Boston, MA–In a first-of-its-kind study, aprepitant (Emend), a centrally acting neurokinin (NK)-1 antagonist indicated for the treatment of chemotherapy-induced nausea and vomiting (CINV), led to a reduction in cough frequency and an improvement in the objective and subjective measures of cough in patients with lung cancer. The study was conducted in the United Kingdom and was presented at the 2015 Palliative Care in Oncology Symposium. In September 2015, aprepitant capsules received an expanded indication for CINV in combination with other antiemetic therapies for use in patients aged ≥12 years and those aged <12 years who weigh at least 30 kg.
"Cough is a complex symptom that has a significant impact on the quality of life of patients, and it is very severe in lung cancer patients," said Amelie Sylvia Mary Harle, MD, PhD, a medical oncologist at the Christie NHS Foundation Trust, Manchester, England.
Approximately 50% of patients with lung cancer report that their cough is severe enough to warrant treatment, and approximately 25% report a painful cough that affects their quality of life.
"The neuronal pathways that control cough are complex," said Dr Harle. "They involve the peripheral nervous system and the central nervous system, but our understanding of these complex pathways is beginning to emerge."
Currently, no evidence-based therapies exist for the treatment of cough in patients with lung cancer. However, the NK-1 pathway is implicated in cough, and aprepitant is a centrally acting NK-1 antagonist currently indicated for the treatment of CINV.
According to Dr Harle, centrally acting NK-1 receptor antagonists have never been tested as a novel antitussive agent in humans, so she and her coinvestigators sought to assess aprepitant's capability to act as an antitussive, using objective daytime ambulatory cough monitoring as the primary end point.
Overall, 20 patients were examined (mean age, 66 years). Of these, 70% were former smokers, 25% current smokers, and 5% never-smokers; 16 had non-small–cell lung cancer, 10 had advanced-stage disease, and 4 were receiving anticancer therapy.
"We used a crossover design to enable a small sample size, because cough varies so much between individuals, and we wanted patients to act as their own controls," said Dr Harle.
The participants received 125 mg of aprepitant on day 1 and 80 mg on days 2 and 3 or matched placebo, after which all the assessments were repeated. After a 3-day washout, patients crossed over to alternative treatment of aprepitant or to placebo for 3 days (days 7-9). The assessments were again repeated, and a toxicity assessment was performed at days 13 to 14.
The primary end point was the comparison of change from baseline in daytime cough counts for aprepitant versus for placebo. "This outcome measure was an objective quantification of cough, using cough recordings from which we could develop a cough frequency," said Dr Harle. The secondary end point was the comparison of change from baseline in cough scores. "These were the subjective assessments, using validated cough questionnaires and standard oncology tools assessing cough," she added.
Significant Reduction in Cough Frequency
"Aprepitant led to a statistically significant reduction in cough frequency," Dr Harle reported. The daytime cough frequency was 15.9 coughs per hour at baseline, 12.8 with aprepitant, and 16.2 with placebo (P = .03). A significant reduction in all cough scores was also demonstrated.
"Regarding the subjective measures, the effect was modest, but interestingly, patients were able to report a difference in all 4 of the measurements that we used," Dr Harle stated. "Even the physician-rated scale, which is quite a blunt instrument, showed improvement."
The adverse events were minimal, and the investigators found aprepitant to be well-tolerated.
This trial is the first to measure the efficacy of aprepitant as a novel antitussive using validated subjective and objective cough measurements in patients with lung cancer. It is also the first trial to investigate a centrally acting NK-1 antagonist in humans. Treatment with aprepitant was associated with significant improvements in objective and subjective scores, suggesting that the NK-1 pathway may be a key component of cough mechanisms in patients with lung cancer.
"We hope these data will inform the design of a definitive trial in the future," said Dr Harle.