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A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy
research-article
Author(s):
R. J. Gralla
1
,
* ,
S. M. Bosnjak
2 ,
A. Hontsa
3 ,
C. Balser
4 ,
G. Rizzi
5 ,
G. Rossi
6 ,
M. E. Borroni
6 ,
K. Jordan
7
Publication date (Electronic):
14 March 2014
Journal:
Annals of Oncology
Publisher:
Oxford University Press
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Abstract
In this multinational, phase III study, the safety and efficacy of NEPA, a convenient, fixed-dose antiemetic combination of netupitant, a highly selective NK 1 receptor antagonist (RA), and palonosetron, a distinct 5-HT 3 RA, were evaluated over multiple cycles of highly and moderately emetogenic chemotherapy. NEPA was shown to be safe, well tolerated and highly effective over 1961 chemotherapy cycles.
Abstract
Background
Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK 1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT 3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.
Patients and methods
This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1–4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).
Results
Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0–120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.
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Most cited references6
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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
P. J. Hesketh, G. Rossi, G. Rizzi … (2014)
introduction Advances in understanding the physiology of chemotherapy-induced nausea and vomiting (CINV) have allowed for improvements in control of CINV with targeted prophylactic medications aimed at inhibiting various molecular pathways involved in emesis. Antiemetic regimens have consequently evolved from the use of dopamine antagonists alone to combination regimens such as a corticosteroid plus a serotonin (5-hydroxytryptamine) type 3 receptor antagonist (5-HT3 RA) with or without a neurokinin-1 (NK1) RA. Such combination regimens have become the standard of care for the prevention of CINV and are currently reflected in international antiemetic guidelines [1]. However, despite the availability of more effective prophylactic regimens, many patients are undertreated and still experience CINV [1], particularly nausea, during the delayed phase after chemotherapy. NEPA is an oral fixed-dose combination of netupitant (NETU), a new highly selective NK1 RA and palonosetron (PALO), a pharmacologically distinct [2] and clinically superior [3–5] 5-HT3 RA. It targets two critical pathways associated with acute and delayed CINV, the serotonin and substance P-mediated pathways. The binding of PALO to the 5-HT3 receptor is distinctly different from older 5-HT3 RAs; recent in vitro data have shown that PALO not only independently inhibits the substance P response, but also enhances this inhibition when combined with NETU [6]. This in vitro synergy combined with PALO's clinical superiority to the older 5-HT3 RAs drove the decision to formulate a fixed-dose combination with NETU, recognizing that this also conveniently offers guideline-based prophylaxis in a single oral dose. A positron emission tomography (PET) study demonstrated that the 300 mg dose of NETU was the minimal dose among those tested (100, 300, and 450 mg), leading to a receptor occupancy in the striatum of >90% [7]. This led to the selection of the doses in the current trial. This phase 2, pivotal study was designed to evaluate three different oral doses of NETU (100, 200, and 300 mg) co-administered with PALO 0.50 mg to determine the most appropriate clinical dose for the fixed-dose NEPA combination for evaluation in the phase 3 clinical program. The 0.50 mg oral PALO dose was selected based on an efficacy trial which evaluated the non-inferiority of three oral PALO doses, 0.25, 0.50, and 0.75 mg, compared with IV PALO 0.25 mg [8, 9] and served as the basis for FDA approval of the 0.50 mg oral dose. As cisplatin is viewed as the most emetogenic chemotherapeutic agent, it was thought to be the most useful setting in initially assessing the antiemetic efficacy of the NETU plus PALO combination (referred to as NEPA throughout). An exploratory 3-day standard aprepitant (APR)/ondansetron arm was also included to assess the relative activity of an approved NK1/5-HT3 RA combination within the context of this trial. patients and methods study design This was a phase 2, multicenter, randomized, double-blind, double-dummy, parallel group study conducted at 29 sites in Russia and 15 sites in Ukraine in 2008. The protocol was approved by ethical review committees for each center, all patients provided written informed consent, and all investigators and site personnel were required to follow Good Clinical Practice, International Conference on Harmonization, and Declaration of Helsinki principles, local laws, and regulations. patients Eligible patients were ≥18 years diagnosed with histologically or cytologically confirmed malignant solid tumors, naïve to chemotherapy, and scheduled to receive their first course of cisplatin-based chemotherapy at a dose of ≥50 mg/m2 either alone or in combination with other chemotherapy agents. Patients were required to have a Karnofsky Performance Scale score of ≥70%, be able to follow study procedures and complete the patient diary. Patients were not eligible if they were scheduled to receive: (i) moderately (MEC) or highly (HEC) emetogenic chemotherapy from day 2 to 5 following chemotherapy, (ii) moderately or highly emetogenic radiotherapy either within 1 week before day 1 or from day 2 to 5, or (iii) a bone marrow or stem cell transplant. Patients were not allowed to receive any drug with potential antiemetic efficacy within 24 h or systemic corticosteroids within 72 h before day 1. They were excluded if they experienced any vomiting, retching, or more than mild nausea within 24 h before day 1. Patients were not to have had any serious cardiovascular disease history or predisposition to cardiac conduction abnormalities, with the exception of incomplete right bundle branch block. Because NETU is a moderate inhibitor of CYP3A4, chronic use of any CYP3A4 substrates/inhibitors/inducers or intake within 1 week (substrates/inhibitors) or 4 weeks (inducers) before day 1 was prohibited. treatment Patients were randomly assigned, stratified by gender, to one of the five treatment groups shown in Figure 1. Figure 1. Treatment schema. PALO, palonosetron; NEPA, combination of PALO + netupitant (NETU); APR, aprepitant; DEX, dexamethasone; OND, ondansetron. NETU, PALO, and APR were administered 60 min before cisplatin on day 1, DEX was administered 30 min before cisplatin on day 1, OND was administered as 50 ml infusion of at least 15 min duration before cisplatin on day 1. Owing to the potential for increased exposure to dexamethasone, the dexamethasone dose in the NK1 arms was reduced to achieve exposure similar to that in the PALO group. Cisplatin (≥50 mg/m2) was administered as a 1- to 4-h infusion; if administered in combination with other chemotherapy, it was administered first. Blinding was maintained with the use of matching identical placebos. Rescue medication was permitted for the treatment of refractory and persistent nausea and vomiting; however, the use of these medications was considered treatment failure. The timing and choice of rescue (excluding 5-HT3 or NK1 RAs) was at the discretion of the investigator. assessments To assess efficacy, each patient completed a diary from the start of cisplatin infusion on day 1 through the morning of day 6 (0–120 h). The diary captured information pertaining to the timing and duration of each emetic episode, severity of nausea, concomitant medications taken including rescue, and the patient's overall satisfaction. An emetic episode was defined as a single vomiting occurrence, a single retching, or any retching combined with vomiting. Severity of nausea was evaluated by the patient on a daily basis (for the preceding 24 h) using a 100-mm horizontal visual analog scale (VAS). The left end (0 mm) was labeled as ‘no nausea’, and the right end (100 mm) was labeled as ‘nausea as bad as it could be’. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120 h) phase post-chemotherapy. Secondary efficacy endpoints included CR rates during the acute (0–24 h) and delayed (25–120 h) phases, and also no emesis, no significant nausea (VAS score of <25 mm), and complete protection (CR + no significant nausea) rates during the acute/delayed/overall phases. Safety was assessed primarily by adverse events, but also by clinical laboratory evaluations, vital signs, physical examination findings, and electrocardiograms (ECGs). statistical analysis The primary aim of this study was to determine whether at least one of three doses of NETU combined with PALO was more effective than PALO alone based on the CR rate during the overall 0–120 h phase. For the sample size calculation, the assumption was an overall CR rate of 70% in the NEPA group(s) and 50% in the PALO group (based, in part, on IV PALO data in patients receiving cisplatin-based chemotherapy). For a one-sided test of difference, using α = 0.0166 (obtained as type I error divided by the number of comparisons = 0.050/3), a sample size of 129 evaluable patients per group was needed to ensure 85% power for each comparison. The number was rounded up to 136 per group for a total of 680 patients. An intent-to-treat approach was used for the efficacy analysis with the full analysis set defined as all patients who were randomized to treatment and received the protocol-required cisplatin and at least one dose of study treatment. The safety analysis population consisted of all patients who received at least one study treatment and had at least one safety assessment after treatment administration. The primary efficacy analysis was carried out using a logistic regression adjusted for gender, where each dose of NEPA was compared with PALO alone. The Holm–Bonferroni method was used to adjust for multiple comparisons. The same logistic regression analysis adjusting for gender was utilized for the secondary efficacy endpoints with no adjustments for multiplicity. A post hoc logistic regression analysis comparing the exploratory APR arm with PALO was also carried out for the efficacy endpoints. The study was not powered for nor analyzed to show a difference between the NEPA groups and the APR-based regimen. The number of patients who experienced treatment-emergent adverse events or ECG abnormalities was listed and summarized by the treatment group. results A total of 694 patients were randomized; 15 patients did not receive study treatment and were not included in the safety population and 677 (98%) patients were included in the full analysis set (Figure 2). Figure 2. Consort diagram of the disposition of patients. Baseline characteristics of the full analysis set were comparable across treatment groups and are reported in Table 1. Table 1. Patient baseline and disease characteristics Characteristic PALO (N = 136) NEPA100 (N = 135) NEPA200 (N = 137) NEPA300 (N = 135) APR + OND (N = 134) Gender (%) Male 57.4 57.0 57.7 57.0 56.0 Female 42.6 43.0 42.3 43.0 44.0 Median age (years) 55.0 55.0 55.0 53.0 55.5 Alcohol consumption (%) No 58.1 58.5 59.1 54.1 56.0 Rarely 37.1 34.8 34.3 37.8 39.6 Occasionally 4.4 6.7 6.6 8.1 4.5 Cancer type (%) Lung/respiratory 30.1 28.9 25.5 25.9 26.1 Head and neck 17.6 20.0 22.6 24.4 19.4 Ovarian 16.9 13.3 14.6 17.8 18.7 Other urogenital 13.2 14.1 18.2 11.1 13.4 Gastric 5.9 6.7 5.1 5.9 6.0 Other GI 7.4 3.0 5.1 4.4 7.5 Breast 2.9 8.1 4.4 5.9 5.2 Other 5.9 6.0 4.4 4.4 3.7 Karnofsky Index (%) 70% 2.9 1.5 2.9 3.0 2.2 80% 30.1 33.3 29.2 24.4 27.6 90% 58.8 57.8 54.7 60.0 61.2 100% 8.1 7.4 13.1 12.6 9.0 Chemotherapya (%) Cisplatin alone 15.4 15.6 14.6 14.1 14.9 Concomitant low 52.9 45.9 56.9 48.1 52.2 Concomitant moderate or high 31.6 38.5 28.5 37.8 32.8 aThe median cisplatin dose was 75 mg/m2 for each group. efficacy For the primary efficacy analysis, all NEPA dose groups showed superior CR rates compared with PALO during the overall phase (Figure 3). CR rates were also significantly higher for all NEPA groups compared with PALO during the delayed phase and significantly higher for NEPA300 during the acute phase. Figure 3. Primary analysis: complete response (no emesis and no rescue) (overall 0–120 h), *P-value from logistic regression versus PALO. NEPA300 was more effective than PALO during all phases for secondary efficacy endpoints of no emesis, no significant nausea, and complete protection, while NEPA100 was superior to PALO for no emesis during the delayed/overall phases, and NEPA200 for no emesis and complete protection for delayed/overall phases and no significant nausea for the delayed phase. NEPA300 consistently demonstrated incremental clinical benefits over the two lower NEPA doses for all secondary efficacy endpoints (Table 2). Table 2. Efficacy endpoints Primary analyses (NEPA versus PALO) Exploratory analysisAPR versus PALO PALO (N = 136) NEPA100 (N = 135) NEPA200 (N = 137) NEPA300 (N = 135) APR + OND (N = 134) Complete response (%) Acute (0–24 h) 89.7 93.3 92.7 98.5%† 94.8 Delayed (25–120 h) 80.1 90.4* 91.2† 90.4* 88.8‡ Overall (0–120 h) 76.5 87.4* 87.6* 89.6† 86.6‡ No emesis (%) Acute 89.7 93.3 92.7 98.5† 94.8 Delayed 80.1 90.4* 91.2† 91.9† 89.6‡ Overall 76.5 87.4* 87.6* 91.1† 87.3‡ No significant nausea (%) Acute 93.4 94.1 94.2 98.5* 94.0 Delayed 80.9 81.5 89.8* 90.4† 88.1 Overall 79.4 80.0 86.1 89.6* 85.8 Complete protection (%) Acute 87.5 89.6 88.3 97.0† 89.6 Delayed 73.5 80.0 87.6† 84.4* 82.1 Overall 69.9 76.3 80.3* 83.0† 78.4 † P ≤ 0.01 from logistic regression versus palonosetron; not adjusted for multiple comparisons, with exception of primary endpoint (CR overall). *P ≤ 0.05 from logistic regression versus palonosetron; not adjusted for multiple comparisons, with exception of primary endpoint (CR overall). ‡ P ≤ 0.05 from post hoc logistic regression versus palonosetron. The CR rates were higher for males than for females; however, the incremental benefit of adding NETU to PALO existed for both genders with differences between the NEPA groups and PALO in overall CR ranging from 13.8% to 15.5% for females and 7.6% to 11.5% for males. The exploratory APR arm showed higher CR and no emesis rates compared with PALO during the delayed/overall phases, but not the acute phase. While it showed numerically higher rates for no significant nausea and complete protection, these were not significantly different from PALO during any time post-chemotherapy. Although no formal comparisons were intended and differences were small, NEPA300 had numerically higher response rates than the multiday APR regimen for all the efficacy endpoints and time intervals. safety The overall incidence, type, frequency, and intensity of treatment-emergent adverse events were comparable across treatment groups. There was no evidence of a dose-related increase in these adverse events for the NEPA groups (Table 3). In total, 106 (15.6%) of the 679 patients experienced at least one treatment-related adverse event. The most common were hiccups and headache. Table 3. Summary of most common (≥2% incidence) treatment-related adverse events Adverse event n (%) PALO (N = 136) NEPA100 (N = 135) NEPA200 (N = 138) NEPA300 (N = 136) APR + OND (N = 134) Patients with any adverse event 67 (49.3) 55 (40.7) 71 (51.4) 68 (50.0) 71 (53.0) Patients with any treatment-related adverse event 17 (12.5) 18 (13.3) 24 (17.4) 21 (15.4) 26 (19.4) Hiccups 5 (3.7) 5 (3.7) 5 (3.6) 7 (5.1) 0 (0) Headache 2 (1.5) 1 (0.7) 3 (2.2) 1 (0.7) 3 (2.2) Leukocytosis 3 (2.2) 2 (1.5) 1 (0.7) 2 (1.5) 1 (0.7) Alanine aminotransferase increased 1 (0.7) 1 (0.7) 3 (2.2) 2 (1.5) 2 (1.5) Aspartate aminotransferase increased 1 (0.7) 1 (0.7) 3 (2.2) 1 (0.7) 2 (1.5) Dyspepsia 2 (1.5) 0 (0) 4 (2.9) 1 (0.7) 0 (0) Bradycardia 0 (0) 1 (0.7) 0 (0) 0 (0) 3 (2.2) Bundle branch block 0 (0) 1 (0.7) 0 (0) 3 (2.2) 0 (0) Anorexia 3 (2.2) 0 (0) 0 (0) 1 (0.7) 0 (0) The majority (95%) of all adverse events were of mild/moderate intensity. Of the 33 (4.9%) patients who experienced a severe adverse event, 9 (1.3%) were considered to be related to study treatments (2 PALO, 3 NEPA200, and 4 APR). Five patients (3 PALO, 1 NEPA100, and 1 NEPA200) had a serious adverse event. All but the NEPA200 patient (who experienced loss of consciousness) were deemed unrelated to study treatment. This patient recovered 30 min after onset; this was the only treatment-related adverse event leading to discontinuation. One patient (NEPA100) died during the study due to multiple organ failure. His death was not considered related to study medication. Changes from baseline in 12-lead ECGs were consistent across treatment groups at each time point during the study. The percent of patients who developed treatment-emergent ECG abnormalities was comparable across groups. discussion This large, pivotal phase 2 study was designed to determine which of three dose combinations of NETU plus PALO would be most appropriate for continued development as a fixed-dose combination in the NEPA phase 3 clinical program. For the primary analysis of CR during the overall phase, all NEPA groups showed superior CR rates compared with PALO alone. All NEPA dose groups also showed superior CR rates during the delayed phase; however, only NEPA300 was superior to PALO during the acute phase. While the NEPA100 group may be the minimally effective dose based on the primary CR results, NEPA300 consistently showed an incremental clinical benefit over the lower NEPA doses for all secondary efficacy endpoints. Although these endpoints were not adjusted for multiple comparisons, NEPA300 was superior to PALO for no emesis, no significant nausea, and complete protection rates during all phases. The CR rate in the PALO control arm was higher than the rates of CR noted in the control arm of earlier trials in HEC evaluating older 5-HT3 RAs with or without the addition of APR [10]. Despite the excellent control rates observed for the PALO control group, the magnitude of benefit associated with the NEPA regimens would still be considered to be clinically relevant (i.e. at least 10 absolute percentage points) during the acute/delayed/overall phases. An exploratory APR-containing arm was included in this trial. The APR arm showed higher CR and no emesis rates compared with PALO during the delayed/overall phases. However, APR was not superior to PALO for CR during the acute phase, nor for no significant nausea and complete protection during any time post-chemotherapy. NEPA arms showed a comparable safety profile to PALO and APR with a similar incidence of adverse events and ECG changes. The adverse event profile was consistent with that for an oncology patient population receiving HEC. All doses of NEPA were very well tolerated with no evidence of a dose response for adverse events, a very low incidence of serious events, and one unrelated death. Despite the gratifying progress made over the past two decades in developing more effective means to prevent CINV, a number of significant challenges remain. As nausea remains a key issue in CINV control with all currently available agents [11], it is noted that NEPA300 was superior to PALO for the prevention of significant nausea. These results should encourage further studies with NEPA in which the control of nausea is the primary endpoint. In addition, certain higher risk groups (e.g. women, younger patients, and non-ethanol consumers) remain susceptible to CINV. While the CR rates were generally lower for females than males, the superiority of NEPA over PALO existed for both genders. While it is well established that implementation of antiemetic guidelines improves CINV control for patients, unfortunately, adherence to guidelines remains unacceptably low [1]. NEPA may improve guideline adherence by providing an all oral single pill of the guideline-recommended antiemetic drug combination for patients at higher risk for CINV. In doing so, NEPA offers the potential to improve effectiveness of antiemetic control without compromising efficacy or safety. In conclusion, the NEPA antiemetic regimens significantly improved prevention of CINV in patients receiving cisplatin-based HEC. While all NEPA doses were highly effective and well tolerated, when considering all endpoints and time intervals, NEPA300 was the most effective dose combination. Based on these findings, the NEPA300 (NETU/PALO) fixed-dose combination was selected for continued development in the phase 3 program. funding This work was supported by Helsinn Healthcare, SA, who provided the study drugs and the funding for this study. disclosure The authors have the following conflicts of interest to disclose: PH: non-compensated consultant for Helsinn Healthcare. MP, G. Rossi, and G. Rizzi: employees of Helsinn Healthcare. RG: advisor for Merck, Helsinn Healthcare, and Eisai. All remaining authors have declared no conflicts of interest.
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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
introduction The pathophysiology of chemotherapy-induced nausea and vomiting (CINV) is multifactorial involving several neurotransmitters and receptors [1]. Combination antiemetic regimens targeting multiple molecular pathways associated with emesis have become the standard of care for prevention of CINV. This is supported by compelling clinical research and antiemetic guidelines [2, 3] which recommend a prophylactic combination of a 5-HT3 receptor antagonist (RA) [palonosetron (PALO) as ‘preferred’] and dexamethasone (DEX) when administering moderately emetogenic chemotherapy (MEC) and a 5-HT3 RA, DEX and a neurokinin-1 (NK1) RA when administering highly emetogenic chemotherapy (HEC). Anthracycline–cyclophosphamide (AC) chemotherapy is still considered to be moderately emetogenic according to regulatory authorities and evidence-based emetogenicity classification schemes [3]. Patients receiving AC tend to have additional patient-related risk factors (e.g. young age, female gender) which put them at greater risk for CINV; studies have shown that the addition of a NK1 RA to the 5-HT3 RA and DEX regimen is beneficial in this setting [4]. Therefore, guidelines recommend that this group of patients also receive a triple-combination antiemetic therapy on day 1. While data support the reputed notion that guideline conformity will improve CINV control for patients, unfortunately, adherence to antiemetic guidelines is suboptimal [5]. Consequently, even with effective agents available, many patients still suffer from CINV, particularly nausea during the delayed (25–120 h) phase following chemotherapy [2]. NEPA is an oral fixed-dose combination of netupitant (NETU), a new highly selective NK1 RA and PALO, a pharmacologically distinct [6] and clinically superior [2] 5-HT3 RA. The unique pharmacological characteristics of PALO result in long-lasting inhibition of the 5-HT3 receptor function. PALO has also been shown to inhibit the cross-talk between the 5-HT3 and NK1 receptors and, recently, the combination of PALO with NETU has been shown to work synergistically in enhancing inhibition of the substance P response compared with either antagonist alone [7]. These findings offer a possible explanation behind its unique efficacy during the delayed phase and also suggest the potential to enhance prevention of delayed CINV when used in combination with NETU. In a phase II dose-ranging study [8] in patients receiving HEC, the NEPA combination of NETU 300 mg + PALO 0.50 mg was the most effective dose studied, with an incremental clinical benefit over lower NEPA doses for all efficacy end points. This was the basis for the selection of the fixed-dose combination in the current trial. This phase III study was designed to demonstrate the superiority of NEPA over PALO in preventing CINV in patients receiving AC-based MEC and to evaluate NEPA's safety. patients and methods study design This was a phase III, multicenter, randomized, double-blind, double-dummy, parallel group study conducted at 177 enrolling sites in 15 countries (Argentina, Belarus, Brazil, Bulgaria, Croatia, Germany, Hungary, India, Italy, Mexico, Poland, Romania, Russia, Ukraine and the United States) between April 2011 and November 2012. The protocol was approved by ethical review committees, all patients provided written informed consent, and all study sites followed GCP, ICH, Declaration of Helsinki principles, local laws and regulations. patients Eligible patients were ≥18 years, naïve to chemotherapy, and scheduled to receive their first course of an AC MEC regimen for treatment of a solid malignant tumor. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Patients were not eligible if they were scheduled to receive: (i) HEC from day 1–5 or additional MEC from day 2–5 following chemotherapy, (ii) radiation therapy to the abdomen or pelvis within 1 week before day 1 or between day 1 and 5, or 3) a bone marrow or stem-cell transplant. Patients were not allowed to receive any drug with known or potential antiemetic efficacy within 24 h before day 1 and were excluded if they experienced any vomiting, retching or mild nausea within 24 h before day 1. Patients were not to have had any serious cardiovascular disease history or predisposition to cardiac conduction abnormalities, with the exception of incomplete right bundle branch block. Because NETU is a moderate inhibitor of CYP3A4, use of any CYP3A4 inducer within 4 weeks, use of a strong or moderate inhibitor within 1 week or scheduled to receive CYP3A4 inhibitors, inducers or certain substrates as concomitant medication was prohibited (supplementary Table S1, available at Annals of Oncology online). treatment Patients were randomly assigned to receive either NEPA (NETU 300 mg/PALO 0.50 mg) plus 12 mg DEX or PALO 0.50 mg plus 20 mg DEX on day 1 of chemotherapy. Due to the increased exposure to DEX when given in combination with NETU [9], the DEX dose in the NEPA group was reduced to achieve DEX exposure similar to that in the PALO group. The 0.50 mg oral PALO dose was selected based on a noninferiority efficacy trial evaluating three oral PALO doses, 0.25, 0.50 and 0.75 mg, compared with i.v. PALO 0.25 mg [10]. NEPA and PALO were administered 60 min and DEX 30 min before chemotherapy on day 1. Patients were stratified by region [United States, Latin America/Mexico, Europe, Commonwealth of Independent States (i.e. former Soviet Republics) and Asia] and age class ( 54, total FLIE score >108) was evaluated. The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed phase after the start of chemotherapy of cycle 1. Key secondary efficacy end points included CR during the acute (0–24 h) and overall (0–120 h) phases; other secondary efficacy end points were complete protection (CR + no significant nausea), no emesis and no significant nausea (VAS score of <25 mm) during the acute, delayed and overall phases while other efficacy end points included FLIE scores during the overall phase. Safety was assessed by adverse events, clinical laboratory evaluations, physical examinations, vital signs and electrocardiograms (ECGs). statistical analysis The primary aim of this study was to demonstrate the superiority of NEPA over PALO based on the proportion of patients with a CR during the delayed phase of cycle 1. The primary efficacy analysis was carried out using a two-sided Cochran–Maentel–Haenszel (CMH) test including treatment, age class and region as strata. NEPA was to be declared superior to PALO if the two-sided P-value was ≤0.05 and in favor of NEPA. A hierarchical procedure was applied to control type I error inflation (i.e. CR during the delayed, acute and overall phases were tested sequentially only if the previous test succeeded). No emesis, complete protection, no signification nausea and FLIE were also analyzed utilizing the CMH test. The sample size was estimated to be 1460 patients (730 per group). The assumption was a responder rate of 60% during the delayed phase for NEPA and 51% for PALO. For a two-sided test of difference, using α = 0.050, a sample size of 661 assessable patients per group was needed to ensure 90% power to detect the 9% difference. This number was increased to 730 per group to ensure an adequate number of assessable patients. The number of patients who experienced treatment-emergent adverse events or ECG abnormalities was listed and summarized by treatment group. The full analysis set population (efficacy analyses) was defined as all patients who were randomized and received protocol-required MEC and study treatment. The safety analysis population consisted of all patients who received study treatment and had at least one safety assessment after the treatment administration. results A total of 1455 patients were randomized into the study. Five patients did not receive the protocol-required MEC and study drug and one additional patient received study drug but not MEC; therefore, 1450 and 1449 patients represented the safety and full analysis set populations, respectively (Figure 1). Figure 1. Consort diagram of the disposition of patients. Baseline characteristics were similar between treatment groups (Table 1). Table 1. Patient baseline and disease characteristics Characteristic NEPA (N = 724) PALO (N = 725) Gender Female 98.2% 97.9% Male 1.8% 2.1% Age (years) Median 54.0 54.0 <55 51.2% 51.3% ≥55 48.8% 48.7% Ethnic group White 79.1% 80.0% Asian 14.0% 14.2% Hispanic 6.4% 5.0% Black 0.1% 0.3% Other 0.4% 0.6% Cancer type Breast 97.7% 97.2% Other 2.3% 2.8% ECOG Performance Status 0 69.6% 69.1% 1 29.6% 30.8% 2 0.8% 0.1% Chemotherapy Cyclophosphamide 99.9% 100% Doxorubicin 68.0% 63.7% Epirubicin 32.0% 36.3% efficacy For the primary efficacy comparison, NEPA was superior to PALO during the delayed phase with a CR rate of 76.9% versus 69.5% (P = 0.001) (Figure 2). CR rates were also significantly higher for NEPA compared with PALO during the acute and overall phases. Figure 2. Complete response (no emesis, no rescue medication). Similarly, NEPA was consistently more effective than PALO during the delayed and overall phases for secondary efficacy end points of no emesis, no significant nausea and complete protection as well as during the acute phase for no emesis (Table 2). For the FLIE assessment, a greater proportion of NEPA-treated patients reported NIDL for the nausea, vomiting and combined domains compared with PALO (Figure 3). Table 2. Secondary efficacy end points NEPA (N = 724) PALO (N = 725) P-value No emesis Acute 90.9% 87.3% 0.025 Delayed 81.8% 75.6% 0.004 Overall 79.8% 72.1% <0.001 No significant nausea Acute 87.3% 87.9% 0.747 Delayed 76.9% 71.3% 0.014 Overall 74.6% 69.1% 0.020 Complete protection Acute 82.3% 81.1% 0.528 Delayed 67.3% 60.3% 0.005 Overall 63.8% 57.9% 0.020 Figure 3. Proportion of patients with no impact on daily living (NIDL) based on Functional Living Index-Emesis (FLIE): Overall 0–120 h. safety The overall incidence, type, frequency and intensity of treatment-emergent adverse events were comparable between the two treatment groups. Among the patients reporting adverse events, the majority (85%) reported adverse events of mild/moderate intensity. Of the 94 NEPA-treated patients who experienced a severe adverse event, only 5 (0.7%) had a severe treatment-related adverse event. The most common treatment-related adverse events were headache and constipation (Table 3). Table 3. Overall summary of adverse events N (%) of patients with NEPA (N = 725) PALO (N = 725) Overall (N = 1450) At least one adverse event (AE) 551 (76%) 507 (69.9%) 1058 (73%) Serious AE 13 (1.8%) 12 (1.7%) 25 (1.7%) Serious treatment-relateda AE 0 0 0 Any treatment-relateda AE 59 (8.1%) 52 (7.2%) 111 (7.7%) Most common treatment-relateda AE Headache 24 (3.3%) 22 (3.0%) 46 (3.2%) Constipation 15 (2.1%) 15 (2.1%) 30 (2.1%) Any treatment-relateda AE leading to discontinuation 0 2 (0.3%) 2 (0.1%) aThose considered by the investigator to be possibly, probably or definitely related to study drug. There were no treatment-related adverse events leading to discontinuation, and there were very few (0.7%) severe and no serious treatment-related adverse events or deaths for NEPA-treated patients. Changes from baseline in 12-lead ECGs were similar between treatment groups at each time point. discussion NEPA, a novel combination of the new NK1 RA, NETU and best-in-class 5-HT3 RA, PALO, has been designed to overcome potential barriers hindering antiemetic guideline adherence by conveniently packaging guideline-recommended agents in a single oral fixed-dose. A single day 1 dose of NEPA along with DEX only on day 1 seems suitable for prevention of CINV through the 5 days after chemotherapy. This large, phase III, registration study was designed to demonstrate the superiority of NEPA over PALO in chemotherapy-naïve patients receiving AC-based MEC. NEPA significantly improved CR rates compared with PALO during all phases after chemotherapy, with the incremental benefit being greatest during the delayed and overall phases. Regardless of the efficacy end-point, NEPA was consistently superior to PALO during the 5-day period following chemotherapy. In particular, NEPA resulted in significantly greater no emesis rates during all phases and no significant nausea and complete protection rates during the delayed and overall phases. The consistent superiority of NEPA over PALO across all end points during the delayed phase is particularly opportune, in that patients are protected during a period which has remained a challenge in most clinical settings. Control of delayed nausea does not reach the same level of benefit as that of emesis and remains a clinical unmet need [2, 3]. Although it was a secondary end point, it is encouraging that NEPA demonstrated a delayed nausea benefit which was also seen in the phase II trial in patients receiving cisplatin-based HEC [8], providing additional support of its efficacy. The utilization of the FLIE instrument confirmed that by improving control of CINV, NEPA significantly reduced the impact of CINV on patients' functioning. This was seen consistently in all domains of the FLIE assessment. As DEX may be associated with a range of side-effects, there is particular interest in minimizing its dose/frequency, especially in patients who experience DEX-related side-effects. Consistent with the recommendation by MASCC/ESMO in the AC setting, DEX was given on day 1 only. Therefore, the complete antiemetic regimen in this study was administered just before chemotherapy. In a study in a similar population of chemotherapy-naïve breast cancer patients, a single dose of PALO plus DEX on day 1 showed similar CR rates as PALO (day 1) plus DEX (day 1–3) [11] (the recommended antiemetic regimen in AC at the time of the study). The authors speculated that the unique pharmacology of PALO may have explained the extended protection in the delayed phase, without the need for multiple day DEX. The response rates seen in the current trial were generally higher than those seen in prior NK1 RA trials [4] where DEX was administered on day 1 only concomitantly with an older generation 5-HT3 RA. The present result validates the guideline recommendations of a single day of DEX in patients receiving AC and provides encouraging evidence that DEX beyond day 1 is not necessary when using NEPA in patients at higher risk for CINV. While AC are still classified by some guideline groups as chemotherapy that present a moderate emetic risk, although separately from other MEC [3], other committees developing antiemetic guidelines have included AC in the high-risk category [12]. This is a simplification related to the fact that the same NK1RA/5-HT3RA/DEX treatment is recommended for both HEC and AC, while, in other MEC, the use of NK1RAs is an option which varies according to the perceived risk. There is already limited data on how NEPA performs in a non-AC MEC population [13]. As already demonstrated in the large phase II trial, NEPA was very well tolerated with a comparable adverse event profile to PALO. There was a very low incidence of treatment-related adverse events, none of which led to discontinuation and no serious treatment-related adverse events or deaths for NEPA-treated patients. There were no cardiac safety concerns for either NEPA or PALO based on cardiac AEs/ECGs. In conclusion, NEPA resulted in superior prevention of CINV than PALO in patients receiving MEC. As a combination agent targeting dual antiemetic pathways, a single dose of NEPA plus DEX offers convenient guideline-based prophylaxis. This provides an opportunity to overcome barriers interfering with guideline adherence and in doing so offers promise for improving control of CINV for patients. funding This work was supported by Helsinn Healthcare, SA who provided the study drugs and the funding for this study. disclosure The authors have the following conflicts of interest to disclose: MA: consultant for Amgen, BMS, Celgene, GSK, Helsinn Healthcare, JnJ, Novartis, Merck, Merck Serono, Pfizer, Pierre Fabre, Roche, Sandoz, Teva and Vifor; received honoraria for symposia lectures for Amgen, Bayer Schering, Cephalon, Chugai, GSK, Helsinn Healthcare, Hospira, Ipsen, JnJ OrthoBiotech, Merck, Merck Serono, Novartis, Pfizer, Pierre Fabre, Roche, Sandoz, Sanofi, Teva and Vifor. HR: currently conducting investigator initiated trial partially funded by Eisai and provided to UCSF. GR, GR and MEB: employees of Helsinn Healthcare. MK: advisory board honoraria received from Helsinn Healthcare. LS: consultant for Eisai and Helsinn Healthcare; on speakers bureau for Eisai. All remaining authors have declared no conflicts of interest. Supplementary Material Supplementary Data
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Pharmacological mechanisms of 5-HT₃ and tachykinin NK₁ receptor antagonism to prevent chemotherapy-induced nausea and vomiting.
Camilo Rojas, Barbara Slusher (2012)
Nausea and vomiting are among the most common and distressing consequences of cytotoxic chemotherapies. Nausea and vomiting can be acute (0-24h) or delayed (24-72 h) after chemotherapy administration. The introduction of 5-HT(3) receptor antagonists in the 90s was a major advance in the prevention of acute emesis. These receptor antagonists exhibited similar control on acute emesis but had no effect on delayed emesis. These findings led to the hypothesis that serotonin plays a central role in the mechanism of acute emesis but a lesser role in the pathogenesis of delayed emesis. In contrast, delayed emesis has been largely associated with the activation of neurokinin 1 (NK(1)) receptors by substance P. However, in 2003, a new 5-HT(3) receptor antagonist was introduced into the market; unlike first generation 5-HT(3) receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed chemotherapy induced nausea and vomiting. Recent mechanistic studies have shown that palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT(3) receptor, positive cooperativity, persistent inhibition of receptor function after the drug is removed and triggers 5-HT(3) receptor internalization. Further, in vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT(3) receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT(3) and NK(1) receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses. Copyright © 2012 Elsevier B.V. All rights reserved.
Author and article information
Journal
Journal ID (nlm-ta): Ann Oncol
Journal ID (iso-abbrev): Ann. Oncol
Journal ID (publisher-id): annonc
Journal ID (hwp): annonc
Title:
Annals of Oncology
Publisher:
Oxford University Press
ISSN
(Print):
0923-7534
ISSN
(Electronic):
1569-8041
Publication date
(Print):
July
2014
Publication date
(Electronic):
14
March
2014
Publication date PMC-release: 14
March
2014
Volume: 25
Issue: 7
Pages: 1333-1339
Affiliations
[1
]Department of Medical Oncology, Albert Einstein College of Medicine, Jacobi Medical
Center, Bronx, USA
Author notes
[*
]
Correspondence to: Dr Richard J. Gralla, Albert Einstein College of Medicine, Jacobi Medical Center,
Bronx, NY 10461 USA. Tel: +1 718 918-6235; E-mail:
richard.gralla@
123456nbhn.net
Article
Publisher ID: mdu096DOI: 10.1093/annonc/mdu096
PMC ID: 4071753
PubMed ID: 24631949
SO-VID: 90eaf376-7a34-48ec-a557-7ead33a95d06
Copyright © © The Author 2014. Published by Oxford University Press on behalf of the European
Society for Medical Oncology.
License:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com
History
Date
received
: 13
December
2013
Date
accepted
: 21
February
2014
Categories
Subject:
Original Articles
Subject:
Supportive Care
ScienceOpen disciplines: Oncology & Radiotherapy
Data availability:
ScienceOpen disciplines: Oncology & Radiotherapy