HR20013, a fixed-dose intravenous combination of fosrolapitant and palonosetron, for the prevention of cisplatin-induced nausea and vomiting: putting the PROFIT trial into perspective

Chemotherapy-induced nausea and vomiting (CINV) still remains distressing adverse events for cancer patients undergoing chemotherapy. Acute-onset CINV resolves within the first 24 hours of chemotherapy initiation, whereas delayed CINV typically develops between 24 and 120 hours of chemotherapy administration and occurs more commonly than acute CINV (1). Prevention of CINV has evolved over time due to significant progress in understanding the complex network of neurotransmitters and neuroanatomical centers through which anticancer agents cause emesis (1,2). Extensive research efforts have led to the development of new classes of antiemetic agents that have significantly improved CINV outcomes. Although 5-hydroxytryptamine-3 receptor antagonists (5-HT₃RAs) did not alter the relative success of acute and delayed control of CINV, the advent of neurokinin-1 receptor antagonists (NK-1RAs) had a significant impact on the prevention of both acute and delayed symptoms (3,4). Early pivotal trials of aprepitant, the first-in-class NK-1RA, demonstrated that a multi-targeted antiemetic regimen including an NK-1RA, a 5-HT₃RA, and dexamethasone (DEX) can substantially improve the control of CINV due to highly emetogenic chemotherapy (HEC) such as cisplatin (5,6). More recently, the antiemetic use of olanzapine, an atypical antipsychotic, has further improved CINV outcomes in the HEC setting. Evidence-based guidelines now recommend a four-drug antiemetic regimen containing olanzapine for the prevention of CINV caused by HEC (7,8).

The randomized, double-blind, phase III study by Zhou et al. evaluated the efficacy and safety of HR20013, a novel fixed-dose intravenous combination of fosrolapitant and palonosetron (PALO), and fosaprepitant (FAPR)/PALO, both combined with DEX for multiple days, in Chinese patients treated with cisplatin (≥60 mg/m²)-based HEC (9). Fosrolapitant is an injectable prodrug formulation of rolapitant that is rapidly converted to rolapitant, its active form, after intravenous administration (9). The antagonistic activity of rolapitant and PALO exhibits unique characteristics within their respective pharmacological classes. While PALO is a second-generation 5-HT₃RA that has both a longer elimination half-life (>40 hours) and a distinctly different receptor-binding profile than older 5-HT₃RAs, rolapitant is a potent, highly selective NK-1RA that remains bound to NK-1 receptors in the brain for a median of 120 hours (2,10). Also, rolapitant has a prolonged elimination half-life of approximately 180 hours, which is longer than that of other NK-1RAs such as aprepitant (9–13 hours), FAPR (an injectable prodrug formulation of aprepitant), netupitant (approximately 90 hours), and fosnetupitant (an injectable prodrug formulation of netupitant) (10,11). Since a fixed-dose intravenous combination of fosnetupitant and PALO (i.e., intravenous NEPA) has already been approved in the USA and European Union, HR20013 might be the second intravenously administered fixed-dose combination of a long-lasting NK-1RA and PALO to be approved for the prevention of CINV (12). Similar to the use of intravenous NEPA, HR20013 enables simultaneous targeting of two critical emetic pathways with single-dose administration and thus offers a simplified approach to implement guideline-recommended prophylaxis against CINV. This should be a welcome clinical improvement since poor adherence of clinicians and oncology nurses to guideline recommendations, particularly for complex multidrug prophylactic regimens used in HEC, is one of the barriers that may contribute to suboptimal CINV control in daily practice (13,14). Guideline-inconsistent prophylaxis has been shown to adversely impact CINV control and patient quality of life (13,14).

When considering the evidence from the PROFIT trial, it is necessary to put the study’s main findings into perspective. It is important to note that the study design includes a primary efficacy endpoint and a key secondary efficacy endpoint. For the primary efficacy endpoint, the rate of complete response (CR; defined as no vomiting and no use of rescue medication) during the standard overall phase (0–120 hours after cisplatin administration) in Cycle 1 was non-inferior with HR20013 versus FAPR/PALO (Table 1), with a risk difference of −0.9% [95% confidence interval (CI): −6.7% to 5.0%] (9). CR rates in the acute and delayed phases were also comparable between the study arms (Table 1). These efficacy results were achieved without any relevant additional toxicity (9).

Taking into account the primary objective of the study, the characteristics of the included patients require some comments. Although the emetogenic potential of chemotherapy agents greatly affects control patterns of CINV, we should keep in mind that, even with the same chemotherapy regimen, several patient-related risk factors, including female sex, younger age, no alcohol consumption, previous history of morning or motion sickness, and previous history of nausea/vomiting, can also affect antiemetic efficacy (15,16). In the PROFIT trial, most patients (70%) were male, while the median age was 60 years and 96% of patients had no history of motion sickness (9). Overall, these data suggest that most patients enrolled in the study may have an intrinsically lower risk of developing CINV and that this may ultimately influence differences in CINV outcomes between study treatments. Interestingly, the two pivotal trials of oral rolapitant in HEC (HEC1 and HEC2) did not achieve similar results in cisplatin-naïve patients who were treated with cisplatin at a dose of 60 mg/m² or greater (17). CR rates in the standard delayed phase (primary efficacy endpoint) were superior in patients receiving rolapitant versus active control (i.e., a 5-HT₃RA plus DEX) in both studies. However, for the key secondary efficacy endpoints of the proportion of patients achieving CR in the acute and overall phases, superiority of the rolapitant-treated group versus the active control group was observed only in the HEC1 study (17). Despite the study features and study implementation for HEC1 and HEC2 studies being identical, there were more male patients in HEC2 (68%) than in HEC1 (58%). A 10% higher number of patients with an intrinsically lower risk of developing CINV may explain the non-significant differences in most CINV outcomes between the rolapitant-treated and control groups in the HEC2 study (17). Additionally, in a large phase III, non-inferiority study comparing FAPR/PALO to aprepitant/PALO in patients receiving the first cycle of cisplatin, an exploratory analysis found that only female sex was independently associated with failure to achieve CR in the standard overall phase (primary efficacy endpoint) (18).

Most patients enrolled in the PROFIT trial were men with lung cancer, and therefore other potential variables of interest could be the frequency of alcohol consumption and smoking history. Although there was no information on these two patient-related factors in the final study report, recently published data also support their significant impact on CINV control. A pooled analysis of two randomized studies evaluating fosnetupitant/PALO versus FAPR/PALO in patients (mostly men with lung cancer) receiving cisplatin-based HEC found that in the overall population, no daily alcohol consumption, no smoking history, a history of motion sickness, and female sex were risk factors independently associated with failure to achieve CR during the standard overall phase in Cycle 1 (19). Since multiple risk factors for CINV may be present in a patient, there is a known relationship between the number of risk factors and antiemetic failure (19). Given the limited information available on prognostic factors for CINV in the PROFIT trial, it remains unclear to what extent patient-related risk factors may have influenced the primary efficacy results observed in the two treatment arms.

Another limitation of the PROFIT trial is related to the concomitant use of prophylactic DEX. In the HR20013 group, patients received DEX 12 mg orally before cisplatin, followed by DEX 3.75 mg orally twice daily on days 2–4 (9). Taking into account the steroid doses used in the FAPR/PALO group, the DEX doses in the HR20013 group were selected to balance well the patients’ total steroid exposure between the treatment groups. While the doses of antiemetic DEX used in the study may be adequate for Chinese patients (20), this may not be true for other ethnic groups, where the lower doses of DEX used in the HR20013 group would be inconsistent with current guideline recommendations (7,8). A distinctive feature in the pharmacokinetics of rolapitant is that the drug is metabolized by the cytochrome P450 (CYP) 3A enzyme, but unlike aprepitant/FAPR and netupitant/fosnetupitant, its use does not require dose adjustments of concomitant medications that are CYP3A substrates. Consequently, no dose adjustments of prophylactic DEX are required when using rolapitant for the prevention of CINV (10). In the pivotal studies HEC1 and HEC2, all patients received guideline-recommended steroid doses consisting of DEX 20 mg orally prior to cisplatin and DEX 8 mg orally twice daily on days 2–4 (17). Importantly, evidence-based antiemetic guidelines currently recommend DEX dose adjustments (i.e., 12 mg on day 1, followed by 8 mg once daily on days 2–4) only when aprepitant/FAPR and netupitant/fosnetupitant are the NK-1RAs used (7,8). In a recent randomized study, a simplified three-drug prophylaxis containing oral NEPA (i.e., a fixed-dose combination of netupitant and PALO) and single-dose DEX was non-inferior to the same regimen with guideline-recommended doses of DEX administered on days 1–4 for the prevention of cisplatin-induced CINV, particularly in patients older than 65 years (21,22). Regardless of the available information on the efficacy of the DEX-sparing strategy in cisplatin, we must keep in mind that the PROFIT study in Chinese patients represents the first large analysis of the antiemetic efficacy of HR20013 in the challenging setting of cisplatin-induced CINV. Therefore, well-designed and adequately powered studies are needed to answer the question of whether the use of guideline-recommended DEX doses can impact the CR rate during the standard overall phase in patients treated with HR20013 against cisplatin-induced CINV.

There is compelling evidence that a number of patients may experience delayed CINV beyond day 5 of chemotherapy initiation (12). In light of this, NK-1RAs are expected to play an important role in the control of CINV occurring beyond the standard delayed phase (24–120 hours after chemotherapy administration). The prolonged elimination half-life of rolapitant may also allow for covering a risk period beyond day 5 of chemotherapy initiation. In the PROFIT trial, the CR rate beyond the delayed phase (120–168 hours after cisplatin administration) was evaluated as a key secondary efficacy endpoint (9). Since the non-inferiority hypothesis was met for the primary endpoint, the study sequentially assessed the superiority of the key secondary endpoint. Unfortunately, the study failed to demonstrate superiority of HR20013 over FAPR/PALO for the CR rate beyond the delayed phase in Cycle 1 (Table 1), with a risk difference of 3.7% (95% CI: −0.9% to 8.2%) (9). This finding is in line with that in the CONSOLE trial, which is another phase III study comparing the efficacy of different NK-1RAs against CINV when used in combination with PALO and DEX in cisplatin-based HEC (12). In the Japanese study, the CR rate in the fosnetupitant/PALO group was similar to that in the FAPR/PALO group beyond the delayed phase (Table 1). Of note, CR rates observed in the PROFIT trial during the acute, delayed, overall and extended overall (0–168 hours after cisplatin administration) phases are also in line with those in the CONSOLE trial (Table 1). However, the CONSOLE trial enrolled mainly men over the age of 55 with lung cancer (12). The aforementioned pooled analysis of two studies with fosnetupitant/PALO also found that in the overall population, only failure to achieve CR during the standard overall phase was an independent risk factor for developing CINV beyond the delayed phase (19). This exploratory analysis suggests that in clinical practice, clinicians should maximize the antiemetic benefit within the first 5 days after cisplatin administration to increase the likelihood that the patient will achieve a CR even beyond the delayed phase. It is important to highlight that a guideline-inconsistent antiemetic prophylaxis was used in the PROFIT trial since not all patients were also administered olanzapine for the prevention of cisplatin-induced CINV (7,8). There is compelling evidence that the addition of olanzapine to a standard three-drug regimen is an effective and safe strategy to improve CINV control in patients receiving HEC (23,24). Furthermore, up to 22% of patients in both treatment groups of the PROFIT trial did not achieve a CR during the standard overall phase, and this finding also supports the need for the use of olanzapine to enhance antiemetic benefit in the cisplatin setting (9).

In summary, the non-inferiority of HR20013 to FAPR/PALO demonstrated in the PROFIT trial highlights the potential of HR20013 as a valuable new addition to the currently available therapeutic armamentarium for the management of CINV. To determine whether HR20013 may represent more than just an option to simplify antiemetic prophylaxis, its efficacy needs to be investigated not only in other ethnic groups but also in patient populations with an intrinsically higher risk of developing CINV, including female patients. It will also be critical that further clinical trials with HR20013 include both the use of olanzapine and guideline-recommended doses of DEX. There is no doubt that we are only in the early stages of clinical development of HR20013.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-62/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-62/coif). L.C. has received consulting fee from Italfarmaco and honoraria for presentations from Berlin-Chemie and Helsinn. The other author has no conflicts of interest to declare.

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References

1. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358:2482-94. [Crossref] [PubMed]
2. Rojas C, Slusher BS. Mechanisms and latest clinical studies of new NK1 receptor antagonists for chemotherapy-induced nausea and vomiting: Rolapitant and NEPA (netupitant/palonosetron). Cancer Treat Rev 2015;41:904-13. [Crossref] [PubMed]
3. Geling O, Eichler HG. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol 2005;23:1289-94. [Crossref] [PubMed]
4. Piechotta V, Adams A, Haque M, et al. Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis. Cochrane Database Syst Rev 2021;11:CD012775. [PubMed]
5. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin Oncol 2003;21:4112-9. [Crossref] [PubMed]
6. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003;97:3090-8. [Crossref] [PubMed]
7. Herrstedt J, Clark-Snow R, Ruhlmann CH, et al. 2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting. ESMO Open 2024;9:102195. [Crossref] [PubMed]
8. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol 2020;38:2782-97. [Crossref] [PubMed]
9. Zhou H, Zhao Y, Zhang M, et al. Randomized, Phase III Trial of Mixed Formulation of Fosrolapitant and Palonosetron (HR20013) in Preventing Cisplatin-Based Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: PROFIT. J Clin Oncol 2025;43:1123-36. [Crossref] [PubMed]
10. Rapoport B, Chua D, Poma A, et al. Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Cancer 2015;23:3281-8. [Crossref] [PubMed]
11. Rashad N, Abdel-Rahman O. Differential clinical pharmacology of rolapitant in delayed chemotherapy-induced nausea and vomiting (CINV). Drug Des Devel Ther 2017;11:947-54. [Crossref] [PubMed]
12. Hata A, Okamoto I, Inui N, et al. Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE. J Clin Oncol 2022;40:180-8. [Crossref] [PubMed]
13. Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol 2012;23:1986-92. [Crossref] [PubMed]
14. Gilmore JW, Peacock NW, Gu A, et al. Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study. J Oncol Pract 2014;10:68-74. [Crossref] [PubMed]
15. Hesketh PJ, Aapro M, Street JC, et al. Evaluation of risk factors predictive of nausea and vomiting with current standard-of-care antiemetic treatment: analysis of two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy. Support Care Cancer 2010;18:1171-7. [Crossref] [PubMed]
16. Mosa ASM, Hossain AM, Lavoie BJ, et al. Patient-Related Risk Factors for Chemotherapy-Induced Nausea and Vomiting: A Systematic Review. Front Pharmacol 2020;11:329. [Crossref] [PubMed]
17. Rapoport BL, Chasen MR, Gridelli C, et al. Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials. Lancet Oncol 2015;16:1079-89. [Crossref] [PubMed]
18. Zhao Y, Zhao B, Chen G, et al. Validation of different personalized risk models of chemotherapy-induced nausea and vomiting: results of a randomized, double-blind, phase III trial of fosaprepitant for cancer patients treated with high-dose cisplatin. Cancer Commun (Lond) 2023;43:246-56. [Crossref] [PubMed]
19. Inui N, Toi Y, Yoneshima Y, et al. Pooled Analysis of Studies Evaluating Fosnetupitant and Risk Factors for Cisplatin-Induced Nausea and Vomiting During the Extended Overall Phase. Adv Ther 2023;40:4928-44. [Crossref] [PubMed]
20. Zhang Z, Yang Y, Lu P, et al. Fosaprepitant versus aprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based chemotherapy: a multicenter, randomized, double-blind, double-simulated, positive-controlled phase III trial. Ann Transl Med 2020;8:234. [Crossref] [PubMed]
21. Celio L, Cortinovis D, Cogoni AA, et al. Dexamethasone-Sparing Regimens with Oral Netupitant and Palonosetron for the Prevention of Emesis Caused by High-Dose Cisplatin: A Randomized Noninferiority Study. Oncologist 2021;26:e1854-61. [Crossref] [PubMed]
22. Celio L, Bartsch R, Aapro M. Dexamethasone-sparing regimens with NEPA (netupitant/palonosetron) for the prevention of chemotherapy-induced nausea and vomiting in older patients (>65 years) fit for cisplatin: A sub-analysis from a phase 3 study. J Geriatr Oncol 2023;14:101537. [Crossref] [PubMed]
23. Navari RM, Qin R, Ruddy KJ, et al. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 2016;375:134-42. [Crossref] [PubMed]
24. Hashimoto H, Abe M, Tokuyama O, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:242-9. [Crossref] [PubMed]