Efficacy of gefapixant, a P2X₃ antagonist, for lung cancer-related cough: a case report

Abstract

Cough is a frequent symptom accompanied by lung cancer. More potent antitussive treatment for this complex and distressing symptom is required, but anti-cancer chemotherapy cannot fully manage the cough. Inhibition of vagal nerves might control coughing in patients with troublesome lung cancer-related cough and P2X₃ inhibitory therapy may be useful for targeting neuronal function. We report the case of a woman in her late 70s who never smoked and had advanced lung cancer. She visited our hospital complaining of serious deterioration of a non-productive cough. She was diagnosed with relapse of lung cancer, but she requested 2-week anti-tussive therapy before second-line chemotherapy. Gefapixant (P2X₃ antagonist) add-on at a dose of 90 mg/day (45 mg twice daily as the usual dosage in Japan) improved her cough as indicated by an improvement in the visual analog scale for cough from 70 to 20 mm and in the Japanese version of the Leicester Cough Questionnaire from 8.2 to 16.3, despite a deterioration in lung cancer after 2 weeks. There are no current guidelines for cough accompanied by lung cancer; however, our findings suggest that P2X₃ inhibition is a potent therapeutic option for lung cancer-related cough.

Introduction

Lung cancer-related cough is a common and distressing symptom. This cough affects the physical, psychological, and social aspects of life in patients and their families. Previous studies that assessed symptoms accompanying lung cancer showed that nearly 80% of patients complained of cough.^1,2 Another study showed moderate to severe cough in approximately 40% of lung cancer cases, even at the early stages.^1–3 Furthermore, anti-cancer chemotherapy cannot fully manage cough. Recently, P2X receptors were reported to be expressed on tumor cells, and their activation induces cancer-related symptoms including cough. ⁴ Therefore, potent anti-tussive treatment remains an important unmet clinical requirement.^1–3 Gefapixant is a first-in-class P2X₃ antagonist, and has recently become available for use in patients with refractory cough. ⁵ We report a patient with small cell lung cancer who was administered gefapixant and showed a drastic improvement in symptomatic cough, despite the progression of lung cancer.

Case report

A 75-year-old female never-smoker visited our hospital complaining of non-productive cough lasting for 2 weeks, despite receiving 45 mg/day of dextromethorphan. A physical examination showed that she had a height of 146 cm, weight of 41.8 kg, and body mass index of 19.1 kg/m². The patient was not considered to have cough variant asthma because there was no history of wheezing and bronchodilator therapy was ineffective. ⁶ Dextromethorphan 45 mg/day was partially effective and was continued. She had been diagnosed with small cell lung cancer of the anatomical stage TNM IVA (c-T3N3M1a) 6 months previously and completed four cycles of chemotherapy with carboplatin plus etoposide 2 months previously. Her cough did not respond to treatment for bronchial asthma and cough variant asthma, but improved according to the chemotherapy for lung cancer as indicated by an improvement in the visual analog scale (VAS) score (range, 0–100; higher score = worse severity) for the assessment of cough from 100 to 20 mm. ¹ Therefore, we assumed that she was suffering from lung cancer-related cough.

A chest radiograph and computed tomography showed worsening of the involvement of mediastinal lymph nodes and pleural effusion. A tumor marker, pro-gastrin-releasing peptide, increased from 365 pg/mL to 662 pg/mL. She was diagnosed with a relapse of small cell lung cancer and recommended second-line chemotherapy. However, she requested 2 weeks of anti-tussive therapy before initiating second-line chemotherapy. Gefapixant, a P2X₃ receptor antagonist, was added at a dose of 90 mg/day (45 mg twice daily as the usual dosage in Japan) to daily dextromethorphan obtained after the patient’s consent for treatment. After 2 weeks, the VAS score for the assessment of cough improved from 70 to 20 mm. ¹ The Japanese version of the Leicester Cough Questionnaire (range, 3–21; low score = worse severity) also improved from 8.2 to 16.3, despite a deterioration in lung cancer (Figure 1). ⁷ No adverse reactions were observed with gefapixant, including the most frequent adverse reaction, taste problems. ⁵ Our university regulations do not require ethics committee approval, but written informed consent was obtained from the patient regarding the publication of her cancer diagnosis and associated clinical data. The reporting of this study conforms to the CARE guidelines. ⁸

Figure 1.

Clinical course of the patient showing that gefapixant, a newly available P2X₃ antagonist, managed a distressing cough, despite the deterioration in lung cancer. The first Pro-GRP measurement (365 pg/mL) was made before treatment. VAS, visual analog scale; J-LCQ, Japanese version of the Leicester Cough Questionnaire; Pro-GRP, pro-gastrin-releasing peptide; wk, weeks after treatment.

Discussion

We present the case of a patient with small cell lung cancer for whom administration of gefapixant, a P2X₃ antagonist, led to a remarkable improvement in a debilitating cough, despite the deterioration of lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. The morbidity related to chronic cough in patients with lung cancer has been underestimated, despite 40% of those who suffer from lung cancer complaining of moderate/severe cough, even in the early stages of disease, regardless of the histological type.^1–3,9,10 According to the CHEST Guideline and Expert Panel Report, cough is also a major quality of life predictor, despite its lack of resolution by palliative therapy in most cases. ¹ The management of cancer symptomatology is a major component of palliative care because when delivered early, it not only improves the quality of life, but also prolongs survival. ¹¹ Additionally, anti-cancer chemotherapy cannot fully manage cough. ¹¹ Therefore, treatment of lung cancer-related cough remains important. Recently, Smith et al. showed that vagal nerve inhibition can control cough in patients with lung cancer. ¹¹ They also speculated that therapies specifically targeting neuronal function, such as P2X₃ inhibition, may be more effective in patients with lung cancer. ¹¹ Recently, ATP-gated P2X receptors expressed on tumor cells and neurons have been shown to play a vital role in modulating tumor development, invasion, progression, and related symptoms of lung cancer-related symptoms, such as refractory cough. ⁴ P2X₃ receptors are ATP-gated ion channels expressed in afferent neurons, such as vagal C and Aδ fibers related to cough sensitization. ¹² A previous study showed a reduction in objective cough frequency in patients treated with 600 mg gefapixant twice daily compared with placebo. ¹³ However, later clinical trials indicated that the efficacy of gefapixant could be retained at a dose as low as 50 mg twice daily. ¹² Recently, Chuang et al conducted a meta-analysis of randomized, controlled trials and showed that gefapixant at doses ≥45 mg twice daily were effective for reducing the frequency of cough and subjective cough severity, but had an increased risk of treatment-related and taste-related adverse events. ¹² On the basis of these data, we administered gefapixant to our patient who showed a noticeable improvement in her cough, despite the advancement of lung cancer. The dose of gefapixant was 45 mg twice daily, which is the usual dosage in Japan, and it did not show any adverse events including taste-related events. This finding suggests that P2X₃ inhibition is an option for refractory lung cancer-related cough.

There are some limitations to this report. The mechanism of cough may differ according to the lung cancer subtype and the histological type.^6,11 Nevertheless, this report suggests that some cases of lung cancer-related cough can be controlled by P2X₃ inhibition. The intractable cough observed in this patient improved dramatically, despite the deterioration in lung cancer. This is an important reminder that, in clinical practice, the diagnosis of lung cancer may be delayed if intractable cough is superficially investigated.

In summary, we present a case of successful use of gefapixant in managing small cell cancer-related cough. Our findings are important because there are currently no guidelines for targeted therapy of symptomatic lung cancer-related cough, and they provide the basis for prospective studies evaluating this unmet clinical need.