Should we not use neurokinin-1 receptor antagonists in the prevention of trastuzumab deruxtecan-induced nausea and vomiting?—Putting the results of the ERICA study into perspective

Approximately 15% of all breast cancers and 15–20% of early-stage breast cancers are driven by human epidermal growth factor receptor 2 (HER2) (1). Intense research efforts have led to an ever-expanding armamentarium of HER2-targeted agents that have helped to dramatically improve survival in patients with this aggressive disease (2). The novel HER2-targeted agent, trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate that contains a tumor-targeting antibody covalently bound to the topoisomerase I inhibitor, deruxtecan (payload) via a cleavable tetrapeptide-based linker (2). The development of T-DXd has led to substantial changes in the management not only of patients with HER2-positive advanced breast cancer but also of a subgroup of patients with HER2-low disease (defined as HER2 1+ positive staining by immunohistochemistry or 2+ in the absence of HER2 gene amplification by in situ hybridization) (2). Despite the impressive clinical activity of single-agent T-DXd in multiple pivotal trials, its toxicity profile can be challenging, with nausea and vomiting being commonly reported adverse events for this agent (3).

The recently published results of the ERICA study represent the first prospective data from a randomized, placebo-controlled trial evaluating the antiemetic benefit in the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with HER2-positive or HER2-low breast cancer undergoing T-DXd therapy (4). Patients in the intervention group received olanzapine (5 mg orally on days 1–6), and a 5-hydroxytryptamine type 3 receptor antagonist (5-HT₃RA), mainly the long-acting agent palonosetron, with dexamethasone (DEX) on day 1, while patients in the reference group received placebo (day 1 through day 6), a 5-HT₃RA, and DEX before chemotherapy initiation. The study met its primary efficacy endpoint, with a significantly higher rate of complete response (CR; defined as no vomiting and no use of rescue medication) in the olanzapine group (70%) than in the placebo group (56%) during the delayed phase (day 2 through day 5) in cycle 1. Interestingly, a significant incremental benefit in CINV control was seen during the persistent phase (day 6 through day 21), with a CR rate of 64% in the olanzapine group versus 44% in the placebo group. The proportion of nausea-free patients was also significantly higher in the olanzapine group than in the placebo group during the delayed phase (57.5% vs. 38%) and the persistent phase (51% vs. 32%). When interpreting the clinical relevance of these results, we should keep in mind that in a recent meta-analysis, the estimated pooled prevalence of nausea and vomiting caused by T-DXd was 76% and 47%, respectively (5). Thus, the meta-analysis indicates that vomiting occurred in roughly one in 2 patients undergoing T-DXd, whereas the ERICA study shows that roughly one in 3 patients treated with olanzapine experienced vomiting and/or took rescue medications in the delayed phase. In addition, the findings regarding nausea control in the olanzapine-treated group are encouraging, as this highly subjective symptom remains a clinical challenge (6). However, we should not overlook that in the ERICA study, nausea still occurred in up to 43% of patients treated with olanzapine during the delayed phase. The pharmacological properties of T-DXd also deserve special consideration when dealing with the prevention of CINV. While T-DXd achieves a long half-life of about 6 days, the linker-payload system enables conjugation with 8 molecules of DXd per antibody (2). The linker is selectively cleaved by lysosomal enzymes, releasing the potent cytotoxic payload preferentially inside tumor cells (2). Despite this, the high membrane permeability of DXd enables release of the payload from the target cell to the extracellular space, leading to the death of surrounding cancer cells (bystander effect) (2). It can be speculated that the long half-life of T-DXd as well as the high membrane permeability of DXd could contribute to both increasing and prolonging patient exposure to the cytotoxic payload released into the plasma. Consequently, this could result in the occurrence of off-target toxicities such as nausea and vomiting. Therefore, evaluating antiemetic benefit also in the persistent phase should be considered a rational approach when designing prospective randomized trials to improve the control of CINV in patients treated with T-DXd.

Although the study design attempts to account for the atypical pattern of onset and persistence of CINV caused by T-DXd, the implications of the ERICA study results for clinical practice should not be overstated, as they represent only a first step forward in pursuing adequate antiemetic coverage in this challenging setting of CINV. It is well known that some patient-related risk factors may also impact the development of CINV, including female sex, younger age, previous history of nausea/vomiting, no history of alcohol use, and prior motion or morning sickness (7). In light of this, it is likely that when clinicians manage breast cancer patients in routine practice, the incidence rates of nausea and vomiting reported in the pivotal clinical trials provide only an approximate representation of the actual emetogenicity of T-DXd. Although subgroup analyses were pre-planned in the ERICA study, the small sample size limits the statistical power of any comparisons to assess the impact of patient-related risk factors for CINV on study outcomes. Based on the currently available evidence, antiemetic guidelines published by the Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO), and the American Society of Medical Oncology (ASCO) have classified T-DXd as moderately emetogenic chemotherapy (MEC) (8,9). Conversely, the National Comprehensive Cancer Network (NCCN) expert panel chose to classify T-DXd as highly emetogenic chemotherapy, similar to the combination of an anthracycline and cyclophosphamide (AC) which is commonly used in the management of breast cancer (10). Regardless of the discrepancy in the emetic-risk category of T-DXd, clinicians should always consider that breast cancer affects a patient population that is inherently at higher risk of developing CINV since nearly all patients are women and approximately one-quarter of breast cancers are diagnosed in patients younger than 50 years of age (11). In the ERICA study, the majority of patients (65%) were 55 years of age or older, while 34% of patients had de novo metastatic disease. Notably, the therapeutic benefit of HER2-targeted agents is reflected in an increased rate of patients initially presenting with de novo metastatic breast cancer in the overall patient population with HER2-positive metastatic disease. Results from a prospective US registry indicate that in a real-world population, nearly half of patients with HER2-positive metastatic breast cancer are currently diagnosed de novo, and a greater proportion of patients with de novo metastatic disease than recurrent disease are younger than 50 years of age (12). The overall shift in the natural history of patients with de novo or recurrent HER2-positive metastatic breast cancer is expected to change the number of patients at higher risk of developing CINV when treated with T-DXd. Interestingly, the MASCC/ESMO guidelines now recommend a three-drug regimen containing an NK-1RA for the prevention of CINV caused by oxaliplatin-based MEC only in women younger than 50 years (8). This highlights the strong impact of both female sex and younger age on the emetogenicity of a moderate-emetic-risk agent with a known potential for delayed CINV.

Regardless of the influence of any patient-related factor for CINV, we should consider that, even with the three-drug prophylactic regimen containing olanzapine, the CR rate is 70% in the ERICA study, supporting the view that the emetogenic potential of T-DXd may be at the higher end of the moderate category. The recently updated MASCC/ESMO guidelines not only have highlighted the need to carry out prospective studies on CINV due to T-DXd but also have emphasized that the emetogenicity of the agent appears to be comparable to that of carboplatin (8). Consequently, the guidelines suggest preventing CINV caused by T-DXd as for carboplatin area under the curve (AUC) ≥5, for which an NK-1RA-containing three-drug combination is recommended (8). Since the emetogenic potential of T-DXd may be underestimated, it is likely that a substantial number of patients in the real world may require more antiemetic prophylaxis than they would receive if the guideline-recommended two-drug regimen for MEC was used, regardless of olanzapine administration. Adding an NK-1RA to the 5-HT₃RA/DEX/olanzapine prophylactic regimen might maximize response rates during the standard overall phase of CINV (day 1 through day 5) after T-DXd administration, but the hypothesis needs to be tested in a well-designed randomized trial. Although CR rates in the standard overall phase were not reported for the ERICA study, an improvement in the proportion of patients achieving overall CR may represent an important clinical goal for two reasons. First, antiemetic failure occurring in the standard overall phase is a risk factor for the development of CINV in the chemotherapy cycles following cycle 1 (11). Therefore, an appropriate prophylactic strategy should maximize the likelihood of achieving CR in the standard overall phase through the use of the most effective antiemetic regimen from the beginning of chemotherapy. Second, in breast cancer patients who received a three-drug combination containing an NK-1RA, palonosetron, and single-dose DEX against CINV due to the AC combination, achieving a CR in the standard overall phase was associated with significantly better control of vomiting and/or more than mild nausea occurring on days 6–21 (i.e., fewer CR failures) over all planned chemotherapy cycles (13). Therefore, in the high-emetic-risk setting of AC, patients who achieve CR in the standard overall phase are more likely to maintain response also in the persistent phase of the chemotherapy cycle.

It is remarkable that in the ERICA study, only a non-significant 8% risk difference in CR rates was observed between treatment groups over the overall phase (i.e., acute + delayed + persistent phases) in cycle 1 (4). This finding supports the suggestion that the addition of an NK-1RA to a three-drug regimen containing olanzapine may achieve a higher rate of CR in both the overall and persistent phases.

In summary, the results of the ERICA study reliably indicate that an olanzapine-containing three-drug regimen is effective in improving the control of CINV in breast cancer patients treated with T-DXd. However, we must be aware that this antiemetic coverage could be suboptimal in a substantial number of patients due to the high emetogenic potential of this agent. Since in the real world a large number of breast cancer patients are expected to receive treatment with T-DXd, well-designed and adequately powered studies are urgently needed to investigate which patient populations might benefit from the use of an NK-1RA. In the meantime, careful clinical judgment is needed in tailoring the most effective antiemetic regimen for individual patients who are scheduled to receive T-DXd. It is critical that patient-related risk factors, such as younger age, prior history of nausea/vomiting, no history of alcohol consumption, and prior morning sickness or motion sickness, drive decision-making about the choice of enhancing antiemetic coverage through the use of an NK-1RA.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-5/coif). L.C. has received consulting fee from Italfarmaco and honoraria for presentations from Berlin-Chemie and Helsinn. The author has no other conflicts of interest to declare.

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