Neurokinin-1 receptor antagonism for the treatment of cough in lung cancer

Background: Effective cough treatments are a significant unmet need. Aprepitant blocks substance P at NK-1 receptors and is licensed for chemotherapy-induced nausea and vomiting. We assessed Aprepitant in vagal tissue and a proof of concept trial in lung cancer patients with cough. Methods: In vitro, isolated vagus nerve sections were placed in grease gap recording chambers and depolarization to test solutions measured. A randomised double-blind crossover trial enrolled lung cancer patients with cough who received aprepitant (125mg day 1, 80mg day 2&3) or matched placebo; following a 3 day wash out, patients crossed over. The primary endpoint was awake cough frequency (coughs/hr(c/h)) and patients reported cough severity and impact. Results: Substance P depolarised guinea pig (0.083mV±0.0066, n=5) and human vagus (0.0875mV, n=2). Aprepitant (10µM) reduced substance P depolarisation by 78% in guinea pig (0.0180mV±0.0080) and 94% in human vagus (0.0050 mV). Twenty lung cancer patients enrolled: mean age 66yrs(±7.69); 60% female; 70% ex, 25% current and 5% non-smokers; performance status 0=25%, 1=55% and 2=25%. 80% had non-small cell cancer, 50% advanced stage and 20% were on cancer therapy. Awake cough frequency improved with aprepitant [baseline 15.9c/h(95%CI 10.1-28.3), aprepitant 12.8(8.7-18.8), placebo 16.2(11.3-23.0), p=0.03]. Patients reported improved cough severity [VAS baseline 57.0mm (95% CI 47.4-67.2), aprepitant 40.8(34.3-47.3), placebo 49.8(44.2-55.4), p=0.008] and impact [Manchester Cough in Lung Cancer Scale, p<0.001]. Conclusions: This is the first study to show NK-1 antagonism has anti-tussive effects in lung cancer, with only 3 days treatment. Vagal inhibition may mediate this effect.