Efficacy and Safety of Rolapitant for Prevention of Chemotherapy

European Journal of Cancer 57 (2016) 23e30

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Original Research

Efﬁcacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy

Bernardo Rapoport a,*, Lee Schwartzberg b, Martin Chasen c, Dan Powers d, Sujata Arora d, Rudolph Navari e, Ian Schnadig f

a The Medical Oncology Centre of Rosebank, Johannesburg, South Africa b The West Clinic, Memphis, TN, USA c William Osler Health Services, Brampton, Ontario, Canada d TESARO, Inc., Waltham, MA, USA e Indiana University School of Medicine e South Bend, South Bend, IN, USA f Compass Oncology, US Oncology Research, Tualatin, OR, USA

Received 21 December 2015; accepted 22 December 2015 Available online 4 February 2016

KEYWORDS Abstract Objective: Rolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown Rolapitant; to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first Chemotherapy- cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy induced nausea and (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of ro- vomiting; lapitant in preventing CINV over multiple cycles of MEC or HEC. Neurokinin-1 receptor Patients and methods: Patients in one phase III MEC, one phase II HEC, and two phase III antagonist; HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combi- Antiemetic; nation with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in Multiple cycles; cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6 Subsequent cycles 8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2e6. Results: Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p Z 0.006), 3 (p < 0.001), 4 (p Z 0.001), and 5 (p Z 0.021). Over cycles 16, time-to-first emesis was significantly longer

* Corresponding author: The Medical Oncology Centre of Rosebank, 129 Oxford Road, Corner Northwold, Saxonwold, Johannesburg, 2196, South Africa. Tel.: þ27 11 880 4169. E-mail address: [email protected] (B. Rapoport). http://dx.doi.org/10.1016/j.ejca.2015.12.023 0959-8049/ª 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 24 B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30

with rolapitant than with control (p < 0.001). The incidence of treatment-related adverse events during cycles 2e6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed. Conclusions: Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated. ª 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and Chemotherapy-induced nausea and vomiting (CINV) is repeat courses of emetogenic cancer chemotherapy [17]. a debilitating side-effect of anticancer treatment that At the 180-mg dose of rolapitant, the mean NK-1 re- significantly impairs quality of life for patients [1,2]. Use ceptor occupancy was >90% in the cortex and 73% in of a 5-hydroxytryptamine type 3 (5-HT3) receptor the striatum at 120 h after a single oral dose [18], antagonist (RA), particularly when combined with consistent with its long half-life (approximately 180 h) dexamethasone, has proven highly efficacious for con- [19]. In addition, rolapitant does not inhibit or induce trolling nausea and vomiting that occur in the acute CYP3A4; therefore, it may reduce the potential for phase (24 h) following administration of emetogenic CYP3A4-mediated drug-drug interactions and decrease chemotherapy; however, its efficacy in controlling CINV the need for dose modification of certain drugs metab- during the delayed phase (>24e120 h) is limited [3]. olized by CYP3A4 [20]. An intravenous version of Because patients with acute CINV became uncommon rolapitant is under investigation. in the clinic following the introduction of 5-HT3 RAs, The efficacy of oral rolapitant (180 mg) in protecting health care professionals may not be aware of delayed against CINV was established in four randomized, CINV. Current antiemetic guidelines recommend the placebo-controlled double-blind studies [21e23].A addition of a neurokinin-1 (NK-1) RA to a 5-HT3 RA greater percentage of patients administered MEC or and dexamethasone in patients receiving highly emeto- HEC demonstrated a complete response (CR: defined as genic chemotherapy (HEC) [3e5]. For patients receiving no emesis and no use of rescue medication) in the moderately emetogenic chemotherapy (MEC), the delayed phase (>24e120 h) in cycle 1 with rolapitant addition of an NK-1 RA is supported for select patients combined with a 5-HT3 RA and dexamethasone with additional CINV risk factors [3,4]. compared with a 5-HT3 RA and dexamethasone alone In clinical practice, patients typically receive four to [21e23]. The proportion of patients in rolapitant and six cycles of chemotherapy. The severity of CINV can control groups who achieved a CR in the delayed phase increase over repeated chemotherapy cycles when CINV (the primary end-point) was 71.3% and 61.6%, respec- protection is not achieved [6e8], and failure to protect tively, in a phase III MEC study (p < 0.001) and 71.4% against delayed CINV can impair protection against and 60.2%, respectively, in two pooled phase III acute CINV in subsequent cycles [8]. Anticipatory cisplatin-based HEC studies (p < 0.001) [21,22].It CINV may also develop, which may compromise should be noted that 53% of patients in the MEC study adherence to anticancer treatment [9]. received anthracycline/cyclophosphamide (AC)based The goal of developing new antiemetics should be to chemotherapy, which is now classified as HEC [3e5]; improve CINV protection throughout the entire at-risk other patients received a variety of MEC agents, the period, with preservation of the benefit over multiple most common of which was carboplatin (30% of pa- chemotherapy cycles while maintaining safety and tients), and a higher CR rate in the delayed phase with tolerability. Improved CINV protection over multiple rolapitant was maintained in this group [21]. In addi- cycles has been shown with the addition of an NK-1 RA tion, in a phase II cisplatin-based HEC study, CR in the to standard therapy in studies of aprepitant [10e13] and delayed phase (a secondary end-point) was achieved by netupitant [14]. However, the use of these agents may be 63.6% and 48.9% of patients in rolapitant and control complicated by their interaction with the cytochrome groups, respectively (p Z 0.045) [23]. Collectively, these P450 3A4 (CYP3A4) enzyme, often necessitating dose data support the recently updated National Compre- adjustment of certain concomitantly administered hensive Cancer Network guidelines that recommend medications [15,16]. rolapitant (category 1) for CINV prevention in patients Rolapitant (VARUBI) is an orally active, long- receiving HEC and in select patients receiving MEC [3]. acting NK-1 RA that was recently approved by the US Patients who completed cycle 1 in the rolapitant Food and Drug Administration in combination with studies had the option to continue the same randomized B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30 25 treatment for up to five additional cycles regardless of placebo approximately 1e2 h before receiving either their response in cycle 1. Here, we report the efficacy and MEC or HEC. All patients received a 5-HT3 RA and safety of rolapitant over multiple cycles of MEC or dexamethasone regimen. Patients in the MEC study HEC in a pooled analysis of the four similarly designed were administered oral granisetron 2 mg on days 1e3 studies: one phase III MEC study (randomized and dexamethasone 20 mg on day 1. Patients in the N Z 1369) [21], one phase II HEC study (randomized cisplatin-based HEC studies were administered intrave- N Z 181) [23], and two phase III HEC studies (ran- nous granisetron 10 mg/kg (intravenous ondansetron domized N Z 1087) [22]. 32 mg in the phase II trial) on day 1 and oral dexamethasone 20 mg on day 1 and 8 mg twice daily on days 2. Patients and methods 2e4. Patients administered taxanes received dexamethasone according to the package insert. Four global, randomized, double-blind, placebo- controlled studies (NCT01500226, NCT00394966, 2.3. Efficacy and safety assessments NCT01499849 and NCT01500213) were conducted in North America, Central and South America, Europe, During the first 5 days after administration of chemo- Asia, and Africa in accordance with the Declaration of therapy in cycle 1, patients used a daily diary to record Helsinki and the International Conference on Harmo- all events of vomiting and use of rescue medication and nisation and Good Clinical Practice (GCP) guidelines. to self-assess nausea. The primary end-point was CR in The institutional review boards at each study site the delayed phase in the phase III studies and CR in the approved the protocols. All patients provided written overall phase (0120 h) in the phase II study. At the end informed consent. of cycle 1, eligible patients were permitted to continue the same randomized treatment regimen for up to five 2.1. Patients additional cycles whether or not they achieved a CR in cycle 1. Response in cycles 2e6 was assessed for the Eligibility requirements for each study included patient exploratory end-points of no emesis or nausea that age 18 years, Karnofsky performance score 60, pre- interfered with normal daily life (a combined measure), dicted life expectancy 4 months (3 months in the no emesis, no interfering nausea, and time-to-first phase II study), and adequate bone marrow, kidney, and emesis. Patients were asked the following two CINV liver function. Patients in the MEC study were required assessment questions on days 6e8 of each subsequent to be naive to MEC or HEC and scheduled to receive a cycle: 1) have you had any episode of vomiting or first course of one or more of the following agents: retching since your chemotherapy started in this cycle? intravenous cyclophosphamide (<1500 mg/m2), doxo- and 2) have you had any nausea since your chemo- rubicin, epirubicin, carboplatin, idarubicin, ifosfamide, therapy started in this cycle that interfered with normal irinotecan, daunorubicin, and/or intravenous cytarabine daily life? (>1 g/m2). The MEC study was designed before AC- Safety variables, including treatment-emergent based chemotherapy was reclassified as HEC; the adverse events (TEAEs), physical and neurological ex- study protocol prespecified that at least 50% of patients aminations, vital signs, electrocardiograms, and clinical enrolled were to receive an AC-based regimen. In the laboratory values, were assessed in all cycles. HEC studies, patients were required to be naive to cisplatin and scheduled to receive their first course of 2.4. Statistical analysis cisplatin-based chemotherapy (70 mg/m2 in the phase II study and 60 mg/m2 in the phase III studies). Post hoc analyses of pooled safety and efficacy data Prior to initiating study drug, patients were not from the four studies were performed for cycles 2e6 permitted to use any of the following medications: 5-HT3 (only data from patients receiving the 180-mg rolapitant RAs, phenothiazines, benzamides, domperidone, can- dose or control were included from the dose-finding nabinoids, NK-1 RAs, or benzodiazepines within 48 h; phase II HEC study). The subsequent cycle efficacy palonosetron within 7 d; or systemic corticosteroids or population consisted of all patients who received at least sedative antihistamines (e.g. dimenhydrinate or diphen- one dose of study drug in a given cycle and were enrolled hydramine) within 72 h of day 1, with the exception of at a GCP-compliant site. Between-group comparisons premedication for chemotherapy (e.g. taxanes). were conducted using the CochraneManteleHaenszel c2 test adjusted for sex and study. Time-to-first emesis 2.2. Treatment was summarized using KaplaneMeier methodology, and the between-group treatment comparison was con- Patients were stratified by sex (and concomitant ducted using a log-rank test in the population of patients emetogenic chemotherapy in the phase II study) and who received study drug at a GCP-compliant site. randomized using an interactive, web-based randomi- p-values <0.05 were considered statistically significant zation system to receive either oral rolapitant 180 mg or and were not adjusted for multiplicity. 26 B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30

The safety population included all patients who 3.2. Efficacy received at least one dose of study drug in a given cycle. Over multiple cycles, a greater proportion of patients in the rolapitant group than the control group reported no 3. Results emesis or interfering nausea (combined measure); the improvement reached statistical significance in cycles 2 3.1. Patients (p Z 0.006), 3 (p < 0.001), 4 (p Z 0.001), and 5 (p Z 0.021, Fig. 2A). A significantly higher proportion Baseline characteristics were balanced between pa- of patients reported no emesis events in the rolapitant tients in the rolapitant and control groups in the group than the control group in cycles 2e6(p < 0.001 overall pooled analysis (Table 1). The majority of for each subsequent cycle, Fig. 2B). A significantly patients in the MEC study were female (80%), and greater percentage of patients reported no interfering breast cancer was the most commonly diagnosed nausea with rolapitant versus control in cycles 2 malignancy (67%) [21]. AC-based chemotherapy (now (p Z 0.010), 3 (p < 0.001), 4 (p Z 0.012), and 5 classified as HEC [3e5]) was received by 53% of pa- (p Z 0.029, Fig. 2C), but not in cycle 6 (p Z 0.682). tients, and carboplatin-based chemotherapy was There was a general trend of decreased CINV over received by 30% of patients; other patients received a repeated cycles in the control group. However, the variety of MEC regimens (Supplemental Table 1) [21]. improvement in no emesis and no interfering nausea In the pooled phase III cisplatin-based HEC studies, (combined and individual measures) with rolapitant the majority of patients were male (63%) and lung relative to control remained generally consistent over cancer was the most commonly diagnosed malignancy multiple cycles. (44%) [22]. KaplaneMeier curves showing time-to-first emesis Patient discontinuations occurred with similar fre- separated in cycle 1 and favored rolapitant over control quencies in both treatment arms for cycle 1 and the with sustained separation that remained consistent over combined cycles 2e6(Fig. 1). The most common reason cycles 2e6(p < 0.001, Fig. 3). for patient discontinuation was completion of the required number of chemotherapy cycles (observed in 3.3. Safety 36.0% of patients overall). This most often occurred after four cycles, a typical treatment course for many The safety dataset comprised 1012 patients who received chemotherapy regimens, with 34.0% and 37.2% of pa- rolapitant and 999 patients who received control in cy- tients discontinuing after cycle 4 in the rolapitant and cles 2e6. Rolapitant was well tolerated over multiple control arms, respectively (Supplemental Table 2). cycles of MEC or HEC, with an incidence of treatment-

Table 1 Baseline demographicsa. Characteristics Rolapitant, 180 mg (n Z 1007) Control (n Z 991) Total (n Z 1998) Age, y, median (range) 58 (20e86) 57 (18e90) 57 (18e90) Sex, n (%) Female 620 (61.6) 625 (63.1) 1245 (62.3) Male 387 (38.4) 366 (36.9) 753 (37.7) Race, n (%) White 806 (80.0) 777 (78.4) 1583 (79.2) Asian 95 (9.4) 97 (9.8) 192 (9.6) Black or African American 23 (2.3) 29 (2.9) 52 (2.6) American Indian/Alaska Native 13 (1.3) 13 (1.3) 26 (1.3) Native Hawaiian/other Paciﬁc islander 1 (0.1) 2 (0.2) 3 (0.2) Multiracial/other/unknown 69 (6.9) 73 (7.4) 142 (7.1) Alcohol consumptionb 0e5 Drinks/week, n/N (%) 890/943 (94.4) 849/922 (92.1) 1739/1865 (93.2) >5 Drinks/week, n/N (%) 53/943 (5.6) 73/922 (7.9) 126/1865 (6.8) Region, n (%) North America 224 (22.2) 226 (22.8) 450 (22.5) Central/South America 109 (10.8) 113 (11.4) 222 (11.1) Europe 554 (55.0) 530 (53.5) 1084 (54.3) Asia/South Africa 120 (11.9) 122 (12.3) 242 (12.1) a Demographics shown are for patients who received the 180-mg rolapitant dose or control during cycles 2e6 at a Good Clinical Practice compliant site. b Data for alcohol consumption were not collected in the phase II study and are based on patients who self-reported alcohol consumption. B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30 27

Randomized (N=2637) MEC (n=1369) Phase II HEC (n=181) HEC1 (n=532) HEC2 (n=555)

Received rolapitant 180 mg in cycle 1 (n=1294) Received control in cycle 1 (n=1301)

Discontinued (n=282) Discontinued (n=302) Consent withdrawn (n=77) Consent withdrawn (n=97) Chemotherapy completed or changed (n=50) Adverse event (n=46) Adverse event (n=38) Chemotherapy completed or changed (n=38) Protocol noncompliance (n=34) Protocol noncompliance (n=32) Death (n=11) Death (n=7) Disease progression (n=2) Disease progression (n=4) Other (n=70)* Other (n=78)*

Entered multiple cycle extension (n=2015)†

Received rolapitant 180 mg in cycles 2–6 (n=1012) Received control in cycles 2–6 (n=999)

Discontinued (n=710) Discontinued (n=701) Chemotherapy completed or changed (n=359) Chemotherapy completed or changed (n=365) Consent withdrawn (n=103) Consent withdrawn (n=99) Adverse event (n=64) Adverse event (n=66) Disease progression (n=50) Disease progression (n=48) Protocol noncompliance (n=44) Protocol noncompliance (n=34) Death (n=13) Death (n=7) Other (n=77)* Other (n=82)*

Completed all 6 cycles (n=302) Completed all 6 cycles (n=298)

Fig. 1. Pooled studies CONSORT flow diagram: *, primary reasons for patient discontinuation in the “other” category include lost to follow-up, lack of efficacy, investigator judgment, and sponsor decision/study closure and y, two patients in the rolapitant group and two patients in the control group discontinued before receiving study drug in cycles 2e6. MEC, moderately emetogenic chemotherapy; HEC, highly emetogenic chemotherapy. related TEAEs similar to that of control. The incidence emesis and no interfering nausea was significantly higher of the most common treatment-related TEAEs, which with rolapitant group than with control over multiple included fatigue, constipation, and headache, was low cycles. (<2%, Table 2). In addition, the incidence of treatment- The rolapitant trials included a diverse population of related TEAEs over multiple cycles remained similar to patients with cancer [21e23], a majority of whom were that observed in cycle 1. The incidence of treatment- at high risk for CINV [1], as 60% of the population in related TEAEs did not increase with each subsequent the pooled analysis was female and over 90% reported cycle, and no cumulative toxicity was observed little or no alcohol consumption. In this pooled analysis, (Supplemental Table 3). For cycles 2e6, the total the treatment arms were well balanced for these risk number of patients discontinuing due to an adverse factors. event, disease progression, or death was low (6.5%, In multiple-cycle studies, the incidence of CINV has 4.9%, and 1.0% of patients, respectively, Fig. 1). generally been found to increase over cycles of chemotherapy [7,8]. In contrast, we observed a trend of 4. Discussion decreased CINV over multiple cycles in the control group; healthier patients may have been more likely to remain in

Rolapitant combined with a 5-HT3 RA and dexameth- the study for reasons such as a greater ability to comply asone provided superior protection against CINV in with clinic visit follow-ups as well as a lower rate of disease patients receiving multiple cycles of MEC or HEC progression or death, whereas those with poor CINV compared with a 5-HT3 RA and dexamethasone alone. control may have been more likely to discontinue after In a pooled analysis of four similarly designed phase II cycle 1. Despite this trend, the improvement in patient- and III studies, the proportion of patients reporting no reported outcomes of no emesis and no interfering 28 B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30

Rolapitant 180 mg Control

100 A. No emesis or interfering nausea 90 p=0.021 p=0.209 p<0.001 p=0.001 80 p=0.006 84.7 84.0 78.6 78.2 80.1 70 75.7 76.9 70.1 70.9 60 67.9 50 40 Patients, % 30 20 10 0 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 n 1006 990 834 826 682 687 378 362 318 312

B. No emesis 100 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 90 95.0 96.2 91.5 90.2 90.0 88.1 80 87.6 82.3 81.6 83.6 70 60 50 40 Patients, % 30 20 10 0 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 n 1006 990 834 826 682 687 378 362 318 312

C. No interfering nausea 100 90 p=0.029 p=0.682 p=0.010 p<0.001 p=0.012 80 86.2 84.6 83.3 79.1 79.5 80.8 80.4 70 74.1 72.2 75.1 60 50 40 Patients, % 30 20 10 0 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 n 1006 990 834 826 682 687 378 362 318 312

Fig. 2. Rates of no emesis and/or no interfering nausea in cycles 2e6. Rates of (A) no emesis or interfering nausea (combined measure), (B) no emesis, and (C) no interfering nausea based on patient response to two yes/no questions about emesis events and nausea interfering with normal daily life. nausea with rolapitant relative to control remained There are challenges inherent in collecting data over generally consistent over multiple cycles. Furthermore, multiple cycles of chemotherapy [6]. In an effort to KaplaneMeier curves showing time-to-ﬁrst emesis facilitate data collection, the rolapitant trials used a demonstrated a consistent improvement favoring rolapi- simple measure of response in cycles 26. Patients tant over control that was sustained over six cycles. answered two yes/no questions about whether nausea or B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30 29

100 Rolapitant Control

Patients without emesis, %* 20

Log-rank p<0.0001 0 1 2 3 4 5 6 Time (cycle) since first chemotherapy Number at risk Rolapitant 1290 815 650 520 292 246 Control 1291 684 536 428 224 185

Fig. 3. Time-to-first emesis over cycles 16. Estimates for the proportions of patients without a first event of emesis in the rolapitant and control arms over cycles 16. vomiting had occurred since the start of chemotherapy cycles of MEC or HEC. Rolapitant was also well- instead of using the 5-d daily diary employed in cycle 1 tolerated, with no increase in the frequency of [21,22]. As is typical with multiple-cycle trials [6], the treatment-related TEAEs and no cumulative toxicity number of enrolled patients decreased over the course of with treatment over multiple cycles. These results sup- six cycles. The frequency of discontinuations in each port the benefit of adding rolapitant to the supportive cycle was similar in rolapitant and control arms. care of a diverse population of patients with cancer Completion of the required number of chemotherapy receiving multiple cycles of MEC or HEC. cycles was the most common reason for discontinuation in both arms and occurred most often after four cycles, Role of the funding source which is a typical course for many chemotherapy regimens. The MEC trial included approximately 50% pa- The phase III studies were designed through a tients receiving AC-based chemotherapy for breast collaboration of academic researchers and the study cancer [21], which is administered over four cycles [24]; sponsor, TESARO, Inc. Study data were collected by completion of chemotherapy in these patients was a clinical investigators, and trials conducts were moni- major reason for the discontinuations in the pooled tored by TESARO, Inc. Statistical analyses were analysis. The number of patients who discontinued due managed by TESARO, Inc., according to a predefined to an adverse event, disease progression, or death was statistical plan; data presented here include post hoc low in both arms. analyses. This manuscript was developed with full In summary, oral rolapitant effectively protected author participation and assistance from a medical against CINV, with sustained benefit over multiple writer in accordance with Good Publication Practice

Table 2 Treatment-related TEAEs in cycle 1 and cycles 26. Category Cycle 1 Cycles 2e6 Rolapitant, Control Rolapitant, Control 180 mg (n Z 1301) 180 mg (n Z 999) (n Z 1294) (n Z 1012) Patients with one or more treatment-related TEAE, n (%)a 90 (7.0) 82 (6.3) 56 (5.5) 68 (6.8) Treatment-related TEAEs (1% of patients in cycle 1 or cycles 2e6), n (%) Fatigue 25 (1.9) 18 (1.4) 13 (1.3) 18 (1.8) Constipation 20 (1.5) 20 (1.5) 12 (1.2) 8 (0.8) Headache 19 (1.5) 18 (1.4) 6 (0.6) 6 (0.6) TEAE Z treatment-emergent adverse event. a Any adverse event considered possibly, probably, or deﬁnitely related to study drug. 30 B. Rapoport et al. / European Journal of Cancer 57 (2016) 23e30

3 and International Committee of Medical Journal [10] de Wit R, Herrstedt J, Rapoport B, et al. Addition of the oral Editors guidelines. All authors had access to full data NK1 antagonist aprepitant to standard antiemetic provides pro- and analyses presented in this manuscript. tection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol 2003;21:4105e11. [11] de Wit R, Herrstedt J, Rapoport B, et al. The oral NK1 antag- Conflict of interest statement onist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of BR has received honoraria for speaking engagements cisplatin-based chemotherapy: a combined analysis of two randomized, placebo-controlled phase III clinical trials. Eur J Cancer from MSD and Roche Malaysia; he has been a 2004;40:403e10. consultant and has had travel/accommodations paid for [12] Herrstedt J, Muss HB, Warr DG, et al. Efficacy and tolerability of by MSD and TESARO, Inc. LS has served as a aprepitant for the prevention of chemotherapy induced nausea consultant for TESARO, Inc. Helsinn, and Eisai. DP is and emesis over multiple cycles of moderately emetogenic e an employee of TESARO, Inc. SA has received con- chemotherapy. Cancer 2005;104:1548 55. [13] Longo F, Mansueto G, Lapadula V, et al. Combination of tracting fees from TESARO, Inc., to direct statistical aprepitant, palonosetron and dexamethasone as antiemetic pro- analyses during this study and outside the submitted phylaxis in lung cancer patients receiving multiple cycles of work. IS has served on an advisory board for TESARO, cisplatin-based chemotherapy. J Clin Pract 2012;66:753e7. Inc. MC and RN have declared no conflicts of interest. [14] Gralla RJ, Bosnjak SM, Hontsa A, et al. 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