Search

The management of chemotherapy-induced nausea and vomiting (CINV) during preparative regimens for Hematopoietic Stem Cell Transplant (HSCT) continues to be a poorly studied area and an unmet patient need. The primary aim of this study was to assess the efficacy of NEPA to prevent N/V both during and after HSCT conditioning. NEPA is a recently approved combination antiemetic, containing fixed doses of netupitant and palonosetron. Nausea, emesis, and nutritional intake, were evaluated from the start of conditioning through day 4 post-transplant. NEPA was administered Days 1, 3 and 6 of conditioning, dexamethasone (Days 1-6) and BEAM (Carmustine (300 mg/m2 D1), Etoposide/Cytarabine (200/400 mg/m2 D2-5), Melphalan (140 mg/m2 D 6)) preparative regimen (Days 1-6) in 17 patients. Patient nausea and emesis was self-reported using daily assessments and rescue therapy was determined using chart review. Two out of 17 patients experienced emesis (11.7%) after all chemotherapy was completed with no emesis in any patient during chemotherapy. During the observation period, 6 patients did not receive rescue medications (35%) and time to first rescue in other patients was a mean of 188.9 hours from the start of chemotherapy (median 172.4, SD 89 hrs). Responses were classified as either complete (CR) or major (MR), with CR defined as: no emesis, mild-moderate nausea for hours 0-264 (6 days of chemotherapy and 5 days post-chemotherapy), and (MR) defined as: 1-2 emesis on only 1 day with any level nausea or no emesis with severe nausea. Five out of 16 patients reported CR (31%) and 11 reported a major response (69%) at their end of treatment (EOT) visit. One patient did not participate in the EOT visit. The patient population in this study was 47% female, 100% Caucasian, the average age was 62 years old and the following diagnoses were included: Peripheral T-cell Lymphoma (24%), Hodgkin lymphoma (23%), mantle cell lymphoma (29%), and Diffuse large B-cell lymphoma (24%). The following expected adverse events were reported amongst 17 treated patients: anemia (82%); neutropenia (65%); lymphocyte decrease (94%); decreased neutrophils (94%); white blood cell decrease (88%); abdominal pain (59%); constipation (53%); diarrhea (59%); abdominal cramping (35%); nausea (82% all grades); bacteremia (29%); hypophosphatemia (24%); and hypokalemia (29%). Constipation was deemed possibly related to NEPA; additional reported adverse events were not related to study drug. In this interim analysis, NEPA plus dexamethasone was effective in preventing emesis with BEAM conditioning with no increase in adverse events prior to HSCT.

Background: Breast cancer (BC) patients receiving anthracycline-cyclophosphamide (AC) chemotherapy (CT) are at risk for developing CINV due not only to the emetogenicity of the CT but also to young age and gender. As recommended by international antiemetic guidelines, targeting multiple molecular pathways involved in emesis related to AC is important for maximizing control of CINV and improving the functional status of BC patients during CT. NEPA is a fixed-dose combination of netupitant (NETU), a highly-selective NK1 receptor antagonist (RA), and palonosetron (PALO), a pharmacologically distinct 5-HT3 RA, that targets dual antiemetic pathways with a convenient single day dose. Methods: This was a multinational, randomized, double-blind, phase 3 study evaluating the efficacy and safety of a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in chemotherapy-naïve patients receiving AC. All patients received oral dexamethasone (DEX) on day 1 (12 mg NEPA arm; 20 mg PALO arm). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) in the delayed phase, 25-120h after CT. The Functional Living Index-Emesis (FLIE) questionnaire with a 5-day recall period was used to assess the impact of CINV on patients’ daily lives as a secondary endpoint. The FLIE consists of 9 nausea-specific (nausea domain) and 9 vomiting-specific (vomiting domain) items that address the effect of nausea and vomiting on daily life. Each item is scored on a 7-point 100 mm visual analog scale with anchors of “none/not at all” and “a great deal”. The proportion of patients with an average item score >6 reflecting “no impact on daily life” (NIDL) (ie, total FLIE score >108, nausea/vomiting domain score >54) was compared for NEPA vs PALO using a Cochran-Maentel-Haenszel test stratified by age class and region. Results: 1455 patients with a mean age of 54 were randomized to receive NEPA or PALO. Treatment groups were similar; 98% were females with BC (97%). As previously reported (ASCO 2013), NEPA showed superior CR rates compared to PALO for the acute 0-24h (88% vs 85%; p = 0.047), delayed (77% vs 70%; p = 0.001) and overall 0-120h (74% vs 67%; p = 0.001) phases. A greater proportion of NEPA-treated patients reported NIDL for nausea, vomiting and combined domains compared to PALO. % Patients with NIDL (Overall 0-120h)NEPA (N = 724)PALO (N = 725)p-valueNausea domain72%66%0.015Vomiting domain90%84%0.001Overall combined79%72%0.0056 patients excluded who did not receive AC or study drug The adverse event (AE) profile was comparable between groups. Most frequently reported treatment-related AEs for NEPA and PALO, respectively, were headache (3.3%, 3.0%) and constipation (2.1%, 2.1%). Conclusions: In this large Phase 3 study of predominantly females with BC receiving AC, NEPA was superior to PALO in preventing CINV and reducing the negative impact of CINV on patients’ daily lives. As a fixed-dose antiemetic drug combination including an NK1 RA and 5-HT3 RA, NEPA offers improved efficacy over PALO alone, with a convenient single-day dose, and oral DEX only on day 1. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-01.

Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy-induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor-binding-selective tracer [(11) C]-GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1 -RO duration. A NK1 -RO of 90% or higher was achieved with all doses in the majority of the tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1 -RO of 90%, C90% , in the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90% . In the ADME study, a single nominal dose of [(14) C]-netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic metabolism. Elimination of90% was predicted at day 29 and was principally via hepatic/biliary route (85%) with a minor contribution of the renal route (5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition, netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys.

Aim NK-1 receptors in sensory nerves, the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity. This study was designed to assess the efficacy and safety of a new NK-1 receptor antagonist, netupitant, in patients with OAB. Methods This was a phase II, multicenter, double-blind study in which adults with OAB symptoms >6 months were randomized to receive 1 of 3 doses of netupitant (50, 100, 200 mg) or placebo once daily for 8 weeks. The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8. Urinary incontinence, urge urinary incontinence (UUI), and urgency episodes were also assessed. Results The primary efficacy endpoint was similar in the treatment groups (−13.85 for placebo to −16.17 in the netupitant 200 mg group) with no statistically significant differences between netupitant and placebo. The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group. Netupitant was well tolerated with most treatment emergent adverse events (AEs) being mild. While the overall incidence of AEs increased with netupitant dose, there was no evidence for this dose dependency based on relationship to treatment, intensity, or time to onset. Conclusions The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms, despite a trend favoring netupitant 100 mg. There were no safety concerns with daily administration of netupitant over 8 weeks. Neurourol. Urodynam. 33:335–340, 2014. © 2013 Wiley Periodicals, Inc.

Neurokinin-1 receptor antagonists (NK1 RAs) are commonly coadministered with a 5-HT3 RA such as palonosetron to prevent nausea and vomiting induced by chemotherapy. Netupitant, a new highly selective NK1 RA, is both a substrate for and a moderate inhibitor of CYP3A4. Three studies were designed to evaluate the potential drug–drug interaction of netupitant with palonosetron and of the fixed dose combination of netupitant and palonosetron, NEPA, with an inhibitor (ketoconazole), an inducer (rifampicin) and a substrate (oral contraceptives) of CYP3A4. Study 1 was a three-way crossover in 18 healthy subjects receiving netupitant alone, palonosetron alone, and the combination of both antiemetics. Studies 2 and 3 were two-way crossover trials where healthy subjects received NEPA (the fixed dose combination of netupitant and palonosetron). In study 2, 36 subjects received NEPA alone (day 1) and in combination with ketoconazole or rifampicin. In study 3, 24 healthy women received ethinylestradiol/levonorgestrel alone or in combination with NEPA (day 1). There were no significant pharmacokinetic interactions between netupitant and palonosetron. Ketoconazole increased netupitant area under curve (AUC) by 140 % and C max by 25 %. Rifampicin decreased netupitant AUC by 83 % and C max by 62 %. NEPA did not significantly affect exposure to ethinylestradiol, while systemic exposure to levonorgestrel increased by 40 %, but this was not considered clinically relevant. There were no clinically relevant interactions between netupitant and palonosetron, or between NEPA and oral contraceptives. The coadministration of NEPA with inhibitors or inducers of CYP3A4 may require dose adjustments. Treatments were well tolerated.

Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P-450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug–drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone. Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes. Netupitant, by inhibiting the CYP3A4, increased the C max and AUCinf of midazolam by 40 and 144 %, respectively, and the C max and AUCinf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant. The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies.

Background and Aims: Chemotherapy-induced acute and delayed emesis involves the activation of multiple pathways, with 5-hydroxytryptamine (5-HT; serotonin) playing a major role in the initial response. Substance P tachykinin NK1 receptor antagonists can reduce emesis induced by disparate emetic challenges and therefore have a clinical utility as broad inhibitory anti-emetic drugs. In the present studies, we investigate the broad inhibitory anti-emetic profile of a relatively new NK1 receptor antagonist, netupitant, alone or in combination with the long acting 5-HT3 receptor antagonist, palonosetron, for a potential to reduce emesis in ferrets and shrews. Materials and Methods: Ferrets were pretreated with netupitant and/or palonosetron, or their combination, and then administered apomorphine (0.125 mg/kg, s.c.), morphine (0.5 mg/kg, s.c.), ipecacuanha (1.2 mg/kg, p.o.), copper sulphate (100 mg/kg, intragastric), or cisplatin (5-10 mg/kg, i.p.); in other studies netupitant was administered to Suncus murinus before motion (4 cm horizontal displacement, 2 Hz for 10 min). Results: Netupitant (3 mg/kg, p.o.) abolished apomorphine-, morphine-, ipecacuanha- and copper sulphate-induced emesis. Lower doses of netupitant (0.03-0.3 mg/kg, p.o.) dose-dependently reduced cisplatin (10 mg/kg, i.p.)-induced emesis in an acute (8 h) model, and motion-induced emesis in Suncus murinus. In a ferret cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis model, netupitant administered once at 3 mg/kg, p.o., abolished the first 24 h response and reduced the 24-72 h response by 94.6 %; the reduction was markedly superior to the effect of a three times per day administration of ondansetron (1 mg/kg, i.p.). A single administration of netupitant (1 mg/kg, p.o.) plus palonosetron (0.1 mg/kg, p.o.) combined with dexamethasone (1 mg/kg, i.p., once per day), also significantly antagonized cisplatin-induced acute and delayed emesis and was comparable with a once-daily regimen of ondansetron (1 mg/kg, p.o.) plus aprepitant (1 mg/kg, p.o.) in combination with dexamethasone (1 mg/kg, i.p.). Conclusion: Netupitant has potent and long lasting anti-emetic activity against a number of emetic challenges indicating broad inhibitory properties. The convenience of protection afforded by the single dosing of netupitant together with palonosetron was demonstrated and also is known to provide an advantage over other therapeutic strategies to control emesis in man.

Introduction. Tachykinins potently contract the isolated urinary bladder from a number of animal species and play an important role in the regulation of the micturition reflex. On the guinea-pig isolated urinary bladder we examined the effects of a new potent and selective NK1 receptor antagonist (netupitant) on the contractions induced by a selective NK1 receptor agonist, SP-methylester (SP-OMe). Moreover, the effects of netupitant and another selective NK1 antagonist (L-733,060) were studied in anesthetized guinea-pigs using two experimental models, the isovolumetric bladder contractions and a model of bladder overactivity induced by intravesical administration of acetic acid (AA). Methods and Results. Detrusor muscle strips were mounted in 5 mL organ baths and isometric contractions to cumulative concentrations of SP-OME were recorded before and after incubation with increasing concentrations of netupitant. In anesthetized female guinea-pigs, reflex bladder activity was examined under isovolumetric conditions with the bladder distended with saline or during cystometry using intravesical infusion of acetic acid (AA). After a 30 min stabilization period, netupitant (0.1-3 mg/kg, i.v.) or L-733,060 (3-10 mg/kg, i.v.) were administered. In the detrusor muscle, netupitant produced a concentration-dependent inhibition (mean pKB = 9.24) of the responses to SP-OMe. Under isovolumetric conditions, netupitant or L-733,060 reduced bladder contraction frequency in a dose-dependent manner, but neither drug changed bladder contraction amplitude. In the AA model, netupitant dose-dependently increased intercontraction interval (ICI) but had no effect on the amplitude of micturition (AM). L-733,060 dose-dependently increased ICI also but this effect was paralleled by a significant reduction of AM. Conclusion. Netupitant decreases the frequency of reflex bladder contractions without altering their amplitude, suggesting that this drug targets the afferent limb of the micturition reflex circuit and therefore may be useful clinically in treating bladder overactivity symptoms.

Background: The objective was to evaluate the cost-effectiveness of NEPA, an oral fixed combination netupitant (NETU, 300 mg) and palonosetron (PA, 0.5 mg) compared with aprepitant and palonosetron (APPA) or palonosetron (PA) alone, to prevent chemotherapy-induced nausea and vomiting (CINV) in patients undergoing treatment with highly or moderately emetogenic chemotherapy (HEC or MEC) in the UK. Scope: A systematic literature review and meta-analysis were undertaken to compare NEPA with currently recommended anti-emetics. Relative effectiveness was estimated over the acute (day 1) and overall treatment (days 1–5) phases, taking complete response (CR, no emesis and no rescue medication) and complete protection (CP, CR and no more than mild nausea [VAS scale

PURPOSE: This review summarizes the recommendations for the prophylaxis of nausea and vomiting in adults receiving highly emetogenic chemotherapy (HEC) which includes cisplatin, mechlorethamine, streptozocin, cyclophosphamide >1500 mg/m(2), carmustine, dacarbazine, and the combination of an anthracycline and cyclophosphamide (AC) administered to women with breast cancer, as agreed at the MASCC/ESMO Antiemetic Guidelines Update meeting in Copenhagen in June 2015.METHODS: A systematic review of the literature using PubMed and the Cochrane Database from 2009 to June 2015 was performed.RESULTS: The NK1-receptor antagonists netupitant (300 mg given in combination with palonosetron 0.5 mg as NEPA) and rolapitant have both completed phase II and III programs and were approved by FDA (both) and EMA (NEPA) in 2014-2015. Addition of one of these agents (or of (fos)aprepitant) to a combination of a serotonin (5-HT)3-receptor antagonist and dexamethasone improved the number of patients with a complete response (no emesis and no rescue medication) days 1-5 after AC HEC with 8-9 % and after non-AC HEC by 8-20 %. Olanzapine has improved control of delayed nausea as compared to aprepitant in a randomized open designed study. In the prophylaxis of delayed nausea and vomiting, metoclopramide is an option instead of aprepitant in patients receiving cisplatin-based chemotherapy and dexamethasone is an option instead of aprepitant in patients receiving AC chemotherapy.CONCLUSIONS: Two new NK1-receptor antagonists (netupitant and rolapitant) have been included in the updated recommendations as additional options to aprepitant or fosaprepitant. Addition of one of these NK1-receptor antagonists to a combination of a 5-HT3-receptor antagonist and dexamethasone is recommended in both non-AC HEC and AC HEC. Olanzapine is included as an option in HEC in particular if nausea is the main symptom.

OBJECTIVES Prevention of chemotherapy-induced nausea and vomiting is critical in older patients with cancer. NEPA is an oral fixed combination of netupitant 300mg, a new NK1 receptor antagonist (RA), and palonosetron 0.5mg, a pharmacologically distinct 5-HT3 RA. This retrospective analysis evaluated the efficacy and safety of NEPA in older patients. METHODS Patients aged ≥65 and ≥70years from one phase II and two phase III trials were considered. Chemotherapy-naive patients with malignant tumors were treated with anthracycline-cyclophosphamide (AC), non-AC-based moderately emetogenic chemotherapy (non-AC MEC), or highly emetogenic chemotherapy (HEC). Following single-dose NEPA, patients received oral dexamethasone on day 1 (AC and non-AC MEC) or days 1-4 (HEC). Efficacy was evaluated through complete response (CR) in cycle 1. Safety was evaluated by AEs and ECGs. Data were summarized by descriptive statistics. RESULTS Overall, 214 patients were ≥65years and 80 were ≥70years. A higher CR was observed in older patients versus the total population; in the acute phase >90% of patients ≥65years experienced CR. Efficacy was maintained over multiple cycles of chemotherapy. No significant nausea rates were generally higher in the older patients versus total population. Similar rates of AEs in the first treatment cycle were reported for patients ≥65years, ≥70years, and total population (72.9% vs 67.5% vs 70.0%, respectively). No cardiac safety concerns were raised. CONCLUSION NEPA is highly effective in older patients receiving MEC or HEC regimens. NEPA is also well tolerated, demonstrating suitability for use in older patients who may have comorbidities

Chemotherapy-induced nausea and vomiting is one of the most worrisome adverse effects of chemotherapy for cancer patients. It can cause severe discomfort and affect the quality of life. In recent years, the incorporation of new drugs has increased the efficacy of antiemetic treatments in the control of emesis associated with chemotherapy. This guideline, in which we give some treatment recommendations with level of evidence and grade of recommendation, provides an update of the previously published guideline of the Spanish Society of Medical Oncology and represents our continued commitment to improving supportive care in cancer patients.

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.

Despite recent progress, chemotherapy-induced nausea and vomiting (CINV), especially delayed CINV, continues to be a problem. Delayed CINV is underestimated and perceived differently by providers and patients. Communication between providers and patients about this side effect may help improve outcomes. This study identifies patients' and providers' perceptions of management and barriers to quality CINV care. Provider and patient versions of a Nausea and Vomiting Management Barriers Questionnaire were developed to address potential barriers. Providers and patients were given opportunities to add detail in open-ended questions. Providers were recruited through the NCCN and the Oncology Nursing Society mailing lists. Patients who received at least 2 cycles of chemotherapy and experienced CINV were recruited through a consortium of advocacy groups. Both providers (n = 141) and patients (n = 299) completed the survey. Providers (41%) and patients (42%) agreed medication side effects were a concern, but more patients (63%) than providers (36%) tried to limit the number of medications taken (P < .0001). Many providers (67%) spontaneously reported barriers to managing CINV, with financial and patient-related factors among the most common. Few patients (10%) reported cost as a barrier, but 37% endorsed the desire "to be strong by not complaining." Barriers to communication and quality care of CINV differ between caregivers and patients. Addressing misconceptions and establishing mutually consistent goals will lead to more effective overall care.

Background The purpose of the study was to compare the effectiveness of olanzapine (OLN) and aprepitant (APR) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Methods A phase III trial was performed in chemotherapy-naive patients receiving cisplatin ≥ 70 mg/m(2) or cyclophosphamide ≥ 500 mg/m(2) and doxorubicin ≥ 50 mg/m(2), comparing OLN to APR in combination with palonosetron (PAL) and dexamethasone (DEX). The OLN, PAL, DEX (OPD) regimen was 10 mg of oral OLN, 0.25 mg of IV PAL, and 20 mg of IV DEX prechemotherapy, day 1, and 10 mg/day of oral OLN alone on days 2-4 postchemotherapy. The APR, PAL, DEX (APD) regimen was 125 mg of oral APR, 0.25 mg of IV PAL, and 12 mg of IV DEX, day 1, and 80 mg of oral APR, days 2 and 3, and 4 mg of DEX BID, days 2-4. Two hundred fifty-one patients consented to the protocol and were randomized. Two hundred forty-one patients were evaluable. Results Complete response (CR) (no emesis, no rescue) was 97% for the acute period (24 hours postchemotherapy), 77% for the delayed period (days 2-5 postchemotherapy), and 77% for the overall period (0-120 hours) for 121 patients receiving the OPD regimen. CR was 87% for the acute period, 73% for the delayed period, and 73% for the overall period in 120 patients receiving the APD regimen. Patients without nausea (0, scale 0-10, MD Anderson Symptom Inventory) were OPD: 87% acute, 69% delayed, and 69% overall; APD: 87% acute, 38% delayed, and 38% overall. There were no grade 3 or 4 toxicities. CR and control of nausea in subsequent chemotherapy cycles were equal to or greater than cycle 1 for both regimens. OPD was comparable to APD in the control of CINV. Nausea was better controlled with OPD. Discussion In this study, OLN combined with a single dose of DEX and a single dose of PAL was very effective at controlling acute and delayed CINV in patients receiving highly emetogenic chemotherapy. CR rates were not significantly different from a similar group of patients receiving highly emetogenic chemotherapy and an antiemetic regimen consisting of APR, PAL, and DEX.

Introduction:NEPA is a fixed dose combination of the NK1-receptor antagonist (RA) netupitant and 5-HT3-RA palonosetron approved for prevention of chemotherapy-induced nausea and vomiting (CINV) in pts receiving highly emetogenic (HEC) on cisplatin-basis or moderately emetogenic Ctx (MEC). NEPA demonstrated safety and efficacy in platinum, anthracycline and cyclophosphamid based Ctx, These drugs are frequently used in regimens for hematology pts. A German non-interventional study investigated NEPA's efficacy and impact on quality of life in adult cancer pts by patient-related outcomes (PRO) and physicians' personal assessment under real life conditions. Primary objective was the evaluation of quality of life (QoL) in adults receiving NEPA for CINV prevention. Secondary endpoints were efficacy and safety of NEPA. Methods: Open label, non-interventional, prospective, national, multicenter study that evaluates CINV prevention and patients' QoL receiving NEPA in pts with either HEC or MEC on up to 2 consecutive Ctx days for at least consecutive 3 cycles. QoL was evaluated by the validated FLIE questionnaires at the end of each Ctx cycle. Efficacy was documented by the treating physicians and via patient diaries for 3 Ctx cycles within 24 hrs and on 4 additional d after Ctx. Safety, additional medication and physicians' overall satisfaction was reported via eCRF. Results: Between June 2015 and Sept 2017 a total of 2429 pts were enrolled with 1997 pts being eligible for the 2nd interim analysis. 1901 pts were included in the efficacy analysis in the 1st, 1808 pts in the 2nd and 1734 pts in the 3rd cycle. Median age was 58 (range of 28-89). A total of 630 evaluable pts received MEC (53% carboplatin based) and 1185 pts received HEC (88% anthracycline/ cyclophosphamide based), PRO with complete response (CR=no nausea, no vomiting, no rescue medication) was analyzed based on patient diaries. Diaries for PRO in MEC-pts (n=401) reported CR in 94% in cycle 1, 85% in cycle 2 and 86% in cycle 3. Efficacy, assessed by physicians (n=630 pts) on a 4-point scale, was rated very good/good for 91%, 93%, and 94% in cycle 1, 2 and 3, respectively. PRO of 896 pts with HEC reported 81% CR in cycle 1, 82% in cycle 2 and 83% in cycle 3. Efficacy, assessed by physicians (1185 HEC pts), was rated very good/good for 88%, 89%, and 90% in cycle 1, 2 and 3, respectively. A high percentage of patients receiving HEC or MEC did not suffer from any emesis (93%, 93% and 94% in cycle 1-3, respectively). Over 85%of pts reported no impact on daily QoL due to vomiting in all 3 cycles with HEC or MEC.The most common treatment emergent adverse events were constipation and insomnia of mild-moderate intensity. Conclusions: NEPA prevented CINV highly effective in the acute and delayed phase of HEC and MEC with no impact on daily life due to vomiting in >85% of pts. Physicians evaluation was concordant to PRO.Safety profile was good. Disclosures Karthaus: Riemser: Consultancy. Schilling:Riemser: Honoraria.

BACKGROUND In the setting of cHL, ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) is the most widely used first line chemotherapeutic treatment and it is well known that this regimen is associated with a high emetic risk (HEC). Palonosetron (PALO) currently represents one of the most effective and implemented drug for CINV prevention, but after many ABVD cycles patients (pts) frequently need to add other antiemetic drugs to obtain a good control of their symptoms. Netupitant (NETU) is the NK1-RA (neurokinin receptor antagonist) component of NEPA, the first antiemetic drug available as oral fixed combination: NETU (300mg) + PALO (0.5mg). Both ABVD drugs and NETU are metabolized by cytochrome P-450 isoform 3A4 (CYP3A4), but respect to other NK1-receptor antagonist available, NETU has demonstrated to have no clinical relevant interaction with chemotherapy drugs like etoposide, cyclophosphamide and docetaxel. However, no data are currently available about the safety profile of NETU in the setting of ABVD treatment; for that reason we started the use of this drug as salvage therapy after PALO failure. METHODS We retrospectively analyzed the cHL pts treated with ABVD at our Center from September 2016 to January 2018. We used PALO + dexamethasone as first-line anti-CINV prophylaxis, while NEPA was introduced as salvage drug for those pts with inadequately controlled CINV. We collected data regarding demographics; diagnosis; planned chemotherapeutic treatment; performed chemotherapeutic treatment; acute, delayed and anticipatory CINV (before and after NEPA); laboratory findings including transaminases, creatinine and electrolytes (before and after NEPA); adverse reactions (before and after NEPA). The primary endpoint of the study was safety of NEPA in ABVD treated pts, while CINV control (no nausea or vomiting) was the secondary endpoint. NEPA-related safety data have been compared to the same data collected at the moment of the last previous PALO-containing regimen. RESULTS Among the 32 pts treated with ABVD during the study period, 13 (41%) received NEPA. Three pts were males and 10 females, and median age was 33 years (range 18-61). According to disease characteristics at diagnosis the planned ABVD administrations were 12 (6 cycles) in 9 pts, 8 (4 cycles) in 3 pts and 4 (2 cycles) in 1 pt. Nine pts completed the planned chemotherapy, 1 pt skipped the last cycle for personal decision, 3 pts are ongoing treatment at the time of analysis. Reasons for shift to NEPA are as follows: acute (grade 2) CINV alone in 3/13 pts; late (grade 2) CINV alone in 3/13 pts; combined acute (4 grade 2, 1 grade 1) and late (4 grade 2, 1 grade 1) CINV in 5/13 pts; combined anticipatory (grade 1), acute (grade 1) and late (grade 2) CINV in 2/13 pts. NEPA was started after a median of 4 ABVD administrations (range 1-10). Globally 53 NEPA administrations were delivered during subsequent cycles (median number of 3 NEPA administrations for each pt, range 1-11). With regard to the primary endpoint, the observed adverse events are listed in Table 1. With regard to the secondary endpoint, anticipatory, acute and delayed CINV were detected in 15%, 77%, 77%, of PALO pts and 15%, 46% and 15% of NEPA pts, respectively (see Table 2) CONCLUSION In our experience NETU did not show drug-drug interaction with ABVD chemotherapy agents, and NEPA administration was globally well tolerated with mild and transient adverse events. Furthermore, in cHL ABVD treated pts who experienced nausea and/or vomiting after failure of PALO + dexamethasone antiemetic prophylaxis, NEPA has demonstrated to be effective in CINV control. In 4 out of 13 cases, after an initial improvement in CINV control, pts subsequently required to shift to anti-CINV third line treatments. On the other hand, the 9 pts who continued on NEPA administration could experience an optimal CINV control immediately after the first administration. At our knowledge no data have been published regarding NEPA toxicities in the ABVD setting. Our safety and efficacy data come from a real life experience of consecutive pts treated homogeneously at a single center and would suggest the use of NEPA as primary anti-CINV prophylaxis in previously untreated cHL pts. Disclosures Rusconi: Celgene: Research Funding.

Palonosetron is the only 5-HT(3) receptor antagonist approved for the treatment of delayed chemotherapy-induced nausea and vomiting (CINV) in moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), the endogenous ligand acting preferentially on neurokinin-1 (NK-1) receptors, not serotonin (5-HT), is the dominant mediator of delayed emesis. However, palonosetron does not bind to the NK-1 receptor. Recent data have revealed cross-talk between the NK-1 and 5HT(3) receptor signaling pathways; we postulated that if palonosetron differentially inhibited NK-1/5-HT(3) cross-talk, it could help explain its efficacy profile in delayed emesis. Consequently, we evaluated the effect of palonosetron, granisetron, and ondansetron on SP-induced responses in vitro and in vivo. NG108-15 cells were preincubated with palonosetron, granisetron, or ondansetron; antagonists were removed and the effect on serotonin enhancement of SP-induced calcium release was measured. In the absence of antagonist, serotonin enhanced SP-induced calcium-ion release. After preincubation with palonosetron, but not ondansetron or granisetron, the serotonin enhancement of the SP response was inhibited. Rats were treated with cisplatin and either palonosetron, granisetron, or ondansetron. At various times after dosing, single neuronal recordings from nodose ganglia were collected after stimulation with SP; nodose ganglia neuronal responses to SP were enhanced when the animals were pretreated with cisplatin. Palonosetron, but not ondansetron or granisetron, dose-dependently inhibited the cisplatin-induced SP enhancement. The results are consistent with previous data showing that palonosetron exhibits distinct pharmacology versus the older 5-HT(3) receptor antagonists and provide a rationale for the efficacy observed with palonosetron in delayed CINV in the clinic.

e22177Background: The approval of oral NEPA, a novel fixed antiemetic combination comprised of the NK1RA netupitant (300 mg) and 5-HT3RA palonosetron (PALO, 0.50 mg), was based on demonstrating sup...

Nausea and vomiting are common in cancer patients. The most common cause of nausea and vomiting is the administration of cytotoxic chemotherapy. Apart from chemotherapy-induced nausea and vomiting (CINV), biological agents may also cause these symptoms. In this review, discussion will be focused on management of nausea and vomiting due to antineoplastic therapies. The cornerstone of effective management of nausea and vomiting secondary to these antineoplastic drugs is the prevention with the use of appropriate guideline-directed combination antiemetic regimen. Type 3 serotonin receptor antagonists (5HT3RAs), neurokinin-1 receptor antagonists (NK1RAs), and dexamethasone are the backbone antiemetic drugs. In recent years, newer drugs and preparations have been introduced for clinical use and include second-generation 5HT3RA, palonosetron; granisetron transdermal patch; the recently introduced NK1RA rolapitant; and the novel oral combined drug NEPA (netupitant plus palonosetron); and last but not least, the atypical antipsychotic olanzapine.

A variety of triple antiemetic regimens are being used to prevent cisplatin-based chemotherapy induced delayed emesis and nausea in cancer patients. We performed a network meta-analysis to compare the efficacies of the different regimens. Electronic searches of the PubMed, Cochrane Library and MEDLINE databases were performed to identify randomized controlled trials, and data were analyzed using JAGS, Stata 14.0 and R project. The primary outcome was a complete response (CR). The secondary outcomes were no vomiting (NV) and no nausea (NN). Among the 398 studies identified, 10 were eligible and included, providing data on nine regimens. In the CR analysis, the absolute rank of netupitant + palonosetron + dexamethasone (NEPA) was 0.8579. In the NV and NN analyses, NEPA's absolute ranks were 0.8631 and 0.7902, respectively. The compliance of patients treated with rolapitant + granisetron + dexamethasone (RGD) was the best due to a low incidence of adverse events, and good compliance was also observed with NEPA. It was difficult to achieve good compliance with aprepitant + granisetron + dexamethasone (AGD). Overall, NEPA was the best regimen, and aprepitant + ondansetron + dexamethasone (AOD) is also worthy of recommendation because of its low cost and good effect. For patients with severe constipation, hiccups, asthenia and/or delayed nausea, RGD is worthy of consideration.

This review provides background information on chemotherapy-induced nausea and vomiting (CINV) classification and pathophysiology and reviews various antiemetic agents for CINV prophylaxis, including corticosteroids, serotonin receptor antagonists (5-HT3 RAs), tachykinin NK1 receptor antagonists (NK1 RAs), and olanzapine. Other less commonly used agents are briefly discussed. Practical considerations are reviewed as well, including emetogenicity of chemotherapeutic regimens, patient-specific risk factors for CINV, principles of CINV management, health economics outcome research, and quality of life. Available data on the newly FDA-approved antiemetic combination netupitant/palonosetron (NEPA) is also reviewed. Prevention of CINV is an important goal in managing patients with cancer and is especially difficult with respect to nausea and delayed CINV. Corticosteroids are a mainstay of CINV prophylaxis and are usually given in combination with other therapies. The 5-HT3 RA palonosetron has shown increased efficacy over other agents in the same class for prevention of delayed emesis with moderately emetogenic chemotherapy and NK1 RAs improve emesis prevention in combination with 5-HT3 RAs and dexamethasone. Olanzapine has shown efficacy for CINV prophylaxis and the treatment of breakthrough CINV. The new combination therapy, NEPA, has been shown to be efficacious for the prevention of acute, delayed, and overall CINV. Risk factors that have been identified for CINV include gender, age, and alcohol intake. It is important to assess the emetogenicity of chemotherapy regimens as well as the potential impact of patient risk factors in order to provide adequate prophylaxis. Acute and delayed CINV are severe, burdensome side effects of chemotherapy; however, new data on prevention and the discovery of new agents can further improve CINV control.

Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU)—a new NK1 RA—and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug–drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates.

The combination of netupitant and palonosetron was approved by the Food and Drug Administration in October 2014 for the prevention of acute and delayed chemotherapy-induced nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic chemotherapy. Netupitant and palonosetron is available as a single capsule to be administered prior to each cycle of chemotherapy. The approval was based on phase II and III data in patients undergoing treatment with moderately and highly emetogenic chemotherapy. Netupitant and palonosetron’s benefits include a convenient dosage form, dual-targeted mechanism, and favorable side effect profile, while its main limitations are cost and potential logistical issues surrounding administration. More studies are needed to adequately determine its role in therapy as well as which patients will derive the most benefit from its use.

Rolapitant is a novel, long-acting neurokinin-1 (NK-1) receptor antagonist. This study evaluated the safety and efficacy of four different doses of rolapitant for prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). This randomized, double-blind, active-controlled, global study was conducted in patients receiving cisplatin-based chemotherapy ≥70 mg/m2. Patients received a 9, 22.5, 90, or 180 mg oral dose of rolapitant or placebo with ondansetron and dexamethasone on day 1 of chemotherapy. The primary end point was complete response (CR; no emesis and no use of rescue medication) in the overall (0 to 120 h) phase of cycle 1. Other assessments were CR in delayed (24–120 h) and acute (0–24 h) phases, no emesis, no significant nausea, and no nausea. Four hundred fifty-four patients were randomized. All doses of rolapitant improved CR with the greatest benefit observed with rolapitant 180 mg vs. active control in the overall phase (62.5 and 46.7 %, p = 0.032) and in the acute (87.6 vs. 66.7 %, p = 0.001) and delayed (63.6 vs. 48.9 %, p = 0.045) phases. Rates for no emesis and no significant nausea were significantly (p

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists, appears to be the most effective agent in its class. Netupitant, is a new NK-1 receptor antagonist with a high binding affinity, a long half-life of 90 hours, is metabolized by CYP3A4, and is an inhibitor of CYP3A4. NEPA is an oral fixed-dose combination of netupitant and palonosetron which has recently been employed in Phase II and Phase III clinical trials for the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy (MEC and HEC). The clinical trials demonstrated that NEPA (300 mg of netupitant plus 0.50 mg of palonosetron) significantly improved the prevention of CINV compared to the use of palonosetron alone in patients receiving either HEC or MEC. The clinical efficacy was maintained over multiple cycles of chemotherapy. NEPA (Akynzeo(®)) has recently been approved by the Food and Drug Administration (FDA) to treat nausea and vomiting in patients undergoing cancer chemotherapy.

The aim of the present study was to investigate the pharmacological activity of Pronetupitant, a novel compound designed to act as prodrug of the NK1 antagonist Netupitant. In receptor binding experiments Pronetupitant displayed high selectivity for the NK1 receptor. In a calcium mobilization assay performed on CHONK1 cells Pronetupitant (100 nM, 15 min preincubation) behaved as an NK1 antagonist more potent than Netupitant (pK(B) 8.72 and 7.54, respectively). In the guinea pig ileum bioassay Pronetupitant antagonized the contractile effect of SP showing a similar potency as Netupitant (pK(B)≈9). Similar results were obtained with 5 min preincubation time while at 2 min only Pronetupitant produced significant effects. In vivo in mice the intrathecal injection of 0.1 nmol SP elicited the typical scratching, biting and licking (SBL) nociceptive response. This effect of SP was dose dependently (0.1-10 mg/kg) antagonized by Pronetupitant given intravenously 2 h before the peptide. Superimposable results were obtained using Netupitant. Pharmacokinetic studies performed in rats demonstrate that Pronetupitant, after i.v. administration, is quickly (few minutes) and completely converted to Netupitant. Collectively the present results indicated that Pronetupitant acts in vitro as selective NK1 antagonist more potent than Netupitant. However based on the short half-life measured for Pronetupitant in rats, the in vivo action of Pronetupitant can be entirely interpreted as due to its conversion to Netupitant.

The present study sought to determine the prevalence of acute and delayed chemotherapy-induced nausea and vomiting (CINV) across ten community oncology settings. The effect of CINV on quality of life (QOL) was also evaluated.Cancer patients who were scheduled for their first cycle of a new chemotherapy regimen were recruited from ten community oncology clinics. Study participants recorded occurrence of CINV by completing a daily diary each day for the first 8 days after treatment during each cycle and the Functional Living Index-Emesis (FLIE) before chemotherapy, at the end of day 1 and day 6 after chemotherapy. Mixed model regression analysis was used to explore the association between occurrence of CINV at cycle 1 and subsequent cycles and its impact on patient QOL.One hundred and fifty-one patients provided information for at least one cycle. During cycle 1, only 33% had neither acute nor delayed CINV. Of the 36% patients who developed acute CINV, 8% developed acute CINV only. Of the 59% who developed delayed CINV, 53% reported delayed only and 47% reported acute and delayed CINV. A similar pattern was seen at cycles 2 and 3. Experience of CINV at cycle 1 was associated with the development of CINV at cycles 2 and 3. Occurrence of CINV significantly interfered with patient QOL as assessed by the FLIE.CINV remained a substantial problem for patients receiving chemotherapy in this community-based sample, especially delayed CINV. CINV significantly interfered with patient QOL and daily functioning.

Purpose This is the first study in which the NK1-receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy. Patients and Methods Eligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide ± doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index–Emesis questionnaire. Results Of 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated. Conclusion The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.

BACKGROUND The authors determined the incidence of acute and delayed chemotherapy-induced nausea and emesis (vomiting) (CINV) among patients receiving highly (HEC) or moderately (MEC) emetogenic chemotherapy. They also assessed whether physicians and nurses accurately recognized the incidence of acute and delayed CINV in their own practices. METHODS A prospective, observational study of adult patients receiving HEC or MEC for the first time was performed. Before patient enrollment, medical oncologists and oncology nurses estimated the incidence of acute (Day 1) and delayed (Days 2–5) CINV after first administration of HEC and MEC in their own practices. Eligible patients from their practices then completed a 6-day diary including emetic episodes, nausea assessment, and antiemetic medication use. Observed incidence rates of acute and delayed CINV were compared with physician/nurse predictions. RESULTS Twenty-four physicians and nurses and 298 eligible patients (67 receiving HEC and 231 receiving MEC) were recruited from 14 oncology practices in 6 countries. Greater than 35% of patients overall experienced acute nausea, whereas 13% experienced acute emesis. Delayed nausea and emesis were observed in 60% and 50% of HEC patients, respectively, and in 52% and 28% of MEC patients, respectively. Delayed symptoms appeared without acute symptoms after HEC (emesis, 38%; nausea, 33%) and MEC (emesis, 19%; nausea, 21%). Physicians and nurses accurately predicted the incidence of acute CINV but underestimated the incidence of delayed nausea and emesis after HEC by 21 and 28 percentage points, respectively, and delayed nausea after MEC by 28 percentage points. Greater than 75% of physicians and nurses underestimated the incidence of delayed CINV after both HEC and MEC. CONCLUSIONS Physicians and nurses markedly underestimated the incidence of delayed nausea and emesis after both HEC and MEC. Delayed nausea and emesis, which may appear even in the absence of acute nausea and emesis, remain important targets for improved therapeutic intervention. Cancer 2004. © 2004 American Cancer Society.

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

120 Background: Antiemetic trials typically evaluate CINV control during acute (Day 1), delayed (Days 2-5), and overall (Days 1-5) phases post-chemotherapy; the daily course of events is often unstudied in the delayed phase. In a head-to-head study evaluating NK1RA-containing regimens, a single dose of NEPA, an oral fixed combination of the NK1RA netupitant and 5-HT3RA palonosetron, was non-inferior to a 3-day regimen of APR and GRAN for overall complete response (no emesis/no rescue use) rates (74% NEPA vs 72% APR/GRAN) in 828 patients receiving cisplatin-based highly emetogenic chemotherapy (HEC). This secondary analysis explores daily rates of breakthrough CINV in this study. Methods: This was a double-blind study in chemotherapy-naïve patients with solid tumors. Daily rates of breakthrough CINV, defined as the % of patients with emesis and/or rescue use were calculated with differences between treatment groups evaluated by the Cochran-Mantel-Haenszel method stratified by sex. Results: While daily rates of patients with breakthrough CINV remained stable between 13%-15.1% for APR/GRAN, they declined from 15.5% to 8% over the 5 days for NEPA, with the difference between groups reaching statistical significance on Day 5 (Table). Percent of total patient days with CINV events were 11.7% [NEPA] and 14.0% [APR/GRAN]. The % of patients with ≥ 3 days of breakthrough CINV were 8.5% and 12.3%, respectively. Conclusions: In this study evaluating guideline-recommended antiemetic regimens for HEC, CINV was prevented in most patients during the overall phase yet breakthrough CINV on individual days differed between treatment groups. APR/GRAN showed a relatively constant rate over time, while NEPA rates decreased and patients had fewer total days with breakthrough. This suggests the need for close monitoring of CINV events during the delayed phase. [Table: see text]

227 Background: PALO (0.50 mg), a distinctive second-generation 5-HT3 receptor antagonist (RA), is a component of the oral fixed combination agent NEPA, the second component being the NK1 RA netupitant. Oral NEPA is approved for acute and delayed CINV prophylaxis after moderately (MEC) and HEC. This study was conducted in support of the NEPA IV formulation (0.25 mg PALO + 235 mg fosnetupitant) administered as a 30-min IV inf, currently under FDA review. Methods: Chemotherapy-naive patients (pts) with solid tumors were randomized (1:1) to receive a single 0.25-mg PALO as a 30-min IV inf or a 30-sec IV bol, 30 min before reference HEC (cisplatin; dacarbazine), with oral dexamethasone (20 mg [D1]; 8 mg BID [D2–4]) (NCT02557035). Primary objective: noninferiority (NI; lower limit of the 99% CI to be > –15% [prespecified NI margin]) in complete response (CR; no emesis/no rescue) in the acute (0–24 h) phase. Secondary objective: safety. Results: 440 pts (median age 59.4 y [25–79]; cisplatin: 97.3%; dacarbazine: 2.7%) were randomized to IV inf (n=225) or IV bol (n=215). Baseline characteristics were similar. Acute CR rate was 82.7% (IV inf) and 86.5% (IV bol), with risk difference of –3.8% (99% CI: –12.2; 4.7) meeting the primary objective of NI. Treatment-emergent AE and study drug-related AE frequency was similar in both arms (Table). One PALO IV inf patient with pre-existing cardiac symptoms, experienced 1 serious AE that eventually lead to death and was considered possibly study drug-related by the investigator. No G≥3 infusion site reactions occurred. No patient in IV inf arm had infusion interruptions. Conclusions: PALO IV inf was noninferior to IV bol in acute CINV prevention after receiving non-AC HEC. Safety profiles were similar. No specific infusion toxicities were observed. The results show that PALO 0.25 mg IV inf is appropriate for the NEPA IV formulation. Clinical trial information: NCT02557035. [Table: see text]

122 Background: NEPA is an oral fixed combination of the selective NK1 receptor antagonist (RA), netupitant (300 mg), and pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), combining two guideline-recommended antiemetic classes in a convenient single capsule. Oral NEPA has shown superior prevention of chemotherapy-induced nausea and vomiting (CINV) over oral PALO, sustained efficacy over multiple cycles, and well-established safety in >1500 patients (pts). To offer additional convenience for health care practitioners and pts, an intravenous (IV) formulation of the NEPA fixed combination (fosnetupitant 235 mg/PALO 0.25 mg) was developed. Methods: This randomized, multinational, double-blind, stratified (by gender/country) phase 3 study in chemotherapy-naïve pts with solid tumors was designed to assess the safety of a single 30-minute infusion of IV NEPA prior to initial/up to 4 repeated cycles of highly emetogenic chemotherapy (HEC). Patients received either IV NEPA or oral NEPA, both with oral dexamethasone on days 1-4. Safety was assessed by treatment-emergent adverse events (TEAEs), laboratory tests, vital signs and ECGs. Results: 404 pts were evaluated for a total of 1312 exposures. Overall, 53% of pts were male with a mean age of 60 years; 99% of pts were white and cisplatin-containing regimen was the HEC for 96% of pts; lung cancer was the most common tumor (55% pts). The AE profiles were similar for both groups in cycle 1 and across all cycles (See Table), with no increased incidence of AEs in subsequent cycles. No infusion site reactions related to IV NEPA occurred. No clinically relevant changes in QTcor cardiac safety concerns were observed. Conclusions: IV NEPA is safe and well-tolerated over multiple cycles with a similar safety profile to oral NEPA in pts receiving HEC. Clinical trial information: NCT02517021. [Table: see text]

Objective To evaluate the efficiency of resources allocation and sustainability of the use of netupitant+palonosetron (NEPA) for chemotherapy-induced nausea and vomiting (CINV) prophylaxis assuming the Italian National Health Service (NHS) perspective. A published Markov model was adapted to assess the incremental cost-utility ratio of NEPA compared with aprepitant (APR) + palonosetron (PALO), fosaprepitant (fAPR) + PALO, APR + ondansetron (ONDA), fAPR + ONDA in patients receiving a highly emetogenic chemotherapy (HEC) and with APR + PALO and fAPR + PALO in patients receiving a moderately emetogenic chemotherapy (MEC). Setting Oncology hospital department in Italy. Methods A Markov model was used to determine the impact of NEPA on the budget of the Italian NHS on a 5-day time horizon, corresponding to the acute and delayed CINV prophylaxis phases. Direct medical costs considered were related to antiemetic drugs, adverse events management, CINV episodes management. Clinical and quality of life data referred to previously published works. The budget impact analysis considered the aforementioned therapies plus PALO alone (for HEC and MEC) on a 5-year time horizon, comparing two scenarios: one considering the use of NEPA and one not considering its use. Primary and secondary outcome measures Incremental cost per quality adjusted life year (QALY) and differential economic impact for the Italian NHS between the two scenarios considered. Results NEPA is more effective and less expensive (dominant) compared with APR + PALO (for HEC and MEC), fAPR + PALO (for HEC and MEC), APR + ONDA (for HEC), fAPR + ONDA (for HEC). The use of NEPA would lead to a 5-year cost decrease of €63.7 million (€42.7 million for HEC and €20.9 million for MEC). Conclusions NEPA allows an efficient allocation of resources for the Italian NHS and it is sustainable, leading to a cost decrease compared with a scenario which does not consider its use.

10090 Background: Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize CINV control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a novel fixed combination of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3RA, has shown superior CINV prevention compared to PALO in cisplatin and AC-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen, with the primary objective being to demonstrate non-inferiority in preventing CINV. Methods: This randomized, double-blind, parallel group Phase III study conducted in an Asian population was designed to compare efficacy and safety of a single oral dose of NEPA with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at -10%. Secondary efficacy endpoints included no emesis and no significant nausea (NSN: < 25mm on 100mm VAS). Results: Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0-1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR; no emesis and NSN rates favored NEPA. Most frequent study drug-related adverse events (AEs) for NEPA included constipation (8.0%) and hiccups (2.7%). The type/incidence/severity of AEs were similar for NEPA and APR/GRAN. Conclusions: In this first study comparing NK1RA regimens and 4 days of DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC. [Table: see text]

Combination antiemetic regimens targeting multiple molecular pathways associated with emesis have become the standard of care for prevention of chemotherapy-induced nausea and vomiting (CINV) related to highly and moderately emetogenic chemotherapies. Antiemetic consensus guidelines from several professional societies are widely available and updated regularly as new data emerges. Unfortunately, despite substantial research supporting the notion that guideline conformity improves CINV control, adherence to antiemetic guidelines is unsatisfactory. While studies are needed to identify specific barriers to guideline use and explore measures to enhance adherence, a novel approach has been taken to improve clinician adherence and patient compliance, with the development of a new combination antiemetic. NEPA is an oral fixed combination of a new highly selective NK1receptor antagonist (RA), netupitant, and the pharmacologically and clinically distinct 5-HT3RA, palonosetron. This convenient antiemetic combination offers guideline-consistent prophylaxis by targeting two critical pathways associated with CINV in a single oral dose administered only once per cycle. This paper will review and discuss the NEPA data in the context of how this first combination antiemetic may overcome some of the barriers interfering with adherence to antiemetic guidelines, enhance patient compliance, and offer a possible advance in the prevention of CINV for patients.