The trial, conducted across multiple centers and registered as NCT03204279, evaluated oral netupitant combined with oral palonosetron, a fixed-dose combination marketed as NEPA. Netupitant blocks the neurokinin-1 (NK1) receptors in the brain that mediate the vomiting reflex, while palonosetron blocks 5-hydroxytryptamine-3 (5-HT3) receptors, both in the gut and in the central nervous system, which are activated by chemotherapy drugs. This dual mechanism targets the two principal signaling pathways that drive CINV. NEPA is already approved for adults, where it has outperformed aprepitant-based regimens in head-to-head comparisons, but the optimal pediatric dose of netupitant had never been established. The new study was designed to close that gap by pairing rigorous pharmacokinetic measurements with clinical efficacy outcomes.

Researchers enrolled 67 patients under 18 years of age, assigning them to one of two netupitant dose groups: a lower dose of 1.33 mg/kg or a higher dose of 4 mg/kg, each delivered with palonosetron at 20 micrograms per kilogram. Infants under three months received reduced weight-based doses of 0.8 or 2.4 mg/kg to account for their immature CYP3A4-mediated metabolism, the liver enzyme system responsible for breaking down netupitant. These pediatric doses were carefully calibrated to reproduce the drug exposures previously shown to be safe and effective in adults receiving 100 or 300 mg of netupitant. Patients were stratified by age, by whether their chemotherapy was highly or moderately emetogenic, and by treatment schedule, ensuring that the analysis could capture differences across the full developmental spectrum from infancy to late adolescence.

The primary efficacy measure was complete response, defined as the absence of both emetic episodes and rescue medication, tracked through a paper diary covering 120 hours after chemotherapy. Among the 65 evaluable patients, complete response rates in the lower-dose group reached 85.3 percent in the acute phase, 70.6 percent in the delayed phase, and 70.6 percent overall. The higher-dose group performed comparably, with rates of 87.1, 71.0, and 67.7 percent respectively. These figures are striking given the study population: 92 percent of the children had already endured previous chemotherapy cycles, and 84 percent had experienced vomiting or retching during prior treatment, both recognized risk factors that predict worse control of nausea.

For children receiving chemotherapy on a single day, the results were remarkable. Complete response rates in this subgroup stood at 92.6 percent in the acute phase, 92.6 percent in the delayed phase, and 88.9 percent overall, figures that closely mirror those achieved in pivotal adult trials of oral NEPA. In contrast, patients receiving multi-day chemotherapy fared considerably worse, with complete response rates of 55.3 percent in the delayed and overall phases. The authors suggest that additional doses of netupitant and palonosetron may be required for multi-day regimens, since each day of chemotherapy could arguably generate its own acute emetic window, blurring the conventional boundary between acute and delayed CINV and complicating comparisons across studies.

The pharmacokinetic analysis revealed how differently children process these drugs compared with adults. Population modeling showed that dose-normalized exposure to netupitant decreased with age, a consequence of allometric scaling, the ontogeny of metabolic enzymes, and the progressive maturation of biliary excretion in early life. Mean netupitant half-life ranged from 74.8 to 201 hours across pediatric age classes, longer than the 56.0 to 93.8 hours typically observed in adults, a property that could prove advantageous for suppressing delayed and even long-delayed CINV beyond the conventional 120-hour window. Palonosetron exposure was likewise higher in younger children, with dose-normalized area under the curve values spanning more than sevenfold between adolescents and infants aged three to six months.

Perhaps the most scientifically intriguing finding was the exposure-response relationship. Graphical exploratory analysis showed a trend toward higher complete response rates as netupitant systemic exposure, measured as the area under the plasma concentration-time curve from zero to infinity, increased during the delayed phase, with a similar but weaker pattern in the overall phase. The correlation did not reach statistical significance, likely because the dataset was sparse, but it provides a pharmacological rationale for favoring the higher 4 mg/kg dose, which achieved mean exposures well above the lower dose without any penalty in tolerability.

Safety data reinforced that profile. Mean treatment exposure was 99 percent for both drugs, indicating the regimen was well accepted. Two-thirds of patients experienced at least one treatment-emergent adverse event, but the incidence was nearly identical between dose groups, and the events themselves, most commonly anemia and thrombocytopenia, were consistent with the expected toxicity of cytotoxic chemotherapy rather than the study drugs. Only three adverse events in two patients, an intraventricular conduction defect, headache, and somnolence, were considered possibly related to treatment. Notably, constipation and diarrhea, a common burden of more intensive antiemetic regimens that families have described forcing them to modify their children’s medication day by day, were not reported at all.

The broader context makes these findings more consequential. A clinical practice guideline for pediatric CINV now recommends palonosetron as the preferred 5-HT3 receptor antagonist, yet surveys have found that more than half of pediatric oncology providers are unaware of such guidelines, and even when guideline-consistent care is delivered, only about 48 percent of children achieve complete vomiting control. A single oral dose combining two complementary mechanisms could dramatically simplify prophylaxis, reducing the pill burden that young patients and their families have described as exhausting when they are already feeling unwell. With no pediatric-friendly oral palonosetron formulation currently available, oral NEPA offers a practical alternative.

The study’s limitations are those familiar to anyone working in pediatric oncology research: small numbers within each age class, particularly among infants, and a heterogeneous mix of solid tumors, leukemias, lymphomas, and brain tumors that can independently influence vomiting. Prior chemotherapy exposure and prior CINV in nearly all participants may also have shaped the treatment effect in ways that remain unresolved, since most antiemetic trials enroll chemotherapy-naive patients. The authors caution against directly extrapolating adult findings to children and call for further research to identify pediatric CINV risk factors and optimize dosing schedules. Still, the conclusion is clear and consequential: a single dose of 4 mg/kg oral netupitant with 20 micrograms per kilogram of palonosetron was effective, well tolerated, and appropriately scaled across childhood, positioning this fixed-dose combination as a strong candidate for the definitive trials that could finally bring adult-level nausea control to children with cancer.

Subject of Research: A phase 2 dose-finding study of oral netupitant-palonosetron (NEPA) for preventing chemotherapy-induced nausea and vomiting in pediatric cancer patients

Article Title: A phase 2 pharmacokinetic and pharmacodynamic dose-finding study of oral NEPA for chemotherapy-induced nausea and vomiting in pediatric patients with cancer

Article References: Patel, P., Arakaev, O., Melnikov, M., Dementieva, N., Bernareggi, A., Chen, T., Spinelli, T., & Chaleff, S. (2026). A phase 2 pharmacokinetic and pharmacodynamic dose-finding study of oral NEPA for chemotherapy-induced nausea and vomiting in pediatric patients with cancer. Supportive Care in Cancer, 34(10), Article 1005. https://doi.org/10.1007/s00520-026-11238-0

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11238-0

Keywords: chemotherapy-induced nausea and vomiting, netupitant, palonosetron, NEPA, pediatric oncology, antiemetics, pharmacokinetics, phase 2 trial, supportive care, 5-HT3 receptor antagonist, NK1 receptor antagonist, dose-finding study