Aprepitant for Cough Suppression in Advanced Lung Cancer

Journal Pre-proof Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial Vanita Noronha, American Board Certified in Hematology and Medical Oncology, Atanu Bhattacharjee, PhD, Vijay M. Patil, DM, Amit Joshi, DM, Nandini Menon, DNB, Srushti Shah, PDCR, Sadhana Kannan, M Sc, Sadaf A. Mukadam, M Tech, Kamesh Maske, MBA, Sandeep Ishi, DM, Kumar Prabhash, DM PII:

S0012-3692(20)30032-5

DOI:

https://doi.org/10.1016/j.chest.2019.11.048

Reference:

CHEST 2814

To appear in:

CHEST

Received Date: 16 July 2019 Revised Date:

24 November 2019

Accepted Date: 25 November 2019

Please cite this article as: Noronha V, Bhattacharjee A, Patil VM, Joshi A, Menon N, Shah S, Kannan S, Mukadam SA, Maske K, Ishi S, Prabhash K, Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial, CHEST (2020), doi: https://doi.org/10.1016/j.chest.2019.11.048. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020 Published by Elsevier Inc under license from the American College of Chest Physicians.

Title: Aprepitant for Cough Suppression in Advanced Lung Cancer: A Randomized Trial

Running title: Aprepitant for cough in lung cancer

Author names: 1. Vanita Noronhaa, American Board Certified in Hematology and Medical Oncology 2. Atanu Bhattacharjeeb, PhD 3. Vijay M. Patila, DM 4. Amit Joshia, DM 5. Nandini Menona, DNB 6. Srushti Shaha, PDCR 7. Sadhana Kannanb, M Sc 8. Sadaf A. Mukadama, M Tech 9. Kamesh Maskec, MBA 10. Sandeep Ishid, DM 11. Kumar Prabhasha, DM

Affiliation list: a: Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India; Homi Bhabha National Institute, India 1

b: Department of Biostatistics, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India; Homi Bhabha National Institute, India c. Current affiliation: Medical officer, Marine Medical Services, Mumbai. (However, affiliation while doing the work related to the current manuscript was Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India; Homi Bhabha National Institute, India) d. Current affiliation: Consultant medical oncologist, NIMS Hospital, Nashik; Khandesh Cancer Center, Dhule; Apex Wellness Hospital, Nashik, India (However, affiliation while doing the work related to the current manuscript was Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India; Homi Bhabha National Institute, India)

Corresponding author: Dr. Kumar Prabhash Professor and Head, Department of Medical Oncology, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai-400012 India Homi Bhabha National Institute, India Email Id: [email protected]

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Phone number: 022-2417-6796

Funding: This work was supported by an intramural grant from the Tata Memorial Center Research Administrative Council (TRAC) [grant number not applicable], a grant from the Indian Cooperative Oncology Network [grant number not applicable], and an unrestricted educational grant from Glenmark Pharmaceuticals Ltd. [grant number not applicable]. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.

Disclosures: •

Dr. Vanita Noronha has received research funding from Amgen, Sanofi India Ltd., Dr. Reddy’s Laboratories Inc., Intas Pharmaceuticals and Astra Zeneca Pharma India Ltd. (all research grants paid to the institution).

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Dr. Kumar Prabhash has received research funding from Dr. Reddy’s Laboratories Inc., Fresenius Kabi India Pvt. Ltd., Alkem Laboratories, Natco Pharma Ltd., BDR Pharmaceuticals Intl. Pvt. Ltd, and Roche Holding AG (all research grants paid to the institution).

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All remaining authors have declared no conflicts of interest.

ABBREVIATIONS LIST:

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1. CTCAE: Common Terminology Criteria for Adverse Events. The Common Terminology Criteria for Adverse Events are a set of criteria for the standardized classification of adverse effects of drugs used in cancer therapy. The CTCAE system is a product of the US National Cancer Institute. 2. ECOG PS: Eastern Cooperative Oncology Group performance status. A scoring system to help determine the activity and fitness level of the patient. A higher score indicates more morbidity and less activity/ fitness level. 3. EORTC QLQ-C30 and QLQ-LC13: EORTC: European Organisation for Research and Treatment of Cancer. The EORTC has developed various validated quality of life questionnaires, including the general QLQ-C30 questionnaire and the lung-specific QLQ-LC13 questionnaire. The QLQ-C30 questionnaire consists of thirty questions, including five multi-item functioning scales (physical, role, social, emotional and cognitive functioning), nine symptom scales (pain, fatigue, nausea/ vomiting, constipation, sleep, appetite, dyspnea and financial impact) and two items that measure overall health/ QoL. The QLQ-LC13 is the lung cancer specific module that has thirteen questions related both to symptoms of lung cancer (cough, hemoptysis, dyspnea, pain) and side-effects of chemotherapy and radiation (mucositis, dysphagia, alopecia and neuropathy). Responses to most questions range from 1 (not at all) to 4 (very much). 4. MCLCS: A questionnaire consisting of ten questions that describe the patient’s cough experience in the preceding week; each question has five possible answers scored as one (never) to five (all the time); score range: 10-50. A high score indicates worse cough impact. 5. NK1: Neurokinin 1. Neurokinin 1 receptor inhibitors are used in oncology for the management of nausea and vomiting. 4

6. QOL: Quality of life. A standard term in oncology and in general life, that indicates the perception of the person regarding his/ her expectations and what he/ she actually is experiencing in terms of how rich and fulfilling his/ her life is and what specific symptoms he/ she has. 7. TMC: Tata Memorial Center, a tertiary level oncology teaching hospital in Mumbai, India. 8. VAS: The Visual Analog Scale, a scale to assess the cough severity. The scale consists of a straight-line measuring 100mm, range is 0 to 100 mm. One end of the line is labelled, ‘No cough (0 mm)’ and the other end is labelled ‘Worst cough ever (100 mm)’. The patient marks a point on the line that best signifies how severe his/ her cough is. A high score signifies worse cough severity.

Abstract Background: Although cough is a common and distressing symptom in lung cancer patients, there is almost no evidence to guide management. Aprepitant, a centrally acting neurokinin-1 inhibitor, significantly decreased cough frequency in a pilot study. Methods: Patients with advanced lung cancer and cough lasting over two weeks despite a cough suppressant, were randomized 1:1 to aprepitant 125 mg orally on day one then 80 mg orally on days two to seven with physician’s choice of antitussive; or to physician’s choice of antitussive alone. Evaluation was at baseline and on days three, seven, nine and twelve. Primary endpoint was subjective cough improvement on day nine, measured by the Visual Analog Scale (VAS) and Manchester Cough in Lung Cancer Scale (MCLCS). Secondary endpoints included quality of life (QoL) as measured by the EORTC QLQ-C30 and QLQLC13 and toxicity.

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Results: Between 2017 and 2018, 128 patients were randomized. Median baseline cough duration was 90 days. Mean VAS scores (in mm) at baseline and day nine were 68 and 39 in the aprepitant arm and 62 and 49 in the control arm respectively, P<0.001; Mean MCLCS scores at baseline and day nine were 33 and 23 in aprepitant arm and 30 and 25 in control arm, P<0.001. Overall QoL was not significantly different between the two arms, however aprepitant led to a significant improvement in the cough-specific QoL domain, P=0.017. Aprepitant did not increase severe adverse events. Conclusions: Aprepitant led to a significant improvement in cough in advanced lung cancer, without increasing severe side-effects. Clinical Trial Registration: Clinical Trials Registry-India, registration number: CTRI/2017/05/008691, available at http://ctri.nic.in

Key words: MCLCS neurokinin Repurposing Antitussive NSCLC Cough

TEXT: Introduction: 6

Cough occurs in 27 to 86% of patients with lung cancer.1 Despite being so common, there is no robust evidence to guide management. In 2017, the American College of Chest Physicians updated the CHEST guidelines for cough management in adult lung cancer patients.2 They recommended identification and treatment of any contributing etiology, cough suppression exercises and endobronchial brachytherapy for a localized lesion causing cough. In patients who required medication, they recommended a stepwise pharmacologic approach starting with demulcents like linctus, then opioids, followed by peripherally acting antitussives like sodium cromoglycate, local anesthetics like benzonatate or nebulized lidocaine, and finally a therapeutic trial of drugs like gabapentin, diazepam, carbamazepine, baclofen, amitriptyline and thalidomide. The committee concluded that the evidence was low quality and there was an urgent need for randomized studies. Aprepitant is a neurokinin 1 (NK1) inhibitor approved for the treatment of chemotherapyinduced nausea and vomiting.3 The antiemetic effect of aprepitant is via blockade of the effects of substance P.4 Substance P has also been implicated in the cough reflex.5 An initial pilot study suggested that aprepitant improved cough in lung cancer patients.6 Cough severity in lung cancer patients usually parallels tumor control. Patients with a good response to systemic therapy have resolution of cough. Thus, the interpretation of the effect of an antitussive medication becomes difficult in patients on systemic therapy. Most patients diagnosed with lung cancer have an initial waiting period of 10 to 14 days for molecular testing prior to the start of systemic therapy.7 This provided us a window of opportunity to test the efficacy of aprepitant for cough. We thus designed a randomized controlled trial to test the efficacy of aprepitant versus physician’s choice of cough medication in patients with advanced lung cancer and cough.

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Materials and methods: Trial design We conducted the trial at Tata Memorial Center (TMC), a tertiary oncology teaching hospital in Mumbai, India. The study was approved by the institutional ethics committee (Institutional Ethics Committee-II of Tata Memorial Center, project number 1841) and monitored by the data safety monitoring sub-committee. All patients provided written informed consent. The trial was conducted according to principles laid down by the International Conference on Harmonization Good Clinical Practice guidelines, Declaration of Helsinki, Schedule Y (Drugs and Cosmetic Act 1940) and guidelines established by the Indian Council of Medical Research. The trial was registered at Clinical Trials Registry-India, registration number: CTRI/2017/05/008691, available at http://ctri.nic.in.

Study population Patients were recruited from the thoracic medical oncology outpatient department of TMC. Eligibility criteria included a diagnosis of advanced lung cancer and cough that had persisted for over two weeks despite a cough suppressant. Patients had to be over 18 years old with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2. Patients were excluded if they were taking aprepitant or pimozide.

Random assignment Patients were randomly assigned 1:1 to aprepitant with physician’s choice of cough medication or physician’s choice of cough medication alone. A permuted block randomization with variable block sizes of 2 or 4 was generated using Stata version 14 ralloc.ado v3.5.2 (Stata Corporation, USA). All study investigators were blinded to block

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size, and sequence in the block. Randomization was carried out by an independent statistician at the Clinical Research Secretariat, TMC.

Study Procedures Aprepitant 125 mg was administered orally on day one followed by 80 mg orally daily on days two to seven. Patients in both arms received physician’s choice of cough medication, dosed according to instructions in the package insert. Baseline routine blood testing included a complete blood count, liver and renal function tests and serum electrolytes. Patients were evaluated for symptomatology and toxicity at baseline and on days three, seven, nine and twelve. Cough was assessed by the Visual Analog Scale [VAS, range 0 to 100 mm; one end labelled, ‘No cough (0 mm)’ and the other end labelled ‘Worst cough ever (100 mm)’; high score signifies worse cough severity]8 and the Manchester Cough in Lung Cancer Scale [MCLCS, a questionnaire consisting of ten questions that describe the patient’s cough experience in the preceding week; each question has five possible answers scored as one (never) to five (all the time); score range: 10-50; high score indicates worse cough impact].9 Both VAS and MCLCS were filled out by the patients, with help from trained research coordinators and social workers. Quality of life (QoL) was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, v.3.0 and QLQ-LC13.10 The QLQ-C30 questionnaire consists of thirty questions, including five multi-item functioning scales (physical, role, social, emotional and cognitive functioning), nine symptom scales (pain, fatigue, nausea/vomiting, constipation, sleep, appetite, dyspnea and financial impact) and two items that measure overall health/QoL. The QLQ-LC13 is the lung cancer specific module that has thirteen questions related both to symptoms of lung cancer (cough, hemoptysis, dyspnea, pain) and side-effects of chemotherapy and radiation (mucositis, dysphagia, 9

alopecia and neuropathy). Responses to most questions range from 1 (not at all) to 4 (very much). Patients filled out the MCLCS, VAS, QLQ-C30 and QLQ-LC13 at baseline and at each visit. Toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE), v.4.03.

Study endpoints Our primary objective was to determine if aprepitant led to a subjective improvement in cough, i.e. decrease in cough severity measured by VAS and decrease in cough impact measured by MCLCS on day nine. Secondary objectives included the effect of aprepitant on QoL as measured by the EORTC QLQ-C30 and QLQ-LC13, the pattern of change in VAS and MCLCS scores on days three, seven and twelve and adverse events.

Statistical analysis We planned for a sample size of 128 patients, which would provide 80% power to detect a significant between-group difference in the change in cough severity and impact as measured by VAS and MCLCS, with a type 1 error of 5% and a medium effect size of 0.5 standard deviation (SD) between baseline and day nine. Analysis was performed using SPSS software, version 20 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) and R Project for Statistical Computing, version 3.6.1[R Core Team (2019). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, URL http://www.R-project.org/]. Demographics, clinical details and toxicity were presented with descriptive statistics, using

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absolute numbers and simple percentages. Analysis was according to the modified intentionto-treat principle; since our primary endpoint required the patient to have completed the subjective cough evaluation forms at baseline and on day nine, we used the ‘full analysis set’ and excluded patients for whom day nine data were not available.11,12 To measure cough severity, the VAS score on day nine was subtracted from the baseline score. The means of the change from baseline scores were calculated for all patients in each arm and the means were compared between the two arms using two-sided Student’s t-test. A P value of <0.05 was considered significant. The effect size was determined with the use of Cohen’s d statistic, which is a measure of the difference between two means divided by an estimate of a pooled standard deviation. As per conventional classification, an effect size of 0.2 was considered small, 0.5 moderate, and 0.8 large.13 Similar methodology was used to evaluate the cough impact using MCLCS. The change in VAS and MCLCS scores from baseline to days three, seven, nine and twelve were explored graphically between the arms. QoL data were scored as per the procedure described in the EORTC scoring manual.14,15 Different subdomain wise QoL data were generated from the QoL dataset. A subdomain wise comparison was performed between the arms, using the linear mixed effect model. The difference in toxicities between the two arms was compared using the Pearson chi-square test or Fisher Exact test. We used complete-case analysis to handle missing data, i.e. the missing observations were excluded from the analysis.16

Results Patients

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Between June 2017 and June 2018, we randomized 128 patients, 64 to each arm. Details of patient enrollment, allocation, therapy and analysis are provided in Fig 1. Pertinent demographics and baseline information are included in Table 1.

Therapy for cough Patients in both arms received physician’s choice of cough medication; additionally, patients in the aprepitant arm received aprepitant. For any patient whose cough was not controlled, another antitussive could be added. Cough medications used were combinations of drugs with varying mechanisms of action.17 Based on the predominant active medication, we classified the cough medications as narcotic derivatives, expectorants/mucolytics, adrenergic blockers or antihistamines. Some patients were started on additional medications like bronchodilators, steroids (for brain metastases), antibiotics and opioids (codeine or morphine for pain), which may have affected the cough severity. Details of the medications prescribed are provided in Table 2.

Cancer-directed therapy In 63 (50%) patients, systemic therapy was started while they were on study, 29 (45%) in the aprepitant arm and 34 (55%) in the control arm, P=0.48. The median time to start of systemic therapy was eight days (IQR, 7 to 10).

Efficacy outcomes:

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Two patients (both in control arm) defaulted after initial randomization; they have been excluded from the efficacy analysis. One patient in each arm did not return for day three assessment but returned for subsequent assessments. Thus, 63 patients (98%) and 61 patients (98%) completed day three assessments in the aprepitant and control arms respectively. On days seven, nine and twelve, the corresponding numbers were 55 (86%) and 56 (90%), 50 (78%) and 45 (73%), and 47 (73%) and 50 (81%) respectively. The VAS and MCLCS scores are provided in e-Table 1. The mean baseline VAS scores were 67.68 mm and 62.2 mm in the aprepitant and control arms respectively. By day nine, these values decreased in both arms to 38.5 mm and 48.57 mm respectively with a difference of mean score change from baseline of -15.55; 95% CI, -11.94 to -19.15; P<0.001; effect size, 0.86 SD (large effect size). The absolute difference in mean VAS score from baseline to day nine in the aprepitant arm was 29.18 mm, which was greater than the accepted minimal important difference (MID) of 17 mm18; the difference in the control arm was 13.63 mm (Figure 2). Similarly, MCLCS scores also decreased in both arms from baseline to day nine, with a greater magnitude of decrease in the aprepitant arm (Figure 3). Details of the QoL analysis are provided in e-Table 2. There was no difference in the overall QoL and in the various domains except for the LCCO, the cough-specific domain of the lung cancer QoL module, in which there was a significant improvement in the aprepitant arm (Figure 4).

Grade of cough and subjective cough improvement: At the start of the study, 0, 60 (94%) and 4 (6%) patients in the aprepitant arm and 1 (2%), 55 (86%) and 7 (11%) patients in the control arm had grades 1, 2 and 3 cough respectively. At the end of study, 1 (2%), 29 (45%), 28 (44%) and 3 (5%) patients in the aprepitant arm and 2 13

(3%), 18 (29%), 35 (57%) and 3 (5%) patients in the control arm had no, grade 1, 2 and 3 cough respectively. The percentage of patients who had a decrease of at least one grade in their cough from baseline to end of study was 50% in aprepitant arm and 35% in control arm, P=0.058.

Adverse events: All patients who started on trial and returned for even one visit have been included in the adverse events analysis. Thus, 125 patients were included in the adverse events analysis, excluding the two patients (control arm) who defaulted after randomization and one patient (aprepitant arm) whose hospital file was missing. 19 patients (15%) experienced grade 3 or higher adverse events, 9 (14%) in aprepitant arm and 10 (16%) in control arm. Severe adverse events were possibly contributed to by the underlying lung cancer and comorbidities and included hyponatremia (aprepitant-3, control arm-5), asymptomatic hypertension (aprepitant arm-2, control arm-4); diarrhea (1), fatigue (1) and anemia (2) in aprepitant arm and transaminase elevation (1) in control arm. Detailed adverse events are provided in the eTable 3.

Discussion To the best of our knowledge, ours is the first randomized trial to demonstrate the benefit of a cough medication in patients with advanced lung cancer. Aprepitant improved cough in patients with advanced lung cancer as evidenced by a significant decrease in cough severity and cough impact. This improvement was also seen in the cough domain of the QoL. The decrease in the cough parameters occurred as early as day three and continued to decrease at subsequent timepoints, until day twelve, the end of the study period. Thus, the onset of action 14

of aprepitant as a cough suppressant, was relatively quick and the effect was sustained over time. Aprepitant represents a new therapeutic option for patients with advanced lung cancer and cough that is not controlled by standard cough medications. With an exponential improvement in survival in advanced lung cancer, focus on QoL and effective symptom control becomes important. The pharmacological management of cough is empiric and not guided by robust evidence.19 Codeine, the most commonly prescribed antitussive once standard over-the-counter cough syrups have failed, is no more effective than placebo in chronic cough caused by upper respiratory tract disorders or chronic obstructive pulmonary disease.20-22 A recent study reported that gabapentin is effective in chronic refractory cough.23 There is practically no evidence for management of cough in lung cancer.2,24,25 Harle and colleagues conducted a pilot study of aprepitant in twenty lung cancer patients with bothersome cough.6 Aprepitant led to a significant decrease in the daytime cough frequency as measured by an ambulatory cough recorder, a decrease in cough severity as measured by the VAS and a decrease in the cough impact as measured by the MCLCS. There were no serious adverse events. Our trial took the concept introduced in the pilot study forward and proved in a randomized controlled study that aprepitant decreases cough in lung cancer patients. An ongoing study is evaluating the role of orvepitant, a selective NK1 receptor blocker, in patients with chronic refractory cough.26 In our study, we administered aprepitant for seven days, and found that patients continued to experience a sustained antitussive effect up to day twelve, i.e. even after stopping aprepitant. There was no increase in > grade 3 adverse events from aprepitant. No patient required a dose reduction or medication hold for management of side-effects. Seven-day dosing of aprepitant is longer than the usual three-day regimen for nausea and vomiting. There are data that the

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long-term use of aprepitant in patients with germ cell tumors and bone marrow transplant patients is possible and does not add to toxicity.27,28A concern arising from long-term aprepitant administration is potential drug interactions, especially with concurrent use of chemotherapy. Aprepitant is extensively metabolized by the cytochrome CYP3A4 system; aprepitant both induces and moderately inhibits CYP3A4. However, trials and clinical experience have shown that aprepitant does not lead to any clinically meaningful drug interactions except with some limited drugs, with no increase in adverse events and no decrease in efficacy of chemotherapeutic agents.29,30 Our trial had some limitations. Although we used validated and well-described subjective cough assessment tools (VAS and MCLCS), we did not objectively measure cough frequency with an ambulatory cough recorder or by inhalation cough challenges. There was no blinding or a placebo arm. These factors should be kept in mind while interpreting the magnitude of the observed effect of aprepitant in our study. We had some patient attrition: 3% at day 3 which increased to 24% by day 12. The amount of missing data was roughly comparable in the two treatment arms. Attrition is a common problem in supportive care and palliative oncology trials. Hui et al. reported that the attrition rate in 18 interventional palliative care trials was 26% (95% CI, 23%-28%) for the primary endpoint and 44% by end of study (95% CI, 41-47%).31 An important drawback of our study was the length of time that aprepitant was administered for, and the relatively short follow-up duration. In lung cancer patients, cough is often a chronic problem and our study did not test whether continuing aprepitant long term or repeating courses of aprepitant might help manage chronic cough in these patients. While our study proved that aprepitant controls cough for a short period, we do not know whether it will be effective for chronic cough which the majority of lung cancer patients are likely to have. During our cough study, 50% of the patients started systemic cancer-directed therapy at a median of eight days from the date of randomization. This may have impacted the cough 16

assessment parameters on days nine and twelve. However, the proportion of patients who were started on systemic therapy was not significantly different in the two arms.

Conclusions: Aprepitant led to a significant improvement in cough in patients with advanced lung cancer, with no increase in severe side-effects. Aprepitant represents a new treatment option for cough in lung cancer patients.

Acknowledgements: 1. Guarantors: Dr. Vanita Noronha and Dr. Kumar Prabhash take responsibility for and are the guarantors of the content of the manuscript, including the data and analysis. 2. Author contributions: VN and KP had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. VN, AB, VMP, AJ, NM, SS, SK, SAM, KM, SI and KP contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript. 3. Financial/nonfinancial disclosures: This work was supported by an intramural grant from the Tata Memorial Center Research Administrative Council (TRAC) [grant number not applicable], a grant from the Indian Co-operative Oncology Network [grant number not applicable], and an unrestricted educational grant from Glenmark Pharmaceuticals Ltd. [grant number not applicable]. Conflict of Interest:

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Dr. Vanita Noronha has received research funding from Amgen, Sanofi/ Aventis and Dr. Reddy’s Laboratories Inc. (all research grants paid to the institution).

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Dr. Kumar Prabhash has received research funding from Dr. Reddy’s Laboratories Inc., Fresenius Kabi India Pvt. Ltd., Alkem Laboratories, Natco Pharma Ltd., BDR Pharmaceuticals Intl. Pvt. Ltd, and Roche Holding AG (all research grants paid to the institution).

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All remaining authors have declared no conflicts of interest.

4. Role of the sponsors: The funding agencies had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.

REFERENCES: 1. Molassiotis A, Smith JA, Bennett MI, et al: Clinical expert guidelines for the management of cough in lung cancer: report of a UK task group on cough. Cough 6:9,2010 2. Molassiotis A, Smith JA, Mazzone P, et al; CHEST Expert Cough Panel. Symptomatic Treatment of Cough Among Adult Patients With Lung Cancer: CHEST Guideline and Expert Panel Report. Chest 151: 861-874,2017 3. Kang HJ, Loftus S, Taylor A, et al: Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 16: 385-94,2015

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4. Prommer E: Aprepitant (EMEND): the role of substance P in nausea and vomiting. J Pain Palliat Care Pharmacother 19:31-9, 2005 5. Sekizawa K, Jia YX, Ebihara T, et al: Role of substance P in cough. Pulm Pharmacol 9: 323-328,1996 6. Harle AS, Smith JA, Molassiotis A, et al: Lofthouse K, Dockry R, Russell P, et al: A placebo-controlled trial of aprepitant for cough in lung cancer. J Clin Oncol 33:29s, 2015 (suppl; abstract 2-2) 7. Vidaver RM, Shershneva MB, Hetzel SJ, et al: Typical Time to Treatment of Patients With Lung Cancer in a Multisite, US-Based Study. J Oncol Pract 12: e643-653, 2016 8. McGarvey LP, Heaney LG, Lawson JT, et al: Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 53: 738743, 1998 9. Molassiotis A, Ellis J, Wagland R, et al: The Manchester cough in lung cancer scale: the development and preliminary validation of a new assessment tool. J Pain Symptom Manage 45: 179-190, 2013 10.Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organisation for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 11. Available online at: http://www.icssc.org/presentations/newdelhi2007/3iche9overviewindia2007.pdf; Last accessed on 8th Aug 2018.

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12. Available online at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm073137.pdf; Last accessed on 8th August 2018. 13. Sedgwick P. Randomised controlled trials: understanding effect sizes. BMJ. 2015 Mar 27;350:h1690 14. Fayers PM, Aaronson NK, Bjordal K, et al, on behalf of the EORTC Quality of Life Group. The EORTC QLQ-C30 Scoring Manual (3rd Edition). Published by: European Organisation for Research and Treatment of Cancer, Brussels 2001. 15. Bergman B, Aaronson NK, Ahmedzai S, et al: The EORTC QLQLC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on Quality of Life. Eur J Cancer 30A:635-642, 1994 16. Little RJ, D'Agostino R, Cohen ML, et a: The prevention and treatment of missing data in clinical trials. N Engl J Med 367:1355-1360, 2012 17. De Blasio F, Virchow JC, Polverino M, et al: Cough management: a practical approach. Cough 10:7, 2011 18. Spinou A, Birring SS. An update on measurement and monitoring of cough: what are the important study end points? J Thorac Dis 6 (Suppl 7): S728-734, 2014 19. Chung KF. Currently available cough suppressants for chronic cough. Lung 186 Suppl1:S82-87, 2008 20. Freestone C, Eccles R. Assessment of the antitussive efficacy of codeine in cough associated with common cold. J Pharm Pharmacol 49: 1045-1049, 1997

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21. Bolser DC, Davenport PW. Codeine and cough: an ineffective gold standard. Curr Opin Allergy Clin Immunol 7:32-36, 2007 22. Smith J,Owen E, Earis J, et al: Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. J Allergy Clin Immunol 117:831-835, 2006 23. Ryan NM, Birring SS, Gibson PG: Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial. Lancet 380: 1583-1589, 2012 24. Harle AS, Blackhall FH, Smith JA, et al: Understanding cough and its management in lung cancer. Curr Opin Support Palliat Care 6: 153-162, 2012 25. Molassiotis A, Bailey C, Caress A, et al: Interventions for cough in cancer. Cochrane Database Syst Rev 5: CD007881, 2015 26. Available online at: https://clinicaltrials.gov/ct2/show/NCT02993822; last accessed on 3rd August 2018 27.Olver IN, Grimison P, Chatfield M, et al; Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Results of a 7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Support Care Cancer 21:1561-8, 2013 28. Jacobse J, Mensink H, van der Stoep-Yap MYEC, et al: Long-term aprepitant for nausea and vomiting associated with gastroparesis in hematopoietic stem cell transplantation. Bone Marrow Transplant2018, doi: 10.1038/s41409-018-0231-4. [Epub ahead of print] 29. Aapro M, Carides A, Rapoport BL, et al: Aprepitant and fosaprepitant: a 10-year review of efficacy and safety. Oncologist 20:450-458, 2015 30. Aapro MS, Walko CM. Aprepitant: drug-drug interactions in perspective. Ann Oncol 21: 2316-2323, 2010 21

31. Hui D, Glitza I, Chisholm G, et al: Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials. Cancer 119: 1098-1105, 2013

TABLES: Table 1: Baseline demographics and disease related information for all patients in the cough study

Characteristic

Aprepitant Arm

Control Arm

(n=64)

(n=64)

Median

53

52

Range

23-73

19-75

Male

44 (69)

39 (61)

Female

20 (31)

25 (39)

Never smoker

39 (61)

43 (67)

Former smoker

23 (36)

19 (30)

Current smoker

0

2 (3)

2 (3)

0

Yes

20 (31)

14 (22)

No

42 (66)

50 (78)

2 (3)

0

Age, years

Sex

Smoking history

Missing information Smokeless tobacco use

Missing information

22

Comorbidities None

39 (61)

38 (59)

Hypertension

6 (9)

7 (11)

Diabetes

2 (3)

4 (6)

COPD/ bronchitis/ asthma

4 (6)

2 (3)

Othera

8 (13)

3 (5)

Multiple (> 1)

5 (8)

10 (16)

Adenocarcinoma

53 (83)

52 (82)

Squamous cell carcinoma

7 (11)

6 (9)

Otherb

4 (6)

6 (9)

None

38 (59)

33 (52)

EGFR activating mutation

12 (19)

16 (25)

EGFR exon 20 resistance mutation

1 (2)

4 (6)

ALK rearranged

9 (14)

10 (16)

Molecular testing not done

4 (6)

1 (2)

Stage III

8 (13)

8 (13)

Stage IV

56 (88)

56 (88)

PS 1

54 (84)

48 (75)

PS 2

10 (16)

15 (23)

0

1 (2)

Histopathology

Molecular drivers detected

Disease stage

ECOG performance status

Not recorded Baseline cough details

23

Duration in days-Median (range)

90 (30-270)

90 (20-1200)

Grade 1

0

1 (2)

Grade 2

60 (94)

55 (86)

Grade 3

4 (6)

7 (11)

None

21 (33)

21 (33)

Grade 1

17 (27)

19 (30)

Grade 2

26 (41)

23 (36)

Grade 3

0

1 (2)

48 (75)

49 (77)

Done, normal

1 (2)

2 (3)

Done, narrowing noted

3 (5)

3 (5)

Done, narrowing noted, BAL positive

2 (3)

2 (3)

10 (16)

8 (13)

Grade of coughc

Baseline dyspneac

Bronchoscopy Not done

Done, endobronchial tumor seen

NOTE: Data presented as No. (%) unless otherwise specified. There were no significant differences in the histological and staging characteristics between the two groups of patients. COPD-Chronic obstructive pulmonary disorder; EGFR-epidermal growth factor receptor; PSperformance status; BAL-bronchoalveolar lavage. a

Other comorbidities included hypothyroidism, cardiac dysfunction, prostatic hypertrophy,

migraine, history of tuberculosis and hepatic dysfunction or a history of hepatitis. b

Other histologies included adenosquamous, pleomorphic, sarcomatoid, large cell

neuroendocrine, poorly differentiated and non-small cell lung cancer, not otherwise specified.

24

c

Grading of the baseline symptoms was done using the Common Terminology Criteria for

Adverse Events (CTCAE), v.4.03

Table 2: Details of medications prescribed for cough and other medications that may have affected the severity of cough Medication prescribed

Aprepitant Arm

Control Arm

(n=64)

(n=64)

64 (100)

0

Narcotic derivatives

29 (45)

29 (45)

Expectorant/mucolytic

25 (39)

24 (38)

Antihistamine

9 (14)

7 (11)

Adrenergic blocker

1 (2)

1 (2)

0

3 (5)

5 (8)

6 (9)

Steroids

4 (6)

6 (9)

Bronchodilators

2 (3)

3 (5)

Antibiotics

11 (17)

6 (9)

Oral opioids

6 (9)

6 (9)

Aprepitant Physician’s choice of cough medication

Not documented Second cough medication prescribed?a Other medications

NOTE: Data presented as No. (%) unless otherwise specified. There was no difference in the use of various suppressants between the two groups.

25

a

Patients were started on aprepitant with physician’s choice of antitussive for cough in the

aprepitant arm, and on physician’s choice of antitussive in the control arm. Patients whose cough was poorly controlled could be started on a second cough medication in addition.

FIGURE LEGENDS: Fig 1: CONSORT diagram of the cough study showing the flow of patients from prescreening, enrollment, randomization, therapy and analysis. a

In the aprepitant arm, all 64 patients were included in the efficacy analysis. For the toxicity

analysis, 63 patients were included; 1 patient’s hospital file was missing, hence the toxicity data for this patient were not available. b

In the control arm, 2 patients defaulted after randomization (both patients were excluded

from the efficacy and toxicity analyses), and 1 patient was withdrawn from the study after day 3 follow-up, as immunohistochemical evaluation of the histopathology revealed a nonlung cancer primary. This patient with the non-lung primary was included in both the efficacy and the toxicity analysis since this patient took aprepitant for 3 days, completed the baseline and day 3 assessments and the toxicity data were available. Thus, in the control arm, 62 patients were included for the efficacy and toxicity analysis.

Fig 2: The mean Visual Analog Scale (VAS) scores at baseline and at timepoints three, seven, nine and twelve in patients on the aprepitant arm and the control arm. Values provided at each timepoint are the mean VAS scores in mm, followed by the standard deviation in brackets. Scores gradually decreased in both arms from baseline to days three, seven, nine 26

and twelve, but the magnitude of improvement was greater in the aprepitant arm as compared to the control arm.

Fig 3: The mean Manchester Cough in Lung Cancer Scale (MCLCS) scores at baseline and at timepoints three, seven, nine and twelve in patients on the aprepitant arm and the control arm. Values provided at each timepoint indicate the mean MCLCS scores, followed by the standard deviation in brackets. These values gradually decreased in both arms from baseline to days three, seven, nine and twelve, but the magnitude of improvement was greater in the aprepitant arm as compared to the control arm.

Fig 4: The mean cough-specific domain scores in the QoL analysis, for patients in the aprepitant arm and the control arm. Values at each timepoint indicate the mean scores for the cough question (followed by the standard deviation in brackets) in the lung cancer module (QLQ-LC13) of the EORTC QoL form. There was improvement in the cough specific QoL domain in patients on the aprepitant arm as compared to the control arm.

FIGURES: Fig 1:

27

Fig 2:

28

Fig 3:

Fig 4:

29

30

Abbreviations: 1. CTCAE: Common Terminology Criteria for Adverse Events. The Common Terminology Criteria for Adverse Events are a set of criteria for the standardized classification of adverse effects of drugs used in cancer therapy. The CTCAE system is a product of the US National Cancer Institute. 2. ECOG PS: Eastern Cooperative Oncology Group performance status. A scoring system to help determine the activity and fitness level of the patient. A higher score indicates more morbidity and less activity/ fitness level. 3. EORTC QLQ-C30 and QLQ-LC13: EORTC: European Organisation for Research and Treatment of Cancer. The EORTC has developed various validated quality of life questionnaires, including the general QLQ-C30 questionnaire and the lung-specific QLQ-LC13 questionnaire. The QLQ-C30 questionnaire consists of thirty questions, including five multi-item functioning scales (physical, role, social, emotional and cognitive functioning), nine symptom scales (pain, fatigue, nausea/ vomiting, constipation, sleep, appetite, dyspnea and financial impact) and two items that measure overall health/ QoL. The QLQ-LC13 is the lung cancer specific module that has thirteen questions related both to symptoms of lung cancer (cough, hemoptysis, dyspnea, pain) and side-effects of chemotherapy and radiation (mucositis, dysphagia, alopecia and neuropathy). Responses to most questions range from 1 (not at all) to 4 (very much). 4. MCLCS: A questionnaire consisting of ten questions that describe the patient’s cough experience in the preceding week; each question has five possible answers scored as one (never) to five (all the time); score range: 10-50. A high score indicates worse cough impact.

5. NK1: Neurokinin 1. Neurokinin 1 receptor inhibitors are used in oncology for the management of nausea and vomiting. 6. QOL: Quality of life. A standard term in oncology and in general life, that indicates the perception of the person regarding his/ her expectations and what he/ she actually is experiencing in terms of how rich and fulfilling his/ her life is and what specific symptoms he/ she has. 7. TMC: Tata Memorial Center, a tertiary level oncology teaching hospital in Mumbai, India. 8. VAS: The Visual Analog Scale, a scale to assess the cough severity. The scale consists of a straight-line measuring 100mm, range is 0 to 100 mm. One end of the line is labelled, ‘No cough (0 mm)’ and the other end is labelled ‘Worst cough ever (100 mm)’. The patient marks a point on the line that best signifies how severe his/ her cough is. A high score signifies worse cough severity.