Future Oncology
`ISSN: 1479-6694 (Print) 1744-8301 (Online) Journal homepage: www.tandfonline.com/journals/ifon20
`Nausea and vomiting in an evolving anticancer
`treatment landscape: long-delayed and
`emetogenic antibody-drug conjugates
`Yeon Hee Park, Giampaolo Bianchini, Javier Cortés, Luca Licata, María
`Vidal, Hirotoshi Iihara, Eric J. Roeland, Karin Jordan, Florian Scotté, Lee
`Schwartzberg, Rudolph M. Navari, Matti Aapro & Hope S. Rugo
`To cite this article: Yeon Hee Park, Giampaolo Bianchini, Javier Cortés, Luca Licata, María Vidal,
`Hirotoshi Iihara, Eric J. Roeland, Karin Jordan, Florian Scotté, Lee Schwartzberg, Rudolph M.
`Navari, Matti Aapro & Hope S. Rugo (2025) Nausea and vomiting in an evolving anticancer
`treatment landscape: long-delayed and emetogenic antibody-drug conjugates, Future
`Oncology, 21:10, 1261-1272, DOI: 10.1080/14796694.2025.2479417
`To link to this article: https://doi.org/10.1080/14796694.2025.2479417
`© 2025 The Author(s). Published by Informa
`UK Limited, trading as Taylor & Francis
`Group.
`Published online: 19 Mar 2025.
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`HELSINN EXHIBIT 2100
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 13
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`REVIEW
`Nausea and vomiting in an evolving anticancer treatment landscape: long-delayed
`and emetogenic antibody-drug conjugates
`Yeon Hee Parka, Giampaolo Bianchinib,c, Javier Cortésd,e,f, Luca Licatab, María Vidalg,h, Hirotoshi Iiharai, Eric J. Roelandj,
`Karin Jordank,l, Florian Scottém, Lee Schwartzbergn, Rudolph M. Navari
` o, Matti Aaprop and Hope S. Rugo q
`aDivision of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
`Republic of Korea; bDepartment of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy; cSchool of Medicine and Surgery, Vita-Salute San
`Raffaele University, Milan, Italy; dInternational Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona, Spain; eIOB Madrid,
`Hospital Beata María Ana, Madrid, Spain; fFaculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid,
`Madrid, Spain; gDepartment of Medical Oncology, Hospital Clinic, Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS,
`Barcelona, Spain; hDepartment of Medicine, University of Barcelona, Barcelona, Spain; iDepartment of Pharmacy, Gifu University Hospital, Gifu,
`Japan; jKnight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; kDepartment of Hematology, Oncology and Palliative
`Medicine, Ernst von Bergmann Hospital, Potsdam, Germany; lDepartment of Medicine V, Hematology, Oncology and Rheumatology, University of
`Heidelberg, Heidelberg, Germany; mInterdisciplinary Cancer Course Department, Gustave Roussy Cancer Institute, Villejuif, France; nRenown Health-
`Pennington Cancer Institute, University of Nevada, Reno, NV, USA; oWorld Health Organization, Mount Olive, AL, USA; pGenolier Cancer Centre,
`Clinique de Genolier, Genolier, Switzerland; qUniversity of California San Francisco Helen Diller Family Comprehensive Cancer Center, San
`Francisco, CA, USA
`ABSTRACT
`Nausea and vomiting are common, distressing side effects associated with chemotherapeutic regi -
`mens, resulting in reduced quality of life and treatment adherence. Appropriate antiemetic prophy -
`laxis strategies may reduce/prevent chemotherapy-induced nausea and vomiting (CINV). Historically,
`investigators assessed antiemetics up to 120 hours after chemotherapy. However, CINV can extend
`beyond this time. Thus, the effect of antiemetics during the long-delayed period (>120 hours) requires
`investigation. Emerging treatment options, including certain antibody-drug conjugates (ADCs), are
`associated
`with high rates of acute and late-onset nausea and vomiting that can last for extended
`duration. With the increasing number of ADCs approved and in development, there is urgency to
`control nausea and vomiting in patients receiving these new therapies. In this narrative review, we
`present the emetogenic potential of ADCs and CINV in the long-delayed period along with antiemetic
`prophylaxis strategies used to date. We also discuss the promising role of the fixed-combination
`antiemetic NEPA ([fos]netupitant plus palonosetron) in controlling long-delayed nausea and vomit -
`ing, addressing characteristics that may contribute to its longer efficacy duration compared to other
`antiemetics. Finally, we highlight encouraging results with NEPA in patients receiving the ADCs
`trastuzumab deruxtecan or sacituzumab govitecan, which suggest NEPA may be an effective antie
`-
`metic prophylaxis in these settings.
`PLAIN LANGUAGE SUMMARY
`Patients with cancer who are treated with chemotherapy often have nausea and vomiting as side
`effects. These symptoms can be very uncomfortable, negatively impact the quality of life, and may
`cause patients to stop treatment. Using the right antinausea and vomiting medications can help to
`reduce symptoms and enable patients to stay on therapy.
`Many studies have looked at how effective different combinations and doses of these medications
`are in reducing or preventing nausea and vomiting in the 5 days after chemotherapy treatment.
`However, it is now clear that nausea and vomiting can last longer than this time period. Newer
`treatments called antibody-drug conjugates (ADCs) are being used to treat patients with cancer but
`may also cause nausea and vomiting after 5 days (known as long-delayed nausea and vomiting). To
`make sure patients receive the best possible care to prevent these symptoms, it is important to
`understand how well antinausea and vomiting medications work over longer periods of time.
`This paper discusses how often this long-delayed nausea and vomiting occurs in patients after they
`have received chemotherapy or ADCs. We also look at different medications that are being used to
`prevent nausea and vomiting, including a drug called NEPA (netupitant and palonosetron). NEPA is
`a combination of two antinausea and vomiting medications. It may be a good option for preventing
`long-delayed nausea and vomiting, as it is effective over longer time periods than other similar
`medications. NEPA has shown very promising results in studies so far.
`ARTICLE HISTORY
`Received 8 October 2024
`Accepted 11 March 2025
`KEYWORDS
`Nausea and vomiting; NEPA;
`netupitant and
`palonosetron; antibody-drug
`conjugates; long-delayed
`CINV; antiemetics
`CONTACT Yeon Hee Park
` yeonh.park@samsung.com
` Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan
`University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul 06351, Republic of Korea
`This article has been corrected with minor changes. These changes do not impact the academic content of the article.
`FUTURE ONCOLOGY
`2025, VOL. 21, NO. 10, 1261–1272
`https://doi.org/10.1080/14796694.2025.2479417
`© 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
`This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
`which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
`The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
`Page 2 of 13
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`1. Introduction
`1.1. Chemotherapy-induced nausea and vomiting
`Chemotherapy-induced nausea and vomiting (CINV) is a side
`effect associated with many anticancer chemotherapies. CINV
`is common and distressing and can impact patients’ lives
`significantly; it can result in decreased quality of life, higher
`cancer-related fatigue [1], and reduced adherence to che -
`motherapy. As a result, CINV is a highly troublesome toxicity
`for patients and impedes their ongoing receipt of chemother
`-
`apy [2–5]. Different antineoplastic treatments can induce dis -
`tinct patterns of emesis. For example, cisplatin induces
`a biphasic course of emesis, and researchers have used it as
`the gold-standard emetic stimulus in many clinical trials [6,7].
`Generally, an initial emesis peak is observed between 6 and
`8 hours after cisplatin administration, followed by a temporary
`reduction in symptoms and a second nausea and emesis
`phase between 24 and 72 hours. This second peak can persist
`over 5 days in many patients [6,8,9]. Based on this biphasic
`pattern, CINV can be classified as “acute” or “delayed,”
`depending on its timing with respect to chemotherapy admin
`-
`istration. Acute CINV occurs within the first 24 hours after
`administration of chemotherapy, while historically, delayed
`CINV has been defined as occurring >24–120 hours after che -
`motherapy [2,10–12].
`Over time, there have been advances in the understand -
`ing of mechanisms by which chemotherapeutic agents can
`induce nausea and vomiting. CINV’s pathophysiology is
`multifactorial and very complex. The two main mechanisms
`of CINV, the peripheral and central pathways, are shown in
`Figure 1. The peripheral pathway is primarily triggered by
`serotonin release in the GI tract, activating 5-hydroxytrypta
`-
`mine-3 (5-HT 3) receptors in the intestine and resulting in
`acute emesis (<24 hours). In contrast, the central pathway is
`mainly triggered by the release of substance P in the brain,
`activating neurokinin-1 (NK
`1) receptors and resulting in
`delayed emesis (>24–120 hours). A more detailed examina -
`tion of the diverse mechanisms underlying CINV can be
`found in Gupta et al. [13] and Farhat et al. [14]. Although
`nausea and vomiting are frequently clinically associated [15]
`and often considered a unified symptom, the precise phy
`-
`siology contributing to nausea is less well characterized,
`and its assessment remains a clinical challenge due to its
`subjective nature [15–19].
`1.2. Antibody-drug conjugate-induced nausea and
`vomiting
`Newly developed treatment options entering clinical practice
`have also been associated with emetogenic potential. Chief
`among these are the antibody-drug conjugates (ADCs), which
`consist of three main components: a monoclonal antibody
`that is aimed at a specific tumor-associated antigen, a potent
`cytotoxic small molecule (the payload), and a linker to connect
`the two [20]. Currently, 15 ADCs have been approved by the
`US Food and Drug Administration, the European Medicines
`Agency, and/or other government agencies for treating hema -
`tologic malignancies and solid tumors, and over 100 ADCs are
`in clinical development [21,22]. Originally, ADCs were not
`expected to cause nausea and vomiting due to the targeted
`release of the payload to tumor cells. However, off-target
`release of the payload in the circulation may result in toxici -
`ties, including nausea and vomiting [23]. These cytotoxic pay -
`loads are suspected to cause nausea and vomiting through
`a similar mechanism as that of CINV, although the exact
`mechanism by which ADCs induce nausea and vomiting
`remains unclear [14]. A meta-analysis that included 169 clinical
`trials involving 22,492 patients investigated over 20 ADCs and
`identified nausea (44.1%) as one of the top three most com -
`mon any-grade adverse events seen, next to lymphopenia
`(53.0%) and neutropenia (43.7%) [24].
`Among ADCs, the anti-HER2–targeted ADC trastuzumab der-
`uxtecan (T-DXd) [25] had a likelihood for any-grade adverse
`events of 98% [24]. Specifically, phase 2 and 3 trials investigating
`T-DXd in breast cancer, lung cancer, colorectal cancer, gastric
`cancer, and different solid tumors all reported a high incidence of
`nausea and vomiting (Table 1) [26–34]. In these studies, treat
`-
`ment-emergent any-grade nausea rates ranged from 55–78%,
`and any-grade vomiting rates ranged from 25–52% [26–34].
`While nausea and vomiting rates showed some variation
`between tumor types, nausea was the most frequent treatment-
`emergent adverse event in each of the trials. As with CINV, ADC-
`induced nausea and vomiting can lead to dose reduction. In
`a recent pooled, post-hoc analysis of clinical trials involving
`Article highlights
`● Chemotherapy-induced nausea and vomiting (CINV) is a common
`and distressing side effect associated with many chemotherapeutic
`drugs and regimens that is highly troublesome for patients and can
`impede ongoing receipt of chemotherapy.
`● CINV has traditionally been classified as “acute” (≤24 hours) or
`“delayed” (>24–120 hours), depending on its timing with respect to
`chemotherapy administration.
`● Some antibody-drug conjugates (ADCs) were unexpectedly found to
`induce nausea and vomiting in a high proportion of patients, with
`nausea being the most frequent treatment-emergent adverse event
`seen in multiple clinical trials.
`● Recognition of the emetogenic potential of ADCs has resulted in
`trastuzumab deruxtecan and sacituzumab govitecan being incorpo -
`rated as emetogenic agents in guidelines.
`Nausea and vomiting beyond the delayed phase
`● It has become clear that CINV can persist beyond 120 hours and this
`phenomenon (“long-delayed” CINV) has been poorly characterized,
`highlighting an unmet need to continue assessing CINV beyond day
`5 after chemotherapy initiation.
`● Some ADCs are associated with long-delayed nausea and vomiting,
`and with the improved progression-free survival seen with ADC
`treatment, this risk is particularly relevant for patients due to the
`long treatment duration.
`Preventing nausea and vomiting in the long-delayed phase
`● The fixed-combination antiemetic NEPA has a long plasma elim -
`ination half-life and duration of receptor occupancy, characteris -
`tics that make it suitable for providing long-lasting antiemetic
`prophylaxis.
`● NEPA had high efficacy in both the traditionally defined delayed
`phase and in multiple studies investigating the effect of NEPA in
`the long-delayed phase.
`● Limited studies on antiemetic prophylaxis for patients treated with
`ADCs have highlighted the need for early and adequate treatment,
`and have shown promising results with NEPA.
`Summary and discussion
`● Effective antiemetic prophylaxis for preventing long-delayed nausea
`and vomiting is a growing unmet need for patients receiving tradi -
`tional chemotherapy or ADCs, and NEPA-based regimens may be
`appropriate in this setting.
`1262
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`1,449 patients receiving T-DXd, the incidence of dose reduction
`due to any-grade nausea and vomiting was 4.8% and 1.4%,
`respectively [35].
`Another ADC associated with high rates of nausea and vomit-
`ing is the anti-Trop-2–targeted ADC sacituzumab govitecan (SG).
`The phase 1/2 single-group, multicenter IMMU-132-01 trial
`enrolled 108 patients with previously treated metastatic triple-
`negative breast cancer to receive SG monotherapy. Overall, 67%
`experienced nausea, and nearly half reported vomiting [36]. In
`addition, the phase 2 open-label TROPHY-U-01 trial reported
`nausea and vomiting rates of 60% and 30%, respectively, in
`patients with metastatic urothelial carcinoma treated with SG
`[37]. The randomized, phase 3 TROPiCS-02 trial compared SG and
`chemotherapy in patients with hormone receptor-positive,
`human epidermal growth factor receptor 2-negative metastatic
`breast cancer and observed higher rates of nausea and vomiting
`among patients treated with SG than those receiving standard
`chemotherapy: nausea rates were 55% and 31%, and vomiting
`rates were 19% and 12% for SG and chemotherapy, respectively
`[38]. Similarly, in the international, multicenter, phase 3 ASCENT
`Figure 1. Pathophysiology of CINV. Two mechanisms resulting in emesis are the peripheral and central pathways. The peripheral pathway is primarily triggered by
`serotonin release in the gastrointestinal tract, activating 5-HT 3 receptors in the intestine and resulting in acute emesis (<24 hours). The central pathway is triggered
`by the release of substance P in the brain, activating NK 1 receptors and resulting in delayed emesis (>24–120 hours).
`5-HT3: 5-hydroxytryptamine-3; CINV: chemotherapy-induced nausea and vomiting; GI: gastrointestinal; NK 1: neurokinin-1.
`Table 1. Nausea and vomiting rates in patients receiving T-DXd in the DESTINY trials. a.
`Nausea, % Vomiting, %
`Trial Reference Patient population Any grade Grade ≥3b Any grade Grade ≥3b
`Treatment-emergent adverse events reported
`DESTINY-Breast01 [26] N = 184
`HER2-positive metastatic breast cancer
`78 8 46 4
`DESTINY-Breast02 [27] N = 404
`HER2-positive metastatic breast cancer
`73 7 38 4
`DESTINY-Breast03 [28] N = 261
`HER2-positive unresectable or metastatic breast cancer
`77 7 52 2
`DESTINY-Lung02 [29] N = 152 (n = 101 5.4 mg/kg; n = 50 6.4 mg/kg)
`Metastatic HER2-mutant non-small cell lung cancer
`67 (5.4 mg/kg)
`82 (6.4 mg/kg)
`4 (5.4 mg/kg)
`6 (6.4 mg/kg)
`32 (5.4 mg/kg)
`44 (6.4 mg/kg)
`3 (5.4 mg/kg)
`2 (6.4 mg/kg)
`DESTINY-CRC01 [30] N = 86
`HER2-expressing metastatic colorectal cancer
`62 6 31 1
`DESTINY-Gastric01 [31] N = 125
`HER2-positive advanced gastric cancer
`63 5 26 0
`DESTINY-PanTumor02 [32] N = 267
`Locally advanced or metastatic HER2-expressing solid tumors
`55 N/A 25 N/A
`Treatment-related adverse events reported
`DESTINY-Breast04 [33] N = 371
`HER2-low metastatic breast cancer
`73 5 34 1
`DESTINY-Lung01 [34] N = 91
`Metastatic HER2-mutant non-small cell lung cancer
`73 9 40 3
`aThe DESTINY trials did not include a consistent recommendation for the use of antiemetics. Many patients were treated with antiemetics after experiencing nausea
`and/or vomiting.
`bAdverse events were graded per National Cancer Institute Common Terminology Criteria for Adverse Events.
`HER2: human epidermal growth factor receptor 2; N/A: not available; T-DXd: trastuzumab deruxtecan.
`FUTURE ONCOLOGY
` 1263
`Page 4 of 13
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`study of 235 patients with metastatic triple-negative breast can-
`cer treated with SG, 57% experienced nausea and 29% experi -
`enced vomiting [39].
`1.3. Antiemetic prophylaxis
`Appropriate antiemetic prophylaxis per evidence-based guide-
`lines [10–12] can reduce CINV. Historically, chemotherapeutic
`agents have been divided into different categories based on
`the emetic risk posed during the acute phase in the absence
`of antiemetic prophylaxis: highly emetogenic chemotherapy
`(HEC) causes CINV in over 90% of patients, moderately emeto -
`genic chemotherapy (MEC) causes CINV in 30–90% of patients,
`and low emetogenic chemotherapy causes CINV in < 30% of
`patients [40]. Evidence-based antiemetic guidelines have clear
`recommendations for CINV. For adult patients, recommenda -
`tions for patients receiving HEC include prophylaxis with com -
`binations of an NK 1 receptor antagonist (RA), olanzapine, a 5-
`HT3 RA, and a corticosteroid (primarily dexamethasone). For
`patients receiving MEC, guidelines recommend a 5-HT 3 RA
`with dexamethasone and an NK 1 RA for select patients [10–
`12]. The greatest impact of 5-HT 3 RAs is primarily during the
`acute phase, while NK1 RAs impact the delayed phase [2]. NK 1
`RAs used for preventing CINV include (fos)aprepitant, (fos)
`netupitant, and rolapitant; 5-HT
`3 RAs include ondansetron,
`granisetron, and palonosetron [10–12].
`The emetogenic potential of T-DXd and SG is increasingly
`being recognized, with incorporation in the list of emetogenic
`agents in guidelines; yet, a lack of agreement remains on their
`level of emetogenicity due to the paucity of evidence. As the
`high rates of nausea and vomiting were not anticipated with
`T-DXd, the DESTINY trials did not explore antiemetic therapy.
`There were no consistent recommendations for antiemetic use
`in the trial protocols, but many patients were reactively trea -
`ted with antiemetics after experiencing nausea and/or vomit -
`ing [26–34]. For example, during DESTINY-Breast04, 51% of
`patients in the T-DXd arm received antiemetic prophylaxis
`administered per local guidelines, but 73% of patients still
`suffered from nausea [33,41]. Moreover, patients perceived
`that nausea and vomiting were worse with T-DXd than with
`standard chemotherapy [42]. National Comprehensive Cancer
`Network (NCCN) guidelines classified T-DXd and SG as highly
`emetogenic [12]. In contrast, the American Society of Clinical
`Oncology (ASCO) guidelines categorized T-DXd as moderately
`emetogenic [10]. The Multinational Association of Supportive
`Care in Cancer and European Society for Medical Oncology
`(MASCC/ESMO) guidelines designated both T-DXd and SG as
`moderately emetogenic, while highlighting that the emetic
`potential falls at the high end of the MEC category [11].
`Therefore, effective antiemetic prophylaxis is required for
`patients receiving T-DXd or SG. Similarly, patients receiving
`other ADCs may require effective antiemetic prophylaxis.
`2. Nausea and vomiting beyond the delayed phase
`2.1. Long-delayed CINV
`Most studies using antiemetics to prevent CINV have prospec -
`tively evaluated the impact up to 120 hours after the
`administration of chemotherapy (i.e., the end of the conven -
`tional delayed phase). However, CINV can persist beyond
`120 hours [43–45], a phenomenon that has been poorly char -
`acterized over the last three decades. Several factors may have
`contributed to the under-recognition of this issue. The evalua -
`tion, prevention, and treatment of nausea and vomiting often
`differ between clinicians and patients, leading to potential
`discrepancies. In addition, in most clinical studies on antie -
`metic therapies, treatment typically lasted only 5 days, and
`there is a lack of research investigating the effects beyond
`this time frame. Consequently, the lack of longer-term data
`may have hindered the identification and understanding of
`this problem. The occurrence of CINV >120 hours is described
`as “long-delayed” CINV (LD-CINV) [46]. This CINV category is
`separate from the concept of chronic nausea and vomiting,
`which is persistent nausea and vomiting in patients with
`advanced cancer that is unrelated to chemotherapy [47].
`While LD-CINV may have a chronic nature, its cause is related
`to antineoplastic therapy.
`Several studies have highlighted the existence of LD-CINV
`as an unmet need. A survey among healthcare professionals in
`Japan assessed the presence of CINV for an extended period (i.
`e., >120 hours) following chemotherapy. The 809 survey
`respondents included physicians (n = 533), pharmacists (n =
`174), and nurses (n = 102). Most respondents (91%) indicated
`they observed patients who experienced CINV on days 5–7
`after chemotherapy [48]. In addition, a meta-analysis found
`that 31% of patients who received HEC (n = 1333) and 24% of
`patients who received MEC (n = 715) reported nausea during
`the long-delayed phase (>120 hours). Vomiting was experi -
`enced by 6% of patients receiving HEC and MEC each during
`this phase. The degree of CINV during the long-delayed phase
`was as severe as during the historically defined delayed phase,
`and patients who experienced nausea or vomiting on days 4
`or 5 were at increased risk of having LD-CINV [46].
`A retrospective, real-world study investigating treatment out -
`comes, resource utilization, and costs associated with antie -
`metics for patients who received cisplatin-based
`chemotherapy found nausea and vomiting occurring on days
`8–14 after chemotherapy [49]. The NCCN guidelines also high
`-
`light that emesis associated with cisplatin reaches its maximal
`intensity at 48–72 hours after administration but can persist
`for 6–7 days [12]. Finally, a prospective real-world study in
`China included a “beyond the risk period” time frame defined
`as days 8–21 from start of chemotherapy and found an inci -
`dence of CINV of 36% in this period among 1110 patients
`receiving HEC or MEC. Nausea was seen in 35% of patients
`and vomiting in 11%. Most patients received antiemetic regi -
`mens; however, only 22% of patients received this per NCCN
`guidelines [50]. Taken together, these data indicate an unmet
`need to continue assessing CINV beyond day 5 after che -
`motherapy initiation.
`2.2. Long-delayed ADC-induced nausea and vomiting
`The existence of long-delayed nausea and vomiting may be
`more relevant than ever with the changing landscape of can
`-
`cer treatment, as ADCs have also been associated with this
`phenomenon. In addition, ADCs are correlated with improved
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`progression-free survival over older treatment regimens [51],
`leading to an extended treatment duration and increased risk
`of long-delayed, ADC-induced nausea and vomiting. Results
`from DESTINY-Breast04 highlighted that T-DXd–induced nau
`-
`sea and vomiting occurred late with extended duration: the
`median time to onset for nausea was 3 days, and the median
`duration was 10 days; the median time to onset for vomiting
`was 9.5 days, and the median duration was 3 days [41]. This
`late onset and extended duration indicate that patients could
`experience nausea for nearly half of the treatment duration
`while receiving T-DXd. As T-DXd treatment can continue for
`several months until disease progression or the occurrence of
`unacceptable toxicities, this continued nausea increases the
`overall burden for patients. While the reasons for the late
`onset remain unclear, the pharmacokinetic profile of T-DXd,
`with its long half-life and slow release of deruxtecan over time,
`may explain the temporal pattern of nausea and vomiting
`observed in clinical trials [52,53]. Similar to T-DXd, nausea
`and vomiting induced by SG could have a late onset and
`extended duration: the median time to onset for any-grade
`nausea was 8 days, with a median duration of 5.5 days; the
`median time to onset for vomiting was 24.5 days, with
`a median duration of 1.5 days [54].
`3. Preventing nausea and vomiting in the
`long-delayed phase
`The need to optimize nausea and vomiting prophylaxis
`beyond the 5-day overall phase is clear [43,44,54–59].
`However, it remains uncertain what the most effective regi -
`men is to provide long-lasting prophylaxis. While antiemetic
`guidelines provide clear, evidence-based recommendations
`for CINV prophylaxis for the first 120 hours after chemotherapy
`administration, guidance for later periods is lacking
`[10,12,60,61]. In addition, because T-DXd and SG have become
`available only recently, no evidence-based guidance for antie
`-
`metic prophylaxis exists for patients treated with these com -
`pounds. MASCC/ESMO guidelines indicate that no definitive
`antiemetic treatment recommendations can currently be
`made for T-DXd or SG. However, they note that the emeto
`-
`genic potential of these ADCs appears comparable to high-
`dose carboplatin. For carboplatin, MASCC/ESMO guidelines
`recommend a three-drug regimen including an NK 1 RA, a 5-
`HT3 RA, and dexamethasone [11]. NCCN recommends
`a regimen with an NK 1 RA, a 5-HT 3 RA, olanzapine, and dex -
`amethasone for agents with high emetic risk such as T-DXd or
`SG [12] (Figure 2). Identifying the most effective antiemetic
`protocols for patients receiving ADCs, including T-DXd and SG,
`is an unmet need to optimize treatment completion and
`efficacy.
`3.1. NEPA (oral and IV) and fosnetupitant single-agent
`plus palonosetron for prevention of LD-CINV
`NEPA is currently the only available fixed-combination antie -
`metic, composed of an NK 1 RA (netupitant [oral] or fosnetupi -
`tant [intravenous]) and a 5-HT 3 RA (palonosetron). NEPA is
`administered as a single dose prior to chemotherapy, offering
`simplicity and convenience while targeting both main emetic
`pathways for effective CINV prophylaxis [62].
`NEPA may be
`a particularly effective regimen for preventing LD-CINV, given
`the much longer plasma elimination half-life of netupitant (88
`hours) compared to the NK
`1 RA aprepitant (9–13 hours)
`[63,64]. In addition, netupitant has demonstrated a long
`Figure 2. Antiemetic recommendations for patients treated with T-DXd or SG. MASCC/ESMO guidelines recommend a 3-drug regimen including an NK 1-receptor
`antagonist, a 5-HT 3-receptor antagonist, and dexamethasone for patients receiving T-DXd or SG. No dexamethasone (or other antiemetic) should be routinely
`administered after day 1. NCCN guidelines recommend a 4-drug regimen including an NK 1-receptor antagonist, a 5-HT 3-receptor antagonist, dexamethasone, and
`olanzapine as the preferred option for patients receiving T-DXd or SG. Dexamethasone and olanzapine should be routinely administered on days 2–4 as well.
`*Netupitant or fosnetupitant is administered with palonosetron as part of the fixed-dose combination agent NEPA.
`5-HT3: 5-hydroxytryptamine-3; ESMO: European Society for Medical Oncology; MASCC: Multinational Association of Supportive Care in Cancer; NCCN: National Comprehensive Cancer
`Network; NK1: neurokinin-1; SG: sacituzumab govitecan; T-DXd; trastuzumab deruxtecan.
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`duration of receptor occupancy: in the striatum, receptor
`occupancy with netupitant reached 90% as early as 2.2 hours
`after administration and remained >75% after 120 hours; in
`the occipital cortex, the anterior cingulate, and the frontal
`cortex, receptor occupancy remained close to 90% up to
`120 hours postdosing [65]. Another study applied pharmaco -
`dynamic modeling using data from previous pharmacokinetic
`studies to estimate the rate, duration, and extent of NK 1
`receptor occupancy in the striatum up to 240 hours after
`netupitant administration. NK 1 receptor occupancy was pre -
`dicted to reach 90% at 2.2 hours after administration, followed
`by a slow decline after 24 hours to 59% at 240 hours [66,67].
`Patients who experience CINV during days 4 and 5 after
`chemotherapy appear to be at increased risk for LD-CINV
`[46,68], indicating a need for effective control in the histori -
`cally defined delayed phase. Superior outcomes with NEPA
`compared with aprepitant regimens have been observed in
`the delayed phase and significantly fewer patients receiving
`NEPA experienced breakthrough CINV and breakthrough sig -
`nificant nausea on individual days 3–5 following chemother -
`apy [69,70]. Several studies have investigated the efficacy of
`NEPA beyond 120 hours after chemotherapy. All studies dis
`-
`cussed here defined complete response as no emesis and no
`use of rescue medication. Single-dose NEPA was compared to
`a 3-day aprepitant regimen in a pragmatic prospective study
`of patients receiving MEC that included an extended overall
`phase up to 144 hours. Complete response rates were signifi
`-
`cantly higher for patients receiving NEPA than those receiving
`an aprepitant regimen during the extended overall phase (0 -
`–144 hours; 77% vs 58%, p = 0.003). Moreover, in the extended
`delayed phase (>24–144 hours), complete response rates were
`numerically higher for NEPA than the aprepitant regimen (90%
`vs 83%, p = 0.159) [45]. Further, a multicenter, open-label,
`phase 2 study evaluated whether NEPA’s efficacy during
`cycle 1 would be maintained over subsequent cycles in
`patients with breast cancer receiving adjuvant anthracycline
`plus cyclophosphamide. Complete response during the overall
`study period significantly improved even in the LD-CINV set
`-
`ting (during days 6–21) over all treatment cycles [44]. The
`efficacy of a single intravenous dose of fosnetupitant in com -
`bination with palonosetron and dexamethasone was assessed
`in a randomized, double-blind, phase 2 study where nausea
`and vomiting rates were recorded until 168 hours after admin
`-
`istration of cisplatin-based chemotherapy. The complete
`response rate with fosnetupitant was numerically higher
`than with placebo during the extended delayed phase (24–
`-
`168 hours; 75% vs 53%) [58]. The phase 3 CONSOLE study
`compared the efficacy of fosnetupitant and fosaprepitant in
`combination with palonosetron and dexamethasone in
`patients receiving cisplatin-based chemotherapy, assessing
`nausea and vomiting rates until 168 hours after treatment
`administration. Complete response rates for fosnetupitant
`and fosaprepitant were similar during the historically defined
`acute, delayed, and overall phases. However, a significantly
`higher complete response rate was observed for fosnetupitant
`(74%) than fosaprepitant (67%, p = 0.0450) during the
`extended overall phase (0–168 hours) and a nearly significant
`difference was seen between fosnetupitant (87%) and fos