Impact of antiemetic prophylaxis on reducing trastuzumab deruxtecan dose modifications in HER2+/HER2-low breast cancer

ABSTRACT

Background

Avoiding unnecessary dose reductions is important for patients with advanced breast cancer (ABC) receiving trastuzumab deruxtecan (T-DXd). Nausea and vomiting, the most common adverse events of T-DXd, frequently necessitate dose reductions, which may impact treatment benefit.

Methods

This retrospective exploratory study investigated the impact of triple antiemetic regimen (TAR) prophylaxis on T-DXd dose preservation over time. Data from 143 human epidermal growth factor receptor 2 (HER2)-positive or HER2-low ABC patients who received ≥2 T-DXd cycles were stratified based on TAR use in the first cycle. TAR included an NK₁ receptor antagonist, a 5-HT₃ receptor antagonist (or fixed netupitant/palonosetron combination), and dexamethasone.

Results

Patients receiving TAR in the first cycle were significantly less likely to require T-DXd dose reductions in subsequent cycles than the non-TAR group (31.3% vs. 66.7%, P = 0.033). The lowest T-DXd dose relative to initial dose for each patient was significantly higher in the TAR group than in the non-TAR group (100% vs. 80.6%, P = 0.001). There was a trend toward a longer median time to T-DXd dose reduction in the TAR group (15.7 vs. 3.9 months; P = 0.183).

Conclusion

These findings suggest that upfront TAR may help maintain the dosing of T-DXd in patients with HER2-positive or HER2-low ABC.

Plain Language Summary

TTrastuzumab deruxtecan (T-DXd) is an effective treatment for some patients with advanced breast cancer. However, many patients experience side effects, especially nausea and vomiting, which can lead doctors to lower the treatment dose. Reducing the dose may interrupt treatment and affect how long patients can stay on therapy. This study looked at whether using a stronger nausea-prevention approach at the start of treatment could help patients stay on their planned T-DXd dose. Researchers reviewed medical records from 143 patients with HER2-positive or HER2-low advanced breast cancer who received at least two cycles of T-DXd. Patients were grouped based on whether they received a three-drug anti-nausea regimen during their first treatment cycle. This regimen included medications that work in different ways to prevent nausea and vomiting. Patients who received the three-drug anti-nausea regimen during their first cycle were less likely to need a dose reduction later compared with patients who did not receive this approach. They also stayed closer to their original T-DXd dose over time. In addition, patients who received the three-drug regimen tended to go longer before needing any dose reduction. These findings suggest that starting a three-drug anti-nausea regimen at the beginning of T-DXd treatment may help patients better tolerate therapy and maintain their planned dose.

1. Introduction

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-targeting antibody, a cleavable tetrapeptide linker, and a DNA topoisomerase I inhibitor payload, has redefined the treatment landscape for patients with HER2-positive and HER2-low advanced breast cancer (ABC) [1]. Pivotal clinical trials have demonstrated the superior efficacy of T-DXd compared to previous standard therapies, with significant improvements in progression-free survival and overall survival across different patient populations [2–4].

Nausea and vomiting are among the most common adverse events associated with T-DXd, affecting 65.9%–72.8% and 27.2%–44% of patients, respectively [2–5], with grade ≥3 nausea and vomiting reported in approximately 6% and 3% of cases [5]. Furthermore, with their early onset and extended duration, these events were key contributors to T-DXd dose reductions, drug interruptions, and discontinuations, potentially compromising efficacy [5].

Although dose intensity has traditionally been viewed as an important determinant of efficacy with cytotoxic chemotherapy, emerging real-world data suggest that its role in patients receiving T-DXd may differ. A retrospective analysis in an ABC population with high disease burden did not demonstrate a clear association between relative dose intensity and progression-free survival, highlighting the need for further prospective evaluation [6]. Nonetheless, treatment-limiting toxicity remains a common driver of dose modification, and strategies that improve tolerability may help support sustained therapy.

Given the prolonged treatment duration of T-DXd due to its durable efficacy, effective upfront antiemetic prophylaxis is essential for maintaining the planned T-DXd dose and optimizing outcomes. In addition to the intrinsic emetogenic potential of T-DXd, individual patient-related risk factors (such as female sex, younger age, prior nausea history, and history of morning sickness during pregnancy) can further increase susceptibility to chemotherapy-induced nausea and vomiting (CINV), underscoring the importance of tailoring antiemetic prophylaxis accordingly [7,8].

Guidelines for prevention and management of T-DXd-associated nausea and vomiting are continuing to evolve as data emerges [9–11], with most recommending prophylaxis using an NK₁ receptor antagonist (RA)-containing regimen [9,10]. However, the real-world impact of this strategy on T-DXd dose reductions remains unclear. The DESTINY trial protocols lacked standardized guidance on antiemetic prophylaxis, and data on antiemetic regimens were not systematically collected or analyzed in these trials [2–4]. This exploratory study investigated the impact of guideline-recommended antiemetic prophylaxis with triple antiemetic regimen (TAR) during the first treatment cycle on maintaining the planned T-DXd dose over time in patients with HER2-positive or HER2-low ABC.

2. Patients and methods

Patients were eligible for inclusion if they had (1) pathologically confirmed HER2-positive or HER2-low breast cancer, as defined by the American Society of Clinical Oncology/College of American Pathologists guidelines [12]; (2) locoregionally recurrent or metastatic disease (i.e., ABC) not amenable to definitive surgery; and (3) received at least two cycles of T-DXd in a non-trial setting. We extracted data regarding clinicopathologic characteristics, T-DXd dose and duration, and antiemetic prophylaxis regimens from the clinical data warehouse of Samsung Medical Center, capturing all consecutive patients who met these criteria between 29 June 2022 through the data cutoff date of 30 September 2024.

Patients were grouped based on whether they received a guideline-recommended TAR during the first cycle of T-DXd. The TAR included either the fixed combination of netupitant/palonosetron (NEPA) with dexamethasone or a regimen comprising an NK₁ RA, a 5-HT₃ RA, and dexamethasone. In March 2023, our institution implemented a policy recommending triple antiemetic prophylaxis with an NK₁ RA-containing regimen (i.e., NEPA) for all patients receiving T-DXd, reflecting alignment with the updated 2023 National Comprehensive Cancer Network (NCCN) classification of T-DXd as highly emetogenic [3,4,13]. Consequently, the non-TAR group was small and consisted primarily of patients who began T-DXd treatment earlier (i.e., between 29 June 2022 and 27 February 2023) than the majority of those receiving TAR (i.e., between 16 September 2022 and 9 September 2024). Each T-DXd treatment cycle was categorized into one of three standard dose levels (5.4 mg/kg, 4.4 mg/kg, or 3.2 mg/kg) based on the closest dose per weight. A T-DXd dose reduction event was defined as a decrease from 5.4 mg/kg to either 4.4 mg/kg or 3.2 mg/kg, or from 4.4 mg/kg to 3.2 mg/kg.

We used Fisher’s exact test for the association between categorical variables and the Mann-Whitney U test to compare continuous variables between groups. Time to T-DXd dose reduction (defined as the interval from the first T-DXd administration to the first dose reduction) was estimated using the Kaplan-Meier method. Data for patients without dose reduction were censored at the last T-DXd administration. The Gehan-Wilcoxon test was used for comparison of time to T-DXd dose reduction. All tests were two-tailed, with P values less than 0.05 considered significant. R (version 4.3.2) was used for all statistical analyses.

The study protocol was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB approval number, 2025–02-094). Patient consent was waived due to the study’s retrospective nature, use of de-identified data, and lack of patient interaction. The study adhered to the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization.

3. Results

Between 29 June 2022 and 30 September 2024, 143 patients with HER2-positive or HER2-low ABC received a median of 6 (range, 2–36) cycles of T-DXd. All patients were female. HER2-positive and HER2-low ABC accounted for 100 (69.9%) and 43 (30.1%) patients, respectively (Table 1). Seventy-seven patients (53.8%) had hormone receptor-positive tumors. Most patients received T-DXd as a third (n = 26, 18.2%) or fourth or later (n = 91, 63.6%) line of systemic treatment. T-DXd was administered at a starting dose of 5.4 mg/kg in 110 (76.9%) patients, while 28 (19.6%) and 5 (3.5%) patients received a reduced starting dose of 4.4 mg/kg and 3.2 mg/kg, respectively.

Table 1.

Patient characteristics.

Characteristics	Overall (N = 143)	Triple antiemetic regimen (TAR) (N = 134)	No TAR (N = 9)	P valuea
Age at the start of T-DXd				0.644
Median (range)	54 (28–83)	55 (30–83)	50 (28–68)
HER2 status				0.057
HER2-positive	100 (69.9%)	91 (67.9%)	9 (100%)
HER2-low	43 (30.1%)	43 (32.1%)	0 (0%)
Hormone receptor status				1
ER-positive, PgR-positive, or both	77 (53.8%)	72 (53.7%)	5 (55.6%)
ER-negative and PgR negative	66 (46.2%)	62 (46.3%)	4 (44.4%)
Line of T-DXd				0.448
1st	2 (1.4%)	2 (1.5%)	0 (0%)
2nd	24 (16.8%)	24 (17.9%)	0 (0%)
3rd	26 (18.2%)	25 (18.7%)	1 (11.1%)
4th or later	91 (63.6%)	83 (61.9%)	8 (88.9%)
Initial T-DXd dose				0.34
5.4 mg/kg	110 (76.9%)	103 (76.9%)	7 (77.8%)
4.4 mg/kg	28 (19.6%)	27 (20.1%)	1 (11.1%)
3.2 mg/kg	5 (3.5%)	4 (3%)	1 (11.1%)
Smoking history				1
Current smoker	2 (1.4%)	2 (1.5%)	0 (0%)
Previous smoker	6 (4.2%)	6 (4.5%)	0 (0%)
Never-smoker	50 (35%)	47 (35.1%)	3 (33.3%)
Not recorded	85 (59.4%)	79 (59%)	6 (66.7%)

^aDerived from comparison between the TAR and non-TAR groups.

Abbreviations: TAR, triple antiemetic regimen; T-DXd, trastuzumab deruxtecan; HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; PgR, progesterone receptor.

Prophylactic TAR was administered to 134 (94%) patients during the first T-DXd cycle; most received NEPA with dexamethasone (n = 127), while the remaining seven received a regimen comprising an NK₁ RA (either fosaprepitant or aprepitant), a 5-HT₃ RA, and dexamethasone (Table 2). Nine (6%) patients who did not receive TAR initially received palonosetron with or without dexamethasone. Baseline characteristics were comparable between the TAR and non-TAR groups (Table 1). As a result of an institutional policy recommending NEPA for all T-DXd recipients unless contraindicated, the non-TAR patients were those who began T-DXd treatment earlier than TAR patients (median first cycle: 19 January 2023, vs. 22 May 2024). All patients with HER2-low disease received TAR from their first T-DXd cycle, as they started treatment after its approval for this indication in Korea on 20 May 2024, aligning with both the NEPA policy and the timing of HER2-low approval.

Table 2.

Antiemetic regimen used during the first cycle of T-DXd.

Antiemetic regimen	First cycle with TAR (N = 134)	First cycle without TAR (N = 9)
NEPA + Dexamethasone	121 (90.3%)	0 (0%)
NEPA + Granisetron patch + Dexamethasone	5 (3.7%)	0 (0%)
NEPA + Granisetron patch + Ondansetron IV + Dexamethasone	1 (0.7%)	0 (0%)
Fosaprepitant + Palonosetron + Dexamethasone	4 (3.0%)	0 (0%)
Fosaprepitant + Granisetron IV + Dexamethasone	1 (0.7%)	0 (0%)
Fosaprepitant + Granisetron patch + Dexamethasone	1 (0.7%)	0 (0%)
Aprepitant + Palonosetron + Dexamethasone	1 (0.7%)	0 (0%)
Palonosetron + Dexamethasone	0 (0%)	5 (55.6%)
Palonosetron + Ramosetron PO	0 (0%)	3 (33.3%)
Palonosetron	0 (0%)	1 (11.1%)

Abbreviations: IV, intravenous; PO, oral; T-DXd, trastuzumab deruxtecan; TAR, triple antiemetic regimen; NEPA, netupitant/palonosetron.

Patients who received TAR during the first cycle were significantly less likely to require T-DXd dose reductions during subsequent cycles than those who did not (42/134 [31.3%] vs. 6/9 [66.7%] with dose reduction, P = 0.033; Figure 1(a)). The lowest T-DXd dose each patient received throughout the study period relative to their initial dose was significantly higher in the TAR group than in the non-TAR group (100% vs. 80.6%, P = 0.001; Figure 1(b)). Among patients who required a T-DXd dose reduction, nausea or vomiting was documented at or before the reduction in 4 of 6 (66.7%) patients in the non-TAR group, compared with 13 of 42 (31.0%) patients in the TAR group. Although the median time to T-DXd dose reduction was longer in the TAR group (15.7 months; 95% confidence interval [CI], 4.1–not reached) than in the non-TAR group (3.9 months; 95% CI, 0.7–not reached), this difference was not statistically significant (P = 0.183; Figure 2).

Figure 1.

Proportions of patients who underwent dose reductions (a) and The lowest T-DXd dose received during the treatment period relative to the initial dose (b). The black bar shows the median dose reduction. The lower and upper hinges of the box plots correspond to the first and third quartiles, respectively. The upper whisker extends from the hinge to the largest value that is no more than 1.5 times IQR from the hinge. The lower whisker extends from the hinge to the smallest value that is no more than 1.5 times the IQR from the hinge.

Abbreviations: T-DXd, trastuzumab deruxtecan; TAR, triple antiemetic regimen; IQR, inter-quartile range.

Figure 2.

Time to T-DXd dose reduction. Data for patients without dose reduction were censored at the last T-DXd administration.

Abbreviations: T-DXd, trastuzumab deruxtecan; TAR, triple antiemetic regimen; HR, hazard ratio; CI, confidence interval.

At the data cutoff (30 September 2024), no patients discontinued T-DXd due to intractable nausea and/or vomiting; 101 (71%) continued to receive T-DXd, while 27 (19%), 6 (4%), 5 (4%) and 2 (1%) patients discontinued due to disease progression, death, pneumonia/pneumonitis, or liver cirrhosis, respectively. Two (1%) patients were lost to follow-up.

4. Discussion

In this real-world retrospective study, guideline-recommended TAR as primary antiemetic prophylaxis was associated with a lower frequency of T-DXd dose reductions and sustained dose in patients with HER2-positive or HER2-low ABC. More than two-thirds of patients who received TAR in the first cycle maintained their initial T-DXd dose throughout treatment, whereas two-thirds of those without TAR required dose reductions. Time-to-event analysis showed a four-fold longer time to dose reduction in the TAR group, though this difference was not statistically significant due to the small sample size in the non-TAR group.

Maintaining relative dose intensity has traditionally been associated with improved long-term outcomes in patients receiving cytotoxic chemotherapy for ABC [14–16], although emerging real-world data suggest this relationship may differ in patients treated with T-DXd. In a pooled analysis of seven T-DXd clinical trials, nausea and vomiting led to dose reductions in 4.8% and 1.4% of patients, respectively [5]. However, given the stringent eligibility criteria and treatment protocols and limited antiemetics information in clinical trials, these rates may underestimate real-world incidence, as evidenced by a recent study [17]. In our study, 48 patients (33.6%) experienced T-DXd dose reductions, underscoring the need to further optimize adverse event prevention and management strategies. Our findings suggest that upfront TAR may be an effective strategy to help support maintenance of the planned T-DXd dose.

As cancer therapies evolve, supportive care must advance alongside them. Early experience with ADCs shaped expectations: trastuzumab emtansine, the first ADC approved for solid tumors, caused minimal nausea and vomiting, leading many to assume that newer ADCs would have similar profiles. In early T-DXd trials, antiemetic use was optional and left to investigator judgment, which may have underestimated the impact of nausea and vomiting on quality of life and treatment adherence. With increasing real-world experience, it became clear that a standard 2-drug regimen was insufficient for many patients receiving T-DXd, prompting broader adoption of a guideline-based 3-drug approach for more effective control. In March 2023, following NCCN’s classification of T-DXd as highly emetogenic, our institution implemented a policy recommending NEPA plus dexamethasone as the standard antiemetic regimen for patients receiving T-DXd, due to its convenient dosing and superior efficacy in preventing nausea and vomiting over a 5-HT₃ RA plus dexamethasone [18–20]. Consequently, most patients in the TAR group received NEPA, while the non-TAR group remained small. It should be also noted that 8 of 9 patients initially on a non-TAR regimen later switched to NEPA. Netupitant has a longer half-life and prolonged receptor occupancy compared to aprepitant, potentially providing extended protection against nausea and vomiting [21]. Our findings offer clinical support for this favorable pharmacokinetic profile.

Limitations of this study include its retrospective single-center design, the small sample size in the non-TAR group, and the relatively short follow-up for patients in the TAR group due to later initiation of T-DXd. The imbalance between groups (n = 9 non-TAR vs. n = 134 TAR) limits statistical power to detect differences and reduces the generalizability of the findings. We also lacked detailed data on the specific reasons for T-DXd dose reductions, which could have influenced dose-reduction patterns. Additionally, patients starting at a reduced T-DXd dose of 3.2 mg/kg (n = 5) had no further reduction options, potentially confounding the analysis. Because our study focused on antiemetic use during the first cycle, the impact of regimen changes at later cycles remains unclear. Interpretation of these findings is further limited by potential temporal bias, as an institutional policy mandating TAR use was introduced during the study period. Despite these limitations, this is the first study exploring the association between antiemetic prophylaxis regimen and T-DXd dose preservation in ABC patients.

5. Conclusion

Our findings of this retrospective study generate the hypothesis that early use of TAR during the first cycle may be associated with better maintenance of T-DXd dosing. To confirm this hypothesis, larger prospective studies, including both observational cohort and interventional designs, are currently in development.

Funding Statement

This paper was not funded.

Article highlights

• Avoiding unnecessary dose reductions is an important clinical consideration for patients with advanced breast cancer (ABC) receiving trastuzumab deruxtecan (T-DXd). Nausea and vomiting are the most frequently reported adverse events with T-DXd and often necessitate dose reductions, which may compromise treatment efficacy.

• This retrospective real-world analysis investigated the impact of triple antiemetic regimen (TAR) prophylaxis in the first cycle on maintaining the planned T-DXd dose over time in patients with human epidermal growth factor receptor 2 (HER2)-positive and HER2-low ABC.

• Patients (n = 143) were grouped based on the use of TAR in the first cycle of T-DXd; TAR consisted of either the fixed combination of netupitant/palonosetron (NEPA) or the combination of a different NK₁ receptor antagonist (RA) and a 5-HT₃ RA, both plus dexamethasone.

• Results showed that patients who received TAR during the first cycle were significantly less likely to require T-DXd dose reductions during subsequent cycles than those who did not.

• The lowest T-DXd dose each patient received relative to their initial dose was also significantly higher in the TAR group than in the non-TAR group.

• This is the first study to explore an association between antiemetic prophylaxis and T-DXd dose preservation in ABC patients.

• Our findings raise the clinically plausible hypothesis that administering TAR during the first cycle may help maintain the planned T-DXd dose and improve clinical outcomes; however, prospective studies are needed to confirm this.

Author contributions

Junghoon Shin and Yeon Hee Park contributed to the study design, conduct, and data collection; analysis and interpretation; and writing and reviewing the manuscript Ji-Yeon Kim, Hee Kyung Ahn, Jin Seok Ahn contributed to data collection, interpretation of data, and writing and reviewing the manuscript. All authors gave their final approval of the manuscript to be submitted. Junghoon Shin and Yeon Hee Park have full access to all the study data and take responsibility for the integrity of the data and the accuracy of analysis.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Editorial assistance was provided by Jennifer Vanden Burgt, an independent consultant from Minneapolis, MN, and funded by Helsinn Healthcare SA, Lugano, Switzerland.

Reviewer disclousres

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethical declaration

The study protocol was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB approval number, 2025–02-094). Patient consent was waived due to the study’s retrospective nature, use of de-identified data, and lack of patient interaction. The study adhered to the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author, Yeon Hee Park. The data are not publicly available due to privacy and ethical considerations.