Abstract
Purpose
Chemotherapy-induced nausea and vomiting (CINV) remains a significant challenge in pediatric oncology, with limited data guiding optimal antiemetic regimens. This phase 2 study evaluated pharmacokinetics (PK), pharmacodynamics, efficacy, and safety of oral netupitant combined with oral palonosetron (NEPA) in pediatric patients receiving highly or moderately emetogenic chemotherapy.
Methods
In this multicenter, randomized, double-blind, dose-finding study, pediatric patients (< 18 years) were stratified by age, chemotherapy emetogenicity, and schedule. Patients received one of two netupitant doses (1.33 or 4 mg/kg) with palonosetron (20 µg/kg). Efficacy was assessed via complete response (CR; no emesis and no rescue medication) during acute (0–24h), delayed (> 24–120h), and overall (0–120h) phases. PK parameters were derived from plasma concentrations of netupitant, its metabolites, and palonosetron. Safety was monitored through adverse events and clinical assessments.
Results
Among 65 evaluable patients, CR rates were 85.3%, 70.6%, and 70.6% in the lower netupitant dose group, and 87.1%, 71.0%, and 67.7% in the higher dose group, for the acute, delayed, and overall phases, respectively. CR was mostly consistent across age groups and chemotherapy emetogenicity. A trend toward increased CR with higher netupitant exposure (AUC0–inf) was observed in the delayed phase. The safety profile was consistent with expectations for cytotoxic chemotherapy, and no new safety signals were observed.
Conclusion
A single dose of 4 mg/kg oral netupitant with oral palonosetron was effective and well-tolerated for CINV prevention in pediatric patients, supporting further investigation of NEPA in this population.
Trial registration
NCT03204279 [2 July 2017 registration date]
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s00520-026-11238-0.
Keywords: Chemotherapy-induced nausea and vomiting, Netupitant, Palonosetron, NEPA, Pediatric
Introduction
Many adult and pediatric patients undergoing chemotherapy experience chemotherapy-induced nausea and vomiting (CINV), which can decrease quality of life and reduce treatment adherence. CINV can lead to side effects such as dehydration, weight loss, anorexia, weakness, increased susceptibility to infection, and decreased mental performance [1–3]. On the basis of timing, CINV can be classified as acute, occurring < 24 h after chemotherapy, or delayed, occurring > 24–120 h after chemotherapy. More recently, studies have suggested that CINV may persist beyond the typical timeframe, leading to the introduction of the concept of long-delayed CINV, which occurs > 120 h after chemotherapy [4].
Chemotherapeutic agents are classified by their emetogenic risk in the absence of antiemetic prophylaxis; highly emetogenic chemotherapy (HEC) causes CINV in > 90% of patients, while moderately emetogenic chemotherapy (MEC) affects 30–90% [5]. Antiemetic guidelines for adults recommend prophylaxis with combinations of a neurokinin-1 (NK1) receptor antagonist (RA), olanzapine, a 5-hydroxytryptamine-3 (5-HT3) RA, and a corticosteroid (primarily dexamethasone) for patients treated with HEC. For those receiving MEC, a 5-HT3 RA with dexamethasone and an NK1 RA for select patients is recommended [6–8].
Given the lack of large trials in pediatric patients, the understanding of antiemetic use and efficacy is less clear compared with adult patients. A clinical practice guideline has been developed for the prevention of acute and delayed CINV in pediatric patients with cancer [9]. For patients receiving HEC, a combination of a 5-HT3 RA, dexamethasone, and (fos)aprepitant is recommended in the acute phase, with possible addition of olanzapine. In the delayed phase, dexamethasone and continuation of olanzapine are recommended. For pediatric patients receiving MEC, a 5-HT3 RA with dexamethasone in the acute phase and consideration of dexamethasone in the delayed phase are recommended. Nevertheless, a cross-sectional study of pediatric oncology providers indicated that over half of survey respondents were not aware of pediatric CINV clinical practice guidelines, potentially leading to suboptimal prophylaxis [10]. Even when current guidelines were followed, one study found a lack of complete control of vomiting in the pediatric population. A total of 71% of patients in the study received guideline-consistent care, but only 48% demonstrated complete control of vomiting [11], highlighting the need for novel or risk-adapted strategies for young patients.
Beyond guideline awareness and adherence, the complexity of multidrug antiemetic regimens may itself limit real-world effectiveness. A qualitative synthesis of children/young people and their families identified a trade-off between taking more antiemetics (e.g., triplet regimens) that may better control CINV and antiemetic side effects, such as constipation, that can exacerbate treatment-related toxicity [3]. Children reportedly adjusted the number/type of antiemetics taken day-to-day to manage this trade-off, and one young person noted the added burden of taking multiple oral medications when already feeling unwell. Simplified regimens that reduce pill burden while maintaining efficacy may therefore help address this gap.
The pediatric clinical practice guideline recommends palonosetron as the preferred 5-HT3 RA for patients at high risk of delayed CINV [9]. Several studies have shown that palonosetron is safe and effective for pediatric patients, and intravenous (IV) palonosetron was approved by the US Food and Drug Administration and European Medicines Agency for patients aged 1 month to < 17 years undergoing initial or repeated courses of MEC or HEC [12, 13]. NEPA, the only available fixed-combination antiemetic, consists of palonosetron and netupitant in its oral form and is administered as a single dose before chemotherapy, offering simplicity and convenience [14]. NEPA is approved for adults but may also be very beneficial for pediatric patients receiving chemotherapy [15]; however, the most effective dose of netupitant for use in pediatric patients in combination with palonosetron is not yet confirmed. Herein, we present results from a phase 2 pharmacokinetics (PK) and pharmacodynamics (PD) dose-finding study of oral netupitant administered concomitantly with oral palonosetron in pediatric patients.
Materials and methods
Study design
This multicenter, randomized, double-blind, dose-finding, phase 2 study assessed PK/PD and safety of oral netupitant administered concomitantly with oral palonosetron in pediatric patients with cancer (NCT03204279).
Pediatric patients (< 18 years) scheduled to receive chemotherapy were enrolled. Key inclusion and exclusion criteria are listed in Online Resource 1. Patients were stratified according to age, emetogenicity of chemotherapy (MEC or HEC), and chemotherapy schedule (day 1 only or multiple days). Age classes were birth to < 1 month, 1 to < 3 months, 3 to < 6 months, 6 to < 12 months, 1 to < 2 years, 2 to < 5 years, 5 to < 12 years, and 12 to < 18 years. In age groups > 12 months, patients were randomized to one of two netupitant dose groups. In younger age groups (< 12 months), safety of the lower netupitant dose was established prior to escalation to the higher dose. For these age classes, patients were not stratified by emetogenicity or chemotherapy schedule.
Netupitant oral liquid formulation doses were 1.33 and 4 mg/kg, with maximum doses of 100 and 300 mg for patients ≥ 75 kg, respectively. These doses were selected to achieve pediatric netupitant exposures comparable with the 100 and 300 mg doses shown to be effective and well tolerated in the adult pivotal trials with oral NEPA [16–18]. Patients < 3 months received lower weight-based doses (0.8 or 2.4 mg/kg) to account for reduced CYP3A4-mediated metabolic capacity in early infancy relative to older age groups [19]. The palonosetron dose was matched to the approved IV dose for pediatric patients: 20 µg/kg, with a maximum 1.5 mg for patients ≥ 75 kg [20]. The maximum study duration was 31 days; the day of enrollment, randomization, and study drug administration was defined as day 1.
The study’s primary objective was to investigate the PK/PD correlation between netupitant exposure and antiemetic efficacy in pediatric patients after a single oral administration of netupitant and concomitant palonosetron. Secondary objectives included assessment of safety and tolerability and evaluation of the PK profile of oral palonosetron with the concomitant administration of netupitant in pediatric patients.
The study was conducted in accordance with International Council for Harmonisation requirements and the Declaration of Helsinki. The study protocol was approved by the relevant independent ethics committees or institutional review boards. For all patients, signed written informed consent by a parent/legal guardian was obtained before study initiation in compliance with the local laws and regulations, as well as signed children’s consent per local requirements.
Assessments
Efficacy outcomes were collected through a paper diary used to record all emetic episodes and the use of rescue medication until 120 h after start of chemotherapy. An emetic episode was defined as one continuous occurrence of vomiting (expulsion of stomach contents) or retching (an attempt to vomit not productive of stomach contents). Complete response (CR) was defined as no emetic episodes and no need for rescue medication during the acute (0–24 h), delayed (> 24–120 h), or overall phases (0–120 h).
Blood samples for PK analysis were collected 2–8, 24–48, and 120–168 h after netupitant administration. For patients ≥ 5 years of age, additional samples were collected after 72–96 h. Concentrations of netupitant, the active netupitant metabolites M1, M2, and M3, and palonosetron were determined at an accredited bioanalytic laboratory (Ardena Biochemical Laboratory, The Netherlands), using validated liquid chromatography with tandem mass spectrometry methods. The lower limit of quantification for netupitant and its metabolites was 2 ng/mL; the lower limit of quantification for palonosetron was 50 pg/mL.
Safety was assessed through adverse event (AE) reporting and physical examinations, clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Safety data were collected through visit 5, occurring 14 (± 3) days post-dose. Treatment-emergent AEs (TEAEs) were classified on the basis of severity according to the grading scales of the Common Terminology Criteria for Adverse Events and on relation to study drug.
Statistical methods
The full analysis set (FAS) included all patients who received chemotherapy and the full planned dose of netupitant and palonosetron. The PK population consisted of all patients who received the entire planned dose of netupitant-palonosetron, and who had one or more measurable concentration of either drug. The safety population included all patients who received at least part of the planned netupitant or palonosetron dose.
Descriptive statistics were used for continuous variables and summaries were presented by treatment group and overall. Efficacy analyses were interpreted in a descriptive manner. For patients who did not provide data about emetic episodes and rescue medication during the 120 h after chemotherapy administration, treatment was considered to have failed with missing data. The number and proportion of patients with CR during the acute, delayed, and overall phases along with the 95% confidence intervals were calculated using the Clopper-Pearson (exact) method and summarized by treatment group, overall, and the different strata for the FAS. Difference in response rates between the netupitant dose groups was calculated using the Miettinen-Nurminen method. Similar analyses were done for patients experiencing no emetic episodes and patients requiring no rescue medication.
Population PK modeling was based on a previous population PK study in adults who received oral NEPA (Helsinn Healthcare SA, data on file). Details are included in Online Resource 1. Individual model-predicted PK parameters were estimated from the final population PK models, on the basis of typical values of the population PK parameters and interindividual variability. Post hoc individual PK parameters were used to derive individual exposure metrics, i.e., area under the plasma concentration-time curve from time zero to infinity (AUC0-inf), dose-normalized AUC0-inf (AUC0-inf/D), maximum plasma concentration (Cmax), and dose-normalized Cmax (Cmax/D) by noncompartmental PK analysis carried out using enriched model-predicted individual PK profiles for each analyte. In addition, the individual time to Cmax (tmax) and half-life were estimated. Descriptive statistics of the individual exposure metrics, specifically arithmetic mean and percentage coefficient of variation, were stratified by treatment group and age class. An exposure-response analysis was performed to explore whether systemic exposure of netupitant correlated with CR in the acute, delayed, or overall phases. PK and exposure-response analyses were performed by Certara Strategic Consulting (Paris, France).
Results
Patients
In total, 67 patients were enrolled and assigned to either the lower-dose (n = 34) or higher-dose (n = 33) netupitant groups (Fig. 1). One patient withdrew prior to receiving study drug; the remaining 66 patients completed the study. Patient demographics and baseline characteristics are listed in Table 1. Median age of the patient population was 4 years (range 0–17), and the majority (59%) were male. For 59% of patients, the chemotherapy lasted multiple days, and 67% of patients received HEC. Patients receiving day 1 only chemotherapy were more likely to receive HEC (85%) compared with patients receiving multiple-day chemotherapy (53%). Most patients had received chemotherapy previously (92%) and had experienced vomiting/retching (84%) and/or nausea (71%) during previous blocks of chemotherapy.
Fig. 1.
Patient disposition
Table 1.
Patient demographics and baseline characteristics
| Characteristic | Lower netupitant dose group (N = 34) | Higher netupitant dose group (N = 32) | Total (N = 66) |
|---|---|---|---|
| Median age, years (range) | 5 (0–17) | 4 (0–16) | 4 (0–17) |
| Age class, n (%) | |||
| 0 to < 1 months | 0 | 0 | 0 |
| 1 to < 3 months | 1 (2.9) | 0 | 1 (1.5) |
| 3 to < 6 months | 3 (8.8) | 2 (6.3) | 5 (7.6) |
| 6 to < 12 months | 4 (11.8) | 5 (15.6) | 9 (13.6) |
| 1 to < 2 years | 3 (8.8) | 4 (12.5) | 7 (10.6) |
| 2 to < 5 years | 6 (17.6) | 6 (18.8) | 12 (18.2) |
| 5 to < 12 years | 8 (23.5) | 8 (25.0) | 16 (24.2) |
| 12 to < 18 years | 9 (26.5) | 7 (21.9) | 16 (24.2) |
| Sex, n (%) | |||
| Male | 21 (61.8) | 18 (56.3) | 39 (59.1) |
| Female | 13 (38.2) | 14 (43.8) | 27 (40.9) |
| Emetogenicity, n (%) | |||
| MEC | 11 (32.4) | 11 (34.4) | 22 (33.3) |
| HEC | 23 (67.6) | 21 (65.6) | 44 (66.7) |
| Chemotherapy schedule, n (%) | |||
| Day 1 only | 13 (38.2) | 14 (43.8) | 27 (40.9) |
| Multiple days | 21 (61.8) | 18 (56.3) | 39 (59.1) |
| Median baseline height, m (range) | 1.14 (0.58–1.91) | 1.02 (0.59–1.78) | 1.07 (0.58–1.91) |
| Median baseline weight, kg (range) | 19.4 (4.7–76.0) | 14.5 (4.9–77.2) | 17.8 (4.7–77.2) |
| Median baseline BSA, m2 (range) | 0.77 (0.27–1.87) | 0.62 (0.28–1.89) | 0.73 (0.27–1.89) |
| ECOG performance status, n (%) | |||
| 0 | 1 (2.9) | 5 (15.6) | 6 (9.1) |
| 1 | 6 (17.6) | 4 (12.5) | 10 (15.2) |
| 2 | 4 (11.8) | 0 | 4 (6.1) |
| Not determined | 23 (67.6) | 23 (71.9) | 46 (69.7) |
| Median time since diagnosis, years (range) | 0.2 (0.0–1.1) | 0.3 (0.0–5.6) | 0.2 (0.0–5.6) |
| Extent at study entry, n (%) | |||
| Localized | 14 (41.2) | 18 (56.3) | 32 (48.5) |
| Metastatic | 9 (26.5) | 9 (28.1) | 18 (27.3) |
| Locally advanced | 11 (32.4) | 5 (15.6) | 16 (24.2) |
| Type of tumor, n (%) | |||
| Solid | 25 (75.8) | 20 (60.6) | 45 (68.2) |
| Leukemia/lymphoma | 5 (15.2) | 5 (15.2) | 10 (15.2) |
| Brain | 3 (9.0) | 8 (24.2) | 11 (16.7) |
| Prior chemotherapy, n (%) | |||
| Yes | 31 (91.2) | 30 (93.8) | 61 (92.4) |
| No | 3 (8.8) | 2 (6.3) | 5 (7.6) |
| Prior vomiting/retching due to chemotherapy, n (%)a | |||
| Yes | 30 (96.8) | 21 (70.0) | 51 (83.6) |
| No | 1 (3.2) | 9 (30.0) | 10 (16.4) |
| Prior nausea due to chemotherapy, n (%)a | |||
| Yes | 24 (77.4) | 19 (63.3) | 43 (70.5) |
| No | 7 (22.6) | 11 (36.7) | 18 (29.5) |
aPercentage calculated from the number of patients with prior chemotherapy
BSA body surface area, ECOG Eastern Cooperative Oncology Group, HEC highly emetogenic chemotherapy, MEC moderately emetogenic chemotherapy
Efficacy
The FAS consisted of 65 patients (n = 34 lower netupitant dose, n = 31 higher netupitant dose). In the lower-dose group, CR rates in the acute, delayed, and overall phases were 85.3%, 70.6%, and 70.6%. In the higher-dose group, CR rates in the acute, delayed, and overall phases were 87.1%, 71.0%, and 67.7%. CR outcomes by age class, emetogenicity, and chemotherapy schedule are listed in Table 2. In the acute phase, CR rates were similar among most age classes and between dose groups. The exception was age class 12 to < 18 years, where the CR rate was 66.7% in the lower-dose group and 42.9% in the higher-dose group. In the delayed phase, CR rates in the different age classes and emetogenicities were generally similar overall and between dose groups. CR rates in the overall phase were similar between dose groups but differences were noted between the age classes, with the age class 12 to < 18 years having the lowest CR rate (43.8%).
Table 2.
Complete response in the acute, delayed, and overall phases in the total population and by dose group/strata
| Patients with CR | Lower netupitant dose group (N = 34) n/N (%) [95% CI]a |
Higher netupitant dose group (N = 31) n/N (%) [95% CI]a |
Group treatment difference, % [95% CI]b | Total (N = 65) n/N (%) [95% CI]a |
|---|---|---|---|---|
| Acute phase (0–24 h) | ||||
| Overall | 29/34 (85.3) [68.9, 95.0] | 27/31 (87.1) [70.2, 96.4] | − 1.8 [− 19.7, 16.6] | 56/65 (86.2) [75.3, 93.5] |
| Age class | ||||
| 1 to < 3 months | 1/1 (100) [2.5, 100.0] | 0 [NE] | - [NE] | 1/1 (100) [2.5, 100.0] |
| 3 to < 6 months | 3/3 (100) [29.2, 100.0] | 2/2 (100) [15.8, 100.0] | 0 [NE] | 5/5 (100) [47.8, 100.0] |
| 6 to < 12 months | 4/4 (100) [39.8, 100.0] | 4/4 (100) [39.8, 100.0] | 0 [NE] | 8/8 (100) [63.1, 100.0] |
| 1 to < 2 years | 3/3 (100) [29.2, 100.0] | 4/4 (100) [39.8, 100.0] | 0 [NE] | 7/7 (100) [59.0, 100.0] |
| 2 to < 5 years | 6/6 (100) [54.1, 100.0] | 6/6 (100) [54.1, 100.0] | 0 [NE] | 12/12 (100) [73.5, 100] |
| 5 to < 12 years | 6/8 (75.0) [34.9, 96.8] | 8/8 (100) [63.1, 100.0] | − 25.0 [− 60.1, 13.5] | 14/16 (87.5) [61.7, 98.4] |
| 12 to < 18 years | 6/9 (66.7) [29.9, 92.5] | 3/7 (42.9) [9.9, 81.6] | 23.8 [− 25.0, 63.4] | 9/16 (56.3) [29.9, 80.2] |
| Emetogenicity | ||||
| MEC | 8/11 (72.7) [39.0, 94.0] | 9/11 (81.8) [48.2, 97.7] | − 9.1 [− 44.0, 27.7] | 17/22 (77.3) [54.6, 92.2] |
| HEC | 21/23 (91.3) [72.0, 98.9] | 18/20 (90.0) [68.3, 98.8] | 1.3 [− 19.0, 23.2] | 39/43 (90.7) [77.9, 97.4] |
| Chemotherapy schedule | ||||
| Day 1 only | 12/13 (92.3) [64.0, 99.8] | 13/14 (92.9) [66.1, 99.8] | − 0.5 [− 28.2, 25.9] | 25/27 (92.6) [75.7, 99.1] |
| Multiple days | 17/21 (81.0) [58.1, 94.6] | 14/17 (82.4) [56.6, 96.2] | − 1.4 [− 26.6, 25.8] | 31/38 (81.6) [65.7, 92.3] |
| Delayed phase (> 24–120 h) | ||||
| Overall | 24/34 (70.6) [52.5, 84.9] | 22/31 (71.0) [52.0, 85.8] | − 0.4 [− 22.3, 21.9] | 46/65 (70.8) [58.2, 81.4] |
| Age class | ||||
| 1 to < 3 months | 1/1 (100) [2.5, 100.0] | 0 [NE] | - [NE] | 1/1 (100) [2.5, 100.0] |
| 3 to < 6 months | 3/3 (100) [29.2, 100.0] | 2/2 (100) [15.8, 100.0] | 0 [NE] | 5/5 (100) [47.8, 100.0] |
| 6 to < 12 months | 2/4 (50.0) [6.8, 93.2] | 2/4 (50.0) [6.8, 93.2] | 0 [− 59.5, 59.5] | 4/8 (50.0) [15.7, 84.3] |
| 1 to < 2 years | 3/3 (100) [29.2, 100.0] | 3/4 (75.0) [19.4, 99.4] | 25.0 [− 43.8, 72.3] | 6/7 (85.7) [42.1, 99.6] |
| 2 to < 5 years | 6/6 (100) [54.1, 100.0] | 6/6 (100) [54.1, 100.0] | 0 [NE] | 12/12 (100) [73.5, 100] |
| 5 to < 12 years | 5/8 (62.5) [24.5, 91.5] | 5/8 (62.5) [24.5, 91.5] | 0 [− 44.5, 44.5] | 10/16 (62.5) [35.4, 84.8] |
| 12 to < 18 years | 4/9 (44.4) [13.7, 78.8] | 4/7 (57.1) [18.4, 90.1] | − 12.7 [− 55.1, 35.0] | 8/16 (50.0) [24.7, 75.3] |
| Emetogenicity | ||||
| MEC | 8/11 (72.7) [39.0, 94.0] | 7/11 (63.6) [30.8, 89.1] | 9.1 [− 29.9, 45.6] | 15/22 (68.2) [45.1, 86.1] |
| HEC | 16/23 (69.6) [47.1, 86.8] | 15/20 (75.0) [50.9, 91.3] | − 5.4 [− 31.5, 22.1] | 31/43 (72.1) [56.3, 84.7] |
| Chemotherapy schedule | ||||
| Day 1 only | 12/13 (92.3) [64.0, 99.8] | 13/14 (92.9) [66.1, 99.8] | − 0.5 [− 28.2, 25.9] | 25/27 (92.6) [75.7, 99.1] |
| Multiple days | 12/21 (57.1) [34.0, 78.2] | 9/17 (52.9) [27.8, 77.0] | 4.2 [− 26.7, 34.6] | 21/38 (55.3) [38.3, 71.4] |
| Overall phase (0–120 h) | ||||
| Overall | 24/34 (70.6) [52.5, 84.9] | 21/31 (67.7) [48.6, 83.3] | 2.8 [− 19.5, 25.3] | 45/65 (69.2) [56.6, 80.1] |
| Age class | ||||
| 1 to < 3 months | 1/1 (100) [2.5, 100.0] | 0 [NE] | - [NE] | 1/1 (100) [2.5, 100.0] |
| 3 to < 6 months | 3/3 (100) [29.2, 100.0] | 2/2 (100) [15.8, 100.0] | 0 [NE] | 5/5 (100) [47.8, 100.0] |
| 6 to < 12 months | 2/4 (50.0) [6.8, 93.2] | 2/4 (50.0) [6.8, 93.2] | 0 [− 59.5, 59.5] | 4/8 (50.0) [15.7, 84.3] |
| 1 to < 2 years | 3/3 (100) [29.2, 100.0] | 3/4 (75.0) [19.4, 99.4] | 25.0 [− 43.8, 72.3] | 6/7 (85.7) [42.1, 99.6] |
| 2 to < 5 years | 6/6 (100) [54.1, 100.0] | 6/6 (100) [54.1, 100.0] | 0 [NE] | 12/12 (100) [73.5, 100] |
| 5 to < 12 years | 5/8 (62.5) [24.5, 91.5] | 5/8 (62.5) [24.5, 91.5] | 0 [− 44.5, 44.5] | 10/16 (62.5) [35.4, 84.8] |
| 12 to < 18 years | 4/9 (44.4) [13.7, 78.8] | 3/7 (42.9) [9.9, 81.6] | 1.6 [− 44.2, 46.1] | 7/16 (43.8) [19.8, 70.1] |
| Emetogenicity | ||||
| MEC | 8/11 (72.7) [39.0, 94.0] | 7/11 (63.6) [30.8, 89.1] | 9.1 [− 29.9, 45.6] | 15/22 (68.2) [45.1, 86.1] |
| HEC | 16/23 (69.6) [47.1, 86.8] | 14/20 (70.0) [45.7, 88.1] | − 0.4 [− 27.4, 27.3] | 30/43 (69.8) [53.9, 82.8] |
| Chemotherapy schedule | ||||
| Day 1 only | 12/13 (92.3) [64.0, 99.8] | 12/14 (85.7) [57.2, 98.2] | 6.6 [− 22.4, 34.6] | 24/27 (88.9) [70.8, 97.6] |
| Multiple days | 12/21 (57.1) [34.0, 78.2] | 9/17 (52.9) [27.8, 77.0] | 4.2 [− 26.7, 34.6] | 21/38 (55.3) [38.3, 71.4] |
aConfidence interval determined with Clopper-Pearson method
bConfidence interval determined with Miettinen-Nurminen method
CI confidence interval, CR complete response, HEC highly emetogenic chemotherapy, MEC moderately emetogenic chemotherapy, NE not evaluable
The proportion of patients with no emetic episodes was 89.2% in the acute phase, 73.8% in the delayed phase, and 72.3% in the overall phase. Outcomes were similar between dose groups. In addition, the number of patients with no emetic episodes was generally similar for the different strata except for chemotherapy schedule. The proportion of patients with no emetic episodes was higher in those receiving chemotherapy on day 1 only compared with those receiving multiple-day chemotherapy (overall phase: 92.6% vs 57.9%). The rates of no rescue medication were 96.9% in the acute phase, 93.8% in the delayed phase, and 93.8% in the overall phase. There were no notable differences overall or between dose groups by age, emetogenicity, and chemotherapy schedule.
PK/PD
The PK population consisted of 64 patients. Final population PK model parameters for netupitant, M1, M2, M3, and palonosetron are presented in Online Resource 2. For netupitant, M1, and M3, the stepwise covariate modeling (SCM) analysis indicated no significant impact of covariates on PK parameters. Therefore, their base population PK models were considered final. For M2, the effect of the serum albumin on systemic clearance (CL/F) was accepted in the final model and for palonosetron, the age effect on CL/F and on volume of central compartment (Vc/F) was accepted in the final model.
Post hoc PK parameters for each age class and netupitant dose are presented in Table 3. In the lower-dose group, the mean AUC0-inf values for netupitant in the different age classes ranged from 2276 to 7637 ng·h/mL; for the higher-dose group, this range was 8617–17,340 ng·h/mL. The netupitant mean AUC0-inf/D and Cmax/D decreased with increasing age, likely because of the expected lower systemic clearance in younger patients due to allometry factors, the ontogenicity of metabolic enzymes, and the progressive maturation of the biliary excretion route with age. The latter may in particular explain higher AUC0-inf/D values of netupitant metabolites in younger patients. The mean elimination half-life of netupitant (74.8–201 h) and its metabolites appeared to be independent of dose group or age class.
Table 3.
Post hoc PK parameters from the final population PK models for netupitant, netupitant metabolites M1, M2, M3, and palonosetron stratified by treatment group and age class
| Parameters, mean (CV%) | Netupitant | M1 | M2 | M3 | Palonosetron | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Lower netupitant dose group | Higher netupitant dose group | Lower netupitant dose group | Higher netupitant dose group | Lower netupitant dose group | Higher netupitant dose group | Lower netupitant dose group | Higher netupitant dose group | Lower netupitant dose Group | Higher netupitant dose group | |
| 1 to < 3 months | ||||||||||
| N | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 |
| Cmax(ng/mL) | 60.8 (NA) | NA | 4.21 (NA) | NA | 41.5 (NA) | NA | NA | NA | 1.82 (NA) | NA |
| Cmax/D(ng/mL/mg) | 16.4 (NA) | NA | 1.13 (NA) | NA | 11.2 (NA) | NA | NA | NA | 19.1 (NA) | NA |
| tmax(h) | 1.5 (NA) | NA | 16.0 (NA) | NA | 2.08 (NA) | NA | NA | NA | 4.00 (NA) | NA |
| AUC0-inf(ng·h/mL) | 4460 (NA) | NA | 1255 (NA) | NA | 1270 (NA) | NA | NA | NA | 94.8 (NA) | NA |
| AUC0-inf/D(ng·h/mL/mg) | 1200 (NA) | NA | 338 (NA) | NA | 342 (NA) | NA | NA | NA | 1006 (NA) | NA |
| t1/2(h) | 164 (NA) | NA | 195 (NA) | NA | 209 (NA) | NA | NA | NA | 42.1 (NA) | NA |
| 3 to < 6 months | ||||||||||
| N | 3 | 2 | 3 | 2 | 3 | 2 | 3 | 2 | 3 | 2 |
| Cmax(ng/mL) | 76.0 (27.1) | 233 (4.25) | 7.35 (17.2) | 22.9 (10.4) | 40.8 (16.6) | 142 (29.6) | 7.98 (34.1) | 15.4 (39.8) | 2.01 (21.9) | 2.47 (24.0) |
| Cmax/D(ng/mL/mg) | 10.0 (38.8) | 11.0 (14.2) | 0.96 (27.2) | 1.09 (20.3) | 5.22 (9.37 | 6.62 (19.9) | 1.02 (30.3) | 0.75 (48.8) | 17.5 (27.3) | 23.8 (22.8) |
| tmax(h) | 1.17 (24.7) | 1.00 (0) | 16.7 (30.2) | 22.0 (0.00) | 1.83 (15.7) | 1.75 (20.2) | 10.0 (0.00) | 11.0 (12.9) | 4.00 (0.00) | 4.00 (0.00) |
| AUC0-inf(ng·h/mL) | 3849 (91.3) | 17,340 (36.4) | 1788 (63.3) | 6214 (18.2) | 928 (40.0) | 5306 (83.0) | 792 (23.3) | 2016 (8.02) | 70.0 (30.6) | 108 (47.2) |
| AUC0-inf/D(ng·h/mL/mg) | 538 (103) | 807 (26.9) | 244 (76.9) | 292(8.33) | 117 (31.5) | 241 (76.1) | 101 (17.7) | 95.1 (1.98) | 613 (32.3) | 1040 (39.5) |
| t1/2(h) | 104 (54.8) | 126 (25.0) | 153 (54.0) | 175 (30.7) | 103 (20.7) | 153 (56.5) | 63.6 (16.2) | 92.5 (50.0) | 27.9 (13.1) | 35.3 (27.1) |
| 6 to < 12 months | ||||||||||
| N | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Cmax(ng/mL) | 133 (71.7) | 255 (31.2) | 13.4 (43.8) | 32.5 (16.7) | 51.1 (17.8) | 113 (13.3) | 15.0 (68.8) | 21.5 (47.2) | 2.64 (40.2) | 2.38 (14.9) |
| Cmax/D(ng/mL/mg) | 13.7 (71.3) | 7.76 (38.8) | 1.39 (47.1) | 0.99 (23.9) | 5.18 (23.2) | 3.41 (15.8) | 1.55 (67.4 | 0.67 (55.7) | 18.1 (36.4) | 14.6 (20.5) |
| tmax(h) | 1.38 (54.5) | 1.25 (23.1) | 12.0 (27.2) | 11.5 (8.70) | 2.29 (25.5) | 1.63 (15.4) | 9.00 (12.8) | 9.00 (12.8) | 4.00 (0.00) | 3.74 (13.5) |
| AUC0-inf(ng·h/mL) | 7637 (113) | 8617 (45.2) | 1688 (46.6) | 3671 (33.6) | 2149 (62.1) | 2282 (31.1) | 1120 (53.5) | 1727 (31.4) | 95.7 (49.8) | 81.3 (25.8) |
| AUC0-inf/D (ng·h/mL/mg) | 791 (114) | 261 (49.7) | 171 (48.7) | 110 (33.2) | 220 (63.9) | 68.7 (31.8) | 115.0 (53.9) | 53.0 (40.9) | 656 (44.4) | 496 (29.8) |
| t1/2(h) | 201 (83.5) | 95.3 (31.1) | 86.8 (40.8) | 70.8 (36.4) | 175 (44.8) | 93.4 (14.6) | 54.5 (39.1) | 52.8 (22.5) | 30.1 (21.3) | 28.7 (12.9) |
| 1 to < 2 years | ||||||||||
| N | 3 | 4 | 3 | 4 | 3 | 4 | 3 | 4 | 3 | 4 |
| Cmax(ng/mL) | 69.5 (19.3) | 275 (38.2) | 9.52 (19.4) | 38.28 (19.3) | 35.5 (8.33) | 123 (15.2) | 7.83 (23.0) | 39.9 (35.6) | 2.08 (22.6) | 2.72 (30.7) |
| Cmax/D (ng/mL/mg) | 5.23 (11.1) | 8.13 (49.5) | 0.74 (31.0) | 1.12 (35.6) | 2.70 (14.5) | 3.77 (48.5) | 0.60 (30.9) | 1.15 (42.1) | 10.4 (18.1) | 15.7 (32.6) |
| tmax(h) | 1.00 (0.00) | 1.25 (23.1) | 16.0 (45.1) | 12.0 (13.6) | 1.67 (17.3) | 1.90 (14.0) | 10.0 (0.00) | 8.00 (0.00) | 3.84 (7.22) | 3.93 (3.56) |
| AUC0-inf(ng·h/mL) | 2276 (29.8) | 9886 (59.6) | 1227 (23.3) | 2751 (24.0) | 657 (18.0) | 2832 (38.4) | 751 (15.9) | 2199 (38.1) | 75.9 (41.3) | 102 (39.1) |
| AUC0-inf/D (ng·h/mL/mg) | 170 (19.9) | 281 (58.5) | 92.5 (19.8) | 85.1 (52.0) | 50.1 (21.2) | 86.6 (52.6) | 57.6 (23.7) | 64.0 (44.3) | 382 (33.3) | 583 (35.4) |
| t1/2(h) | 74.8 (21.5) | 109 (38.9) | 81.6 (37.0) | 41.5 (25.4) | 87.5 (7.89) | 104 (20.3) | 60.4 (10.0) | 32.3 (14.7) | 29.1 (19.9) | 31.7 (14.4) |
| 2 to < 5 years | ||||||||||
| N | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 6 |
| Cmax(ng/mL) | 74.0 (32.3) | 266 (55.0) | 10.8 (19.6) | 38.0 (45.5) | 39.5 (13.5) | 110 (22.7) | 11.4 (25.4) | 41.3 (56.6) | 3.11 (16.6) | 3.57 (56.3) |
| Cmax/D (ng/mL/mg) | 4.21 (70.4) | 5.43 (74.7) | 0.57 (37.8) | 0.77 (62.0) | 2.13 (44.5) | 2.15 (43.0) | 0.60 (39.4) | 0.84 (69.5) | 11.2 (45.3) | 14.2 (64.3) |
| tmax(h) | 1.08 (18.8) | 1.17 (44.3) | 17.7 (31.6) | 13.7 (37.5) | 1.83 (14.1) | 1.67 (15.5) | 9.67 (8.45) | 9.33 (11.1) | 3.82 (10.2) | 3.75 (10.9) |
| AUC0-inf(ng·h/mL) | 3135 (44.0) | 14,404 (131) | 1287 (16.4) | 3905 (52.2) | 1046 (36.8) | 3140 (83.1) | 983 (18.9) | 3304 (58.8) | 117 (20.9) | 168 (91.2) |
| AUC0-inf/D (ng·h/mL/mg) | 180 (75.4) | 324 (151) | 70.3 (47. 6) | 78.9 (75.8) | 59.4 (71.4) | 66.5 (107) | 51.4 (35.3) | 67.7 (76.2) | 421 (47.5) | 668 (89.8) |
| t1/2(h) | 88.2 (32.8) | 126 (93.3) | 73.1 (32.4) | 68.7 (54.0) | 103 (21.0) | 103 (49.0) | 54.8 (25.0) | 53.1 (30.5) | 32.2 (8.72) | 36.4 (50.8) |
| 5 to < 12 years | ||||||||||
| N | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Cmax(ng/mL) | 67.9 (32.1) | 213 (20.1) | 11.1 (9.58) | 38.2 (24.0) | 33.1 (23.4) | 101 (21.0) | 12.3 (32.5) | 39.0 (48.2) | 3.04 (16.2) | 3.15 (21.4) |
| Cmax/D (ng/mL/mg) | 1.98 (36.4) | 2.35 (25.7) | 0.33 (28.1) | 0.43 (35.1) | 0.95 (25.3) | 1.12 (27.1) | 0.35 (32.0) | 0.45 (53.5) | 5.95 (22.2) | 7.12 (34.4) |
| tmax (h) | 1.06 (16.6) | 1.06 (16.6) | 12.0 (15.4) | 12.3 (28.2) | 1.56 (20.5) | 1.56 (20.5) | 8.50 (10.9) | 8.75 (17.0) | 3.60 (9.28) | 3.64 (11.9) |
| AUC0-inf (ng·h/mL) | 2676 (35.0) | 10,154 (70.7) | 970 (35.6) | 3504 (56.0) | 816 (67.8) | 2483 (45.0) | 848 (24.4) | 3001 (70.6) | 114 (28.8) | 112 (34.1) |
| AUC0-inf/D (ng·h/mL/mg) | 78.2 (44.8) | 114 (76.2) | 28.5 (41.1) | 39.1 (59.9) | 23.0 (66.5) | 26.7 (43.6) | 24.6 (27.6) | 33.2 (71.4) | 215 (23.4) | 250 (40.6) |
| t1/2 (h) | 79.5 (30.3) | 93.5 (38.8) | 51.4 (35.6) | 53.0 (43.8) | 86.3 (38.6) | 85.7 (27.5) | 43.3 (19.7) | 46.5 (42.5) | 31.2 (16.0) | 29.8 (19.5) |
| 12 to < 18 years | ||||||||||
| N | 9 | 6 | 9 | 6 | 9 | 6 | 9 | 6 | 9 | 6 |
| Cmax (ng/mL) | 76.8 (27.3) | 274 (15.6) | 11.7 (28.2) | 34.4 (19.8) | 42.1 (23.0) | 131 (12.1) | 11.9 (39.1) | 35.6 (36.7) | 3.46 (26.2) | 3.57 (14.4) |
| Cmax/D (ng/mL/mg) | 1.05 (19.6) | 1.11 (20.0) | 0.16 (29.2) | 0.14 (20.7) | 0.57 (11.3) | 0.53 (16.3) | 0.16 (35.8) | 0.14 (33.1) | 3.17 (26.3) | 2.89 (18.0) |
| tmax(h) | 1.11 (19.8) | 1.25 (21.9) | 14.0 (47.4) | 13.0 (21.2) | 1.79 (15.4) | 1.92 (10.7) | 9.11 (11.6) | 9.33 (11.1) | 4.00 (0.17) | 3.87 (5.47) |
| AUC0-inf(ng·h/mL) | 3107 (54.9) | 12,266 (26.9) | 1197 (53.7) | 4226 (19.3) | 1202 (58.9) | 3470 (34.2) | 977 (55.7) | 2973 (30.9) | 152 (43.0) | 166 (25.6) |
| AUC0-inf/D (ng·h/mL/mg) | 39.8 (33.7) | 49.8 (28.1) | 15.3 (33.2) | 17.1 (21.7) | 15.4 (42.4) | 14.1 (35.2) | 12.7 (35.0) | 12.0 (29.6) | 138 (38.5) | 135 (28.7) |
| t1/2(h) | 92.1 (33.2) | 111 (17.5) | 62.6 (48.7) | 77.4 (25.1) | 117 (37.7) | 116 (19.9) | 50.3 (35.4) | 54.5 (27.3) | 37.6 (23.0) | 41.1 (13.8) |
AUC0-inf average area under the plasma concentration-time curve from time zero to infinity, AUC0-inf/D dose-normalized AUC0-inf, Cmax maximum plasma concentration, Cmax/D dose normalized Cmax, CV coefficient of variation, NA not available, PK pharmacokinetics, t1/2 half-life, tmax the time to Cmax
Exposure to palonosetron was also higher in younger patients with AUC0-inf/D values ranging from 135 (12 to < 18 years) to 1040 ng·h/mL/mg (3 to < 6 months), and Cmax/D values ranging from 2.89 (12 to < 18 years) to 23.8 ng/mL/mg (3 to < 6 months).
The exposure-response correlation between netupitant exposure (AUC0-inf and Cmax) and CR in the acute, delayed, and overall phases was investigated using graphical exploratory data analysis. For the primary endpoint, there was a trend toward increased CR with increasing netupitant AUC0-inf in the delayed phase (Fig. 2). The correlation did not reach statistical significance, likely due to data sparseness. No trend correlation was observed between CR and netupitant Cmax. A similar trend of increased CR with increasing netupitant AUC0-inf was seen in the overall phase, but no apparent correlation was observed for the acute phase (data not shown).
Fig. 2.
Graphical exploratory data analysis for netupitant. Black circles are observed data points; red solid line is the locally estimated scatterplot smoothing of the data. The gray area represents the 95% confidence interval of data. AUC0-inf, average area under the plasma concentration-time curve from time zero to infinity; Cmax, maximum plasma concentration
Safety
The safety population consisted of 66 patients. Mean treatment exposure (administered drug volume/planned drug volume) was 99% for both netupitant and palonosetron. Most patients (44; 66.7%) experienced one or more TEAE; the overall TEAE incidence was nearly identical in the lower and higher netupitant dose groups (64.7% vs 68.8%). TEAEs reported in > 5% of total patients are listed in Table 4. The incidence of TEAEs was similar in the different strata and no TEAEs led to study drug discontinuation. Three TEAEs in two patients were considered possibly related to study drug: intraventricular conduction defect in the lower-dose group and headache and somnolence in the higher-dose group. Five serious TEAEs were reported in three patients in the higher-dose group: febrile neutropenia (n = 2), stomatitis (n = 1), neutropenic sepsis (n = 1), and urinary tract infection (n = 1); none were considered related to study drug. There were no deaths and no safety concerns for hematology and blood chemistry parameters.
Table 4.
Treatment-emergent adverse events occurring in > 5% of patients overall
| TEAE, n (%) | Lower netupitant dose group (N = 34) | Higher netupitant dose group (N = 32) | Total (N = 66) |
|---|---|---|---|
| Any | 22 (64.7) | 22 (68.8) | 44 (66.7) |
| Anemia | 9 (26.5) | 7 (21.9) | 16 (24.2) |
| Thrombocytopenia | 10 (29.4) | 6 (18.8) | 16 (24.2) |
| Leukopenia | 8 (23.5) | 4 (12.5) | 12 (18.2) |
| Neutropenia | 3 (8.8) | 6 (18.8) | 9 (13.6) |
| Stomatitis | 2 (5.9) | 5 (15.6) | 7 (10.6) |
| Pyrexia | 1 (2.9) | 5 (15.6) | 6 (9.1) |
| Febrile neutropenia | 2 (5.9) | 3 (9.4) | 5 (7.6) |
| Vomiting | 2 (5.9) | 3 (9.4) | 5 (7.6) |
| Increased alanine aminotransferase | 3 (8.8) | 1 (3.1) | 4 (6.1) |
TEAE treatment-emergent adverse event
No patient in either dose group reported constipation or diarrhea as a TEAE
Discussion
There is an unmet need to determine the most effective antiemetic regimen for CINV prevention in pediatric patients. The needs in this population may differ from the adult setting, as highlighted by differences in antiemetic guidelines. Palonosetron is currently recommended as the preferred 5-HT3 RA for pediatric patients, combined with (fos)aprepitant for those receiving HEC [9], a recommendation further supported by a recent meta-analysis synthesizing evidence across pediatric antiemetic regimens [3]. In adult patients, NEPA has shown improved efficacy compared with aprepitant regimens [21, 22]. In addition, netupitant has an extended half-life compared with aprepitant in adults and a long duration of receptor occupancy [15, 23, 24]. A combination of palonosetron and netupitant may also be an effective regimen for the pediatric population.
Results from this study show that concomitant treatment with oral netupitant and oral palonosetron was effective and safe for preventing CINV in pediatric patients receiving HEC or MEC. Both tested doses of netupitant (1.33 and 4 mg/kg) were effective in preventing CINV in acute, delayed, and overall phases, with limited differences between doses. The proportion of patients who demonstrated CR was generally similar for the two dose groups, as well as among age classes. A positive correlation was observed between CR rate and netupitant AUC0-inf in both the delayed and overall phases; however, these results were not statistically significant, likely due to the data sparseness.
Efficacy results were comparable between the pediatric population and published results in adults for patients receiving chemotherapy on day 1 only. For pediatric patients, CR rates were 92.6% during the acute phase, 92.6% during the delayed phase, and 88.9% in the overall phase. These results are similar to CR rates seen in pivotal phase 2/3 trials with oral NEPA in adult patients [16–18]. A phase 2 dose-finding study in adult patients receiving cisplatin-based chemotherapy on day 1 compared doses of 100, 200, and 300 mg netupitant plus palonosetron. CR rates with the three netupitant doses ranged from 92.7 to 98.5% in the acute phase, 90.4–91.2% in the delayed phase, and 87.4–89.6% in the overall phase, with no clear dose-dependent differences [16]. Although efficacy outcomes observed in the present study appeared broadly comparable to those reported in adult NEPA studies, caution is warranted when extrapolating findings between pediatric and adult populations, as antiemetic efficacy and patient-related risk factors are not always concordant across age groups. Therefore, dedicated pediatric studies remain essential to establish optimal antiemetic strategies for children receiving chemotherapy.
CR rates for patients receiving multiple-day chemotherapy were 55.3% in the delayed and overall phases and 81.6% in the acute phase. A study assessing single-dose NEPA plus dexamethasone in adult patients with sarcoma receiving multiple-day chemotherapy found CR rates of 100% in the acute phase and 88.9% in the delayed and overall phases during cycle 1 [25]. These results suggest that additional doses of netupitant and palonosetron may be necessary in multiple-day chemotherapy settings for pediatric patients, although direct comparison between these studies cannot be made, given the differences in populations and types of multiple-day chemotherapy. Further research would be needed to assess the most effective dosing frequency. In this study, the acute phase was uniformly defined as the first 24 h following the start of chemotherapy, regardless of whether patients received single-day or multiday treatment. In multiday regimens, each chemotherapy day could be considered to have its own acute phase, followed by a delayed phase, blurring the lines between outcomes on acute and delayed CINV. The lack of a standardized definition complicates interpretation and comparison of CR rates across different treatment schedules.
The TEAE profile was as expected for patients receiving cytotoxic chemotherapy and consistent with the established safety profile for oral NEPA in adults [16–18]. The most common TEAEs to occur during the study were anemia and thrombocytopenia; both were reported in 16 (24%) patients and were not related to study drugs.
The mean exposure to netupitant was similar for the different pediatric age classes to that seen in adults after administration of 100 and 300 mg oral netupitant. In the higher netupitant dose group, individual AUC0-inf results ranged between 2890 and 52,407 ng·h/mL in pediatric patients, while AUC0-inf results from 117 adult patients treated with 300 mg netupitant and 0.50 mg palonosetron ranged from 3064 to 55,802 ng·h/mL (Helsinn Healthcare SA, data on file). The average half-life of netupitant was 74.8–201 h in pediatric age groups and this appeared to be independent of dose and age class. In comparison, the range of netupitant half-life from several studies in adult patients was 56.0–93.8 h [26]. The long half-life of netupitant in pediatric patients could be very beneficial for the efficacy of netupitant in the delayed phase, as well as for preventing long-delayed CINV. The higher dose of netupitant did not lead to an increase in TEAEs, and a trend toward increased CR with increasing netupitant exposure was observed in the delayed phase. Therefore, the dose of 4 mg/kg (2.4 mg/kg for patients aged < 3 months) up to a maximum of 300 mg for patients weighing ≥ 75 kg appears appropriate for future studies with the oral formulation in the pediatric population.
The mean half-life of palonosetron in pediatric age classes ranged from 27.9 to 42.1 h, compared with 43.8–65.7 h in adult patients [26]. Palonosetron PK parameters following concomitant oral treatment with netupitant were similar to those seen in a study in pediatric patients after 20 µg/kg palonosetron administered intravenously as single or multiple courses with dexamethasone [27]. The recommended dose of 20 µg/kg (maximum 1.5 mg) for pediatric patients is higher than the dose used in oral NEPA for adults (0.5 mg); this difference is likely due to metabolic differences [12, 13]. Currently, pediatric-friendly formulations for oral palonosetron are not available [9]. Thus, the provision of oral NEPA provides a possible alternative to another efficacious antiemetic agent.
Beyond its PK and tolerability profile, oral NEPA’s simplicity as a dual-agent single-dose regimen may offer a practical advantage over triple or quadruplet regimens in pediatric patients. As noted in the “Introduction” section, children and families have described a trade-off between more intensive antiemetic regimens and the burden of antiemetic-related side effects, such as constipation, prompting some to modify day-to-day medication use [3]. In the current study, constipation and diarrhea were not reported as treatment-emergent adverse events in any patient in either dose group.
The current study had several limitations that are common in pediatric research. The numbers of patients in the different age groups were low, particularly in the younger age classes. In addition, patients included in the study had heterogeneous characteristics and varied diagnoses, including solid tumors, leukemia/lymphoma, and brain tumors (Table 1), which may differentially affect vomiting independent of chemotherapy. Studies investigating and comparing antiemetic use in the pediatric population are limited and often small, as recruiting patients for these supportive care studies can be challenging [28]. Additionally, the majority of patients (92%) had previously received chemotherapy and experienced CINV (84% vomiting/retching, 71% nausea) due to chemotherapy. Prior CINV is a recognized risk factor for subsequent CINV and may potentially influence the antiemetic treatment effect, although this has not been established since most antiemetic trials have been conducted in chemo-naïve patients. This remains an important consideration for interpreting the generalizability of the current findings. The need to obtain both parent and child consent can lead to conflicts, and younger children may have difficulties understanding what the trial entails or may have unrealistic expectations of the outcomes [29]. As a result, significant evidence gaps exist in antiemetic use in the pediatric population. More research is needed to identify risk factors for CINV in pediatric patients. Furthermore, the overall picture of which antiemetics are most effective remains incomplete, including knowledge of optimal dosing and schedules of antiemetics. Recruitment of infants and very young children remains particularly challenging in pediatric supportive care studies. Future investigations may benefit from international collaborative networks, extended enrollment periods, dedicated recruitment strategies for infants, and population PK approaches that maximize the information obtained from limited blood sampling, which together may help generate more robust evidence in younger age groups.
In conclusion, the current study shows that a single dose of 4 mg/kg oral netupitant administered concomitantly with 20 µg/kg (maximum 1.5 mg) oral palonosetron in pediatric patients receiving HEC or MEC was effective and well-tolerated, and appropriate for use in future studies in pediatric patients. Further research is needed to optimize prevention of nausea and vomiting in children receiving chemotherapy.
Supplementary Information
Below is the link to the electronic supplementary material.
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Acknowledgements
The authors would like to acknowledge and thank the patients and their families, investigators, and the study teams at the centers participating in this study. We thank Maria Elisa Borroni for clinical study management, Riccardo Bezzo for data management, and Corinna Lanzarotti for statistical analysis. Editorial and medical writing assistance was provided by Judith Land, PhD, CMPP, of Aptitude Health, The Hague, the Netherlands, funded by Helsinn Healthcare SA. The authors are fully responsible for all content and editorial decisions for this manuscript.
Author contributions
PP and TC contributed the interpretation of data, reviewing the manuscript critically, approval of the version to be published, and agreement to be accountable for all aspects of the work; OA, MM, ND, AB, and SC all contributed the conception or design, acquisition, analysis, and interpretation of data, reviewing the manuscript critically, approval of the version to be published, and agreement to be accountable for all aspects of the work; TS contributed the conception or design, acquisition, analysis, and interpretation of data, reviewing the manuscript critically, approval of the version to be published, and agreement to be accountable for all aspects of the work.
Funding
Helsinn Healthcare provided financial support for the study.
Data availability
De-identified data may be made available upon request to qualified researchers, subject to approval by the institutional ethics committee.
Declarations
Ethics approval
The study was conducted in accordance with International Council for Harmonisation requirements and the Declaration of Helsinki. The study protocol was approved by the relevant independent ethics committees or institutional review boards.
Consent to participate
For all patients, signed written informed consent by a parent/legal guardian was obtained before study initiation in compliance with the local laws and regulations, as well as signed children’s consent per local requirements.
Consent for publication
Not applicable.
Competing interests
P. Patel: Nothing to declare. O. Arakaev: Nothing to declare. M. Melnikov: Nothing to declare. N. Dementieva: Nothing to declare. A. Bernareggi: Clinical Pharmacology Consultant, Italy. Nothing to declare. T. Chen: Employee of Helsinn Healthcare. T. Spinelli: Employee of Helsinn Healthcare. S. Chaleff: Nothing to declare.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Navari RM, Aapro M (2016) Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 374:1356–1367. 10.1056/NEJMra1515442 [DOI] [PubMed] [Google Scholar]
- 2.Fernández-Ortega P, Caloto MT, Chirveches E, Marquilles R, San Francisco J, Quesada A, Suárez C, Zorrilla I, Gómez J, Zabaleta P, Nocea G, Llombart-Cussac A (2012) Chemotherapy-induced nausea and vomiting in clinical practice: impact on patients’ quality of life. Support Care Cancer 20:3141–3148. 10.1007/s00520-012-1448-1 [DOI] [PubMed] [Google Scholar]
- 3.Walker R, Dias S, Phillips RS (2024) Antiemetic medications for preventing chemotherapy-induced nausea and vomiting in children: a systematic review and Bayesian network meta-analysis. Support Care Cancer 32:747. 10.1007/s00520-024-08939-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Park YH, Bianchini G, Cortés J, Licata L, Vidal M, Iihara H, Roeland EJ, Jordan K, Scotté F, Schwartzberg L, Navari RM, Aapro M, Rugo HS (2025) Nausea and vomiting in an evolving anticancer treatment landscape: long-delayed and emetogenic antibody-drug conjugates. Future Oncol 21:1261–1272. 10.1080/14796694.2025.2479417 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Grunberg SM, Warr D, Gralla RJ, Rapoport BL, Hesketh PJ, Jordan K, Espersen BT (2011) Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicity–state of the art. Support Care Cancer 19:S43–S47. 10.1007/s00520-010-1003-x [DOI] [PubMed] [Google Scholar]
- 6.Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Lyman GH (2020) Antiemetics: ASCO guideline update. J Clin Oncol 38:2782–2797. 10.1200/JCO.20.01296 [DOI] [PubMed] [Google Scholar]
- 7.Herrstedt J, Clark-Snow R, Ruhlmann CH, Molassiotis A, Olver I, Rapoport BL, Aapro M, Dennis K, Hesketh PJ, Navari RM, Schwartzberg L, Affronti ML, Garcia-Del-Barrio MA, Chan A, Celio L, Chow R, Fleury M, Gralla RJ, Giusti R, Jahn F, Iihara H, Maranzano E, Radhakrishnan V, Saito M, Sayegh P, Bosnjak S, Zhang L, Lee J, Ostwal V, Smit T, Zilic A, Jordan K, Scotté F (2024) 2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. ESMO Open 9:102195. 10.1016/j.esmoop.2023.102195 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.National Comprehensive Cancer Network (2025) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Antiemesis. Version 2.2025. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed 5 Jan 2026
- 9.Patel P, Robinson PD, Cohen M, Devine K, Gibson P, Holdsworth MT, Neumann E, Orsey A, Phillips R, Spinelli D, Thackray J, van de Wetering M, Woods D, Cabral S, Sung L, Dupuis LL (2022) Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: a clinical practice guideline. Pediatr Blood Cancer 69:e30001. 10.1002/pbc.30001 [DOI] [PubMed] [Google Scholar]
- 10.Bloomhardt H, Rubin M, Xue Y, Jin Z, Masino L, Seidel D, Hijiya N, Beauchemin M (2024) Pediatric oncology provider perspectives and patient/family perceptions of chemotherapy-induced nausea and vomiting management: experiences at an academic medical center. Pediatr Blood Cancer 71:e30883. 10.1002/pbc.30883 [DOI] [PubMed] [Google Scholar]
- 11.Ben-Kenan RF, Stafford LK, Temkit M, Brown J, Walsh A (2025) Vomiting despite adherence to guidelines: suboptimal control of vomiting in pediatric cancer patients. Pediatr Blood Cancer 72:e31372. 10.1002/pbc.31372 [DOI] [PubMed] [Google Scholar]
- 12.Kovács G, Wachtel AE, Basharova EV, Spinelli T, Nicolas P, Kabickova E (2016) Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study. Lancet Oncol 17:332–344. 10.1016/S1470-2045(15)00520-3 [DOI] [PubMed] [Google Scholar]
- 13.Chaudhary NK, John RR, Boddu D, Mahasampath G, Nesadeepam N, Mathew LG (2019) Palonosetron is a better choice compared with ondansetron for the prevention of chemotherapy-induced nausea and vomiting (CINV) in a resource-limited pediatric oncology center: results from a randomized control trial. J Pediatr Hematol Oncol 41:294–297. 10.1097/MPH.0000000000001357 [DOI] [PubMed] [Google Scholar]
- 14.Aapro M, Jordan K, Scotté F, Celio L, Karthaus M, Roeland E (2022) Netupitant-palonosetron (NEPA) for preventing chemotherapy-induced nausea and vomiting: from clinical trials to daily practice. Curr Cancer Drug Targets 22:806–824. 10.2174/1568009622666220513094352 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Akynzeo 300 mg/0.5 mg hard capsules [summary of product characteristics] (2020) Helsinn Birex Pharmaceuticals Ltd
- 16.Hesketh PJ, Rossi G, Rizzi G, Palmas M, Alyasova A, Bondarenko I, Lisyanskaya A, Gralla RJ (2014) 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 25:1340–1346. 10.1093/annonc/mdu110 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gralla RJ, Bosnjak SM, Hontsa A, Balser C, Rizzi G, Rossi G, Borroni ME, Jordan K (2014) 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. Ann Oncol 25:1333–1339. 10.1093/annonc/mdu096 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Aapro M, Rugo H, Rossi G, Rizzi G, Borroni ME, Bondarenko I, Sarosiek T, Oprean C, Cardona-Huerta S, Lorusso V, Karthaus M, Schwartzberg L, Grunberg S (2014) 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 25:1328–1333. 10.1093/annonc/mdu101 [DOI] [PMC free article] [PubMed]
- 19.de Wildt SN, Kearns GL, Leeder JS, van den Anker JN (1999) Cytochrome P450 3A. Clin Pharmacokinet 37:485–505. 10.2165/00003088-199937060-00004 [DOI] [PubMed] [Google Scholar]
- 20.Aloxi (palonosetron HCl) injection for intravenous use [summary of product characteristics] (2018) Helsinn Birex Pharmaceuticals Ltd
- 21.Navari RM, Binder G, Bonizzoni E, Clark-Snow R, Olivari S, Roeland EJ (2021) Single-dose netupitant/palonosetron versus 3-day aprepitant for preventing chemotherapy-induced nausea and vomiting: a pooled analysis. Future Oncol 17:3027–3035. 10.2217/fon-2021-0023 [DOI] [PubMed] [Google Scholar]
- 22.Zelek L, Navari R, Aapro M, Scotté F (2023) Single-dose NEPA versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy. Cancer Med 12:15769–15776. 10.1002/cam4.6121 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Emend (fosaprepitant) for injection, for intravenous use [prescribing information] (2022) Merck Sharp & Dohme LLC
- 24.Baron-Hay S, Aapro M, Bernareggi A, Schwartzberg L (2019) Timing flexibility of oral NEPA, netupitant-palonosetron combination, administration for the prevention of chemotherapy-induced nausea and vomiting (CINV). Support Care Cancer 27:1309–1317. 10.1007/s00520-019-4640-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Badalamenti G, Incorvaia L, Messina C, Musso E, Casarin A, Ricciardi MR, De Luca I, Bazan V, Russo A (2019) One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients. Support Care Cancer 27:3593–3597. 10.1007/s00520-019-4645-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Gilmore J, Bernareggi A (2019) Complementary pharmacokinetic profiles of netupitant and palonosetron support the rationale for their oral fixed combination for the prevention of chemotherapy-induced nausea and vomiting. J Clin Pharmacol 59:472–487. 10.1002/jcph.1338 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hara J, Kosaka Y, Koh K, Matsumoto K, Kumamoto T, Fujisaki H, Ishida Y, Suzuki R, Mochizuki S, Goto H, Yuza Y, Koga Y (2021) Phase III study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in pediatric patients. Jpn J Clin Oncol 51:1204–1211. 10.1093/jjco/hyab079 [DOI] [PubMed] [Google Scholar]
- 28.Bloomfield FH (2015) The challenges of research participation by children. Pediatr Res 78:109–110. 10.1038/pr.2015.75 [DOI] [PubMed] [Google Scholar]
- 29.Crane S, Broome ME (2017) Understanding ethical issues of research participation from the perspective of participating children and adolescents: a systematic review. Worldviews Evid Based Nurs 14:200–209. 10.1111/wvn.12209 [DOI] [PMC free article] [PubMed] [Google Scholar]
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