Reviews on Recent Clinical Trials

Reviews on Recent Clinical Trials Send Orders for Reprints to reprints@benthamscience.ae 193 Reviews on Recent Clinical Trials, 2017, 12, 193-201 REVIEW ARTICLE ISSN: 1574-8871 eissn: 1876-1038 : An NK-1 Receptor Antagonist for the Prevention of Chemotherapy-Induced Nausea and Vomiting BENTHAM SCIENCE Bernardo L. Rapoport* The Medical Oncology Centre of Rosebank, Johannesburg, South Africa Abstract: Background: Nausea and vomiting are among the most feared side effects of chemotherapy and can prevent cancer patients from completing their treatment regimens. is a highly selective neurokinin-1 (NK-1) receptor antagonist with very good oral activity, central nervous system penetration and a long (180-hour) plasma half-life. Unlike other available NK-1 receptor antagonists, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4. AR TIC LE H ISTORY Received: September 30, 2016 Revised: March 14, 2017 Accepted: March 20, 2017 DOI: 10.2174/1574887112666170406104854 Methods: Findings from recent phase II and III clinical trials of rolapitant in patients receiving highly or moderately emetogenic chemotherapy are reviewed and discussed. Results: The addition of a single-dose of rolapitant to combination 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone regimens provided increased protection against chemotherapyinduced nausea and vomiting, a benefit that encompassed the entire at-risk period investigated (0-120 hours after initiation of chemotherapy) in patients receiving highly or moderately emetogenic chemotherapy. was well tolerated by patients in these trials, with the overall frequency of treatment-related adverse events similar in patients receiving rolapitant (7.0%) and active placebo (6.3%). Conclusion: s favorable toxicity profile and lack of CYP3A4-related drug-drug interactions indicate that it would be a suitable treatment for older patients or those with multiple comorbidities, who are likely to be receiving a number of concomitant medications. Future studies should focus on the role of rolapitant in the control of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy, specific chemotherapy agents or high-dose chemotherapy and stem cell support. Keywords: Antiemetics, chemotherapy-induced nausea and vomiting, highly emetogenic chemotherapy, moderately emetogenic chemotherapy, multiple cycles, neurokinin-1 receptor antagonists, phase III clinical trials, rolapitant. 1. INTRODUCTION In the absence of appropriate prophylactic treatment, more than 90% of patients receiving highly emetogenic chemotherapy (HEC) and 30% to 90% of patients receiving moderately emetogenic chemotherapy (MEC) will experience nausea and vomiting [1]. Chemotherapy-induced nausea and vomiting (CINV) has a deleterious effect on healthrelated quality of life (HRQoL) [2] and is one of the most feared side effects of chemotherapy [3]. Furthermore, CINV can prevent patients from completing their chemotherapy regimens or result in dose delays or reductions [4, 5], and it has a significant impact on resource utilization [6]. CINV is driven by a complex multifactorial cascade involving numerous molecular interactions and typically manifests in a biphasic pattern, with acute CINV occurring in the *Address correspondence to this author at The Medical Oncology Centre of Rosebank, 129 Oxford Road, Corner Northwold, Saxonwold, Johannesburg, 2196, South Africa; Tel: +27 11 880 4169; E-mail: brapoport@rosebankoncology.co.za 1876-1038/17 $58.00+.00 first 24 hours after chemotherapy administration and delayed CINV occurring between 24 and 120 hours after treatment [1]. Activation of receptors in the gastrointestinal tract and central nervous system (CNS) by chemotherapy-induced release of neurotransmitters results in afferent signals being sent to the vomiting center in the medulla of the brain. In turn, this triggers efferent impulses to the salivation center, abdominal muscles, respiratory center and cranial nerves, causing vomiting to occur [1, 5]. Nausea is related to vomiting (and may often precede it); however, the pathways driving nausea may be different from those responsible for emesis, with nausea being more common in the delayed than the acute phase [5]. A number of patient features have been identified that increase susceptibility to CINV, including female sex, age <55 years, a history of nausea or vomiting, anxiety, fatigue or motion sickness, impaired quality of life and limited alcohol use [7, 8]. Two of the main receptors involved in the pathophysiology of CINV are the hydroxytryptamine type 3 (5-HT3) receptors and the neurokinin (NK)-1 receptors, which are predominantly involved in the acute and delayed phases of 2017 Bentham Science Publishers

194 Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 Bernardo L. Rapoport CINV, respectively [1]. Stimulation of NK-1 receptors in the gastrointestinal tract may also play a role in mediating acute CINV [9]. In recent years, emetic prophylaxis has focused on the blockade of 5-HT 3 and NK-1 receptors. 5-HT 3 receptor antagonists were first introduced in the early 1990s and have shown particular efficacy in the acute phase of CINV [10]. NK-1 receptor antagonists have been available for prevention of delayed CINV since 2003; they include aprepitant [11-13], fosaprepitant (a prodrug of aprepitant that is administered intravenously) [14], netupitant (administered as a fixed oral combination with the 5-HT 3 receptor antagonist palonosetron) [15, 16] and rolapitant [17-19]. Current guidelines recommend using an NK-1 receptor antagonist together with a 5-HT 3 receptor antagonist and dexamethasone in patients receiving HEC and a 5-HT 3 receptor antagonist and dexamethasone in patients receiving MEC, with further addition of an NK-1 receptor antagonist in patients with additional risk factors [5, 20, 21]; the recently updated Multinational Association of Supportive Care in Cancer (MASCC) and European Society for Medical Oncology (ESMO) guidelines now also recommend the inclusion of an NK-1 receptor antagonist in anti-cinv regimens for patients receiving carboplatin. (Varubi, Tesaro, Inc.) is a new, highly selective oral NK-1 receptor antagonist exhibiting a long (180- hour) plasma half-life [22]. Unlike other available NK-1 receptor antagonists, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4 [23]; therefore, dose adjustment of concomitantly administered drugs metabolized by CYP3A4 (such as dexamethasone) is not required [24]. was approved by the US Food and Drug Administration in 2015 for use in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, HEC. This review focuses on the mechanism of action, pharmacokinetics, efficacy and tolerability of rolapitant for the prevention of CINV in patients receiving HEC or MEC. 2. METHODS PubMed and Google Scholar were searched with the keywords SCH 619734, SCH619734, or Varubi. Published preclinical and clinical studies were included in the review, together with relevant abstracts presented at major international congresses. 3. ROLAPITANT 3.1. Mechanism of Action demonstrated high, subnanomolar binding affinity to the human NK-1 receptor (Ki = 0.66 nm) and was highly selective (>1000-fold) for the human NK-1 receptor over the human NK-2 and NK-3 receptors in in vitro binding studies [25]. In ferrets, acute and delayed emesis induced by cisplatin was blocked by rolapitant in a dose-dependent manner [25]. Initial clinical investigation with rolapitant focused on NK-1 receptor occupancy based on positron emission tomography (PET) in 14 healthy subjects [26]. PET scans with the radiolabeled tracer NK-1 ligand 11 C-GR 205171 were performed at baseline and repeated 120 hours after rolapitant administration. concentrations above 348 ng/ml, achieved at 120 hours with the 200-mg dose level (in salt form; equivalent to rolapitant in freebase form), corresponded to more than 90% NK-1 receptor occupancy in the cerebral cortex. Taken together, these findings indicate that rolapitant is a high-affinity, selective, competitive NK-1 receptor antagonist with very good oral activity and CNS penetration. 3.2. Pharmacokinetics In a single-dose, dose-escalation phase I study performed in 14 healthy volunteers, oral rolapitant was rapidly absorbed, with dose-proportional increases in exposure, maximum plasma concentration and area under the dose-concentration curve [26]. With a single 180-mg dose, maximum plasma concentration was 9 ng/ml, with time to maximum concentration of approximately 4 hours [24]. Pharmacokinetics were not influenced by administration of a high-fat meal [24]. The half-life of rolapitant (approximately 180 hours) [22] is longer than that of other NK-1 receptor antagonists [27-29] and supports a single-dose regimen. A populationbased pharmacokinetic analysis found no difference in plasma rolapitant exposure between patients who responded to treatment and those who did not; exposure was not affected by patient variables such as age, gender, race, chemotherapy regimen, creatinine clearance, liver function, concomitant medications or neutrophil count [30]. is primarily metabolized by the CYP3A4 enzyme. Unlike other marketed NK-1 receptor antagonists [27-29], rolapitant does not inhibit or induce CYP3A4, with no demonstrated effect on the pharmacokinetics of the sensitive CYP3A4 substrate midazolam [23]. However, concurrent use of strong CYP3A4 inducers such as rifampin should be avoided, as these may significantly reduce plasma concentrations of rolapitant [24]. is also a moderate inhibitor of the CYP2D6 enzyme, the breast cancer resistance protein (BCRP) and P-glycoprotein [24]. Caution should be exercised when using rolapitant concomitantly with CYP2D6, BCRP and P-glycoprotein substrates with a narrow therapeutic index [24]. 3.3. Efficacy of for CINV Prophylaxis The efficacy of rolapitant in preventing CINV when added to a 5-HT 3 receptor antagonist and corticosteroid has been evaluated in one phase II and two phase III clinical trials in patients receiving HEC [17, 18] and one phase III clinical trial in patients receiving MEC or anthracycline and cyclophosphamide [19]. Patients included in these studies were required to be 18 years old and have a Karnofsky Performance Status score 60, a predicted life expectancy 4 months ( 3 months for the phase II study) and adequate bone marrow, kidney and liver function. Patients were excluded if they had already received HEC (or MEC in the phase III MEC study). The studies were designed to reflect clinical practice in that any combination of chemotherapeutic drugs could be used as long as it included cisplatin in the HEC studies and at least one of the following agents in the MEC study: intravenous (IV) cyclophosphamide (<1500 mg/m ),

for CINV Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 195 Table 1. Efficacy outcomes with rolapitant versus active control in cycle 1 of phase II and phase III clinical trials. Phase II HEC a [17] Phase III HEC-1 b,c [18] Phase III HEC-2 b,c [18] Phase III MEC c,d [19] Outcome, % (n = 90) Active Control (n = 91) (n = 264) Active Control (n = 262) (n = 271) Active Control (n = 273) (n = 666) Active Control (n = 666) Complete response Delayed phase (>24-120 h) 64* 88 63* 49 67 47 73 84 70 58 74 56 70* 83 62 79 60 7 83 69 62 80 58 No emesis Delayed phase (>24-120 h) 91 67 49 47 78 86 75 62 76 59 73* 86 71 65 82 64 80 88 79 69 85 67 No significant nausea Delayed phase (>24-120 h) 64* 86* 63 47 73 42 73* 86* 72* 65 79 63 75 90 73 69 86 73 82 71 69 85 67 No nausea Delayed phase (>24-120 h) 53 50* 42 61 39 58 73 55 47 44 48 65 45 45 66 42 *P < 0.05; P < 0.01; P 0.001 versus active control. a or identical placebo were administered orally 1-2 hours prior to chemotherapy on day 1. All patients received intravenous ondansetron 32 mg + oral dexamethasone 20 mg on day 1 then oral dexamethasone 8 mg twice daily on days 2-4. b or identical placebo were administered orally 1-2 hours prior to chemotherapy on day 1. All patients received intravenous granisetron 10 μg/kg + oral dexamethasone 20 mg on day 1 then oral dexamethasone 8 mg twice daily on days 2-4. Patients who were treated with taxanes received dexamethasone according to the package insert. c The efficacy evaluation was performed in the modified intent-to-treat population, defined as those who received 1 dose of the study drug at a study site compliant with Good Clinical Practices. d or identical placebo were administered orally 1-2 hours prior to chemotherapy on day 1. All patients received oral granisetron 2 mg + oral dexamethasone 20 mg on day 1, then oral granisetron 2 mg once daily on days 2-3. Patients who were treated with taxanes received dexamethasone according to the package insert. HEC = highly emetogenic chemotherapy, MEC = moderately emetogenic chemotherapy, = not reported. doxorubicin, epirubicin, carboplatin, idarubicin, ifosfamide, irinotecan, daunorubicin or IV cytarabine (>1 g/m ). No restrictions were placed on tumor type or use of concomitant medications (including CYP3A4 inducers or inhibitors). In each of the studies, the primary endpoint was the proportion of patients who experienced a complete response (CR) in cycle 1, defined as no emesis and no use of rescue medication; in the phase II study, the primary endpoint was assessed for the whole 120-hour emetic at-risk period, while it was assessed for the delayed phase (>24-120 hours) in the phase III studies. Rescue therapy was permitted at the discretion of the investigator in patients who experienced intolerable nausea and/or vomiting during the study. Nausea, vomiting and rescue therapy use were self-recorded by patients in a study diary; nausea was assessed using a 100-mm visual analog scale (VAS), with significant nausea defined as a VAS score 25 mm and any nausea defined as a VAS score 5 mm. Patients were able to continue with their randomized antiemetic regimen for up to five additional cycles, irrespective of whether they attained a CR in cycle 1. 3.3.1. Phase II Clinical Trial The phase II clinical trial was a global, multicenter, randomized, double-blind, dose-finding study (NCT00394966) performed to determine whether addition of rolapitant to active antiemetic therapy prevented CINV across the 120- hour emetic risk period in patients receiving HEC ( 70 mg/m 2 cisplatin-based chemotherapy) [17]. Patients were randomized to rolapitant 9 mg (equivalent to 10 mg rolapitant hydrochloride; n = 91), 22.5 mg (25 mg; n = 91), 90 mg (100 mg; n = 91) or (200 mg; n = 90) or placebo (n = 91), administered approximately 2 hours before the first dose of chemotherapy on day 1 of cycle 1. All patients also received IV ondansetron 32 mg and oral dexamethasone 20 mg before chemotherapy on day 1, then dexamethasone 8 mg twice daily on days 2, 3 and 4. Because the study involved multiple comparisons, the CR rate was analyzed in a stepwise manner, starting with the highest dose of rolapitant compared with active control, then sequentially testing for the next lower dose if the previous comparison was statistically significant. A statistically significantly greater CR rate was reported in the rolapitant group compared with the activecontrol group in the overall phase (P = 0.032), as well as the acute phase (P = 0.001) and the delayed phase (P = 0.045), of cycle 1 (Table 1). CR rates were consistently greater in all other rolapitant dose groups (except the 9 mg group in the acute phase) than in the active-control group; however, these differences did not reach statistical significance. Compared with the active-control group, the rolapitant group also reported significantly greater rates of no emesis and no significant nausea across all phases of CINV (Table 1). During cycle 1, 14% of rolapitant recipients required rescue medication compared with 25% in the active-control group,

196 Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 Bernardo L. Rapoport Table 2. Baseline demographics and characteristics of patients enrolled in the phase III trials of rolapitant. Baseline Characteristics, n (%) (n = 264) HEC-1 [18] HEC-2 [18] MEC [19] Active Control (n = 262) (n = 271) Active Control (n = 273) (n = 666) Active Control (n = 666) Females 110 (42) 112 (43) 88 (32) 87 (32) 531 (80) 536 (80) >5 units alcohol/week 11 (4) 29 (11) 26 (10) 21 (8) 29 (4) 41 (6) Geographic region North America Central/South America Europe Asia/South Africa 42 (16) 28 (11) 133 (50) 61 (23) 45 (17) 28 (11) 134 (51) 55 (21) 17 (6) 37 (14) 173 (64) 44 (16) 19 (7) 43 (16) 165 (60) 46 (17) 216 (32) 31 (5) 312 (47) 107 (16) 229 (34) 32 (5) 299 (45) 106 (16) Primary tumor site Breast Colon/rectum Head and neck Lung Ovary Stomach Other 7 (3) 52 (20) 106 (40) 23 (9) 11 (4) 64 (24) 9 (3) 0 55 (21) 98 (37) 25 (10) 9 (3) 66 (25) 5 (2) 45 (17) 129 (48) 10 (4) 23 (8) 58 (21) 17 (6) 0 45 (16) 134 (49) 6 (2) 25 (9) 46 (17) 417 (63) 38 (6) 5 (<1) 102 (15) 33 (5) 8 (1) 63 (9) 428 (64) 27 (4) 6 (<1) 118 (18) 23 (3) 9 (1) 55 (8) Nausea with previous cancer treatment Chemotherapy Radiotherapy 13 (5) 14 (5) 3 (1) 6 (2) 2 (<1) 3 (1) 2 (<1) 2 (<1) 2 (<1) Concomitant use of taxanes during cycle 1 HEC = highly emetogenic chemotherapy, MEC = moderately emetogenic chemotherapy. 50 (19) 57 (22) 39 (14) 39 (14) 199 (3) 185 (28) with a longer time to first emesis or rescue medication use (P = 0.011). Interestingly, the Kaplan-Meier curves for time to first emesis or rescue medication showed clear separation between rolapitant and active control as early as 6 hours, and the two curves remained separated thereafter, indicating that the benefit for rolapitant was evident in the acute phase and sustained through the delayed phase. The results of this study, together with that of the phase I PET study, led to the selection of the rolapitant 180-mg dose (equivalent to 200 mg rolapitant hydrochloride) for further evaluation in phase III trials. 3.3.2. Phase III Clinical Trials 3.3.2.1. HEC Two global, multicenter, randomized, double-blind phase III studies (NCT01499849 and NCT01500213) were performed to evaluate the efficacy and tolerability of rolapitant for prevention of CINV in more than 1000 patients receiving HEC ( 70 mg/m 2 cisplatin-based chemotherapy) [18]. The studies were of identical design, though performed at different centers. Eligible patients were randomized to receive rolapitant (equivalent to 200 mg in salt form) or matched placebo, administered approximately 1-2 hours before the first dose of chemotherapy on day 1 of cycle 1. All patients also received IV granisetron 10 μg/kg plus oral dexamethasone 20 mg approximately 30 minutes before chemotherapy and oral dexamethasone 8 mg twice daily on days 2-4. Patients who were administered taxanes received doses of dexamethasone according to the package insert. It should be noted that current practice guidelines recommend an NK-1 receptor antagonist, a 5-HT 3 receptor antagonist and dexamethasone for prevention of CINV in patients receiving HEC [5, 20, 21]; however, when the protocols for these studies were developed, it was standard practice to use a twodrug combination of a 5-HT 3 receptor antagonist and dexamethasone in HEC. In order to reconcile the study design with current guidelines, the protocol allowed for the prescription of rescue medications where clinically indicated or patient withdrawal from the study and administration of the NK-1 receptor antagonist aprepitant at subsequent cycles of chemotherapy. Baseline characteristics of the patients enrolled in the studies are shown in Table 2. Within each study, treatment groups were well balanced with respect to risk factors for CINV, although there were differences in the populations between studies: HEC-1 had a higher percentage of females, patients from North America and patients using concomitant taxanes, while HEC-2 had a greater proportion of patients from Europe. Tumor types also differed between the two studies. The primary endpoint (CR rate in the delayed phase of cycle 1) was achieved in significantly more patients in the rolapitant group than the active-control group in HEC-1 (odds ratio [OR] 1.9; 95% confidence interval [CI] 1.3-2.7; P = 0.0006) and HEC-2 (OR 1.4; 95% CI 1.0-2.1; P = 0.0426; Table 1). Because the primary endpoint was met in both studies and there was no indication that the treatment effect

for CINV Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 197 Complete response No emesis No clinically significant nausea No nausea Complete protection (n = 535) 382 (71%) 447 (84%) 3 (69%) 404 (76%) 460 (86%) 391 (73%) 396 (74%) 472 (88%) 386 (72%) 298 (56%) 377 (70%) 280 (52%) 350 (65%) 433 (81%) 339 (63%) Active control (n = 535) 322 (60%) 410 (77%) 313 (59%) 340 (64%) 422 (79%) 330 (62%) 358 (67%) 442 (83%) 350 (65%) 237 (44%) 344 (64%) 223 (42%) 295 (55%) 393 (73%) 287 (54%) Odds ratio (95% CI) P value 1.6 (1.3-2.1) 1.6 (1.1-2.1) 1.6 (1.2-2.0) 1.8 (1.4-2.3) 1.6 (1.2-2.3) 1.7 (1.3-2.2) 1.4 (1.1-1.8) 1.6 (1.2-2.3) 1.4 (1.1-1.8) 1.6 (1.2-2.0) 1.3 (1.0-1.7) 1.5 (1.2-2.0) 1.5 (1.2-2.0) 1.5 (1.2-2.1) 1.5 (1.2-1.9) 0.0001 0.0045 0.0005 <0.0001 0.0022 <0.0001 0.0108 0.0090 0.0174 0.0002 0.0304 0.0004 0.0006 0.0033 0.0013 0.5 1 2 4 Favors active control Favors rolapitant Fig. (1). Efficacy response rates with rolapitant versus active control in cycle 1 of phase III clinical trials in patients treated with HEC (pooled analysis in the modified intent-to-treat population) [18]. for CR varied across the studies, it was considered appropriate to pool the results of the two studies. In the pooled analysis, 71% of rolapitant recipients versus 60% of active-control recipients achieved a CR in the delayed phase of cycle 1 (OR 1.6; 95% CI 1.3-2.1; P = 0.0001; Fig. 1). A significantly higher CR rate was also reported with rolapitant in the acute phase and the overall phase in the HEC-1 study and pooled analysis; however, these endpoints were not met in the HEC- 2 study (Table 1; Fig. 1). In the same way, the addition of rolapitant to active therapy produced a significantly higher rate of no emesis, no clinically significant nausea, no nausea and complete protection (defined as no emesis, no use of rescue medication and a maximum VAS score for nausea <25 mm) across the delayed, acute and overall phases of cycle 1 in the HEC-1 study and pooled analysis, with the exception of no nausea in the acute phase in the HEC-1 study (Table 1; Fig. 1). In the HEC-2 study, by contrast, rolapitant produced significantly better outcomes than active control with respect to no emesis in the delayed phase and no nausea in the delayed and overall phase, whereas differences between rolapitant and active control did not reach statistical significance for the other endpoints (Table 1). It is unclear why some of the secondary endpoints were not met in the HEC-2 study, though this may have stemmed in part from the aforementioned differences in patient population between the trials (Table 2), on account of which one population may have inherently been more susceptible to CINV than the other. Kaplan-Meier curves for each treatment group showing time to first emesis or use of rescue medication began to favor rolapitant over active control in the acute phase (around 6 hours), with sustained separation during the delayed phase (Fig. 2A), supporting the hypothesis that rolapitant protects against CINV across the whole 120-hour at-risk period. Interestingly, among the patients who did not achieve a CR in the acute phase, more of those in the rolapitant group than in the active-control group had a CR during the delayed phase. 3.3.2.2. MEC The efficacy of rolapitant in patients treated with MEC has been evaluated in a global, multicenter, randomized, double-blind phase III study (NCT01500226) [19]. This was the first prospective prespecified study to show primary prophylaxis with an NK-1 receptor antagonist for delayed-phase CINV in a population receiving MEC not based exclusively on an anthracycline plus cyclophosphamide [31]. Eligible patients were randomized to receive rolapitant (equivalent to 200 mg rolapitant hydrochloride) or matched placebo, administered approximately 1 to 2 hours before the first dose of chemotherapy on day 1 of cycle 1. All patients also received oral granisetron 2 mg plus oral dexamethasone 20 mg approximately 30 minutes before chemotherapy and oral granisetron 2 mg on days 2-3. Patients administered taxanes received doses of dexamethasone according to the package insert. There were no ethical issues with this treatment design, as guidelines at the time of the study indicated that a two-drug regimen of a 5-HT 3 receptor antagonist plus dexamethasone was appropriate for MEC [5, 20, 21]. The two treatment groups were well balanced at baseline (Table 2). The majority of patients were female (80%), with 64% having breast cancer as their primary tumor site. This is of note, as younger women with breast cancer are more prone to chemotherapy-induced nausea than other populations [32]. Compared with those in the active-control group, patients in the rolapitant group were 60% more likely to achieve a CR in the delayed phase of cycle 1 (OR 1.6; 95% CI 1.2-2.0; P = 0.0002) or the overall phase of cycle 1 (OR 1.6; 95% CI 1.3-2.0; P < 0.0001), although no significant between-treatment difference was reported in the acute phase (Table 1). Significant benefit was also reported with rolapitant in terms of no emesis during the delayed and overall phases; however, no statistically significant differences between treatment groups in rates of no significant nausea or no nausea were reported (Table 1). Kaplan-Meier curves for

198 Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 Bernardo L. Rapoport A Patients without emesis or use of rescue medication (%) Number at risk Active control Active control 100 () 90 P = 0.0001 for between-group comparison 80 70 60 50 40 30 20 10 Acute phase Delayed phase 0 0 24 48 72 96 120 Time or use of rescue medication (h) 535 535 408 448 361 411 339 391 328 376 B Patients without emesis or use of rescue medication (%) 100 90 80 70 60 50 40 30 Number at risk Active control 666 666 P < 0.0001 for between-group comparison 20 Acute 10 phase 0 Delayed phase 0 24 48 72 96 120 533 552 482 507 Active control () Fig. (2). Estimates for proportions of patients without emesis or use of rescue medication (modified intent-to-treat population) in (A) the pooled phase III HEC studies [18] and (B) the phase III MEC study [19]. Reprinted from The Lancet Oncology, Vol. 16, No. 9, Bernardo L. Rapoport et al., "Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials," pp. 1079-89, Copyright 2015, and The Lancet Oncology, Vol. 16, No. 9, Lee S. Schwartzberg et al., "Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial," pp. 1071-8, Copyright 2015, with permission from Elsevier. 430 481 398 462 each treatment group showing time to first emesis or use of rescue medication began to favor rolapitant over active control at around 12 hours, with sustained separation during the delayed phase (Fig. 2B). When this study was designed, chemotherapy regimens based on an anthracycline plus cyclophosphamide were considered moderately emetogenic, and patients receiving this treatment were eligible for participation; however, anthracycline plus cyclophosphamide was recategorized as highly emetogenic after initiation of the trial [33]. A prespecified logistic regression analysis, adjusting for sex, geographic region, age and use of an anthracycline plus cyclophosphamide chemotherapy, was performed to account for this change in classification. This analysis found that the benefit of rolapitant on CR in the delayed and overall phase was maintained whether or not patients were treated with an anthracycline plus cyclophosphamide. While carboplatin is classified as MEC by the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), the incidence of emesis in patients receiving MEC ranges from 30% to 90%, and carboplatin is known to have a higher emetogenic potential than other moderately emetogenic agents [5, 20, 21]; indeed, the MASCC/ESMO guidelines now place carboplatin in a category separate from MEC for antiemetic regimen recommendations. An analysis was recently performed in the subgroup of patients in the rolapitant/mec phase III study [19] that were treated with carboplatin-based chemotherapy [34]. In this subanalysis, significantly higher response rates were achieved in the rolapitant group than in the active-control group in terms of CR, no emesis, no nausea and complete protection in the overall and the delayed phase. The absolute benefit observed with rolapitant in the carboplatin subgroup was 16.7% for the measure of CR in the delayed phase. It should be noted that in a recent trial of fosaprepitant in patients receiving MEC, a CR was achieved by 78.9% of patients who received fosaprepitant and.5% of patients in the control group (P < 0.001); while approximately 53% of the patients enrolled received carboplatinbased chemotherapy, the study was not designed to assess differences in efficacy across different MEC subgroups [35]. Nonetheless, when considered together with the findings of Hesketh and colleagues subgroup analysis of rolapitant in

for CINV Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 199 patients receiving carboplatin-based chemotherapy [34], these data suggest that there may be a class effect of NK-1 receptor antagonists on carboplatin-induced nausea and vomiting. 3.4. Multiple Cycle Extension Failure to protect against CINV in the first cycle of chemotherapy can translate to reduced CINV control in subsequent chemotherapy cycles [36, 37]. The rolapitant clinical trial program allowed analysis of the efficacy of treatment over six cycles of chemotherapy; findings from the four randomized controlled trials previously described have been reported as a pooled analysis [38]. The composite exploratory endpoint of no emesis and no nausea interfering with daily life was reported by significantly more rolapitant recipients than active-control recipients across multiple cycles, reaching statistical significance in cycles 2-5. A clear separation of the Kaplan-Meier time-to-first-emesis curve favored rolapitant as early as cycle 1 and remained consistent over subsequent cycles (P < 0.001). 3.5. Health-Related Quality of Life with The impact of rolapitant on HRQoL was assessed in the phase II and III clinical trials using the Functional Living Index Emesis (FLIE) questionnaire, administered on day 6 of cycle 1, and reported as a total score derived from 18 questions on a seven-point scale. No impact on daily life from symptoms of CINV was defined as a total FLIE score of >108. In the phase II study, 65.1% of rolapitant recipients reported no impact on daily life compared with 44.4% of patients in the active-control group (P = 0.005) [17]. Likewise, in the phase III MEC study, significantly more patients assigned to rolapitant (73%) than to active control (67%) reported no effect on daily life (P = 0.0270) [19]. In the pooled phase III HEC studies, however, the proportion of patients reporting no effect on daily life did not significantly differ between the rolapitant and active-control groups (76% vs. 71% for the pooled HEC analysis; P = 0.0821) [18]. 3.6. Safety and Tolerability of The safety profile of NK-1 receptor antagonists is similar to that of other classes of antiemetic agents [39], with the most commonly reported treatment-emergent adverse events (AEs) being fatigue, constipation, neutropenia, alopecia, diarrhea and headache [40]. Across the four randomized controlled trials, rolapitant was well tolerated, with a similar frequency of treatment-related AEs (7.0%) to that seen in the active-control group (6.3%) [40]. In the phase II HEC study, treatment-related AEs reported with an incidence 2% and more frequently with rolapitant than with control were fatigue (3% vs. 2%) and somnolence (2% vs. 0%) [17]. In the phase III HEC and MEC studies, the incidence of the most common treatment-related AEs was <3% in both the rolapitant and active-control groups [18, 19]. No deaths considered related to rolapitant were reported in the clinical trial program, and no serious adverse events (SAEs) were reported in the phase III studies. In the phase II study, three SAEs were reported that may have been related to treatment (dizziness in the 9 mg group, elevated blood creatinine in the 90 mg group and convulsions in the 90 mg group). In an integrated safety analysis of all four randomized trials, the incidence of treatment-emergent AEs was similar between the rolapitant and control arms in patients who used concomitant CYP2D6, BCRP or CYP3A4 substrate drugs [40]. This suggests that the risk of drug interactions is low when rolapitant is coadministered with such drugs, although caution should be exercised when using rolapitant concomitantly with CYP2D6, BCRP and P-glycoprotein substrates with a narrow therapeutic index. 3.7. Practice Guidelines Current guidelines recommend using an NK-1 receptor antagonist together with a 5-HT 3 receptor antagonist and dexamethasone in patients receiving HEC, and a 5-HT 3 receptor antagonist and dexamethasone, with further addition of an NK-1 receptor antagonist in patients with additional risk factors, in patients receiving MEC [5, 20, 21]. While identified risk factors for CINV include female sex and younger age (<55 years) [7], these factors were not predictors of emesis incidence in a prospective study of patients receiving carboplatin-based chemotherapy [41]. At present, the ASCO and NCCN guidelines for CINV treatment do not include routine prophylaxis with an NK-1 receptor antagonist in patients administered carboplatin-based chemotherapy [5, 21, 33]. However, there is a growing body of literature that suggests that inclusion of an NK-1 receptor antagonist should be considered. As previously discussed, a clinically meaningful benefit (16.3% absolute benefit) was observed in terms of CR in the delayed phase with addition of rolapitant to a 5-HT 3 receptor antagonist and dexamethasone in patients treated with carboplatin-based chemotherapy [34], and several other studies of different NK-1 receptor antagonists also indicate that a triple-drug antiemetic regimen may provide clinical benefit in patients treated with carboplatin [42]. The MASCC/ESMO CINV guidelines suggest that an absolute benefit exceeding 10% is sufficient to warrant a change in treatment recommendation [43], and these guidelines were recently updated to include carboplatin as a special case requiring inclusion of an NK-1 receptor antagonist along with a 5-HT 3 receptor antagonist and dexamethasone in anti- CINV regimens [20]. FUTURE DIRECTIONS / CONCLUSION The robust clinical trial program for rolapitant has demonstrated that a single dose of rolapitant, administered prior to chemotherapy, increases protection against CINV when added to a 5-HT 3 receptor antagonist plus dexamethasone. This benefit is achieved across the entire at-risk period in patients undergoing either HEC or MEC without any relevant additional toxicity. Interestingly, rolapitant demonstrated sustained efficacy over multiple cycles of therapy, which is an important consideration in the context of the adverse impact that CINV can have on patient adherence to cytotoxic treatment. Furthermore, two of the three studies in HEC indicated that significantly more patients receiving rolapitant than active control did not have clinically significant nausea across the overall at-risk period, which is particularly interesting given that nausea has often been viewed as resistant to treatment, particularly in the delayed phase [44]. This may be because nausea is part of a multisymptom

200 Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 Bernardo L. Rapoport cluster [45], making it difficult to assess objectively. Indeed, adequate control of nausea remains an unmet clinical need, and the development and evaluation of future CINV therapies should emphasize nausea control [46, 47]. A promising recent line of inquiry has centered on the atypical antipsychotic olanzapine, which may have antiemetic activity via antagonist actions at 5-HT 3 and dopaminergic receptors [48, 49]. Initial single-institution phase III trials were positive [50] but had methodological shortcomings [51]. However, a multicenter, randomized, double-blind phase III trial designed to evaluate the effects of olanzapine on nausea in patients receiving cisplatin or cyclophosphamide-doxorubicin chemotherapy found that patients receiving olanzapine in addition to aprepitant/fosaprepitant and dexamethasone were less likely to experience nausea in the acute, delayed or overall phases than those receiving placebo plus aprepitant/fosaprepitant and dexamethasone [52]. The favorable toxicity profile of rolapitant, together with its lack of relevant drug-drug interactions, suggests that it would be a suitable treatment for older patients or those with multiple comorbidities who may be likely to be receiving a number of concomitant medications. Future work should examine the role of rolapitant in patients with chemoradiotherapy-induced nausea and vomiting, in those with germ cell tumors receiving multiple-day chemotherapy treatment and in those receiving high-dose chemotherapy and stem cell support. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST BLR has received honoraria and expenses from Herron, Merck and Co. and Tesaro, has sat on advisory boards for Herron, Merck and Co. and Tesaro and has received research funding from Merck and Co. and Tesaro. ACKNOWLEDGEMENTS Hannah Mace, MPharmacol, and Jeremy Kennard, PhD (Ashfield Healthcare Communications, Middletown, CT, USA), drafted and revised the manuscript based on input from the author, and Joshua Safran (Ashfield Healthcare Communications) copyedited and styled the manuscript per journal requirements. REFERENCES [1] Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapyinduced nausea and vomiting. N Engl J Med. 2016; 374: 1356-67. [2] Sommariva S, Pongiglione B, Tarricone R. Impact of chemotherapy-induced nausea and vomiting on health-related quality of life and resource utilization: A systematic review. Crit Rev Oncol Hematol 2016; 99: 13-36. [3] Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: Insights from experienced patients with ovarian cancer. Support Care Cancer 2005; 13: 219-27. [4] Vidall C, Dielenseger P, Farrell C, et al. Evidence-based management of chemotherapy-induced nausea and vomiting: A position statement from a European cancer nursing forum. Ecancermedicalscience 2011; 5: 211. [5] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Antiemesis. Version 2. 2016 [cited: 27 July 2016]. Available from: https://www.nccn.org/professionals/physi cian_gls/pdf/antiemesis.pdf [6] Schwartzberg L, Harrow B, Lal LS, Radtchenko J, Lyman GH. Resource utilization for chemotherapy-induced nausea and vomiting events in patients with solid tumors treated with antiemetic regimens. Am Health Drug Benefits 2015; 8: 273-82. [7] Molassiotis A, Aapro M, Dicato M, et al. Evaluation of risk factors predicting chemotherapy-related nausea and vomiting: Results from a European prospective observational study. J Pain Symptom Manage 2014; 47: 839-48 e4. [8] Dranitsaris G, Bouganim N, Milano C, et al. Prospective validation of a prediction tool for identifying patients at high risk for chemotherapy-induced nausea and vomiting. J Support Oncol 2013; 11: 14-21. [9] Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008; 358: 2482-94. [10] Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis. Support Care Cancer 2007; 15: 1023-33. [11] Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin-- the Aprepitant Protocol 052 Study Group. J Clin Oncol 2003; 21: 4112-9. [12] Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebocontrolled trial in Latin America. Cancer 2003; 97: 3090-8. [13] Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Canc 2010; 18: 423-31. [14] Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol-ease. J Clin Oncol 2011; 29: 1495-501. [15] Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: A randomized dose-ranging pivotal study. Ann Oncol. 2014; 25: 1340-6. [16] Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol 2014; 25: 1328-33. [17] Rapoport B, Chua D, Poma A, et al. Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Canc 2015; 23: 3281-8. [18] Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: Two randomised, activecontrolled, double-blind, phase 3 trials. Lancet Oncol 2015; 16: 1079-89. [19] Schwartzberg LS, Modiano MR, Rapoport BL, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial. Lancet Oncol 2015; 16: 1071-8. [20] MASCC/ESMO. Antiemetic guideline. Version 1.1. 2016 [cited: 27 July 2016]. Available from: http://www.mascc.org/assets/guidelines-tools/mascc_antiemetic_guidelines_english_2016_v.1.2.pdf [21] Hesketh PJ, Bohlke K, Lyman GH, et al. Antiemetics: American Society of Clinical Oncology focused guideline update. J Clin Oncol 2016; 34: 381-6.

for CINV Reviews on Recent Clinical Trials, 2017, Vol. 12, No. 3 201 [22] Gan TJ, Gu J, Singla N, et al. for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg 2011; 112: 804-12. [23] Poma A, Christensen J, Pertikis H, Arora S, Hedley M. and its major metabolite do not affect the pharmacokinetics of midazolam, a sensitive cytochrome P450 3A4 substrate. Support Care Canc 2013; 21: S154. Abstract 441. [24] Varubi [package insert]. Waltham, MA: Tesaro. 2015. [25] Duffy RA, Morgan C, Naylor R, et al. (SCH 619734): A potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets. Pharmacol Biochem Behav 2012; 102: 95-100. [26] Poma A, Christensen J, Davis J, et al. Phase 1 positron emission tomography (PET) study of the receptor occupancy of rolapitant, a novel NK-1 receptor antagonist. J Clin Oncol 2014; 32(Suppl): Abstract e20690. [27] Akynzeo [package insert]. Woodcliff Lake, NJ: Eisai Inc. 2015. [28] Emend for injection [package insert]. Whitehouse, NJ: Merck Sharp & Dohme Corp. 2016. [29] Emend [package insert]. Whitehouse, NJ: Merck Sharp & Dohme Corp. 2015. [30] Wang X, Wang J, Kansra V. Population pharmacokinetics of rolapitant in patients with chemotherapy-induced nausea and vomiting. European Cancer Congress; Vienna, Austria; 25-29 Sept. 2015: Poster 1588. [31] Olver I. Role of rolapitant in chemotherapy-induced emesis. Lancet Oncol 2015; 16: 1006-7. [32] Roscoe JA, Morrow GR, Colagiuri B, et al. Insight in the prediction of chemotherapy-induced nausea. Support Care Canc 2010; 18: 869-76. [33] Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011; 29: 4189-98. [34] Hesketh PJ, Schnadig ID, Schwartzberg LS, et al. Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-based chemotherapy. Cancer 2016; 122: 2418-25. [35] Weinstein C, Jordan K, Green SA, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: results of a randomized, double-blind phase III trial. Ann Oncol 2016; 27: 172-8. [36] Ellebaek E, Herrstedt J. Optimizing antiemetic therapy in multipleday and multiple cycles of chemotherapy. Curr Opin Support Palliat Care 2008; 2: 28-34. [37] Kim HK, Hsieh R, Chan A, et al. Impact of CINV in earlier cycles on CINV and chemotherapy regimen modification in subsequent cycles in Asia Pacific clinical practice. Support Care Canc 2015; 23: 293-300. [38] Rapoport B, Schwartzberg L, Chasen M, et al. Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy. Eur J Canc 2016; 57: 23-30. [39] Navari RM. The safety of antiemetic medications for the prevention of chemotherapy-induced nausea and vomiting. Expert Opin Drug Saf 2016; 15: 343-56. [40] Barbour S, Wang X, Poma A, et al. Low risk of drug interactions with rolapitant is coadministered with CYP2S6 or BCRP substrates: integrated safety results. European Cancer Congress; Vienna, Austria; 25-29 Sept. 2015: Poster 1529. [41] Waqar SN, Mann J, Baggstrom MQ, et al. Delayed nausea and vomiting from carboplatin doublet chemotherapy. Acta Oncol 2016; 55: 700-4. [42] Jordan K, Jahn F, Aapro M. Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): A comprehensive review. Ann Oncol 2015; 26: 1081-90. [43] Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapyinduced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21(Suppl 5): v232-43. [44] Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptaminereceptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: A URCC CCOP randomised controlled trial. Lancet Oncol 2005; 6: 765-72. [45] Olver IN, Eliott JA, Koczwara B. A qualitative study investigating chemotherapy-induced nausea as a symptom cluster. Support Care Canc 2014; 22: 2749-56. [46] Ng T, Mazzarello S, Wang Z, et al. Choice of study endpoint significantly impacts the results of breast cancer trials evaluating chemotherapy-induced nausea and vomiting. Breast Cancer Res Treat 2016; 155: 337-44. [47] Ng TL, Hutton B, Clemons M. Chemotherapy-induced nausea and vomiting: Time for more emphasis on nausea? Oncologist 2015; 20: 576-83. [48] Bymaster FP, Calligaro DO, Falcone JF, Marsh RD, Moore NA, Tye NC, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996; 14: 87-96. [49] Bymaster FP, Falcone JF, Bauzon D, Kennedy JS, Schenck K, DeLapp NW, et al. Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine. Eur J Pharmacol. 2001; 430: 341-9. [50] Hocking CM, Kichenadasse G. Olanzapine for chemotherapyinduced nausea and vomiting: A systematic review. Support Care Canc 2014; 22: 1143-51. [51] Fonte C, Fatigoni S, Roila F. A review of olanzapine as an antiemetic in chemotherapy-induced nausea and vomiting and in palliative care patients. Crit Rev Oncol Hematol 2015; 95: 214-21. [52] Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med. 2016; 375: 134-42.