Open access Original research BMJ Open: first published as 10.1136/bmjopen-2019-030114 on 6 February 2020. Downloaded from Neurokinin-1 antagonist orvepitant for EGFRI- induced pruritus in patients with cancer: a randomised, placebo- controlled phase II trial Bruno Vincenzi ,1 Mike Trower ,2 Ajay Duggal ,3 Pamela Guglielmini ,4 Peter Harris ,2 David Jackson ,5 Mario E Lacouture ,6 Emiliangelo Ratti ,2 Giuseppe Tonini ,1 Andrew Wood ,7 Sonja Ständer 8 To cite: Vincenzi B, Trower M, ABSTRACT Strengths and limitations of this study Duggal A, et al. Neurokinin-1 Objective To evaluate the efficacy of orvepitant (10 or antagonist orvepitant for 30 mg given once daily, orally for 4 weeks), a neurokinin-1 EGFRI- induced pruritus ► The RELIEVE 1 study was the first randomised, in patients with cancer: a receptor antagonist, compared with placebo in reducing double- blind, placebo- controlled study of a neuroki- randomised, placebo- controlled the intensity of epidermal growth factor receptor inhibitor nin-1 antagonist for epidermal growth factor recep- phase II trial. BMJ Open (EGFRI)- induced intense pruritus. tor inhibitor- induced pruritus. 2020;10:e030114. doi:10.1136/ Design Randomised, double- blind, placebo- controlled ► Patients reported scores for the primary endpoint of bmjopen-2019-030114 clinical trial. reduction of itch intensity on a daily basis using an ► Prepublication history for Setting 15 hospitals in Italy and five hospitals in the UK. interactive voice response system. this paper is available online. Participants 44 patients aged ≥18 years receiving an ► Effects on sleep and quality of life were also To view these files, please visit EGFRI for a histologically confirmed malignant solid tumour measured. the journal online (http:// dx. doi. and experiencing moderate or intense pruritus after EGFRI ► Itch is a subjective symptom and thus susceptible to org/ 10. 1136/ bmjopen- 2019- treatment. a placebo effect. 030114). Intervention 30 or 10 mg orvepitant or placebo tablets ► The enrolment target was not reached because of recruitment problems in the target population. BV and MT contributed equally. once daily for 4 weeks (randomised 1:1:1). Primary and secondary outcome measures The Received 01 March 2019 primary endpoint was change from baseline in mean http://bmjopen.bmj.com/ Revised 11 December 2019 INTRODUCTION Accepted 13 January 2020 patient- recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary While targeted biological therapies have outcome measures were NRS score, verbal rating increased patient survival for several tumour scale score, Skindex-16 and Leeds Sleep Evaluation types, they are linked with a variety of adverse Questionnaire at each study visit (baseline, weeks 1, events (AE), particularly dermatological 4, 8); rescue medication use; EGFRI dose reduction; AEs, including acneiform rash, hair changes, and study withdrawal because of intense uncontrolled mucositis, xerosis/fissures, paronychia and pruritus. pruritus. Epidermal growth factor receptor on September 30, 2021 by guest. Protected copyright. Results The trial was terminated early because of inhibitors (EGFRI) specifically are associ- recruitment challenges; only 44 of the planned 90 patients ated with these dermatological AEs that were randomised. All patients were analysed for efficacy can require dose modification or treatment and safety. Mean NRS score change from baseline to interruptions and thus interfere with these week 4 was −2.78 (SD: 2.64) points in the 30 mg group, potentially life- prolonging therapies.1–5 Rash, −3.04 (SD: 3.06) points in the 10 mg group and −3.21 (SD: xerosis and pruritus have the greatest impact © Author(s) (or their 1.77) points in the placebo group; the difference between on patient quality of life.5–7 Pruritus inci- employer(s)) 2020. Re- use orvepitant and placebo was not statistically significant. dence reported in clinical trials of anti- EGFR permitted under CC BY-NC. No No safety signal was detected. Adverse events related to monoclonal antibodies (mAb) and small- commercial re- use. See rights orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) molecule EGFRIs ranges from 8% to 69% and permissions. Published by were all of mild or moderate severity. BMJ. depending on the agent involved.8 9 EGFRI- Conclusions Orvepitant was safe and well tolerated. For numbered affiliations see induced pruritus may be under- reported or No difference in NRS score between the orvepitant and end of article. incompletely reported in clinical studies.10 placebo groups was observed at the week 4 primary In a survey of patients with cancer and survi- Correspondence to endpoint. A number of explanations for this outcome are vors, pruritus is common and debilitating.11 12 Dr Mike Trower; possible. Lacouture et al reported that pruritus occurs mike. trower@ nerretherapeutics. Trial registration number EudraCT2013-002763-25. com in approximately half of all patients treated Vincenzi B, et al. BMJ Open 2020;10:e030114. doi:10.1136/bmjopen-2019-030114 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-030114 on 6 February 2020. Downloaded from with EGFRIs.4 Finally, in a review of interviews conducted NK1 antagonist that blocks SP signalling.51–53 These with 100 patients taking mainly EGFR mAbs, 72% of compounds are active in the well-characterised NK1 patients reported experiencing pruritus.13 A safe and receptor pharmacodynamic gerbil foot- tapping model, effective cancer- supportive care therapy to ameliorate in preclinical models of anxiety,51–54 and, as reported the itching burden these patients experience is urgently above, in the gerbil scratching behaviour model.28 29 In needed. humans both compounds have pharmacokinetic prop- Neurokinin-1 (NK1) receptors are 7-transmembrane erties consistent with once-daily oral dosing sufficient receptors with a preferred peptide agonist ligand of to achieve therapeutic plasma exposures that have high substance P (SP).14 SP produced by peripheral skin sensory levels of central NK1 receptor occupancy.55 56 Thus, orve- nerve fibres is thought to promote itching via activation pitant would be expected to achieve antipruritic efficacy of NK1 receptors on keratinocytes and mast cells causing similar to that of aprepitant in patients suffering from local inflammatory and vasodilatory effects.15 Interestingly, intense itch as a result of EGFRI treatment. The RELIEVE Gerber et al reported that mast cells significantly accumu- 1 study evaluating the efficacy and safety of orvepitant is late in the lesional skin of patients treated with EGFRIs and the first randomised, double- blind, placebo- controlled suggested that the antipruritic activity of the NK1 receptor study of an NK1 antagonist for EGFRI- induced pruritus. antagonist aprepitant in this population is achieved by blocking the activation of mast cell NK1 receptors by SP, METHODS thereby preventing the release of mast cell histamine Patient and public involvement and other proinflammatory/pruritogenic mediators.16–18 The indication, research questions and study endpoint Recently, another receptor, the Mas- related G- protein outcome measures were selected based on the authors’ coupled receptor member X2, has been shown to be acti- expert understanding in the care of affected patients, vated in humans by SP, and this interaction may contribute their needs and therapy preferences, without direct additionally to the proinflammatory effects mediated by communication of the study design to patients. Expe- mast cell degranulation.19 SP and the NK1 receptor are rience from guideline work, which involved patients’ also widely expressed centrally and have a role in transmis- preferences, was also carried over into the study design. sion of the peripheral itch signal via the spinal superficial Patients were not involved in the recruitment nor conduct dorsal horn to higher brain centres for processing.20 In of the study, nor the interpretation of results. No commit- rodents scratching behaviour can be blocked by neuro- ment was made to disseminate the results to study partic- toxic destruction of spinal NK1 receptor-expressing ipants. Patients assessed the burden of the intervention neurons,21 22 and Tac1 (the gene encoding SP)-expressing themselves. Patients were not invited to contribute to the spinal neurons have also been linked to the promotion writing nor editing of this document for either readability of scratching behaviour.23 Intradermal injection of SP or accuracy. in humans causes pruritus, erythema and oedema.24–26 http://bmjopen.bmj.com/ Study design and enrolment Scratching behaviour induced by intradermal injection The primary objective of this exploratory phase II, multi- of either SP or an NK1 agonist or topical administration centre, randomised, double- blind, placebo- controlled of a hapten in animals can all be profoundly reduced by clinical trial was to evaluate the efficacy of orvepitant NK1 antagonist treatment, including both orvepitant and compared with placebo in reducing the intensity of aprepitant.27–30 These data suggest that the NK1 receptor intense EGFRI- induced pruritus. Pruritus intensity was system is involved in itch signalling and therefore blockade measured primarily by change from baseline in patient- of these pathways with NK1 receptor antagonists represents recorded numerical rating scale (NRS) score ranging on September 30, 2021 by guest. Protected copyright. a potentially promising therapy for pruritic conditions, from 0 (no itch) to 10