FormalPara Key Summary Points

Fosnetupitant, a phosphorylated prodrug formulation of netupitant, is a novel neurokinin-1 (NK1) receptor antagonist for intravenous administration that has high selectivity and affinity for NK1 receptors.

Simulation of NK1 receptor binding occupancy in the brain (striatum) by fosnetupitant 235 mg suggested high NK1 receptor occupancy of a longer duration than with fosnetupitant 81 mg.

The incidence of treatment-related injection site reactions (ISRs) was lower with fosnetupitant than fosaprepitant (both administered in combination with palonosetron and dexamethasone) in patients receiving highly emetogenic chemotherapy (HEC).

Fosnetupitant had non-inferior efficacy to that of fosaprepitant with regard to the overall complete response rate.

Fosnetupitant has a low risk of ISRs and effectively prevents chemotherapy-induced nausea and vomiting after HEC when administered in combination with palonosetron and dexamethasone, particularly in the beyond-delayed phase (i.e., 120–168 h after administration of chemotherapy).

Introduction

Nausea and vomiting are commonly reported non-hematological toxicities associated with chemotherapy [1, 2]. Indeed, chemotherapy-induced nausea and vomiting (CINV) is often ranked by patients as one of the most distressing and feared consequences of chemotherapy [2,3,4]. Thus, it is important that CINV is successfully managed in order to avoid refusal of chemotherapy or decreased compliance impacting the benefits of chemotherapy. Additionally, uncontrolled CINV can have a negative impact on patient quality of life (QOL) [1, 5] and severe CINV can be associated with significantly reduced overall survival and progression-free survival [6].

Aggressive prevention of CINV is recommended for highly emetogenic chemotherapy (HEC), defined as any treatment where CINV occurs in more than 90% of patients, and for moderately emetogenic chemotherapy (MEC), defined as any treatment where CINV occurs in 30–90% of patients [2]. Effective prevention of CINV should include not only the acute phase (i.e., within 24 h after chemotherapy administration) but also the delayed phase (i.e., at least 24 h after chemotherapy administration) [2]. Historically, late-onset CINV has been defined as any time from the day after chemotherapy administration up to 120 h after administration [2], often after the patient has left the hospital.

Several guidelines for CINV recommend triplet prophylactic treatment with a neurokinin-1 (NK1) receptor antagonist, serotonin 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, and dexamethasone, or quartet treatment including olanzapine for HEC [7,8,9,10]. With regards to MEC, guidelines generally recommend a 5-HT3 receptor antagonist and dexamethasone, with addition of a NK1 receptor antagonist for agents such as carboplatin or for patients who have risk factors for CINV [7, 8, 10, 11].

The NK1 receptor antagonist fosnetupitant, a phosphorylated prodrug formulation of netupitant, was approved as a CINV prophylactic agent in Japan in 2022 [12]. In the USA and European Union, an intravenously administered fixed-dose combination of fosnetupitant 235 mg and the 5-HT3 receptor antagonist palonosetron 0.25 mg (NEPA), as well as an orally administered fixed-dose combination of netupitant 300 mg and palonosetron 0.5 mg, has also been approved for the prevention of CINV [13, 14]. However, in Japan, development focused on administration of fosnetupitant as a single agent, rather than as part of a fixed-dose combination [15, 16].

The aim of this commentary is to describe the mechanism of action, antiemetic efficacy, and tolerability of single-agent fosnetupitant in the prevention of CINV, and to discuss its clinical application, in order to aid optimal use.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Mechanism of Action of Fosnetupitant

CINV is mediated by serotonin and activation of its receptors (mainly 5-HT3 receptors) or substance P and activation of NK1 receptors [2]. Activation of 5-HT3 receptors is mainly involved in acute-phase CINV, while NK1 receptors and their ligand, substance P, are believed to play a major role in delayed-phase CINV [2, 17]. Delayed-phase CINV typically occurs 24 h–5 days after treatment and is predominantly mediated by substance P binding to NK1 receptors in the central nervous system [18], primarily in regions involved in the vomiting reflex (i.e., nucleus tractus solitarius and area postrema) [19].

Fosnetupitant is a novel NK1 receptor antagonist for intravenous administration, which has high selectivity and affinity for NK1 receptors [20, 21].

Pharmacokinetics and Pharmacodynamics of Fosnetupitant

After administration, fosnetupitant is rapidly converted to its active form, netupitant, by phosphatases distributed widely through the body [21, 22], giving fosnetupitant a half-life of 0.6 h [23]. Netupitant is eliminated slowly, with a half-life of approximately 70 h [23], and is primarily metabolized in the liver by cytochrome P450 (CYP) 3A to three active metabolites [24, 25], with little contribution from renal excretion [26]. Netupitant is an inhibitor of CYP3A [27], so drug interactions with other drugs metabolized by CYP3A have been reported in clinical practice [28, 29].

In a pharmacokinetic/pharmacodynamic analysis, simulation of NK1 receptor binding occupancy in the brain (striatum) by fosnetupitant 235 mg suggested high NK1 receptor occupancy of a longer duration than with fosnetupitant 81 mg (Fig. 1). The NK1 receptor occupancy was maintained at 50% or higher for 168 h after administration of fosnetupitant 235 mg, with occupancy levels of 86.6%, 83.8%, 79.9%, 74.7%, 68.2%, 60.3%, and 51.5% at 24, 48, 72, 96, 120, 144, and 168 h after infusion, respectively (data presented as an abstract at The 43rd Annual Scientific Meeting of the Japanese Society of Clinical Pharmacology and Therapeutics, Yokohama, Japan, November–December 2022) [30].

Fig. 1
figure 1

Longitudinal simulation of neurokinin-1 (NK1) receptor occupancy in the brain (striatum) with fosnetupitant. h hours [30]

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Safety of Fosnetupitant

A summary of treatment-related adverse events (TRAEs) reported in at least 5% of patients in the phase 2–3 studies of fosnetupitant conducted in Japan, as well as injection site reactions (ISRs) reported in at least 2% of patients, is shown in Table 1. The most common any-grade TRAEs among patients receiving fosnetupitant for the prevention of cisplatin-based HEC included constipation and hiccups, which were similarly common in the comparator groups (i.e., placebo or fosaprepitant) (Table 1) [15, 23]. Furthermore, the proportion of patients with TRAEs was similar after a single cycle of chemotherapy (cycle 1) and across multiple cycles of chemotherapy (cycles 2–4) [15]. In the CONSOLE-BC study, the most common any-grade TRAEs were headache, diarrhea, urticaria, malaise, and decreased appetite (Table 1) [16].

Table 1 Safety summary of the most common treatment-related adverse events (i.e., reported in at least 5% of patients) and injection site reactions (i.e., reported in at least 2% of patients) in the phase 2–3 studies conducted in Japan
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The incidence of any-grade treatment-related ISRs was lower with fosnetupitant than with fosaprepitant [15, 16]. The most common treatment-related ISR with fosaprepitant was injection site pain [15, 16], but this was rarely reported with fosnetupitant (Table 1) [15, 16, 23].

Therapeutic Efficacy of Fosnetupitant

The efficacy of fosnetupitant against CINV has been reported in one phase 2 study [23] and two phase 3 studies [15, 16]. A summary of the efficacy data of single-agent fosnetupitant 235 mg administered in combination with palonosetron and dexamethasone from these studies is shown in Table 2.

Table 2 Summary of key efficacy data for fosnetupitant 235 mg in combination with palonosetron 0.75 mg and dexamethasone
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The phase 2 study was a multicenter, placebo-controlled, double-blind, randomized study designed to evaluate the efficacy of fosnetupitant for the prevention of CINV when administered in combination with palonosetron 0.75 mg and dexamethasone in Japanese patients (n = 594) scheduled to receive cisplatin (at least 70 mg/m2)-based HEC [23]. Two doses of fosnetupitant were evaluated, 81 mg or 235 mg, compared with placebo [23]. Dexamethasone was initially administered at a dose of 9.9 mg in the fosnetupitant group and 13.2 mg in the placebo group, with additional doses of dexamethasone 6.6 mg on days 2–4 [23]. The primary endpoint of overall (0–120 h) complete response (CR) rate adjusted by sex and age category was improved with both doses of fosnetupitant versus placebo (Table 2), with a statistically significant difference between the fosnetupitant 235 mg and placebo groups (adjusted difference, 22.0%; 97.5% confidence interval [CI] 11.7, 32.3%; P < 0.001) [23]. CR rates for the acute and delayed phases and for the period of 24–168 h were also higher with fosnetupitant 235 mg than with placebo, and fosnetupitant 235 mg was more effective than placebo across all secondary efficacy endpoints (Table 1) [23].

In the two randomized, double-blind, phase 3 studies, fosnetupitant 235 mg was evaluated for the prevention of CINV [15, 16]. The CONSOLE study was conducted to determine the efficacy and safety of fosnetupitant and fosaprepitant, both in combination with palonosetron and dexamethasone, in Japanese patients (N = 785) receiving cisplatin (at least 70 mg/m2)-based HEC [15]. The overall CR rate, stratified by sex and age, during a single chemotherapy cycle (the primary endpoint) was noninferior with fosnetupitant versus fosaprepitant (75.2% vs 71.0%; Table 1), with a Mantel–Haenszel common risk difference of 4.1% (95% CI − 2.1, 10.3); superiority was not demonstrated [15]. CR rates in the acute and delayed phases were also similar between treatment groups (Table 1); however, an exploratory post hoc analysis using a last-observation-carried-forward approach for missing values for the CR evaluation showed that the CR rate during 0–168 h was significantly higher with fosnetupitant than with fosaprepitant [31]. Over multiple chemotherapy cycles (i.e., cycles 2–4), the overall CR rate was approximately the same as that in the single chemotherapy cycle, and efficacy of fosnetupitant was maintained through the study observation period [15].

The CONSOLE-BC study was conducted to evaluate the safety of fosnetupitant and fosaprepitant, both in combination with palonosetron and dexamethasone, in Japanese patients (N = 102) receiving doxorubicin + cyclophosphamide or epirubicin + cyclophosphamide (AC/EC)-based HEC [16]. Similar to the CONSOLE study, fosnetupitant showed no large difference in efficacy compared to fosaprepitant in CONSOLE-BC [16]. The overall CR rate, adjusted by age, was 45.9% (23/51 patients; 95% CI 33.2, 58.6) in the fosnetupitant group and 51.3% (25/49 patients; 95% CI 37.3, 65.2) in the fosaprepitant group (Table 1) [16].

Clinical Application of Fosnetupitant for Prevention of CINV

As demonstrated by the clinical data, fosnetupitant has a low risk of ISRs (e.g., erythema, induration, pain, swelling, thrombophlebitis, pruritus, vein discoloration, extravasation, and local reaction at the injection site) and effectively prevents CINV after HEC when administered in combination with palonosetron and dexamethasone, particularly in the beyond-delayed phase (i.e., 120–168 h).

With regards to safety, ISRs are particularly problematic with fosaprepitant, especially among patients receiving anthracyclines [32,33,34,35,36,37]. Rates of fosaprepitant-associated ISRs of up to 96% have been reported during AC/EC therapy [32, 33, 35,36,37]. Contrastingly, frequencies of ISRs with fosnetupitant were 0–1.0% in the Japanese studies [15, 16, 23], similar to multinational data showing rates of ISRs of 1.0% with intravenously administered NEPA in patients with breast cancer after one cycle of AC [38]. Thus, fosnetupitant can be considered a NK1 receptor antagonist with a low risk of ISRs in routine clinical practice.

The overall CR rate of fosnetupitant in the CONSOLE study was comparable with multinational data for the fixed combination intravenously administered NEPA (overall CR rate 76.8%) [39]. While the efficacy of fosnetupitant tended to be higher than that of fosaprepitant overall (i.e., 0–120 h), fosnetupitant may be beneficial in the beyond-delayed phase after administration of anticancer drugs.

In the past, the evaluation period of antiemetic therapy was often set at 0–120 h after the administration of anticancer drugs; however, following results of a large surveillance study conducted in Japan reporting that approximately 15–25% of patients had residual nausea 120 h after treatment with antiemetic therapy for prevention of CINV associated with cisplatin-based HEC, non-cisplatin-based HEC, or MEC [40], the evaluation period for CINV was extended (to 0–168 h) in the phase 2 and CONSOLE studies [15, 23]. In the CONSOLE study, CR rates of fosnetupitant and fosaprepitant for 0–168 h were 73.2% and 66.9%, and for 120–168 h were 86.5% and 81.4%, respectively [15]. Also, Kaplan–Meier curves for time to treatment failure (i.e., time to first emetic event or use of rescue medication) showed a separation after 96 h, with a favorable trend in the fosnetupitant group (hazard ratio 0.789; 95% CI 0.610, 1.021; P = 0.071). The plasma half-life of netupitant, an active form of fosnetupitant, was approximately 70 h [13, 23], which is longer than that of aprepitant (9–13 h), an active form of fosaprepitant [41, 42]. These differences might contribute to the longer-lasting effect of fosnetupitant, beyond 120 h; however, further investigation of the potential influence of patient or treatment factors is warranted. The results of the CONSOLE study were consistent with results of Tamura and colleagues [40], suggesting that a longer time period (0–168 h) than the traditional period used in clinical studies should be considered to evaluate the usefulness of antiemetics. Indeed, long-lasting CINV beyond day 8 has been reported in patients with cancer receiving moderately to highly emetogenic chemotherapy [43, 44]. Fosnetupitant might be a favorable treatment option for patients in whom the prevention of long-lasting CINV is required in the clinical setting. Furthermore, as confirmed in the CONSOLE study, the efficacy of fosnetupitant lasts from chemotherapy cycle 1 to cycle 4 [15], suggesting that it might be helpful for clinicians and patients in preventing CINV during multi-cycle chemotherapy.

Fosnetupitant was shown to be effective in patients with CINV receiving AC/EC, with an overall CR rate of 45.9% (23 of 51 patients; 95% CI 33.2, 58.6) in the CONSOLE-BC study. Since the primary endpoint of this study was to evaluate the safety of fosnetupitant, the sample size was not sufficient to determine the efficacy of fosnetupitant. Further, there was an imbalance of patients who had a history of motion sickness, a known CINV risk factor [11, 45], which might have affected the efficacy results [16]. Therefore, further investigation that focuses on the efficacy of fosnetupitant for Japanese patients receiving AC/EC is warranted.

Convenience is also an important consideration when choosing an antiemetic drug. Fosaprepitant is a lyophilized powder requiring reconstitution prior to infusion [41]. In contrast, fosnetupitant, available in Japan, is a liquid preparation, and it does not need to be dissolved during preparation [46]. Studies of other agents have shown that preparation time for a liquid formulation is significantly shorter than that for a lyophilized formulation [47]. Fosnetupitant is conveniently administered with palonosetron and dexamethasone in an infusion bag and can be administered in the 30 min immediately before administration of chemotherapy. Therefore, fosnetupitant can be considered to reduce the medical burden in clinical settings and contribute to more convenient antiemetic therapy.

Future Perspectives

In addition to safety and efficacy, medical costs have recently become an important issue in many therapeutic areas. Instead of simply comparing the cost of drugs for CINV prevention, a cost-effectiveness analysis is needed that considers each country’s healthcare system. Furthermore, medical burden, healthcare resources (e.g., emergency admissions or number of visits), patient convenience, and productivity losses should also be considered.

Fosnetupitant, a long-acting NK1 receptor antagonist, is a promising antiemetic agent, but the patients evaluated in clinical studies were limited to those with certain cancer types. In the future, it will be necessary to confirm the efficacy and safety of antiemetic therapy including fosnetupitant in various cancers. In addition, since combination therapy with olanzapine has been reported to have better outcomes for HEC [48, 49], the efficacy of combination therapy with palonosetron + dexamethasone + fosnetupitant + olanzapine for the prevention of CINV associated with HEC should also be investigated. Furthermore, studies are currently underway to investigate the usefulness of NEPA for MEC with a high risk of emesis (e.g., NCT04817189), and more evidence on the use of fosnetupitant in MEC is also required to better inform its positioning relative to other agents in this indication.

Conclusion

Fosnetupitant administered in combination with palonosetron and dexamethasone has a low risk of ISRs and a high antiemetic potency, particularly in the beyond-delayed phase (i.e., 120–168 h), and could contribute to more convenient antiemetic therapy via a reduction in daily medical burden in clinical settings.