evaluable patients.

The treatment effect of cetuximab compared to placebo was analysed using an analysis of covariance (ANCOVA) model, with patients included as fixed effects and baseline scores as covariates. The five day mean differences in pain from baseline were modelled as a function of treatment, period, patient, and baseline. Percentage reductions in pain across treatments were compared using a Wilcoxon rank sum test, accounting for period (Koch’s adaption). Dichotomized pain reductions were analysed using McNemar’s test. The sensitivity of the signal was assessed by excluding patients who, retrospectively, were considered to have insufficient pain at baseline, and by using an area under the curve (AUC) analysis, of the 14 days following treatment.

The mean daily pain scores were plotted by treatment type and point estimates of the effects were plotted with 90% confidence intervals. 30% and 50% reductions in pain scores were plotted by treatment. The correlation between monofilament testing and recorded pain scores was calculated. A simple bio-marker analysis was performed. Unless otherwise stated, analyses were performed on a modified-ITT basis (see Figure 2), using SAS version 9.3 and R version 3.2.2.

Trial management

The trial was managed by three oncologists (CK, MC, SM) and two trial nurses. FSS, an independent non-profit academic foundation contributed to protocol development, managed randomization and secured blinding, built, maintained and quality controlled the database, managed the IDMC, performed statistical analyses and participated in writing this report. Merck KGaA provided trial medication and placebo and a grant used exclusively for the conduct of the trial. The trial was registered at ClinicalTrials.gov (NCT02490436) and approved by the Norwegian Regional Committees for Medical and Health Research Ethics (REK # 2015/618), by Sorlandet Hospital institutional review board, and by the Norwegian Medicines Agency (EudraCTnr 2015-001 195-21 ). The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Results

Fifteen patients (eight with CN, seven with CRPS) were randomized between 12/2015 and 08/2016 and this is shown in Figure 2. One patient was removed from the trial in period one due to a grade 2 allergic reaction to cetuximab. This patient was replaced, as per protocol, and with the exception of the CONSORT diagram and safety report, is not included in any of the results.

Baseline data (Figure 3) and results for the evaluable and per protocol-defined modified intention to treat (mITT; n=14) population are shown. Individual patient pain scores can be found in the electronic supplement.

Primary outcome

The primary outcome was evaluable for the 14 patients in the mITT population. Patients reported an adjusted mean reduction in daily average pain scores of 1.73 points (90% Cl 0.80 - 2.66) after the blinded cetuximab infusion, conferring a 1.22 point larger adjusted mean reduction than after the placebo infusion (90% Cl -0.10 - 2.54; p = 0.126), see Figure 4.

Two patients (CN; 003 and CRPS; 007) exhibited insufficient pain scores (<4) prior to the blinded cetuximab infusion for valid testing. Exploratory analyses with these patients’ data sets omitted (’’exploratory population”, Figure 2) strengthened the signal of clinical effectiveness, yielding a 1.70 point difference in mean reduction of NP favoring blinded cetuximab over placebo (90% Cl 0.1 1 - 3.28; p=0.082), see Figure 3.

Secondary outcomes

Eight of the 14 (57%) patients were considered clinical responders, based on a reduction in average daily pain of >50% compared to baseline, for at least one day during the 14 days after a single blinded cetuximab infusion (14% after placebo; p=0.096).

Comparison of baseline scores with the mean daily average pain measured during the fixed assessment period (days 4-8) after blinded treatment yielded > 50% pain reduction in five of 14 (36%) patients (see Figure 4a). This signal was strengthened by limiting analysis to those 12 patients who had undergone valid testing (’’exploratory population”, as shown in Figure 2). In this group, 33% reported a > 50% average daily pain reduction after blinded cetuximab, compared to 0% after placebo; p= 0.045. Furthermore, seven (58%) of the 12 patients that were evaluable in period 3 reported > 50% reduction on the corresponding days after their second infusion of cetuximab, compared to 14% after placebo (Figure 5a), conferring to a pain reduction of 2.77, compared to baseline (90% Cl 1.39 - 4.14), see Figure 4.

Area under the curve (AUC) analysis of average pain scores demonstrated greater pain reduction in the 14 days after treatment with cetuximab than after treatment with placebo (p = 0.078), see Figure 4b. This signal was strengthened by limiting analysis to only those 12 patients who had undergone valid testing of their NP (’’exploratory population”, Figure 2) (p=0.055).

The time course of changes in average pain scores for the three periods (Figure 4b) demonstrates a shorter duration of pain score reduction after placebo compared to either of the active treatments. Only one of 14 patients had their maximum reduction in five-day average pain scores following blinded cetuximab treatment during the window pre-specified for primary endpoint measurement (4-8 days after infusion). Separate displays for patients with CN and CRPS (Figure 4c and 4d) indicate that the maximum response to blinded treatment appeared earlier for patients with CN (day 3) than for those with CRPS (day 14). In each of the two NP entities, four of seven patients were considered clinical responders.

Nine (64%) of 14 patients reported improvement in overall health satisfaction seven days after a single dose of blinded cetuximab, compared to four of 14 patients after placebo.

Patients were treatment-refractory and on stable doses of analgesics at the time of inclusion. Use of rescue pain medication was limited and remained stable during this short cross-over trial, with the notable exception of one clinical responder who demonstrated a particularly dramatic analgesic response and then pain recurrence during the wash-out period (CRPS; 015, see electronic supplement). Of nine patients that used opioids at baseline (Figure 3), one clinical responder (CRPS; 014) discontinued use completely during the trial.

Exploratory monofilament testing was performed in six patients who reported allodynia prior to treatment. There was a negative correlation between mechanical pain threshold and current pain score (r = -0.71 , p < 0.001 ), see electronic supplement.

Baseline levels of selected biomarkers of potential pathophysiological relevance and their association to treatment response can be found in the electronic supplement.

Results of additional predefined secondary outcomes including pain interference and functional scores showed similar trends as results for average pain scores shown in Figure 4. See electronic supplement.

Safety

The IDMC found the trial satisfactory with regard to conduct and safety measurements.

AEs are listed in Figure 6. One patient experienced an anaphylactoid reaction to cetuximab . Two related grade 3 serious AEs (pain recurrence during wash-out and subsequent opioid overdose) occurred, neither of which was associated with cetuximab (see Table 2). Skin rash (n=12) and nausea and vomiting (n=7) were the most frequent AEs reported after blinded cetuximab.

Discussion

Results of this trial support a new concept of NP relief, through EGFR inhibition with cetuximab. It is the first randomized, placebo-controlled clinical trial of an EGFR-I for this indication. Findings are consistent with several reported clinical observations (22-24, 34), and with recent comprehensive research supporting a possible critical role of the EGFR in pain regulation (21 ) (35).

All patients had chronic, severe and therapy-resistant NP. It is therefore clinically relevant that 36% of patients experienced at least 50% reduction in average pain after a single blinded infusion of cetuximab, during the five pre-specified days for primary endpoint assessment (see Figure 4a). Equally encouraging are the 14-day AUC comparisons of average pain scores, favoring blinded cetuximab over placebo. This clinically more meaningful analysis discounts the rigid timing of the trial’s primary endpoint evaluation which in itself is not crucial for establishing a clinical signal of eefectiveness By the same token, the fact that eight of fourteen patients (57%) reported at least 50% reduction in average daily pain for at least one of the 14 days after a single cetuximab infusion is a promising signal among patients with chronic, severe, treatment refractory NP due to difficult- to-treat entities such as CN and CRPS.

The secondary pain intensity, pain interference, function and health satisfaction outcomes consistently reflect the positive impact that pain reduction had on patients’ functionality and overall well-being. Together, these results are encouraging and should be considered in light of the four to ten patients necessary to achieve a 50% pain reduction in one patient with NP using currently available medications (4, 13, 14).

This trial required patients to have an average pain intensity of at least 6 out of 10.(36) Despite this, two patients had inadequate baseline pain scores to allow for valid testing of cetuximab in period 2. Exploratory analyses excluding these two patients (“exploratory population”, Figure 2) therefore give more valid indications of the effectiveness of cetuximab as a treatment for NP.

Pain reduction was consistently greatest after the second infusion of cetuximab (open-label, period 3). While placebo-type responses may have contributed to this, it is important to consider that long-standing pain may induce a cycle of chronicity, requiring longer treatment duration to reach maximum effect. It is therefore tempting to speculate that repeated dosing may have contributed to the greater pain reduction reported in the third period.

Rapid cetuximab-induced pain relief was accompanied by reversal of allodynia in this trial (see electronic supplement). The blood-brain barrier limits cetuximab access to the central nervous system. It is therefore plausible that direct inhibition of pain-related events in peripheral nerves led to pain reduction and that a peripheral mechanism involving the EGFR was crucial in generating the central symptoms of sensitization. The EGFR is known to be expressed in nociceptive sensory neurons and its increased expression there following nerve injury, has been described previously (37, 38). Furthermore, recent preclinical research in rodent NP models fully corroborates the findings of previous clinical observations and this POC trial, by demonstrating the robust anti-hyperalgesic effectiveness of small molecule EGFRIs (21 , 35).

The associations of baseline levels of potential biomarkers with clinical response to cetuximab presented in the electronic supplement are exploratory, but intriguing to examine in larger studies. Some of these, such as brain-derived neurotrophic factor and MMP9 have been implicated in the pathophysiology of NP. Epiregulin, one of the at least 1 1 EGFR ligands, has been shown to be involved in chronic pain syndromes in mouse models. Unfortunately, testing for this ligand in our samples was inconclusive due to unreliable assay performance in humans.

The early, fixed and relatively short duration of measurement of the primary and several secondary outcomes is a shortcoming of this trial. When the trial was planned there was limited knowledge about the timing of the effects of cetuximab when used to target NP. Nadir pain scores following cetuximab infusion were reported both before and after the pre-specified primary outcome assessment window (4-8 days after infusion). As such, only one of the 8 cetuximab clinical responders reported their maximal pain reduction within this window. The two NP entities represented in this trial appeared to display different temporal responses (Figures 4c and 4d), whereby patients with CN responded more rapidly than those with CRPS, possibly reflecting different underlying pathophysiologies. Capture of maximum NP relief as well as functional outcomes may have been optimized by measurement over a longer period, as indicated by the exploratory AUC analyses. Although not a major goal of the trial, the benefit of including patients with different underlying pathophysiologies is that it strengthens generalizability of the concept of EGFR-ls as a treatment option for NP.

The mild to moderate degree of cetuximab-related side-effects reported in this trial are consistent with those described in cancer patients. Oncologists have acknowledged the acceptability of these side effects throughoutmore than ten years of widespread use. Feasibility of EGFR-inhibitors in the setting of severe NP is underlined by the fact that eight of fourteen patients chose to take oral EGFR-inhibitors upon study completion based on their experiences of positive benefit to side-effect ratio during the trial.

The limited sample size precludes generalizability of the trial findings. Future trials testing EGFR-inhibitors in NP should ideally include repetitive dosing of EGFR-ls, longer follow-up and later primary endpoint assessment. Testing should be done in larger and homogenous samples, ensuring sufficiently high baseline pain scores for valid testing of analgesic effect.

Conclusion

Results of the present randomized, placebo-controlled POC trial indicate that EGFR inhibitor may be an important new treatment option for NP. The high response rate among treatment- resistant patients and the magnitude of pain relief seen in those patients who benefited from treatment are encouraging and fully align with new preclinical findings, as well as previous clinical observations.

Biomarker analysis

Method:

Blood for exploratory biomarker analysis was drawn prior to each patient’s first treatment. Samples were immediately centrifuged at 4 °C and plasma fractions divided into aliquots and stored at -80 °C.

The laboratory analysis was performed at the Natural and Medical Sciences Institute, Reutlingen, Germany, using commercially available ELISAs (Epigen, NRG2, NRG3 using kits from LifeSpan, Seattle, USA; Epiregulin using a kit from Abeam, Cambridge, UK; CBL with an ELISA from mybioscoure, San Diego, USA) or ELISAs (BTC, NT-3) and multiplexed Luminex immunoassays (NT-4, HB-EGF, EGF, Amphiregulin, NRG1 beta, TGF-alpha, custom-made multiplex kit) from R&D (Minneapolis, USA). The remaining analytes (AFP, BDNF, CA_125, CEA, CKJMB, EGF ENA_78, FABPJieart, Factor_VII, GH, ICAM_1 , IL1_beta. -6, - 8, -10, - 12p40, -13, -15, -16, -18, IgE, Insulin, Leptin, MCP_1 , MDC, MIP_1_alpha/beta, MMP_3, -9, SCF, TF, TNF-alpha, TPO, TSH, VEGF) were measured using kit components of the multiplexed immunoassay, provided by Myriad RBM, Austin, TX, USA. After dilution with assay diluents human plasma samples were introduced into one of the capture microsphere multiplexes followed by incubation at room temperature for 1 h. Reporter antibodies were added followed by incubation for an additional hour at room temperature. Streptavidin- phycoerythrin solution was added for development and incubated for 1 h at room temperature. For control purposes, calibrators and controls were included on each microtiter plate. Standard curve, control, and sample QC were performed to ensure proper assay performance. Samples were tested in singles. Analysis was performed using a Luminex 100/200 instrument and data were interpreted using the software developed and provided by Myriad RBM.

Result:

The following markers appear to be of special interest for further exploration, based on their pathophysiological relevance and potential associations with the analgesic effect to cetuximab.

Table ES1: 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; ^*Participants with insufficient baseline pain scores (<4) are omitted from this analysis (see Figure 2 in manuscript;“exploratory population’’).

Claims

1 . An in vitro method for predicting the likelihood that a patient suffering from neuropathic pain is likely to respond to a neuropathic pain treatment with an EGFR inhibitor wherein the method comprises determining in a sample obtained from said patient the abundance of at least one biomarker selected from the group comprising BDNF, MDC, MIP1_beta; MMP9, NRG2 and SCF, wherein the abundance of said at least one biomarker above, equal to, or below the threshold value for said at least one biomarker in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

2. Method according to claim 1 , wherein the abundance of said at least one biomarker is determined at baseline prior to treatment with an EGFR inhibitor.

3. Method according to claim 1 or claim 2, wherein the biomarker abundance in the patient sample is determined using a bead-based assay, or by means of an enzyme-linked immunosorbent assay.

4. Method according to any one of claims 1 -3, wherein the at least one biomarker is BDNF and wherein an abundance of BDNF below or equal to its threshold value of 3ng/ml BDNF in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

5. Method according to any one of claims 1 -3, wherein the at least one biomarker is MDC and wherein an abundance of MDC below or equal to its threshold value of 300pg/ml MDC in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

6. Method according to any one of claims 1 -3, wherein the at least one biomarker is MMP9 and wherein an abundance of MMP9 below or equal to its threshold value of 200ng/ml MMP9 in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

7. Method according to any one of claims 1 -3, wherein the at least one biomarker is NRG2 and wherein an abundance below or equal to its threshold value of 8ng/ml NRG2 in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

8. Method according to any one of claims 1-3, wherein the at least one biomarker is MIP1 and wherein an abundance of MIP1_beta equal to or above its threshold value of 1 10pg/ml MIP1_beta in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

9. Method according to any one of claims 1-3, wherein the at least one biomarker is SCF and wherein an abundance of SCF equal to or above its threshold value of 210pg/ml SCF in said patient sample indicates that the patient is likely to respond to a neuropathic pain treatment comprising the administration of an EGFR inhibitor.

10. Method according to any one of claims 1-9, wherein the abundance of at least two biomarkers in said patient sample is determined and wherein the at least two biomarkers comprise NRG2.

1 1. Method according to claim 10, wherein the abundance of at least two biomarkers is determined, wherein the biomarkers include NRG2 and one further biomarker selected from BDNF, MDC, MIP1_beta, MMP9, or SCF.

12. Method according to claim 1 1 , wherein the biomarker abundance of NRG2 and SCF is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of equal to or greather than its threshold value of 210 pg/ml SCF in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

13. Method according to claim 1 1 , wherein the biomarker abundance of NRG2 and BDNF is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of BDNF below or equal to its threshold value of 3ng/ml BDNF in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

14. Method according to claim 1 1 , wherein the biomarker abundance of NRG2 and MDC is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of MDC below or equal to its threshold value of 300pg/ml MDC in said patient sample indicates that said patient is likely to respond a neuropathic pain treatment with an EGFR inhibitor.

15. Method according to claim 1 1 , wherein the biomarker abundance of NRG2 and MIP1_beta is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of MIP1_beta equal to or greater than its threshold value of 1 10pg/ml MIP1_beta in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

16. Method according to claim 1 1 , wherein the biomarker abundance of NRG2 and MMP is determined and wherein a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of MMP9 below or equal to its threshold value of 200ng/ml MMP9 in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

17. Method according to any one of claims 1 -15, wherein the EGFR inhibitor is to be administered by means of infusion.

18. Method according to any one of claims 1 -15, wherein the EGFR inhibitor is an oral EGFR inhibitor.

19. Method according to any one of claims 1 -16, wherein the EGFR inhibitor is panitumumab.

20. Method according to any one of claims 1 -16, wherein the EGFR inhibitor is cetuximab.

21 . Method according to any one of claims 1 -16, wherein the EGFR inhibitor is necitumumab.

22. Method according to any one of claims 1 -16, wherein the EGFR inhibitor is matuzumab.

23. Method according to claim 18, wherein the oral EGFR inhibitor is afatinib.

24. Method according to claim 18, wherein the oral EGFR inhibitor is erlotinib.

25. Method according to claim 18, wherein the oral EGFR inhibitor is gefitinib.

26. Method according to claim 18, wherein the oral EGFR inhibitor is lapatinib.

27. Method according to claim 18, wherein the oral EGFR inhibitor is neratinib.

28. Method according to claim 18, wherein the oral EGFR inhibitor is vandetanib.

29. Method according to claim 18, wherein the oral EGFR inhibitor is dacomitinib.

30. Method according to claim 18, wherein the oral EGFR inhibitor is rocilentinib.

31 . Method according to claim 18, wherein the oral EGFR inhibitor is osinertinib.

32. Method according to claim 18, wherein the oral EGFR inhibitor is nazartinib.

33. Method according to claim 18, wherein the oral EGFR inhibitor is avitinib

34. Method according to claim 18, wherein the oral EGFR inhibitor is PF-06747775.

35. Method according to claim 18, wherein the oral EGFR inhibitor is ASP-8273

36. Method according to any one of claims 1 -34, wherein the patient is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

37. Method according to any one of claims 1 -35, wherein the patient sample is or is derived from a blood or plasma sample from said patient.

38. Method according to any one of claims 1 -36, wherein said neuropathic pain is non- compressive neuropathic pain.

39. Method according to any one of claims 1 -36, wherein said neuropathic pain is toxic neuropathic pain.

40. Method according to any one of claims 1 -36, wherein said neuropathic pain is metabolic neuropathic pain.

41 . Method according to any one of claims 1 -36, wherein said neuropathic pain is traumatic neuropathic pain.

42. Method according to any one of claims 1 -36, wherein said neuropathic pain is autoimmune neuropathic pain.

43. Method according to any one of claims 1 -36, wherein said neuropathic pain is caused by infection.

44. Method according to any one of claims 1 -36, wherein said neuropathic pain is congential or hereditary neuropathic pain.

45. Method according to any one of claims 1 -36, wherein said neuropathic pain is a complex regional pain syndrome (CRPS).

46. Method according to any one of claims 1 -36, wherein said neuropathic pain is cancer induced neuropathic pain.

47. EGFR inhibitor for use in the treatment of neuropathic pain in a patient afflicted with analgesic treatment-refractory neuropathic pain, wherein said patient is characterized by the abundance of at least two biomarkers selected from BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient which is equal to, below or above the respective biomarker threshold values for said at least two biomarkers indicating that said patient is likely to respond to said neuropathic pain treatment, wherein the at least two biomarkers include NRG2 and wherein the abundance of NRG2 is below or equal to its threshold value of 8ng/ml NRG2.

48. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 47, wherein the patient is characterized by a biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2 and a biomarker abundance of BDNF below or equal to its threshold value of 3ng/ml BDNF.

49. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 47, wherein the patient is characterized by biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2and a biomarker abundance of SCF equal to or above its threshold value of 200 pg/ml SCF.

50. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 47, wherein the patient is characterized by biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2and a biomarker abundance of MDC below or equal to its threshold value of <300pg/ml MDC.

51. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 47, wherein the patient is characterized by biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2and a biomarker abundance of MIP1_beta equal to or above its threshold value of 110pg/ml MIP1_beta.

52. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 46, wherein the patient is characterized by biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml NRG2and a biomarker abundance of MMP9 below or equal to its threshold value of 200ng/ml MMP9.

53. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 46-51 , wherein the sample from said patient is a blood or plasma sample.

54. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 46-52, wherein the patient is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

55. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 47-54, wherein the EGFR inhibitor is cetuximab.

56. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 46-53, wherein the EGFR inhibitor is panitumumab.

57. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 46-53, wherein the EGFR inhibitor is matuzumab.

58. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 46-53, wherein the EGFR inhibitor is necitumumab.

59. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 46-53, wherein the EGFR inhibitor is an oral EGFR inhibitor.

60. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is afatinib.

61. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is erlotinib.

62. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is gefitinib.

63. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is lapatinib.

64. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is neratinib.

65. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is vandetanib.

66. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is dacomitinib.

67. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is rocilentinib.

68. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is olmutinib.

69. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is osimertinib.

70. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is nazartinib.

71. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is avitinib.

72. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is PF-06747775.

73. EGFR inhibitor for use in the treatment of neuropathic pain according to claim 59, wherein the EGFR inhibitor is ASP8273.

74. EGFR inhibitor for use in the treatment of neuropathic pain according to any one of claims 47-73, wherein the patient is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

75. Method of treating a patient afflicted with neuropathic pain who is likely to respond to neuropathic pain treatment based on his biomarker status comprising administering to said patient an EGFR inhibitor. (90)

76. Method according to claim 75, wherein the patient’s biomarker status indicating that said patient is a likely candidate to respond to a neuropathic pain treatment with an EGFR inhibitor comprises determining the biomarker abundance of at least one of BDNF, MDC, MIP1_beta_MMP9, NRG2 and SCF in a sample from said patient and wherein the at least one biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml in said patient sample indicates that the patient is likely to respond to said neuropathic pain treatment.

77. Method according to claim 75 or 76, wherein the method comprises determining the abundance of a second biomarker in the patient sample, wherein the second biomarker is selected from the group of BDNF, MDC, MIP1_beta_MMP9, and SCF.

78. Method according to claim 77, wherein biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml and a biomarker abundance of BDNF below or equal to its threshold value of 3ng/ml BDNF in said patient sample indicates that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

79. Method according to claim 77, wherein biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml and a biomarker abundance of SCF greater than or equal to its threshold value of 200pg/ml SCF in said patient sample indicate that said patient is likely to respond to a neuropathic pain treatment with an EGFR inhibitor.

80. Method according to claim 77, wherein biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml and a biomarker abundance of MDC below or equal to its threshold value of 300pg/ml MDC in said patient sample indicate that said patient is likely to respond a neuropathic pain treatment with an EGFR inhibitor.

81 . Method according to claim 77, wherein biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml and a biomarker abundance of MMP9 below or equal to its threshold value of 200pg/ml MMP9 in said patient sample indicate that said patient is likely to respond a neuropathic pain treatment with an EGFR inhibitor.

82. Method according to claim 77, wherein biomarker biomarker abundance of NRG2 below or equal to its threshold value of 8ng/ml and a biomarker abundance of MIP1_beta greater than or equal to its threshold value of 1 10pg/ml MIP1_beta in said patient sample indicate that said patient is likely to respond a neuropathic pain treatment with an EGFR inhibitor.

83. Method according to any one of claims 75-82, wherein the EGFR inhibitor administered to said patient is one of cetuximab, panitumumab, necitumumab, or matuzumab.

84. Method according to any one of claims 75-82, wherein the EGFR inhibitor administered to said patient is one of afatinib, erlotinib, gefitinib, lapatinib, neratinib, vandetanib, dacomitinib, neratinib, rocilentinib, olmutinib, osimertinib, nazartinib, PF- 06747775, or ASP8273.

85. Method according to any one of claims 75-84, wherein the patient is suffering from neuropathic pain with an average pain intensity of >6 in a numerical rating scale from 0-10 and wherein said patient has a baseline score of > 13/38 according to the PainDETECT questionnaire.

86. Method of treating neuropathic pain in a patient according to any one of claims 75-85, wherein the patient is suffering from analgesic treatment-refractory neuropathic pain.

87. Method of treating neuropathic pain in a patient according to claim 86, wherein the neuropathic pain is one of non-compressive neuropathic pain, compressive neuropathic pain, toxic neuropathic pain, metabolic neuropathic pain, traumatic neuropathic pain, autoimmune neuropathic pain, neuropathic pain caused by infection, cancer treatment-induced neuropathic pain, congential or hereditary neuropathic pain and complex regional pain syndrome (CRPS).

88. Method of treating neuropathic pain in a patient according to any one of claims 75-87, wherein the sample from said patient is a blood or plasma sample.

89. Method of treating neuropathic pain in a patient according to any one of claims 75-88, wherein the biomarker values are determined at baseline prior to treatment with an EGFR inhibitor.