Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial

Abstract

ObjectiveTo evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus.DesignRandomised, double-blind, placebo-controlled clinical trial.Setting15 hospitals in Italy and five hospitals in the UK.Participants44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment.Intervention30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1).Primary and secondary outcome measuresThe primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus.ResultsThe trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was −2.78 (SD: 2.64) points in the 30 mg group, −3.04 (SD: 3.06) points in the 10 mg group and −3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity.ConclusionsOrvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible.Trial registration numberEudraCT2013-002763-25.

Neurokinin 1 Receptor Antagonists for Pruritus

“…No significant difference in treatment for moderate-to-severe AD. 70 % improvement in patients with mild AD Phase III RCT Orvepitant Pruritus caused by EGFRI [ 78 ] Oral orvepitant 10 and 30 mg vs placebo once daily 4 weeks 44 Mean NRS score change from baseline to week 4 was − 2.78 points in the 30 mg group, − 3.04 in the 10 mg group and − 3.21 in the placebo group. No significant difference between orvepitant and placebo AEs: related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity Phase II RCT AE adverse event, CT clinical trial, NRS Numeric Rating Scale, RCT randomised controlled trial, SCORAD SCORing of Atopic Dermatitis, WI-VAS Worst Itch-Visual Analogue Scale …”

“…Preclinical data from a Mongolian Gerbil model of scratching behaviour administered with orvepitant found a profound antipruritic effect with the inhibition of hindlimb scratching [ 77 ]. A subsequent randomised, double-blind, placebo-controlled clinical trial was undertaken to evaluate the efficacy of orvepitant for epidermal growth factor receptor inhibitor (EGFRI)-induced pruritus [ 78 ] (Table 3 ). Oral orvepitant, 10 or 30 mg/day, was given for 4 weeks and compared to placebo in 44 patients.…”

“…Oral orvepitant, 10 or 30 mg/day, was given for 4 weeks and compared to placebo in 44 patients. Although orvepitant was safe and well tolerated, there was no significant difference in antipruritic effects as assessed by NRS score between orvepitant and placebo at either dosage [ 78 ].…”

Dermatological side effects of immunotherapy drugs and targeted cancer therapies: Importance of dermatology and oncology collaboration

“…14 A recent study investigating the effectiveness of orvepitant, a neurokinin antagonist, against placebo, did not show improvement in EGFR inhibitor induced pruritus. 16 Seborrheic dermatitis like eruption can be an adverse event of many targeted therapies including EGFR inhibitors, VEGFR inhibitors, and BRAF inhibitors. 17,18 Treatment options are topical antifungals and topical steroids.…”

Emerging Therapeutic Options for Chronic Pruritus

“…Finally, a randomised, placebo-controlled, phase II trial evaluated orvepitant in patients (n = 44) experiencing severe pruritus caused by EGFRIs, revealing no benefits over placebo [71].…”