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Background NEPA, a combination antiemetic of a neurokinin‐1 (NK1) receptor antagonist (RA) (netupitant [oral]/fosnetupitant [intravenous; IV]) and 5‐HT3RA, palonosetron] offers 5‐day CINV prevention with a single dose. Fosnetupitant solution contains no allergenic excipients, surfactant, emulsifier, or solubility enhancer. A phase III study of patients receiving cisplatin found no infusion‐site or anaphylactic reactions related to IV NEPA. However, hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, particularly fosaprepitant in patients receiving anthracycline‐cyclophosphamide (AC)‐based chemotherapy. This study evaluated the safety and efficacy of IV NEPA in the AC setting. Materials and Methods This phase IIIb, multinational, randomized, double‐blind study enrolled females with breast cancer naive to highly or moderately emetogenic chemotherapy. Patients were randomized to receive a single 30‐minute infusion of IV NEPA or single oral NEPA capsule on day 1 prior to AC, in repeated (up to 4) cycles. Oral dexamethasone was given to all patients on day 1 only. Results A total of 402 patients were included. The adverse event (AE) profiles were similar for IV and oral NEPA and consistent with those expected. Most AEs were mild or moderate with a similarly low incidence of treatment‐related AEs in both groups. There were no treatment‐related injection‐site AEs and no reports of hypersensitivity or anaphylaxis. The efficacy of IV and oral NEPA were similar, with high complete response (no emesis/no rescue) rates observed in cycle 1 (overall [0–120 hours] 73.0% IV NEPA, 77.3% oral NEPA) and maintained over subsequent cycles. Conclusion IV NEPA was highly effective and safe with no associated hypersensitivity and injection‐site reactions in patients receiving AC. Implications for Practice As a combination of a neurokinin‐1 (NK1) receptor antagonist (RA) and 5‐HT3RA, NEPA offers 5‐day chemotherapy‐induced nausea and vomiting prevention with a single dose and an opportunity to improve adherence to antiemetic guidelines. In this randomized multinational phase IIIb study, intravenous (IV) NEPA (fosnetupitant/palonosetron) was safe and highly effective in patients receiving multiple cycles of anthracycline‐cyclophosphamide (AC)‐based chemotherapy. Unlike other IV NK1RAs, the IV NEPA combination solution does not require any surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. Hypersensitivity reactions and anaphylaxis have been reported with other IV NK1RAs, most commonly with fosaprepitant in the AC setting. Importantly, there were no injection‐site or hypersensitivity reactions associated with IV NEPA., Netupitant and palonosetron (NEPA) is a combination antiemetic that offers five‐day prevention of chemotherapy‐induced nausea and vomiting with a single dose. This article evaluates the safety and efficacy of intravenous NEPA in the setting of anthracycline/cyclophosphamide chemotherapy.

Objectives Breast cancer (BC) patients represent a high-risk population for experiencing chemotherapy-induced nausea and vomiting (CINV), since they frequently receive highly emetogenic anthracycline-cyclophosphamide–based (AC) chemotherapy, and are often female and young, two predisposing risk factors for CINV. Guidelines recommend the combination of a neurokinin-1 receptor antagonist (NK1RA), 5-hydroxytryptamine-3 RA (5-HT3RA), and dexamethasone (DEX) for CINV prophylaxis in AC-treated patients. This post-hoc analysis evaluated the efficacy of NEPA, a fixed combination of netupitant (NETU [NK1RA]) and palonosetron (PALO [5-HT3RA]) in BC patients from two phase III studies. Methods Overall, 1460 BC patients received AC (Study 1) or non-AC (Study 2) therapy over 6060 cycles. Randomized patients received DEX with either NEPA or oral PALO (Study 1), or NEPA or aprepitant+oral PALO (Study 2) before chemotherapy. Results In AC-receiving patients, overall complete response (CR) rates with NEPA+DEX were statistically significantly higher than oral PALO+DEX rates (cycles 1–4: 73.9% vs 65.9%, 80.0% vs 66.0%, 83.6% vs 69.9%, 83.6% vs 74.4%, respectively). Overall, no significant nausea (NSN) rates were also superior with NEPA+DEX vs oral PALO+DEX (respectively, 74.2%–79.9% vs 68.5%–74.9%). A greater proportion of NEPA+DEX patients experienced “no-impact-on-daily-life” due to CINV (78.4% vs 71.4%) in cycle 1. In non-AC–receiving patients, prophylaxis with NEPA+DEX resulted in high CR and NSN rates across 1–4 chemotherapy cycles; no formal comparison with the control arm was performed. Conclusion NEPA+DEX administered as a single dose is an effective option for preventing CINV in BC patients receiving AC and non-AC, across multiple chemotherapy cycles. Clinical trials registration numbers Study 1: NCT01339260 , Study 2: NCT01376297 .

Palonosetron (PALO) is one of the two active components of NEPA, the fixed-combination antiemetic comprising netupitant (oral)/fosnetupitant (IV) and PALO. To increase the convenience of NEPA administration, especially for patients with swallowing difficulties, an IV NEPA formulation has been developed, where PALO is administered as a 30-minute infusion instead of the approved 30-second bolus.To determine the efficacy and safety of the PALO component used in IV NEPA.Noninferiority, double-blind, and randomized Phase 3 trial in chemotherapy-naive adult patients with cancer requiring highly emetogenic chemotherapy. Patients were randomized to receive a single dose of PALO 0.25 mg administered IV either as a 30-minute infusion or as a 30-second bolus before highly emetogenic chemotherapy. The primary objective was to demonstrate noninferiority of the 30-minute infusion vs. 30-second bolus in terms of complete response (CR; no emesis and no rescue medication) in the acute phase. Secondary efficacy endpoints were CR in the delayed and overall phases and no emesis and no rescue medication in all phases. Safety was a secondary endpoint.Overall, 440 patients received study treatment. In the infusion group, 186 (82.7%) patients reported CR in the acute phase vs. 186 (86.5%) patients in the bolus group, demonstrating the noninferiority of PALO infusion vs. bolus (P 0.001). Secondary endpoints showed similar results between the two treatment groups.PALO 0.25-mg 30-minute IV infusion was noninferior to 30-second IV bolus in terms of CR rate in the acute phase. These results support the use of PALO 0.25 mg as a component of IV NEPA.

Purpose Antiemetic guidelines recommend co-administration of targeted prophylactic medications inhibiting molecular pathways involved in emesis. NEPA is a fixed oral combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3 RA. NEPA showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with oral PALO in a single chemotherapy cycle; maintenance of efficacy/safety over continuing cycles is the objective of this study. Methods This study is a multinational, double-blind study comparing a single oral dose of NEPA vs oral PALO in chemotherapy-naïve patients receiving anthracycline/cyclophosphamide-based chemotherapy along with dexamethasone 12 mg (NEPA) or 20 mg (PALO) on day 1. The primary efficacy endpoint was delayed (25–120 h) complete response (CR: no emesis, no rescue medication) in cycle 1. Sustained efficacy was evaluated during the multicycle extension by calculating the proportion of patients with overall (0–120 h) CR in cycles 2–4 and by assessing the probability of sustained CR over multiple cycles. Results Of 1455 patients randomized, 1286 (88 %) participated in the multiple-cycle extension for a total of 5969 cycles; 76 % completed ≥4 cycles. The proportion of patients with an overall CR was significantly greater for NEPA than oral PALO for cycles 1–4 (74.3 vs 66.6 %, 80.3 vs 66.7 %, 83.8 vs 70.3 %, and 83.8 vs 74.6 %, respectively; p ≤ 0.001 each cycle). The cumulative percentage of patients with a sustained CR over all 4 cycles was also greater for NEPA (p

Antiemetic guideline recommendations are inconsistent as to whether a neurokinin-1 receptor antagonist (NK1 RA) should be administered with a 5-hydroxytryptamine-3 (5HT3) RA + dexamethasone (DEX) in patients receiving carboplatin. Patients receiving cisplatin routinely receive an NK1 RA-containing regimen with a resulting 14–22 % benefit in no emesis rates over a 5-HT3 RA/DEX control. Recent studies suggest a similar benefit in patients receiving carboplatin. NEPA is the first fixed antiemetic combination agent and comprises the highly selective NK1 RA, netupitant, and pharmacologically distinct 5-HT3 RA, palonosetron (PALO). This paper presents the efficacy of NEPA in the subset of patients receiving carboplatin in a phase 3 trial (NCT01376297), in the context of aprepitant (APR) data in the carboplatin setting. One hundred ninety-six patients (47 % of all study patients: n = 145 NEPA + DEX; n = 51 APR + PALO + DEX) received carboplatin in a multinational, double-blind, randomized phase 3 study. Complete response (CR: no emesis/rescue) and no significant nausea (NSN: score ≤25 on 100 mm visual analog scale) rates were calculated. Cycle 1–4 overall (0–120 h) CR rates were similar for NEPA (80, 91, 92, and 93 %) and APR (82, 88, 88, and 90 %). Overall NSN rates were also similar (NEPA 84–96 %; APR 82–90 %). Response rates for NEPA and APR regimens were similar and consistent with prior studies evaluating the contribution of adding NK1 RAs in patients receiving carboplatin. Considering such evidence, guideline groups/practitioners should consider giving a NK1 RA antiemetic triplet in patients receiving carboplatin.

Patients with gynecological cancers are at high risk for chemotherapy-induced nausea and vomiting (CINV) after platinum-based chemotherapy (CT). NEPA (300-mg netupitant, 0.50-mg palonosetron) is the first oral fixed-combination antiemetic. Pivotal trials demonstrated the superiority of oral NEPA over intravenous palonosetron in preventing CINV after highly emetogenic (anthracycline-cyclophosphamide-based [AC] and cisplatin-based [non-AC]) CT. This post hoc subset analysis considered patients with gynecological cancer receiving cisplatin- or carboplatin-based CT from 1 pivotal trial and from 1 multicycle safety trial to evaluate the efficacy of oral NEPA in preventing CINV.Single-dose NEPA was given before CT in combination with dexamethasone. The efficacy end points for the acute (0-24 hours), delayed (25-120 hours), and overall (0-120 hours) CINV phases after CT included complete response (CR; no emesis, no rescue medication) and no significant nausea (25 mm on a 0- to 100-mm visual analog scale). Safety was also assessed.For cisplatin-induced CINV, NEPA achieved high CR rates (acute phase:90%; delayed, overall phases: ≥85%). For carboplatin-induced CINV, NEPA was also highly effective, with high acute, delayed, and overall CR rates (cycle 1:75%; cycles 2-4:95%). No significant nausea rates were more than 90% and more than 80% in the acute and delayed phases, respectively, for patients receiving cisplatin or carboplatin. NEPA was well tolerated.Results suggest that oral NEPA is effective and safe in preventing CINV in patients with gynecological cancers treated with cisplatin- or carboplatin-based CT. Single fixed-combination NEPA is a convenient option for CINV prevention in high-risk CINV patients.

Background NEPA, an oral fixed combination of the NK1RA netupitant (300 mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50 mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline–cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed. Patients and methods This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy-naive patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30 min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1–4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms. Results A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed. Conclusions Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.

Background. Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a 5-hydroxytryptamine-3 receptor antagonist, a neurokinin-1 receptor antagonist (NK1RA), and corticosteroid therapy. NEPA is a fixed combination of netupitant and palonosetron. The primary objective of this analysis was to document the safety profile, including cardiac safety, of NEPA + dexamethasone in comparison with current therapies across all phase II/III trials. Materials and Methods. This pooled analysis was based on data from 3,280 patients in 4 randomized, double-blind clinical trials. Patients were categorized into 1 of 3 pooled groups on the basis of actual treatment received: NEPA + dexamethasone, palonosetron + dexamethasone, and aprepitant + ondansetron/palonosetron + dexamethasone. Safety was assessed by number and frequency of adverse events (AEs) and changes from baseline electrocardiogram measures. Results. Most patients were female and younger than 65 years of age. Demographic characteristics varied among studies and pooled groups. Frequencies of treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs) were similar across groups. TEAEs were mostly mild and consistent with expected chemotherapy and disease-related AEs (hematologic events, hair loss, general weakness). TRAEs in ≥2% of patients were headache and constipation. Frequencies of cardiac TEAEs were similar across groups, with QT prolongation (1.6%), tachycardia (1.1%), and dyspnea (0.9%) the most common. Serious cardiac TEAEs were rare. Conclusion. NEPA was well-tolerated, with an AE profile as expected for the regimen. Sample size, demographic characteristics, study design, chemotherapy, and antiemetic regimen differences across the four studies may have contributed to differences in frequencies of neutropenia and alopecia. Adding an NK1RA to a CINV prophylaxis regimen can improve outcomes without additional toxicity.

Background: Patients (pts) with breast cancer (BC) are at high risk for developing chemotherapy-induced nausea and vomiting (CINV) due to the emetogenicity of chemotherapy (often AC-based) and predisposing risk factors including young age and female gender. For pts receiving AC, antiemetic guidelines recommend prophylactic administration of an NK1 receptor antagonist (RA), a 5-HT3 RA, and dexamethasone (DEX). NEPA is the first fixed combination agent approved in oncology; comprised of a highly selective NK1 receptor antagonist (RA), netupitant (300 mg), and the pharmacologically/clinically distinct 5-HT3 RA, palonosetron (PALO 0.50 mg). NEPA has shown superior complete response (no emesis/no rescue use) rates compared with oral PALO in a Phase 3 trial in pts receiving AC (Aapro, Ann Oncol 2014) and in that study's BC subset. Despite progress in prevention of vomiting, nausea control remains suboptimal, particularly in the delayed phase (days 2-5), and debate exists whether NK1 RAs improve nausea control. The objective of this post-hoc analysis was to evaluate whether NEPA showed nausea and associated quality-of-life (QOL) benefits in the subset of patients with BC in this trial. Methods: The subset of chemotherapy-naïve BC pts from this multinational, randomized, double-blind Phase 3 study were included in this analysis. Patients received either a single dose of NEPA or oral PALO prior to AC along with oral DEX 12 mg (NEPA) or 20 mg (PALO). No significant nausea (NSN: max Results: 1412 patients with BC were included for a total of 5839 AC cycles. NSN rates were similar for both groups in the acute phase, superior for NEPA during cycles 1, 2 and 4 in the delayed phase, and superior for NEPA during cycles 1-4 in the overall phase. Overall NSN (0-120h)NEPA + DEXOral PALO + DEXP ValueCycle 174.2% (N = 708)68.5% (N = 704)0.016Cycle 277.0% (N = 621)71.1% (N = 636)0.015Cycle 378.2% (N = 586)72.7% (N = 594)0.027Cycle 479.9% (N = 542)74.9% (N = 550)0.040 This corresponded with a significantly greater proportion of NEPA patients reporting NIDL compared with PALO due to nausea (71% vs 65%; p=0.007) in cycle 1. Conclusions: While other NK1RAs have not consistently shown benefit in improving nausea control over 5-HT3RA + DEX, in this study NEPA significantly improved prevention of nausea over oral PALO in BC patients receiving AC. In addition, NEPA was superior to PALO in reducing the negative impact of nausea on patients' daily functioning. As the first fixed antiemetic drug combination, NEPA is highly effective and offers the convenience of a single dose administered with DEX on Day 1 only. Citation Format: Rugo HS, Aapro M, Rizzi G. Nausea control and quality-of-life benefit with NEPA, the first combination antiemetic agent, in patients with breast cancer receiving anthracycline/cyclophosphamide (AC) chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-06.

Background: International antiemetic guidelines recommend co-administration of an NK1 receptor antagonist (RA) and a 5-HT3 RA in breast cancer (BC) patients receiving anthracycline cyclophosphamide (AC) chemotherapy as this population is at increased risk of developing CINV. NEPA, a novel, oral fixed-dose combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and the 5-HT3 RA, palonosetron (PALO 0.50 mg), was previously reported to be superior to oral PALO after a single cycle (Aapro et al, Annals of Oncology 2014) and multiple cycles (Aapro et al, ASCO 2014) of chemotherapy. This posthoc analysis evaluates sustained efficacy over multiple cycles when censoring patients who experienced CINV in the previous cycle. Methods: This was a multinational, randomized, double-blind, parallel group study evaluating the efficacy/safety of single oral doses of NEPA versus oral PALO in chemotherapy-naïve patients receiving multiple cycles of anthracycline-based chemotherapy. All patients also received oral dexamethasone (DEX) 12 mg (NEPA) or 20 mg (PALO), only on Day 1. Overall (0-120 h) complete response (CR: no emesis, no rescue medication) was the efficacy endpoint evaluated. The analysis of sustained CR evaluates the probability that patients would remain complete responders over 4 cycles by censoring continuing patients who failed to have a CR in the prior cycle. A Kaplan Meier method and log-rank test comparing NEPA with oral PALO were utilized. Results: 1455 patients were randomized; 1286 participated in the multiple cycle extension after cycle 1. Treatment groups were comparable with 98% females and 97% with BC; the mean age was 54. The percentage of patients who experienced a CR in cycle 1 and who sustained a CR over cycles 2-4 was greater for NEPA than for oral PALO (p Time since first chemotherapyNEPA + DEXOral PALO + DEXCycle 174.3% (N = 724)66.6% (N = 725)Cycle 268.5% (N = 485)57.1% (N = 434)Cycle 365.7% (N = 423)52.7% (N = 348)Cycle 463.6% (N = 375)50.6% (N = 300) Conclusions: This multiple cycle analysis indicates that NEPA, a novel, fixed-dose antiemetic combination, more effectively demonstrates sustained control of CINV over multiple cycles than oral PALO. As females with breast cancer represent a particularly challenging population in terms of emesis control, it is especially crucial that antiemetic recommendations are followed to allow these patients to maintain their quality of life and continue their treatment plan over multiple cycles of chemotherapy. NEPA offers effective guideline-recommended prophylaxis in a convenient single dose. Citation Format: Matti Aapro, Hope Rugo, Giada Rizzi. Evaluation of sustained antiemetic efficacy over repeated cycles of anthracycline-cyclophosphamide (AC)-based chemotherapy: A phase 3 study of NEPA, a fixed-dose combination of netupitant and palonosetron for prevention of chemotherapy-induced nausea and [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-01.

Purpose This study aims to compare the efficacy and safety of oral palonosetron with intravenous (IV) palonosetron for the prevention of cisplatin-related chemotherapy-induced nausea and vomiting (CINV). Methods A multinational, randomized, double-blind study enrolling adult chemotherapy-naive patients with malignant solid tumors scheduled to receive cisplatin-based highly emetogenic chemotherapy (HEC). Patients received oral palonosetron (0.50 mg) or IV palonosetron (0.25 mg), each with oral dexamethasone. The primary objective was to demonstrate non-inferiority in terms of patients with a complete response (CR, no emesis/no rescue medication) within the acute phase (0–24 h after chemotherapy administration). Results Of the 743 patients randomized, 739 received study medications and 738 were included in the full analysis set. The CR rate in the acute phase was high for both groups (oral 89.4 %; IV 86.2 %). As this difference in proportions (stratum-adjusted Cochran-Mantel-Haenszel method) was 3.21 % (99 % confidence interval (CI) −2.74 to 9.17 %), non-inferiority was demonstrated (since the lower limit of the 99 % CI was closer to zero than the predefined margin of 15 %). Treatment-emergent adverse events (TEAEs) related to the study drug were rare (oral 3.2 %; IV 6.5 %). No TEAEs related to study drug leading to discontinuation were reported. Conclusion Non-inferiority of oral versus IV palonosetron was demonstrated. The CR rate in the acute phase was >86 % in both patient groups. The safety profiles were comparable.

NEPA is an oral single, fixed-dose combination of netupitant, a new highly selective NK1 RA and palonosetron (PALO), a pharmacologically/clinically distinct 5-HT3 RA. It delivers antiemetic guideline-recommended prophylaxis by targeting two critical molecular pathways associated with chemotherapy-induced nausea/vomiting. This Phase III study demonstrated the superiority of NEPA compared with PALO., Background Antiemetic guidelines recommend co-administration of agents that target multiple molecular pathways involved in emesis to maximize prevention and control of chemotherapy-induced nausea and vomiting (CINV). NEPA is a new oral fixed-dose combination of 300 mg netupitant, a highly selective NK1 receptor antagonist (RA) and 0.50 mg palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3 RA, which targets dual antiemetic pathways. Patients and methods This multinational, randomized, double-blind, parallel group phase III study (NCT01339260) in 1455 chemotherapy-naïve patients receiving moderately emetogenic (anthracycline–cyclophosphamide) chemotherapy evaluated the efficacy and safety of a single oral dose of NEPA versus a single oral dose (0.50 mg) of PALO. All patients also received oral dexamethasone (DEX) on day 1 only (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy end point was complete response (CR: no emesis, no rescue medication) during the delayed (25–120 h) phase in cycle 1. Results The percentage of patients with CR during the delayed phase was significantly higher in the NEPA group compared with the PALO group (76.9% versus 69.5%; P = 0.001), as were the percentages in the overall (0–120 h) (74.3% versus 66.6%; P = 0.001) and acute (0–24 h) (88.4% versus 85.0%; P = 0.047) phases. NEPA was also superior to PALO during the delayed and overall phases for all secondary efficacy end points of no emesis, no significant nausea and complete protection (CR plus no significant nausea). NEPA was well tolerated with a similar safety profile as PALO. Conclusions NEPA plus a single dose of DEX was superior to PALO plus DEX in preventing CINV following moderately emetogenic chemotherapy in acute, delayed and overall phases of observation. As a fixed-dose antiemetic drug combination, NEPA along with a single dose of DEX on day 1 offers guideline-based prophylaxis with a convenient, single-day treatment.

This study was designed to determine the appropriate clinical dose of netupitant (NETU), a new NK1 receptor antagonist (RA), to combine with the 5-HT3 RA, palonosetron (PALO) in a fixed-dose antiemetic combination (NEPA). All NEPA doses provided superior prevention of chemotherapy-induced nausea and vomiting compared with PALO, with NEPA300 (300mg NETU + 0.50 mg PALO) being the best dose studied., Background NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120 h) phase. Results All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0–24 h), delayed (25–120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

NEPA is the fixed combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant and the 5-hydroxytryptamine-3 receptor antagonist palonosetron. The intravenous (i.v.) formulation of NEPA (fosnetupitant 235 mg/palonosetron 0.25 mg) was developed to enhance the convenience of NEPA administration. In a phase 3 study, i.v. NEPA showed acceptable safety with low risk for injection-site reactions. This study evaluated the pharmacokinetics and safety of i.v. NEPA in cancer patients. This was a single-center, single-dose phase 1 study in patients receiving highly emetogenic chemotherapy. Patients received a 30-min infusion of i.v. NEPA plus oral dexamethasone (12 mg) prior to chemotherapy, and oral dexamethasone (8 mg/daily) on days 2–4. Twenty-four patients received the complete i.v. NEPA infusion volume. Fosnetupitant maximum plasma concentration (Cmax) was reached at the end of infusion and decreased to Fosnetupitant conversion to netupitant occurred rapidly in cancer patients. Netupitant and palonosetron pharmacokinetic profiles in i.v. NEPA were similar to those reported for oral NEPA. i.v. NEPA was well tolerated with a similar safety profile to oral NEPA. i.v. NEPA provides additional administration convenience. Clinical trial registration number: EudraCT 2015-004750-18.

11594 Background: NEPA, a combination antiemetic agent [NK1 receptor antagonist (RA) netupitant (oral) or fosnetupitant (IV) + 5-HT3RA palonosetron] offers 5-day CINV prevention with a single-dose. Unlike other IV NK1RAs, the fosnetupitant solution does not require a surfactant, emulsifier, or solubility enhancer and contains no allergenic excipients. In a Phase 3 study in pts receiving cisplatin-based CT, there were no infusion site or anaphylactic reactions related to IV NEPA. In contrast, hypersensitivity reactions and anaphylaxis have been reported with IV aprepitant, fosaprepitant and rolapitant, with the highest rate (35%) for fosaprepitant in the AC setting. This study (NCT03403712) evaluates the safety of IV NEPA in BC pts receiving repeat cycles of AC CT. Methods: This was a Phase 3b, double-blind study in females with BC naïve to highly/moderately emetogenic CT. Pts were randomized 1:1 to receive a single 30-min infusion of IV NEPA or a single oral NEPA capsule on Day 1, prior to AC. Oral dexamethasone was also given to all patients before CT. The primary objective was a safety evaluation of IV NEPA based primarily on treatment-emergent adverse events (TEAEs). No formal between groups statistical comparison was planned. Results: 402 pts were treated with IV NEPA or oral NEPA and included in the safety population. The AE profiles were similar for the two groups; cycle 1 results are reported (Table). Comparable complete response (no emesis, no rescue) rates were seen during the cycle 1 overall phase (0-120h) (73.0% IV NEPA, 77.2% oral NEPA). Conclusions: There were no infusion-site AEs related to IV NEPA and no anaphylaxis reported for either formulation. Consistent with the pivotal study, IV NEPA is safe and effective in pts receiving AC. As a simplified single-dose formulation, IV NEPA may be better tolerated than other NK1 RAs. Clinical trial information: NCT03403712. [Table: see text]

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.

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

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]

In this multinational, phase III study, the safety and efficacy of NEPA, a convenient, fixed-dose antiemetic combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a distinct 5-HT3 RA, were evaluated over multiple cycles of highly and moderately emetogenic chemotherapy. NEPA was shown to be safe, well tolerated and highly effective over 1961 chemotherapy cycles., Background Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC. Patients and methods This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1–4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue). Results Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0–120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles. Conclusions NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.

9597 Background: Controversy continues whether a NK1RA should be added to a 5HT3RA + dexamethasone (DEX) in pts receiving carbo, with inconsistent guideline recommendations by NCCN, ASCO, and MASCC...

Aim: As emesis is more difficult to suppress once it occurs, preventing chemotherapy-induced nausea and vomiting from the initial cycle through repeated cycles is essential for an optimal patient-centered approach to cancer management. NEPA is a novel, fixed-dose combination of a new NK1 receptor antagonist (RA), netupitant (NETU 300 mg), and palonosetron (PALO 0.50 mg), a pharmacologically distinct 5-HT3 RA. NEPA is designed to overcome barriers hindering guideline adherence by targeting two molecular pathways with a single, oral fixed-dose product. NEPA was previously shown to be superior to PALO after a single chemotherapy (CT) cycle; maintenance of efficacy over multiple cycles has been evaluated in a combined dataset from 2 pivotal trials. Methods: These large multinational, randomized studies assessed the efficacy/safety of a single oral dose of NEPA (vs PALO or aprepitant+PALO) in chemotherapy-naive patients receiving multiple cycles of either anthracycline-based (AC) moderately emetogenic CT (MEC) [study 1] or non-AC based MEC or highly emetogenic CT (HEC) [study 2]. All patients also received oral dexamethasone (DEX). Efficacy endpoints were complete response (CR: no emesis, no rescue) and no significant nausea (max Results: 1033 NEPA-treated patients participated in 4428 total cycles in these two trials; 76% completed at least 4 cycles. Overall CR and no significant nausea rates were high and were maintained across 4 cycles of CT with rates being modestly lower in patients receiving AC MEC compared to non-AC MEC and HEC. CR No Significant Nausea (N=AC/non-AC/HEC) AC MEC Non-AC MEC HEC AC MEC Non-AC MEC HEC Cycle 1 (N=724/235/74) 74% 80% 84% 75% 85% 82% Cycle 2 (N=635/212/68) 80% 88% 79% 77% 87% 87% Cycle 3 (N=598/196/63) 84% 91% 91% 78% 89% 92% Cycle 4 (N=551/181/52) 84% 92% 85% 80% 94% 85% The type/incidence of AEs was typical for a diverse cancer population receiving chemotherapy and raised no safety concerns. Conclusions: This is the largest multiple cycle dataset for an antiemetic and provides confidence in the preservation of benefit with NEPA over multiple cycles of AC- and non-AC MEC and HEC. NEPA, a highly convenient, guideline-based antiemetic combination may result in greater adherence and consequently improved emetic control. Disclosure: M.S. Aapro: Consultant, Research Funding, Honoraria: Helsinn Healthcare; R. Gralla: Consultant: Helsinn Healthcare and Eisai Inc.; M. Karthaus: Consultant: Helsinn Healthcare; L. Schwartzberg: Consultant: Helsinn Healthcare & Eisai Inc.; G. Rossi: Employee: Helsinn Healthcare; G. Rizzi: Employee: Helsinn Healthcare; M.E. Borroni: Employee: Helsinn Healthcare; M. Palmas: Employee: Helsinn Heathcare; H.S. Rugo: Consultant and Research Funding: Helsinn Healthcare; K. Jordan: Consultant and Honoraria: Helsinn Healthcare, Merck.

9502 Background: Antiemetic guidelines recommend co-administration of targeted prophylactic medications aimed at inhibiting several molecular pathways involved in emesis. NEPA is a novel, fixed-dos...

Background Cyclophosphamide (CTX), a commonly used alkylating agent in the treatment of hematological malignancies and solid tumor diseases, is a prodrug metabolized to its active metabolite primarily via CYP2B6 with minor contribution of CYP3A4. CTX is also converted to neurotoxic and inactive metabolites mainly via CYP3A4. NEPA is a unique fixed-dose antiemetic combination of netupitant (NETU), a highly-selective NK1 receptor antagonist (RA) and palonosetron (PALO), a pharmacologically distinct 5-HT3 RA. Superiority of NEPA over PALO in preventing chemotherapy-induced nausea and vomiting was recently demonstrated in solid tumors. Although no significant drug-drug interactions between NETU, a moderate CYP3A4 inhibitor, and CTX are expected, NEPA has the potential to impact CTX metabolism and CTX-related toxicities. Methods This multinational, randomized, double-blind, parallel group study evaluated 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 moderately emetogenic (anthracycline-CTX) chemotherapy for solid tumors during cycle 1 and during a multicycle extension, in the adjuvant, neoadjuvant or metastatic setting. All patients also received oral dexamethasone (DEX) on Day 1 (12 mg in the NEPA arm and 20 mg in the PALO arm). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) in the delayed (25-120 hr) phase. Overall safety was assessed through reporting of adverse events. Results 1450 and 1286 patients were included in the safety population for cycle 1 and the multicycle extension, respectively; 76% of all patients completed cycle 4. Treatment groups were comparable with the overall population being female (98%) and white (80%), with a mean age of 54 years. The median CTX total dose in both groups was 1000 mg. Overall, the percentage of patients with at least one treatment-emergent adverse event (AE) was slightly higher for NEPA compared with PALO in cycle 1 but similar during the multicycle extension. The most commonly reported AEs were neutropenia, alopecia, and leukopenia, all known complications associated with CTX and anthracyclines. Frequencies of these AEs were comparable between treatment groups (36% vs 37%; 24% vs 23%; 22% vs 22%, respectively for NEPA vs PALO during the multicycle extension). All other AEs were reported by Conclusion There was no indication in this large study of increased adverse events in patients receiving NEPA compared with those who received PALO after single or repeated cycles of CTX and anthracycline chemotherapy. As a convenient, fixed-dose dual-pathway antiemetic drug combination, NEPA has potential utility in hematologic malignancies and solid tumors. Disclosures: Schwartzberg: Helsinn Healthcare, SA: Consultancy, Honoraria; Eisai Inc: Consultancy, Honoraria. Rizzi:Helsinn Healthcare, SA: Employment. Rossi:Helsinn Healthcare, SA: Employment. Palmas:Helsinn Healthcare, SA: Employment. Karthaus:Helsinn Healthcare, SA: Consultancy. Aapro:Helsinn Healthcare, SA: Consultancy, Honoraria, Research Funding.

e20716 Background: NEPA is a fixed-dose combination of netupitant (NETU), a highly selective NK1 receptor antagonist and palonosetron (PALO), a pharmacologically and clinically distinct 5-HT3receptor antagonist. Recent clinical trials have been conducted to definitively establish the superiority of the combination, NEPA, over single agent PALO in the prevention of CINV following a single cycle of highly (HEC) and moderately (MEC) emetogenic CT. This study was designed to examine the tolerability and efficacy of NEPA over multiple cycles of HEC and MEC. Methods: Trial design: multinational, randomized, double-blind, parallel group, phase III study assessing the safety and efficacy of a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) administered only on day 1 of each cycle, and given with concomitant oral dexamethasone on day 1 (with MEC) and days 1-4 (when given with HEC) prior to repeated cycles of HEC or MEC. A standard arm 3-day oral aprepitant + PALO + dexamethasone was included as a control group with an unbalanced 3:1 (NEPA : aprepitant) randomization ratio. There was no limit to the number of chemotherapy cycles allowed. Safety was the primary objective of the study as assessed by adverse events; secondary variables included ECGs, left ventricular ejection fraction, cardiac troponin levels and laboratory tests. Efficacy was assessed as the proportion of patients with complete response (no emesis, no rescue medication). Results: 413 patients were randomized in this study with the last patient visit occurring on 13 September, 2012. The analyses will be completed by March 2013 and will be fully available by ASCO 2013. Conclusions: Few large randomized trials have documented safety and efficacy of antiemetic control with multiple cycles of chemotherapy, and especially with HEC. The in depth safety profile will provide new information for all study arms over multiple cycles. NEPA is designed to provide maximal convenience while providing high degrees of antiemetic control throughout the patient’s full course of chemotherapy. Clinical trial information: NCT01376297.

9512 Background: Further progress in preventing CINV will require the introduction of novel agents providing maximal convenience and with efficacy for nausea as well as vomiting. NEPA is a single dose combination of NETU, a novel NK1 receptor antagonist (RA) and PALO, a pharmacologically distinct 5-HT3RA. This study was designed to determine the proper dose of NETU to combine with PALO. Methods: This was a randomized, double-blind, parallel group study in chemotherapy-naïve patients (pts) undergoing cisplatin-based HEC. Four study arms compared 3 oral doses of NEPA (NETU 100, 200, 300mg + PALO 0.50 mg) with oral PALO 0.50 mg, all given on day 1. All pts received oral dexamethasone (DEX) days 1-4. An exploratory aprepitant (APREP) + ondansetron/DEX arm was included. The primary endpoint was complete response (CR: no emesis, no rescue) in the overall (0-120h) phase. Results: 694 pts were enrolled with comparable characteristics across groups: males (57%), median age 55. Common cancers: lung (27%), head and neck (21%). Median cisplatin dose: 75 mg/m2. All NEPA groups showed superior CR rates compared with PALO during the overall and delayed phases, with NEPA300also superior to PALO during the acute phase. NEPA300was also superior to PALO during all phases for no emesis, no significant nausea and complete protection with incremental benefits over lower NEPA doses. AEs were comparable across groups with no dose-response. The % of pts developing ECG changes was comparable across groups. Conclusions: Each NEPA dose resulted in superior CR rates compared with PALO. NEPA300was the best dose studied, with an advantage over lower doses for all efficacy endpoints (including nausea). NEPA doses were well tolerated with similar safety profiles to PALO and APREP. NEPA combined with DEX is superior to PALO plus DEX in prevention of CINV following HEC. [Table: see text]

LBA9514 Background: Management of CINV has been refined over the past several decades and CINV can now be managed with targeted prophylactic medications aimed at inhibiting several molecular pathways involved in emesis. NEPA, a fixed-dose combination of netupitant (NETU), a new NK1 receptor antagonist (RA) and palonosetron (PALO), a pharmacologically distinct 5-HT3RA, targets these dual antiemetic pathways and has been shown to uniquely work synergistically in vitro. Methods: This was a multinational, randomized, double-blind, parallel group study assessing the efficacy and safety of a single oral dose of NEPA (NETU 300mg + PALO 0.50 mg) versus a single oral 0.50 mg dose of PALO in 1,455 chemotherapy-naive patients (pts) receiving anthracycline-based chemotherapy (all pts received oral dexamethasone (DEX) 12 mg (NEPA) or 20 mg (PALO) on Day 1). The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the delayed (25-120h) phase. Results: Treatment groups had comparable demographic characteristics with the majority of the population being female (98%) and white (80%), with a mean age of 54 yrs; 97% pts had breast cancer. NEPA showed superior CR rates compared to PALO during the delayed, acute, and overall phases. NEPA was also superior to PALO during the delayed/overall phases for complete protection, no emesis, and no significant nausea. Most frequently reported study drug-related adverse events (AEs) for NEPA included headache (3.3%) and constipation (2.1%). The majority of adverse events for NEPA-treated pts were mild/moderate and there were very few (0.7%) severe drug-related AEs. The type and frequency of AEs were comparable between NEPA and PALO. There was no evidence of any cardiac safety concerns for NEPA or PALO. Conclusions: NEPA, a novel single-day fixed-dose combination targeting dual antiemetic pathways, is superior to PALO (both associated with DEX) in preventing CINV in pts receiving MEC. Clinical trial information: NCT01339260. [Table: see text]