Phase IIIb Safety and Efficacy of Intravenous NEPA for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients with Breast Cancer Receiving Initial and Repeat Cycles of Anthracycline and Cyclophosphamide (AC) Chemotherapy

Abstract

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.

A Pragmatic Study Evaluating NEPA Versus Aprepitant for Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy

“…There are currently multiple options of oral and IV NK 1 RAs for clinicians to choose from. Most clinical studies evaluating the efficacy of the NK 1 RAs have been conducted in the cisplatin HEC setting [7–9, 12, 13, 17, 23], with just a few studies in the AC [10, 18, 24] non‐AC MEC [25], or combined AC/non‐AC MEC settings [26, 27]. Consistent with the earlier results in the cisplatin‐based HEC settings, a clear benefit of the NK 1 RA‐containing triplet over the 5‐HT 3 RA/DEX doublet was established in both the AC and non‐AC MEC settings.…”

Netupitant/Palonosetron: A Review in Chemotherapy-Induced Nausea and Vomiting

“…In the trials, (fos)netupitant/palonosetron was administered as a single dose before the start of each chemotherapy cycle. Unless otherwise specified, the oral formulation was used as a fixed-dose combination of netupitant/palonosetron 300 mg/0.5 mg and the IV formulation was used as a fixed-dose combination of fosnetupitant/palonosetron 235 mg/0.25 mg [ 17 , 20 – 25 ]. In addition, all patients received dexamethasone (see Tables 1 , 2 , 3 and 4 for details).…”

“…Evidence for the efficacy of IV fosnetupitant/palonosetron in the prevention of CINV is drawn from two randomised, double-blind, parallel group, multinational phase III trials (NCT02517021 [ 17 ] and NCT03403712 [ 25 ]), both of which were primarily conducted to evaluate the safety of the IV formulation. The two trials were of similar design, each comparing IV fosnetupitant/palonosetron (administered as a 30-min infusion) with oral netupitant/palonosetron (taken 60 min before chemotherapy) in chemotherapy-naïve adults.…”

“…The two trials were of similar design, each comparing IV fosnetupitant/palonosetron (administered as a 30-min infusion) with oral netupitant/palonosetron (taken 60 min before chemotherapy) in chemotherapy-naïve adults. NCT02517021 enrolled adults with solid tumours ( n = 404) who were scheduled to receive up to four cycles of non-AC HEC (with 96% of patients receiving cisplatin-based HEC) [ 17 ]; NCT03403712 enrolled women with breast cancer ( n = 404) who were scheduled to receive up to four cycles of AC-based chemotherapy (with 60% of patients receiving epirubicin plus cyclophosphamide and 40% receiving doxorubicin plus cyclophosphamide) [ 25 ].…”

Netupitant/palonosetron (NEPA) and dexamethasone for prevention of emesis in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide: a multi-cycle, phase II study

“…CINV events were vomiting and/or moderate-to-severe nausea the planned 4 cycles of AC-containing chemotherapy, and the very low dropout rate reinforces the clinical relevance of the study findings. More recently, in a registration trial that assessed the safety of intravenous NEPA compared to oral NEPA, both in combination with single-dose dexamethasone, in breast cancer patients treated with AC, the proportion of patients receiving oral NEPA (n = 202) who achieved an overall CR ranged from 77 to 87% over cycles 1-4 [17]. However, only approximately 50% of patients completed all 4 cycles of treatment in this study.…”