Abstract
Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0–24 h), delayed (24–120 h), overall (0–120 h), and beyond-delayed (120–168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0–168 and 120–168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.
INTRODUCTION
Chemotherapy-induced nausea and vomiting (CINV) is among the most distressing side effects of chemotherapy and adversely affects patients’ QOL and prognosis.1,2) Antiemetic therapy against CINV has recently been established owing to the advent of drugs with novel mechanisms of action, such as neurokinin-1 receptor antagonists (NK1 RA) and multi-acting receptor-targeted antipsychotics.3,4) In Japan, the risk of CINV is classified into high, moderate, mild, and minimal emetic risk.5) In patients with high emetogenic risk, combining NK1 RA, 5-hydroxytryptamine receptor subtype 3 antagonists (5-HT3 RA), and steroidal drugs is generally recommended.6,7) The control rates of CINV in the acute phase (for the first 24 h after administration) of the current standard antiemetic therapy with cisplatin (CDDP)-based regimens are satisfactory. However, existing strategies to control CINV symptoms after 24 h, in the delayed period, remain insufficient.8) Various validation studies on CINV in the delayed period have been conducted, including the administration of fosaprepitant (F-APR) multiple times during one course,9) and staggering the dose of aprepitant (APR)10); however, these are insufficient. In particular, the chemotherapeutic agent, CDDP, is associated with delayed nausea onset and can cause severe CINV, as reported for a continuous regimen of bleomycin, etoposide, and cisplatin therapy.9)
Fosnetupitant (F-NTP) was launched in Japan in March 2022 after receiving approval from the Food and Drug Administration in 2014 as a novel NK1 RA. Compared to F-APR, F-NTP has a longer half-life and non-inferior antiemetic activity,11) with a tendency to cause fewer injection site reactions.12) However, there are no reports comparing F-NTP with oral APR. Furthermore, no reports have compared these three drugs in clinical practice. This study examined the antiemetic effects of NK1 RA during the first week after the administration of anticancer drugs and compared the real-life clinical efficacy of F-NTP against CINV with those of F-APR and APR using retrospective clinical data. In particular, the therapeutic effect on days 6–7, which has not yet been adequately validated, was investigated.
MATERIALS AND METHODS
Study PopulationThis single-center retrospective study compared the efficacy of F-NTP with those of F-APR and APR. The study continuously enrolled patients on CDDP-based regimens who used NK1 RA at our hospital from January 12, 2020, to March 31, 2023. The base case population comprised the F-NTP group. The efficacies in the APR and FAPR subgroups were compared. All the patients completed their first course of anticancer therapy. Patients with inappropriate antiemetic schedules (n = 10) were excluded. Patients with no chart documentation of antiemetic monitoring (n = 3) and those in whom anticancer therapy was interrupted during the first course (n = 2) were also excluded. All groups received NK1 RA, 5-HT3 RA (granisetron for the 19 patients in the APR group and palonosetron for patients in the other groups), and prophylactic antiemetic therapy with dexamethasone. This study was approved by the Ethics Committee of the Kitasato University Hospital (Approval No. B22-231) and was conducted in accordance with the principles of the Declaration of Helsinki. Patient consent was obtained using the opt-out method.
Data CollectionData on patients’ sex, age, ECOG performance status, cancer type, stage, and recurrence, actual CDDP dose, concomitant use of anticancer drugs, concomitant radiation therapy, history of alcohol consumption, smoking history, and concomitant use of olanzapine were collected from electronic medical records. CINV, injection site reactions, constipation, and hiccups were investigated as treatment-related adverse events. CINV was evaluated up to 168 h after the first course, and the proportion of patients with complete response (CR) (patients with no emesis and no additional antiemetic medication during the treatment period) and time-to-treatment-failure (TTF) (time to first emetic event or use of rescue medication) were analyzed. The extended overall (0–168 h) period was further subdivided into acute (0–24 h), delayed (24–120 h), overall (0–120 h), and beyond-delayed (120–168 h) periods. The severity of adverse events was defined using the Common Terminology Criteria for Adverse Events v5.0.
Statistical AnalysisTo compare patient characteristics, Fisher’s exact test was used for categorical variables, while the Mann–Whitney U test was used for continuous variables. Fisher’s exact test was used to compare the CR between F-NTP and F-APR, and between F-NTP and APR. Risk factor analysis was performed using factors that had been identified as potential clinical risk factors, including the use of F-NTP. Based on previous reports,13,14) the following five factors were selected: sex, age, alcohol consumption, CDDP dose, and F-NTP use. Univariate and multivariate logistic regression analyses were performed to analyze risk factors for treatment failure (non-CR). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the risk factors for non-CR between 0–168 and 120–168 h. TTF curves were evaluated using Kaplan–Meier survival analysis, and the log-rank test was used to compare each curve. All statistical analyses were performed using SPSS version 29 (IBM Corporation, Armonk, NY, U.S.A.). Results with p-values <0.05 were considered statistically significant.
RESULTS
Patient CharacteristicsIn total, 422 patients treated with CDDP-based regimens were enrolled in this study. The demographic characteristics of patients in the F-NTP (n = 88), F-APR (n = 66), and APR (n = 268) groups based on prophylactic antiemetic therapy are summarized in Table 1. Real-world data revealed specific differences in the proportion of cancer types in each NK1 RA group. Among the population difference parameters, the proportion of gynecological malignancies was higher in the APR group; therefore, the number of women was higher than that in other groups. Age was significantly higher in the F-APR group than in the F-NTP group (p = 0.041). Regarding performance status, the APR group had a higher number of patients with a status of 0 than the F-NTP group. Cancer stage was more advanced in the F-APR group than in the F-NTP group (p = 0.007), and stage I was more common in the APR group than in the F-NTP group (p = 0.036). The CDDP dose was lower in the F-APR and APR groups than in the F-NTP group (both p < 0.001). Concomitant use of anticancer drugs and a combination with radiotherapy were more common in the APR group than in the F-NTP group (both p < 0.001). The APR group had fewer patients with a history of drinking alcohol and smoking than the F-NTP group (both p < 0.001).
Table 1. Patient Characteristics (
n = 422)
| Characteristics | F-NTP (n = 88) | F-APR (n = 66) | p-Value | APR (n = 268) | p-Value |
|---|
| Sex, No. (%) | | | 0.408a) | | <0.001c) |
| Male | 74 (84.1) | 52 (78.8) | | 128 (47.8) | |
| Female | 14 (15.9) | 14 (21.2) | | 140 (52.2) | |
| Age, years (median, range) | 65 (36–79) | 68 (41–86) | 0.041b) | 63 (17–85) | 0.258d) |
| ECOG performance status, n (%) | | | 0.687a) | | 0.020c) |
| 0 | 69 (78.4) | 54 (81.8) | | 238 (88.8) | |
| 1 | 19 (21.6) | 12 (18.2) | | 27 (10.1) | |
| 2 | 0 (0) | 0 (0) | | 3 (1.1) | |
| Tumor type, n (%) | | | —a) | | — c) |
| Lung cancer | 31 (35.2) | 0 (0) | | 114 (42.5) | |
| Head and neck cancer | 31 (35.2) | 24 (36.4) | | 0 (0) | |
| Esophageal cancer | 15 (17.1) | 35 (53.0) | | 1 (0.4) | |
| Biliary tract cancer | 6 (6.8) | 6 (9.1) | | 8 (3.0) | |
| Gynecological cancer | 0 (0) | 0 (0) | | 100 (37.3) | |
| Urothelial carcinoma | 0 (0) | 0 (0) | | 26 (9.7) | |
| Others | 5 (5.7) | 1 (1.5) | | 19 (7.1) | |
| Cancer stage, n (%) | | | 0.007a) | | 0.036c) |
| I | 8 (9.1) | 5 (7.6) | | 58 (21.6) | |
| II | 16 (18.2) | 16 (24.2) | | 41 (15.3) | |
| III | 36 (41.0) | 11 (16.7) | | 107 (39.9) | |
| IV | 28 (31.8) | 34 (51.5) | | 62 (23.1) | |
| Recurrence | 1 (1.1) | 3 (4.5) | | 33 (12.3) | |
| CDDP dose, mg (median, range) | 80 (18–100) | 70 (20–100) | <0.001b) | 70 (18.5–100) | <0.001d) |
| Concomitant anticancer drugs, n (%) | 58 (65.9) | 41 (62.1) | 0.734a) | 256 (95.5) | <0.001c) |
| Combined with radiation, n (%) | 54 (61.4) | 47 (71.2) | 0.233a) | 59 (22.0) | <0.001c) |
| Alcohol consumption, n (%) | 57 (64.8) | 34 (51.5) | 0.102a) | 72 (26.9) | <0.001c) |
| Smoking history, n (%) | 72 (81.8) | 47 (71.2) | 0.126a) | 143 (53.4) | <0.001c) |
| Prophylactic administration of olanzapine, n (%) | 7 (8.0) | 11 (16.7) | 0.129a) | 11 (4.1) | 0.165c) |
F-NTP, fosnetupitant; F-APR, fosaprepitant; APR, aprepitant; ECOG, Eastern Cooperative Oncology Group; CDDP, cisplatin. a) Fisher’s exact test of F-NTP vs. F-APR. b) Mann–Whitney U test of F-NTP vs. F-APR. c) Fisher’s exact test of F-NTP vs. APR. d) Mann–Whitney U test of F-NTP vs. APR.
The CR rates during the extended overall (0–168 h) period are shown in Fig. 1. The CR during the extended overall period was significantly higher in the F-NTP group than in the F-APR (64.8 vs. 48.5%; p = 0.049) and APR (64.8 vs. 47.0%; p = 0.005) groups. Table 2 shows the patient population who achieved CR at each time point. The CR at each time point was significantly higher in the F-NTP group than in the F-APR group during the beyond-delayed (120–168 h) period (78.4 vs. 63.6%; p = 0.048). Compared to those in the APR group, the results were significantly higher in the acute (0–24 h; 97.7 vs. 90.3%; p = 0.022), delayed (24–120 h; 67.0 vs. 54.1%; p = 0.035), overall (0–120 h; 67.0 vs. 53.4%; p = 0.026), and beyond-delayed (120–168 h; 78.4 vs. 61.2%; p = 0.003) periods.
Table 2. Comparison of the CR Rate of F-NTP
vs. F-APR and F-NTP
vs. APR
| Period | F-NTP | F-APR | p-Value | APR | p-Value |
|---|
| Acute (0–24 h) | 86 (97.7) | 62 (93.9) | 0.403a) | 242 (90.3) | 0.022b) |
| Delayed (24–120 h) | 59 (67.0) | 40 (60.6) | 0.497a) | 145 (54.1) | 0.035b) |
| Overall (0–120 h) | 59 (67.0) | 39 (59.1) | 0.316a) | 143 (53.4) | 0.026b) |
| Beyond-delayed (120–168 h) | 69 (78.4) | 42 (63.6) | 0.048a) | 164 (61.2) | 0.003b) |
CR, complete response; F-NTP, fosnetupitant; F-APR, fosaprepitant; APR, aprepitant. Data are primarily depicted as numbers (cumulative percentage, %). a) Fisher’s exact test of F-NTP vs. F-APR. b) Fisher’s exact test of F-NTP vs. APR.
Patient characteristics were not well established using real-world data, and the influence of clinically potent confounding factors and F-NTP was analyzed. The results of univariate and multivariate analyses of the risk factors for non-CR during the extended overall (0–168 h) period are presented in Table 3. F-NTP use, which had the highest CR rate from 0–168 h, was included in the univariate analysis, along with sex, age, alcohol consumption history, and actual CDDP dose, all of which were significant, except for alcohol consumption history. The F-NTP group had a lower risk of non-CR than the other groups (OR, 0.488; p = 0.004). A multivariate analysis incorporating all these risk factors for non-CR outcomes was then performed using data from the literature and medical perspectives.13,14) F-NTP use was an independent factor that significantly reduced the risk of non-CR compared to the other drugs (OR, 0.575; p = 0.048).
Table 3. Risk Factors for Non-CR in the Extended Overall Period (0–168 h)
| Factor | Univariate analysis | Multivariate analysis |
|---|
| OR | 95% CI | p-Value* | OR | 95% CI | p-Value* |
|---|
| Female sex | 3.497 | 2.319–5.273 | < 0.001 | 3.677 | 2.293–5.896 | < 0.001 |
| Age | 0.969 | 0.952–0.987 | < 0.001 | 0.976 | 0.958–0.995 | 0.013 |
| Alcohol consumption | 0.727 | 0.490–1.077 | 0.112 | 1.141 | 0.730–1.783 | 0.563 |
| CDDP dose | 0.998 | 0.989–1.008 | 0.708 | 1.012 | 1.001–1.023 | 0.040 |
| F-NTP | 0.488 | 0.300–0.795 | 0.004 | 0.575 | 0.332–0.994 | 0.048 |
CR, complete response; OR, odds ratio; CI, confidence interval; CDDP, cisplatin; F-NTP, fosnetupitant * Logistic regression analysis.
Table 4 shows the results of the univariate and multivariate analyses of the risk factors for non-CR in the beyond-delayed (120–168 h) period. Using the same method as before, univariate analysis of the F-NTP group, which had the highest CR rate in the beyond-delayed (120–168 h) period, showed significant results for all except the actual CDDP dose, which reduced the risk of non-CR in the F-NTP group compared to that in the other groups (OR, 0.443, p = 0.004). Multivariate analyses were performed using the methods described above. The results showed that in the beyond-delayed period, as in the extended overall period, F-NTP was an independent factor that predominantly reduced the risk of non-CR compared to the other groups (OR, 0.505, p = 0.027).
Table 4. Risk Factors for Non-CR in the Beyond-Delayed Period (120–168 h)
| Factor | Univariate analysis | Multivariate analysis |
|---|
| OR | 95%CI | p-Value* | OR | 95%CI | p-Value* |
|---|
| Female sex | 2.224 | 1.477–3.350 | <0.001 | 2.076 | 1.300–3.314 | 0.002 |
| Age | 0.973 | 0.956–0.991 | 0.004 | 0.979 | 0.960–0.997 | 0.024 |
| Alcohol consumption | 0.615 | 0.403–0.939 | 0.024 | 0.841 | 0.532–1.329 | 0.457 |
| CDDP dose | 1.001 | 0.991–1.010 | 0.905 | 1.011 | 0.999–1.022 | 0.066 |
| F-NTP | 0.443 | 0.255–0.771 | 0.004 | 0.505 | 0.276–0.923 | 0.027 |
CR, complete response; OR, odds ratio; CI, confidence interval. * Logistic regression analysis. CDDP, cisplatin; F-NTP, fosnetupitant.
Figure 2 shows the results of comparing each curve using the log-rank test. While there was no difference in TTF for the F-NTP group compared to the F-APR group (p = 0.077), TTF for the F-NTP group was longer compared to that for the APR group (p = 0.005). The f-NTP group showed a tendency for the effect to persist beyond 120 h.
Adverse EventsAdverse events by grade for injection site reactions, constipation, and hiccups are shown in Table 5. The incidence of injection site reactions was significantly lower in the F-NTP group than in the F-APR group (5.7 vs. 28.8%, p < 0.001). However, there was no significant difference compared with the APR group (5.7 vs. 3.7%; p = 0.540). No significant difference was observed in the incidence of constipation between the F-NTP and F-APR groups (71.6 vs. 66.7%, p = 0.596). However, the incidence was significantly higher than in the APR group (71.6 vs. 56.0%; p = 0.012). The incidence of hiccups was significantly higher in the F-NTP group than in the F-APR group (35.2 vs. 12.1%, p = 0.001), while there was no significant difference compared to that in the APR group (35.2 vs. 24.6%; p = 0.072).
Table 5. Comparison of the Adverse Event Incidence Rate in F-NTP
vs. F-APR and F-NTP
vs. APR Groups
| F-NTP | F-APR | p-Value | APR | p-Value |
|---|
| Injection site reactions | 5 (5.7) | 19 (28.8) | < 0.001a) | 10 (3.7) | 0.540b) |
| Grade 1 | 4 (4.5) | 14 (21.2) | | 10 (3.7) | |
| Grade 2 | 1 (1.1) | 3 (4.5) | | 0 (0) | |
| Grade 3 | 0 (0) | 2 (3.0) | | 0 (0) | |
| Constipation | 63 (71.6) | 44 (66.7) | 0.596a) | 150 (56.0) | 0.012b) |
| Grade 1 | 42 (47.7) | 27 (40.9) | | 90 (33.6) | |
| Grade 2 | 15 (17.0) | 17 (25.8) | | 59 (22.0) | |
| Grade 3 | 6 (6.8) | 0 (0) | | 1 (0.4) | |
| Hiccups | 31 (35.2) | 8 (12.1) | 0.001a) | 66 (24.6) | 0.072b) |
| Grade 1 | 22 (25.0) | 6 (9.1) | | 49 (18.3) | |
| Grade 2 | 8 (9.1) | 2 (3.0) | | 17 (6.3) | |
| Grade 3 | 1 (1.1) | 0 (0) | | 0 (0) | |
F-NTP, fosnetupitant; F-APR, fosaprepitant; APR, aprepitant. a) Fisher’s exact test of F-NTP vs. F-APR. b) Fisher’s exact test of F-NTP vs. APR.
DISCUSSION
High emetogenic risk regimens, including CDDP, often cause uncontrolled CINV and affect subsequent treatment.2) Our findings from real-world data indicate that prophylactic antiemetic therapy with F-NTP prevents CINV more effectively than existing F-APR and APR therapies. In this study, we found that real-world data revealed variations in the backgrounds of patients who received each NK1 antagonist. Therefore, on adjustment in the multivariate analysis, F-NTP use was found to be an independent factor influencing CR. This effect was particularly evident between 120–168 h of treatment. This period has not been studied extensively and is one of the problems associated with a high emetogenic risk regimen8,15); therefore, we believe that our findings will significantly contribute to the continuation of treatment in the future. As shown in the TTF curve, the percentage of treatment failures on days 5–6 (120–144 h) was lower in the F-NTP group, indicating a difference in efficacy not only during the extended overall period but especially during the beyond-delayed period.
Our study directly compared the CR of the F-NTP, F-APR, and APR groups one week after the first dose of the CDDP-based regimen. Our results suggest that the efficacy of F-NTP is superior to that of the other agents. One reason for this is the long elimination half-life of F-NTP. The elimination half-lives of the active metabolites of F-APR and APR in healthy subjects were 14.0 ± 6.0 and 13.9 ± 4.8 h, respectively.16,17) On the other hand, the elimination half-life of the active metabolite of F-NTP was considerably longer, at 70.4 ± 22.3 h.18) For details of each period, a CONSOLE study of patients receiving CDDP (≥70 mg/m2) demonstrated the non-inferiority of the F-NTP group to the F-APR group in terms of the CR rate from 0–120 h after anticancer drug administration.11) The CR rates in the extended overall (0–168 h) and beyond-delayed (120–168 h) periods in the F-NTP and F-APR groups were 73.2 vs. 66.9 and 74.5 vs. 68.4%, respectively. Contrastingly, the CR rate in the extended overall (0–168 h) period in the F-APR group was extremely low (48.5%). The major reason for this is the variability in patient backgrounds compared with that in clinical trials. Moreover, approximately half of the patients had no history of alcohol consumption, and many had head, neck, and esophageal cancers, which are frequently treated using radiation therapy. Retrospective data showed variations in patient background in each group; however, after adjustment in the multivariate analysis, F-NTP use was independently effective compared to other drugs (F-APR and APR). However, no clinical studies have compared the efficacy of F-NTP and APR for the treatment of CINV. A study on the oral fixed-dose combination of netupitant and palonosetron (NEPA) is available outside Japan, and it has been studied in comparison to APR + granisetron.19) In that study, there was no difference in CR during the early treatment period; however, CR with NEPA was significantly higher on day five. The differences in the later stages of treatment were similar to those observed in the present study. However, it should be noted that the route and dose of administration differed, and granisetron was used in all APR groups. In addition, because patients tend to be older in clinical practice than in clinical trials, it is necessary to consider the possibility that patient compliance may have been an issue with the orally ingested drugs, such as APR, compared to injectable drugs such as F-NTP or F-APR which are pre-integrated into the regimen.20)
Regarding the beyond-delayed (120–168 h) period, a recent meta-analysis reported that among patients on high-emetic risk regimens, 31% experienced nausea and 6% experienced vomiting.21) Few studies have reported the effective prevention of CINV during this period in terms of the duration of action. These results provide insight into the effect of F-NTP in the beyond-delayed (120–168 h) period.
Regarding adverse events, the F-NTP group showed a significantly lower incidence of injection site reactions than the F-APR group, which may be problematic for injectable drugs. Although many injection site reactions with F-APR have been reported in clinical practice,22,23) two reasons can be inferred for the lack of injection site reactions with F-NTP. First, there is the possibility of less vascular irritation. According to the “Report of Examination (Pharmaceutical Safety and Environmental Health Bureau),” which summarizes the results of the examination and evaluation of the drug, many reports of vascular irritation owing to F-APR have been documented, including venous necrosis in rats.24) In contrast, F-NTPs caused less severe effects, such as edema and inflammation, after paravalvular administration in rabbits.25) The second reason is the conversion site of the active metabolite; in particular, F-NTP, a prodrug, is converted into its active metabolite–netupitant–in the body, and exerts a strong antiemetic effect. F-NTP is converted to its active metabolite in vitro in the liver and across other major organs, and the conversion efficiency in peripheral vessels is quite low (1.3% in 30 min).12) Therefore, the injection site reaction is considered extremely low compared to that of F-APR. In the aforementioned CONSOLE-BC study, the total incidence of adverse events in the F-NTP and F-APR groups was similar; the F-NTP group had a lower incidence of injection site reactions, while the F-APR group had a higher incidence of gastrointestinal symptoms.12) This trend is similar to that observed in the present study. Constipation and hiccups should be treated with caution, as these side effects themselves can induce nausea and vomiting when they become severe. However, the large proportion of patients with Grade 1 adverse effects in the analysis indicates that these side effects were well-tolerated if treated promptly.
This study has some limitations. First, because real-world data were collected from a single center, variations in patient backgrounds were inevitable. There were differences between F-NTP, F-APR, and APR due to factors such as sex, age, performance status, tumor type and cancer stage, CDDP dose, concomitant anticancer drugs, combination with radiation, as well as a history of drinking alcohol and/or smoking. Women, in particular, are at risk of CINV,26) and since the ratio of women in the APR group was higher in this study, we cannot rule out the possibility that sex differences may have influenced the results. Therefore, we controlled for as many confounding factors as possible in the multivariate analysis. Second, we could not obtain information on the presence or absence of hyperemesis gravidarum and motion sickness, which have been reported as risk factors for CINV.13,14) Similarly, the administration method of dexamethasone was intravenous and oral, and the number of days of administration was also different, so it was difficult to analyze.
In conclusion, the efficacy of F-NTP in managing CINV was superior to that of F-APR and APR during the extended overall study period. F-NTP significantly reduced nausea and vomiting during cancer drug therapy and managed CINV without significant side effects.
Conflict of Interest
The authors declare no conflict of interest.
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