Support Care Cancer (2010) 18:423431 DOI 10.

1007/s00520-009-0680-9

ORIGINAL ARTICLE

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
Bernardo L. Rapoport & Karin Jordan & Judith A. Boice & Arlene Taylor & Carole Brown & James S. Hardwick & Alexandra Carides & Timothy Webb & Hans-Joachim Schmoll

Received: 31 March 2009 / Accepted: 8 June 2009 / Published online: 1 July 2009 # Springer-Verlag 2009

Abstract Purpose Aprepitant was shown previously to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving an anthracycline and cyclophosphamide (AC)-based regimen. This study
B.L.R., K.J., J.A.B., A.T., C.B., J.S.H., A.C., T.W., and H.J.S. are responsible for the work described in this manuscript. All authors were involved in at least one of the following: study conception, study design, data acquisition, data analysis, statistical analysis, and data interpretation. All authors were involved in drafting the manuscript and/or revising the manuscript for important intellectual content. All authors provided final approval of the version to be published. NCT registry number: NCT00337727. B. L. Rapoport Medical Oncology Center of Rosebank, Johannesburg, South Africa K. Jordan : H.-J. Schmoll Departments of Internal Medicine and Oncology/Hematology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany J. A. Boice (*) Merck Research Laboratories, Rahway, NJ, USA e-mail: judith_boice@yahoo.com A. Taylor : C. Brown : J. S. Hardwick : A. Carides Merck Research Laboratories, Upper Gwynedd, PA, USA T. Webb Genesis Cancer Center, Hot Springs, AR, USA

assessed aprepitant in patients receiving a broad range of MEC regimens with a variety of tumor types. Methods This phase III, randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, nave to MEC or highly emetogenic chemotherapy, who were scheduled to receive a single dose of at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant, ondansetron, and dexamethasone) or a control regimen (ondansetron and dexamethasone) administered orally. Primary and key secondary efficacy endpoints were proportions of patients with no vomiting and complete response (no vomiting and no rescue medication), respectively, during the 120 h post-chemotherapy. Results Of 848 randomized patients, 77% were female, and 52% received non-AC-based antineoplastic regimens. Significantly, more patients in the aprepitant group achieved no vomiting and complete response, regardless of whether they received AC or non-AC regimens, in the 120 h after chemotherapy. Overall, the incidences of adverse events were generally similar in the aprepitant (62.8%) and control groups (67.2%). Conclusions The aprepitant regimen provided superior efficacy in the treatment of CINV in a broad range of patients receiving MEC (non-AC or AC) in both no vomiting and complete response endpoints. Aprepitant was generally well tolerated. These results show the benefit of including aprepitant as part of the standard antiemetic regimen for cancer patients receiving MEC. Keywords Aprepitant . NK1 antagonist . Moderately emetogenic chemotherapy . MEC . Nausea and vomiting . CINV

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Introduction Despite significant progress in its management, nausea and vomiting continues to be among the most feared side effects of cancer patients receiving chemotherapy [1]. Uncontrolled nausea and vomiting can limit the effectiveness of cancer therapy and reduce patient quality of life [2]. The incidence of chemotherapy-induced nausea and vomiting (CINV) is primarily determined by the dose and type of chemotherapeutic agent(s) administered. Published classification schemes for emetogenicity of chemotherapeutic agents generally concur that agents such as cyclophosphamide, anthracyclines (doxorubicin and epirubicin), carboplatin, irinotecan, and oxaliplatin should be defined as moderately emetogenic [35]. Current antiemetic guidelines for moderately emetogenic chemotherapy (MEC) recommend different treatments depending on the type of MEC being used. For MEC regimens based on an anthracycline and cyclophosphamide (AC), the antiemetic recommendation is the use of an NK1 receptor antagonist plus a 5-HT3 receptor antagonist and dexamethasone prior to chemotherapy followed by an NK1 receptor antagonist and/or dexamethasone following chemotherapy [4, 5]. For MEC regimens not based on cyclophosphamide/anthracyclines, the guidelines generally recommend the use of a 5-HT3 receptor antagonist and dexamethasone prior to chemotherapy followed by dexamethasone or (alternatively) a 5-HT3 receptor antagonist following chemotherapy [46]. Several large clinical studies have established that addition of an NK1 receptor antagonist to a 5-HT3 receptor antagonist and dexamethasone improved prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC), both in the acute phase (024 h) and delayed phase (25120 h) after chemotherapy [79]. Recent results from a large study in breast cancer patients showed that aprepitant added to ondansetron and dexamethasone was effective in preventing CINV in breast cancer patients receiving AC [10]. However, there is also a need to improve the prevention of
Table 1 Study drug schedule Regimen Study medication Dose Day1 Aprepitant (n =430) Control (n =418) Aprepitant Ondansetron Dexamethasone Aprepitant Ondansetron Dexamethasone

CINV in cancer patients receiving non-AC MEC regimens, as the control is still suboptimal in these patients [11]. This study of aprepitant in a broad population of cancer patients was designed to investigate the ability of aprepitant to prevent nausea and vomiting induced by a range of MEC agents in a diverse group of cancer patients. The study compared an aprepitant regimen to an active control regimen in preventing CINV throughout the acute and delayed phases (0120 h (overall phase)) after initiation of chemotherapy. The primary hypothesis was that the aprepitant regimen would be more effective in reducing vomiting induced by a broad spectrum of MEC regimens, but that the safety and tolerability of the two regimens would be similar. A key secondary hypothesis was that the aprepitant regimen would be superior to the active control regimen with respect to complete response (defined as no vomiting and no administration of rescue therapy) in the first 120 h post-initiation of chemotherapy. Another secondary hypothesis was that the aprepitant regimen would be superior to the control regimen for time to first emetic event.

Patients and methods Study design This study (protocol 130) was a prospective, randomized, double-blind, parallel-group trial conducted under in-house blinding conditions at sites in the USA, Mexico, Canada, Chile, Brazil, Peru, Colombia, Panama, Hong Kong, Australia, South Africa, France, Germany, Israel, and Russia between January 2007 and December 2008. The study focused on patients receiving an initial cycle of MEC (cycle 1). The results presented here are for cycle 1 only. Patients were assigned to one of two treatment groups and instructed to take a daily dose of the study drug according to the regimens listed in Table 1. Patients used a diary to report episodes of vomiting, use of rescue therapy, and

Day2 80 mg po Placebo po bid Placebo po 8 mg po bid

Day3 80 mg po Placebo po bid Placebo po 8 mg po bid

125 mg po 1 h prior to chemotherapy 8 mg po 3060 min prior to chemotherapy; 8 mg po 8 h after first dose 12 mg po 30 min prior to chemotherapy Placebo po 1 h prior to chemotherapy 8 mg po 3060 min prior to chemotherapy; 8 mg po 8 h after first dose 20 mg po 30 min prior to chemotherapy

po orally, bid every 12 h

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daily nausea assessments from the initiation of chemotherapy infusion (0 h) until the morning of day 6 (120 h) after infusion. In this study, ondansetron was chosen as the 5-HT3 receptor antagonist, and dexamethasone was chosen as the corticosteroid, and the doses for both are consistent with the recommendation in the aprepitant product label for prevention of CINV in the MEC population ([10] aprepitant prescribing information). The dexamethasone dose was reduced in the aprepitant regimen due to the observation that coadministration of aprepitant approximately doubles dexamethasone serum levels [12]. If a patient was scheduled to receive a taxane as part of chemotherapeutic regimen, they were premedicated with non-study drug dexamethasone in order to prevent hypersensitivity reactions and thus were not given study drug dexamethasone just prior to chemotherapy. Patients scheduled to receive paclitaxel were administered two 20 mg oral doses of dexamethasone, one 12 h and another 6 h prior to paclitaxel. Patients scheduled to receive docetaxel were given 8 mg dexamethasone orally, twice daily, one day prior to, the day of, and one day after the start of docetaxel treatment. The primary efficacy endpoint was the proportion of patients reporting no vomiting during the 5 days following initiation of chemotherapy. The key secondary efficacy endpoint was the overall complete response (no emetic episodes and no administration of rescue therapy) during the 5 days (120 h) following the initiation of chemotherapy. Patients Male and female patients 18 years of age, nave to moderately or HEC [35], with histologically confirmed malignancies, Karnofsky scores 60, a predicted life expectancy 4 months, and scheduled to be treated with a single dose of one or more of the following MEC agents were eligible to participate: any IV dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin, cyclophosphamide IV (<1,500 mg/m2), or cytarabine IV (>1 g/m2). Patients were excluded if they had a symptomatic primary or metastatic central nervous system malignancy (asymptomatic patients were allowed), were scheduled to receive any dose of cisplatin, had received or were to receive radiation therapy to the abdomen or pelvis in the week prior to treatment, had vomited in the 24 h prior to treatment, had a history of treatment with MEC or HEC [3], had an active infection or any uncontrolled disease other than malignancy, or had abnormal laboratory values (absolute neutrophil count <1,500/mm3, white blood cell count <3,000/mm3, platelet count <100,000/mm3, aspartate transaminase >2.5 upper limit of normal, alanine transaminase >2.5 upper limit of normal, bilirubin >1.5 upper

limit of normal, creatinine >1.5 upper limit of normal). Patients taking systemic corticosteroid therapy at any dose were excluded; however, topical and inhaled corticosteroids were permitted. Prior to initiation of the study, an informed consent agreement explaining the procedures of the study, together with the potential risks, was read by and explained to each patient. Each patient or patient representative signed and received a dated copy of the informed consent form and was assured of his/her freedom to withdraw from participation in the study at any time. Assessments During the first 120 h after initiation of chemotherapy, patients recorded the time and date of nausea and vomiting episodes in a diary. A vomiting episode was defined as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retches (an attempt to vomit that is not productive of stomach contents), distinct episodes being defined as those separated by at least 1 min. Patients assessed nausea daily using a 100-mm horizontal visual analog scale (VAS). If rescue therapy was taken, patients recorded the drug and the date and time of administration. Statistical analysis Patients who met the inclusion and exclusion criteria were stratified by gender and assigned to one of the two treatment groups according to a computer-generated, random, blinded allocation schedule. This was a doubleblind study, with in-house blinding. The investigator, study nurse, study participant, and sponsor personnel remained blinded to the treatment group assignments. To ensure inhouse blinding, the randomized allocation schedule was generated by an assistant statistician who was otherwise uninvolved with the study. A sample size of 395 assessable patients per regimen would have yielded approximately 99% power to detect the superiority of the aprepitant regimen as measured by the proportion of patients reporting no vomiting during the 120 h following initiation of chemotherapy, assuming that the response rate for the standard regimen would be approximately 60% (comparable to a previous Merck & Co. study with AC-based MEC in breast cancer patients [10]) and that the true aprepitant regimen effect would be 15% points higher than the standard regimen. Based on the same sample size and assuming a two-sided 5% significance level for testing the key secondary efficacy hypothesis relating to the complete response endpoint, the study had 80% power to detect superiority for the aprepitant regimen, assuming a response rate for the standard regimen of approximately 40% (comparable to the previous study described in [10]) and

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that the true aprepitant regimen effect is 10% points higher than the standard regimen. The primary efficacy analysis compared the aprepitant regimen to the control regimen with respect to the proportion of patients reporting no vomiting 0 to 120 h following initiation of chemotherapy. The key secondary efficacy analysis compared the aprepitant regimen to the control regimen with respect to the proportion of patients reporting complete response 0 to 120 h following initiation of chemotherapy. The treatment comparisons utilized a logistic regression model that included terms for treatment, gender, and investigative center. The centers were combined to form three region groups (North America, Central and South America, and International) to avoid sparse data problems. The consistency of the treatment effect across gender and across investigative center was explored by including the treatment-by-gender and treatment-byinvestigative center interaction term (one at a time) in the logistic regression model. If the p value for testing the interaction term was greater than 0.10, then the interaction term was considered not significant. For the primary and key secondary analyses, all p values for interaction terms were greater than 0.10. The final model did not include treatment interaction terms. Unlike the primary and key secondary endpoints, the statistical significance for the other endpoint tests was based on Hochbergs multiple comparison procedure, using the p values from the logistic regression model or the logrank statistic [13]. The Log-rank test stratifying on gender was used for the treatment comparison. The proportions reported for the two chemotherapy subgroups (AC and nonAC) were calculated (number of patients with favorable response/number of patients included in corresponding subgroup) but not included in a model for treatment group comparisons. Safety and tolerability were assessed in all patients by statistical and clinical review of all safety parameters, including adverse events and laboratory values. Laboratory safety tests were performed three times, once at baseline, once between days 6 and 8, and once between days 14 and 29. Treatment comparisons were made with respect to the proportion of patients who reported one or more adverse event(s), drug-related adverse event(s), or serious adverse event(s) during the study drug therapy period plus 14 days post-therapy or drug-related adverse event(s) leading to discontinuation of study therapy. Fisher s exact test was used to make treatment comparisons for incidence of adverse events for the pre-specified categories (patients with one or more adverse events, drug-related adverse events, serious adverse events, and study discontinuations due to adverse events). National Cancer Institute (NCI) toxicity criteria (version 3.0) were used to assign toxicity grades to all laboratory test results. These criteria were also

used to assign toxicity grades to all adverse events based on an assessment by the investigator.

Results Patients Of the 949 patients screened for inclusion in the study, 101 patients (10.6%) were excluded during screening and not randomized (Fig. 1). The remaining 848 patients were randomly allocated to either the aprepitant treatment regimen or the control regimen. Five patients (four in the aprepitant regimen group and one in the standard regimen group) were randomized into the study even though they did not meet all eligibility criteria. That inclusion and exclusion criteria were not met for these five patients was reported retrospectively to the study coordinators and study sponsor. These five patients were administered study drug, were included in the safety analysis, and met criteria to be included in the analyzed patient population. The analysis of efficacy was based on the full analysis set population, which included those patients who received MEC, took a dose of study drug, and completed at least one posttreatment efficacy assessment. All patients who received at least one dose of study drug were included in the safety analyses. Patient characteristics are listed in Table 2. Both treatment groups were similar with respect to baseline characteristics. The majority of patients were female (652/ 848, 77%) and white (583/848, 69%) with an average age of 57 years. Breast cancer was the most common diagnosed malignancy (52% of randomized patients), followed by colorectal cancer (20%), lung cancer (13%), and ovarian cancer (4.6%). Forty-eight percent of patients received a chemotherapy regimen consisting of an anthracycline (doxorubicin and epirubicin) and cyclophosphamide. Ninety-nine percent of patients who received cyclophosphamide chemotherapy also received an anthracycline. The proportion of patients who had a history of motion sickness or vomiting associated with pregnancy was slightly lower in the aprepitant regimen group than in the standard therapy regimen group. There were no clinically meaningful differences between treatment groups in the percentage of patients who completed treatment, and the reasons for discontinuation were similar between treatment groups. The study medication disposition indicates that greater than 98% of patients completed all their medication according to the protocol, and the proportion was similar in both treatment groups. Overall, there were no meaningful differences between the treatment groups in the reasons why patients did not complete the study or study medication (Fig. 1).

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Screened (n = 949)

427

Excluded (n = 101) Ineligible (n = 66) Withdrew consent (n = 22) Deviated from protocol (n = 11) Adverse event (n = 1) Trial Terminated (n = 1)

Randomized (n=848)

Allocated to aprepitant regimen (n = 430)

Allocated to control regimen (n = 418)

Discontinued (n = 18) Adverse event (n = 5) Protocol deviation (n = 4) Lost to follow-up (n = 5) Withdrew consent (n = 3) Other (n = 1)

Discontinued (n= 12) Adverse event (n = 3) Lost to follow-up (n = 4) Withdrew consent (n = 5)

Included in efficacy analysis (n = 425)

Included in efficacy analysis (n = 407)

Excluded (n = 5) No chemotherapy (n = 1) No efficacy data (n = 1) No chemotherapy start date (n = 3)

Excluded (n = 11) No chemotherapy (n = 3) No efficacy data (n = 3) No chemotherapy start date (n = 5)

Fig. 1 Study flow chart. Patient disposition during study

Table 2 Patient characteristics

Characteristics

Percent of patients Aprepitant regimen (n =430) Control regimen (n =418) 77.8 22.2 55.9 (12.6) 9.8 17.9a 52.6 20.0 13.3 3.3 51.2 48.8

Female Male Age, years Mean (SD) History of motion sickness History of vomiting during pregnancy Primary diagnosis Breast cancer Colon cancer Lung cancer Ovarian cancer Chemotherapy regimen non-AC AC

76.0 24.0 57.1 (11.8) 5.6 14.2a 50.1 20.0 11.8 5.8 53.5 46.5

SD standard deviation, AC anthracycline/cyclophosphamidebased chemotherapy

a

Only female patients considered for vomiting during pregnancy

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Efficacy: all chemotherapies The primary efficacy endpoint was the proportion of patients reporting no vomiting during the 5 days (0 to 120 h) following initiation of chemotherapy. In this overall phase, significantly more patients in the aprepitant group reported no vomiting compared to those in the control group (76.2% vs 62.1%, p <0.001; Fig. 2a). There was no evidence of treatment by subgroup interactions. In both the acute (024 h) and delayed phases (25120 h), significantly more patients in the aprepitant group reported no vomiting compared to the control group (92.0% vs 83.7%, nominal p <0.001, and 77.9% vs 66.8%, nominal p <0.001, respectively; Fig. 2b, c). The key secondary efficacy endpoint was overall complete response, defined as no emetic episodes and no administration of rescue therapy during the 5 days (0 120 h) following chemotherapy. Significantly, more patients in the aprepitant group reported complete response compared to the control group (68.7% vs 56.3%, p <0.001; Fig. 2a). In addition, significantly more patients in the aprepitant group reported complete response compared to the control group in both the acute and delayed phases (89.2% vs 80.3%, nominal p <0.001, and 70.8% vs 60.9%, nominal p <0.01, respectively; Fig. 2b, c). KaplanMeier curves for time to first vomiting, regardless of use of rescue therapy, in the first 120 h after chemotherapy are shown in Fig. 3. The KaplanMeier curves depict the cumulative percentage of patients who remained vomiting-free since the initiation of chemotherapy and show that the time to first vomiting was longer in patients in the aprepitant group compared with the control group (nominal p <0.001). The proportion of patients with no significant nausea (maximum nausea VAS<25 mm) in the first 120 h following chemotherapy, regardless of whether or not the patient took rescue therapy, was significantly higher in the aprepitant group compared to the control group (73.6% vs 66.4%, respectively, nominal p <0.05). In order to compare the no vomiting and complete response endpoints between the aprepitant and control groups in patients receiving different types of chemotherapy regimens, a post hoc analysis of patients who received AC versus non-AC chemotherapy was carried out. Efficacy: AC-based chemotherapies Among those receiving AC-based chemotherapy, more patients in the aprepitant group reported no vomiting compared to those in the control group, in the overall phase as well as in the acute and delayed phases (68.3% vs 52.9%, 86.9% vs 76.0%, and 70.4% vs 59.8%, respectively; Fig. 2), consistent with previous results [10]. Similarly, more

patients in the aprepitant group compared to the control group reported complete response in all phases (62.8% vs 47.1%, 84.3% vs 72.5%, and 64.8% vs 52.9% for overall, acute, and delayed phases, respectively). Efficacy: non-AC-based chemotherapies Among those receiving non-AC-based chemotherapy regimens, more patients in the aprepitant group reported no vomiting compared to those in the control group in all phases (overall: 83.2% vs 71.3%; acute: 96.5% vs 91.6%; delayed: 84.5% vs 73.9%; Fig. 2) and complete response in all phases (overall: 73.9% vs 65.5%; acute: 93.4% vs 88.1%; delayed: 76.1% vs 69.0%; Fig. 2). Tolerability The adverse event profile and most common adverse events (5%) are summarized by treatment group in Table 3. Adverse events were reported by 551 (65%) of the 848 randomized patients and were generally similar in the aprepitant and standard regimen groups. No significant differences between the aprepitant regimen and the standard regimen were identified in adverse event categories. The most frequently reported adverse events in both the aprepitant regimen and standard regimen groups were constipation, fatigue, headache, and diarrhea. With the exception of constipation, all 95% confidence intervals for the treatment difference contained zero, suggesting the two treatment groups are comparable (data not shown). For constipation, the incidence was lower in the aprepitant regimen, but the upper bound of the 95% confidence interval is close to zero (data not shown). NCI toxicity grades for the most common adverse events were generally grades 1 and 2 with none greater than grade 3. Nausea and vomiting were reported as clinical adverse events if they occurred after the treatment period (day 6 or greater) or if the investigator determined that the event was serious, drug-related, or if the event resulted in study discontinuation. There were 19 patients (4.4%) in the aprepitant group and 11 patients (2.6%) in the control group who experienced an adverse event of nausea. Of these patients, three in the aprepitant group had grade 4 nausea. There were nine patients (2.1%) in the aprepitant group and six patients (1.4%) in the control group with an adverse event of vomiting. Of these patients, one in the aprepitant group had grade 4 vomiting. In addition, there were 11 patients (2.6%) in each of the aprepitant and control groups who had an adverse event of neutropenia. Four patients in each group had grade 4 neutropenia while one patient in the aprepitant group had grade 5 neutropenia. The incidence of febrile neutropenia was low and similar in the two groups: five patients (1.2%) in the aprepitant group

Support Care Cancer (2010) 18:423431 Fig. 2 No vomiting and complete response. Bar graph showing percentage of patients achieving no vomiting and complete response endpoints during the 120 h following chemotherapy administration. Complete response is defined as no vomiting and no use of rescue medication. p values are for pre-specified between-group comparisons (using Hochbergs multiple comparison procedure [13], with the p values from the logistic regression model). The # symbol indicates significance (p<0.05) for between-group comparisons. AC anthracycline/ cyclophosphamide-based chemotherapy, gray bars aprepitant regimen, white bars control regimen. Acute phase=024 h post-chemotherapy, delayed phase=25120 h post-chemotherapy, overall phase=0120 h post-chemotherapy

429

Overall Phase
All Chemo Regimens
100
p < 0.01 p < 0.01 324 292 252

AC
100
#

Non-AC

100 90 80 70

90 80 70
136 # # 125

90
188

80
144 167 133

70

Patients (%)

Patients (%)

60 50 40 30 20 10 0
No Vomiting

229

60
108

Patients (%)

60 50 40 30 20 10 0

50 40 30 20 10 0

96

Comple te Re sponse

No Vomiting

Comple te Re sponse

No Vomiting

Comple te Re sponse

Aprepitant Regimen (n=425) Control Regimen (n=407)

Aprepitant Regimen (n=199) Control Regimen (n=204)

Aprepitant Regimen (n=226) Control Regimen (n=203)

Acute Phase
All Chemo Regimens AC
100
# 378 340 326 # p < 0.01 390 #

Non-AC
211 178

100 90 80 70

p < 0.01

100
172 155

218 185

90 80 70

90
167

80
148

70

Patients (%)

Patients (%)

60 50 40 30 20 10 0
No Vomiting Comple te Re sponse

60 50 40 30 20 10 0
No Vomiting Complete Response

Patients (%)

60 50 40 30 20 10 0
No Vomiting Complete Response

Aprepitant Regimen (n=424) Control Regimen (n=406)

Aprepitant Regimen (n=198) Control Regimen (n=204)

Aprepitant Regimen (n=226) Control Regimen (n=202)

C
100 90 80 70

Delayed Phase
All Chemo Regimens
100
p < 0.01 p < 0.01 331 301 272

AC
100 90
# 140 129 122 108 # # 191

Non-AC

90 80 70

80
150

172 140

70

Patients (%)

Patients (%)

60 50 40 30 20 10 0
No Vomiting Complete Response

60 50 40 30 20 10 0

Patients (%)

248

60 50 40 30 20 10 0

No Vomiting

Comple te Re sponse

No Vomiting

Complete Re sponse

Aprepitant Regimen (n=425) Control Regimen (n=407)

Aprepitant Regimen (n=199) Control Regimen (n=204)

Aprepitant Regimen (n=226) Control Regimen (n=203)

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Fig. 3 KaplanMeier curves for time to first vomiting episode during the first 120 h following chemotherapy administration. Solid line aprepitant regimen, dashed line control regimen

and three patients (0.7%) in the control group. One patient in each group had grade 4 febrile neutropenia.

Discussion CINV is a potent and feared side effect of antineoplastic therapy. CINV can limit the efficacy of cancer treatments and has a strong negative effect on patient quality of life. Antiemetic therapy should aim to minimize or eliminate CINV in all cancer patients receiving chemotherapy in as large a patient population as possible. This large phase III clinical trial is the first pivotal study to evaluate aprepitant in patients receiving MEC other than ACbased chemotherapy. The study evaluated the effectiveness of
Table 3 Clinical adverse events

the NK1 receptor antagonist aprepitant as a component of a triple regimen (with dexamethasone and a 5-HT3 receptor antagonist) for the prevention of CINV in a diverse population of patients including men and women with a variety of tumor types receiving a broad range of moderately emetogenic chemotherapies. In this expanded setting of MEC regimens and diverse patients, the addition of aprepitant to the antiemetic regimen of ondansetron and dexamethasone was superior to ondansetron and dexamethasone alone, resulting in greater proportions of patients reporting no vomiting and complete response over the 5 days following chemotherapy (overall phase). Regardless of age category, gender, region group, and most race groups, the aprepitant regimen provided better control than the standard regimen with respect to the no vomiting and complete response endpoints. Of note, proportions of responders were higher in males than in females and the treatment group differences were smaller in males. These results will be explored in more detail in subsequent reports. Also of note, the proportion of patients with no significant nausea in the overall phase was significantly higher in the aprepitant group compared to the control group. In contrast to a previous trial in breast cancer patients receiving AC-based MEC [10], this study found that the aprepitant regimen provided a significant improvement over the control regimen for the complete response in all phases (acute, delayed, and overall) in patients receiving AC- and non-AC-based MEC. The previous study in the more limited patient population found significant differences between the aprepitant and control groups only in the acute and overall phases, and those differences were restricted to patients receiving AC-based MEC, the sole population of patients evaluated in that study.

Percent of patients Aprepitant regimen (n =430) Adverse events Patients with one or more adverse events Drug-relateda Serious Discontinuations due to adverse events Discontinuations for any reason Specific adverse events (5%) Constipation Fatigue Headache Diarrhea Anorexia Alopecia Asthenia 62.8 7.2 2.8 0.2 4.2 8.6 10.9 10.0 9.8 8.1 6.5 6.3 67.2 9.3 4.8 0.5 2.9 13.4 9.8 12.2 11.2 8.9 7.7 5.5 0.195 0.318 0.150 0.619 Control regimen (n =418) p valueb

Considered by the investigator to be possibly, probably, or definitely related to the study drug p values are from Fisher s exact test and are only shown for pre-specified comparisons

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431 2. Oo TH, Hesketh PJ (2005) Drug insight: new antiemetics in the management of chemotherapy-induced nausea and vomiting. Nat Clin Pract Oncol 2(4):196201 3. Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, Aapro MS, Gandara D, Lindley CM (1997) Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol 15(1):103109 4. Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, Morrow GR, Chinnery LW, Chesney MJ, Gralla RJ, Grunberg SM (2006) American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24(18):29322947 5. Roila F, Fatigoni S (2006) New antiemetic drugs. Ann Oncol 17 (Suppl 2ii):96100 6. Jordan K, Sippel C, Schmoll HJ (2007) Guidelines for antiemetic treatment of chemotherapy-induced nausea and vomiting: past, present, and future recommendations. Oncologist 12(9):11431150 7. Campos D, Pereira JR, Reinhardt RR, Carracedo C, Poli S, Vogel C, Martinez-Cedillo J, Erazo A, Wittreich J, Eriksson LO, Carides AD, Gertz BJ (2001) Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 19(6):17591767 8. Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, Chawla SP, Carides AD, Ianus J, Elmer ME, Evans JK, Beck K, Reines S, Horgan KJ (2003) The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebocontrolled trial in patients receiving high-dose cisplatinthe Aprepitant Protocol 052 Study Group. J Clin Oncol 21(22):4112 4119 9. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie MG, Eldridge K, Hipple A, Evans JK, Horgan KJ, Lawson F (2003) Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapyinduced nausea and vomiting. Results from a randomized, doubleblind, placebo-controlled trial in Latin America. Cancer 97 (12):30903098 10. Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD, Raftopoulos H, Grunberg SM, Gabriel M, Rodgers A, Bohidar N, Klinger G, Hustad CM, Horgan KJ, Skobieranda F (2005) Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol 23(12):28222830 11. Ihbe-Heffinger A, Ehlken B, Bernard R, Berger K, Peschel C, Eichler HG, Deuson R, Thodtmann J, Lordick F (2004) The impact of delayed chemotherapy-induced nausea and vomiting on patients, health resource utilization and costs in German cancer centers. Ann Oncol 15(3):526536 12. McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL, Hesney M, Lines CR, Petty KJ, Deutsch PJ, Murphy MG, Gottesdiener KM, Goldwater DR, Blum RA (2003) Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 74(1):1724 13. Hochberg Y, Tamhane AC (1987) Multiple comparison procedures. Wiley, New York

The results from the present study demonstrated the benefit of the aprepitant-containing, triple antiemetic regimen for a broad range of MEC regimens. The addition of dexamethasone to aprepitant in the delayed phase (analogous to current guidelines for HEC) should be investigated in further studies to explore whether it may be possible to improve upon the current results in patients receiving MEC. The patients on the aprepitant regimen had significantly more vomiting-free time than those on the standard regimen (nominal p <0.001, based on log-rank test) during the overall phase. The KaplanMeier curves start to separate at 6 h, and the difference between the treatment groups becomes significant at approximately 12 h following chemotherapy administration. Subsequently, the superiority of the aprepitant regimen becomes evident. These data clearly show that in this patient population, the effects of aprepitant are not confined to the delayed phase but are evident early in the acute phase as well. As in previous studies, aprepitant was generally well tolerated, with an overall pattern of clinical and laboratory adverse events generally similar to that of the control group. There were no notable differences in adverse events between the groups of patients who received the aprepitant regimen and control regimen. Additionally, there was no evidence to suggest that the addition of aprepitant resulted in adverse events caused by interactions with any of the diverse chemotherapeutic agents used. The addition of aprepitant to an antiemetic regimen of ondansetron and dexamethasone resulted in significantly improved prevention of CINV for patients receiving a broad range of MEC regimens.
Acknowledgements This study was funded by Merck & Co., Inc., manufacturer of aprepitant. The authors wish to acknowledge Dr.s Theodore Reiss and Stuart Green for contributions to the protocol design and Dr. Reiss for guidance throughout the course of the study. Conflicts of interest J.A.B., A.T., C.B., J.S.H., and A.C. are employees of Merck & Co., Inc. who may own stock and/or hold stock options in the Company. B.L.R., K. J., and H.J.S. have served as scientific advisors to Merck & Co., Inc.

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