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Editor’s Note: Novel HER2 antibody-drug conjugates (ADCs) have profoundly changed the clinical practice of breast cancer treatment, and managing their adverse reactions is a concern for clinicians. Although nausea and vomiting caused by novel HER2 ADCs in clinical trials are mostly mild adverse events, current international guidelines classify T-DXd as an anti-tumor drug with moderate to high emetic risk, and some patients may require effective antiemetic and prophylactic treatment regimens. A randomized, double-blind, placebo-controlled phase II trial (ERICA study) published in the Annals of Oncology explored the use of olanzapine-based prophylactic antiemetic therapy in patients treated with such novel HER2 ADCs, showing positive results.
Study Background
T-DXd (trastuzumab deruxtecan) is an antibody-drug conjugate targeting HER2, which has become the standard treatment for HER2-positive (IHC 3+ or IHC 2+/ISH+) and HER2-low expressing (IHC 1+ or IHC 2+/ISH-) unresectable or metastatic breast cancer. Nausea and vomiting are common adverse events associated with T-DXd. In clinical trials related to T-DXd, the incidence of any grade of nausea and vomiting ranged from 65.9% to 77.7% and 27.2% to 45.7%, respectively.[2-5] Although the proportion of treatment interruptions due to nausea and vomiting is low, these symptoms can still significantly impact patients’ quality of life. In the DESTINY-Breast04 study, the median duration of initial nausea and vomiting caused by T-DXd was 10 days and 3 days, respectively, indicating a certain degree of “persistence” of these symptoms.[6] Currently, the NCCN clinical practice guidelines classify T-DXd as a high emetic risk anticancer drug, while the MASCC/ESMO and JSCO guidelines classify it as a moderate emetic risk drug, similar to carboplatin.[7-9].
Olanzapine is an atypical antipsychotic that has shown good efficacy in treating chemotherapy-induced nausea and vomiting. Olanzapine exerts its therapeutic effects on refractory nausea and vomiting by blocking various neurotransmitter receptors, including dopamine D1-4 receptors, serotonin 5-HT2A, 5-HT2C, 5-HT3, and 5-HT6 receptors. Previous studies have shown that olanzapine at doses of 5 mg and 10 mg is equally effective in preventing chemotherapy-induced nausea and vomiting, but the 5 mg dose has a lower incidence of adverse events.[10-11] Additionally, lower doses of olanzapine have been shown to reduce the risk of delayed nausea and vomiting in Japanese patients undergoing highly emetogenic chemotherapy.[12].
Study Methods
The ERICA study is a multicenter, randomized, double-blind, placebo-controlled phase II trial designed to evaluate the efficacy and safety of olanzapine in preventing delayed and persistent nausea and vomiting caused by T-DXd treatment. Patients were randomly assigned to receive either olanzapine 5 mg or placebo once daily from day 1 to day 6, along with a serotonin 3 receptor antagonist and dexamethasone. The researchers defined three periods for the occurrence of nausea and vomiting:
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Acute phase, 0-24 hours after T-DXd administration;
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Delayed phase, 24-120 hours after T-DXd administration;
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Persistent phase, 120-504 hours after T-DXd administration.
The primary endpoint of the study was the complete response (CR) rate during the delayed phase. Secondary endpoints included CR rates during the acute phase, persistent phase, and overall, as well as the rates of no nausea during each period.
Study Results
From November 2021 to September 2023, a total of 168 patients were enrolled from 43 research centers in Japan. Among them, 162 patients (80 in the olanzapine group and 82 in the placebo group) were included in the per-protocol set (PPS). The median age of patients was 60 years (olanzapine group) and 57 years (placebo group), and nearly all patients were female. In the 162 patients in the PPS, 61.1% (99 patients) were HER2 positive, and 38.9% (63 patients) were HER2 low expressing. Approximately 50% of patients in both groups received T-DXd as second or third-line treatment for metastatic disease.
Primary Endpoint: CR Rate during the Delayed Phase
In the delayed phase, the CR rate in the olanzapine group was significantly higher than that in the placebo group. Specifically, 70.0% (56/80) of patients in the olanzapine group achieved CR, compared to 56.1% (46/82) in the placebo group, with a difference of 13.9%, and a two-sided 60% confidence interval of 6.9% to 20.7% (P=0.047). This result indicates that olanzapine has a significant advantage in preventing delayed nausea and vomiting caused by T-DXd.
Pre-planned subgroup analyses showed that in the delayed phase, the olanzapine group consistently demonstrated better results across all major subgroups, although caution is needed in interpreting results due to the small number of patients in some subgroups. For example, in HER2 positive patients, the CR rate in the olanzapine group was 72.5% (37/51), while in the placebo group it was 58.3% (28/48); in HER2 low expressing patients, the CR rate in the olanzapine group was 62.1% (18/29), compared to 50.0% (17/34) in the placebo group.
Logistic regression analysis did not identify any prognostic or predictive factors for CR in the delayed phase. This suggests that individual differences among patients may have a minimal impact on treatment response in the current study, and the efficacy of olanzapine may be more consistent.
Secondary Endpoints
In the persistent phase, the CR rate in the olanzapine group was also higher than that in the placebo group (63.9% vs 44.4%), with a difference of 19.4% (95% CI: 2.4% to 35.3%).
In the delayed phase, the no nausea rate in the olanzapine group was 57.5% (46/80), while in the placebo group it was 37.8% (31/82), with a difference of 19.7% (95% CI: 3.1% to 34.6%). In the persistent phase, the no nausea rates were 51.4% (37/72) and 31.9% (23/72), respectively, with a difference of 19.4% (95% CI: 2.9% to 35.1%).
Furthermore, throughout the 21-day observation period, the daily CR rate and no nausea rate in the olanzapine group were significantly higher than those in the placebo group; the complete control (CC) rate and overall control (TC) rate for these symptoms also showed similar beneficial trends, indicating the sustained efficacy of olanzapine throughout the treatment cycle.
△ CR rates, no nausea rates, TC rates, and CC rates in the olanzapine and placebo groups in the PPS population
△ Daily CR rates (A) and no nausea rates (B) in both groups
Patient-Reported Outcomes
According to patient-reported adverse events (PRO-CTCAE) assessments, the incidence of appetite loss in the olanzapine group was lower (any grade: 60.0% vs 80.7%), and the interference with daily activities was also less (any grade: 41.3% vs 73.5%). Additionally, the incidence of diarrhea in the olanzapine group was lower (any grade: 51.3% vs 67.5%), indicating a potential advantage of olanzapine in improving overall patient symptoms.
Safety
In terms of safety, the adverse events in the olanzapine group were primarily drowsiness (25.0%) and hyperglycemia (7.5%), both of which were low-grade, with no events of grade ≥3. In contrast, the incidence of drowsiness in the placebo group was 10.8%, with no hyperglycemia reported. Furthermore, the incidence of appetite loss (26.3% vs 45.8%) and diarrhea (7.5% vs 19.3%) in the olanzapine group was also lower than that in the placebo group, consistent with the PRO-CTCAE assessment results.
△ Any grade and ≥3 grade adverse events in the safety analysis set
Study Conclusion
This double-blind randomized controlled study observed nausea and vomiting symptoms related to T-DXd treatment at different periods for intervention. The results indicate that the combination of olanzapine 5 mg with serotonin 3 receptor antagonists and dexamethasone shows good efficacy and acceptable safety in preventing delayed and persistent nausea and vomiting caused by T-DXd treatment. These results suggest that olanzapine can serve as an effective preventive measure to improve the quality of life for patients receiving T-DXd treatment. Further research is needed to confirm the efficacy and safety of olanzapine in different types of cancer patients and to explore the optimal use of olanzapine in preventing and treating nausea/vomiting in patients undergoing T-DXd treatment.
References
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[1] Sakai H, Tsurutani J, Ozaki Y, et al. A randomized, double-blind, placebo-controlled phase II study of olanzapine-based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B). Ann Oncol. 2025;36(1):31-42. doi:10.1016/j.annonc.2024.09.001
[2] Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12): 1143-1154.
[3] Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20.
[4] Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med.2019;382(7):610-621.
[5] Fehm T, Cottone F, Dunton K, et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2024;25(5):614-625.
[6] Rugo HS, Jacot W, Tokunaga E, et al. 185O Trastuzumab deruxtecan (TDXd) vs treatment of physicians’ choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): a detailed safety analysis of the randomized, phase III DESTINY-Breast04 trial. ESMO Open. 2023;8(1):101374.
[7] NCCN Clinical Practice Guidelines in Oncology. Antiemesis. Available at https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Accessed July 20, 2024.
[8] 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(2):102195. doi:10.1016/j.esmoop.2023.102195.
[9] Iihara H, Abe M, Wada M, et al. 2023 Japan Society of Clinical Oncology Clinical Practice Guidelines update for antiemesis. Int J Clin Oncol. 2024;29(7):873-888.
[10] Chow R, Navari RM, Terry B, et al. Olanzapine 5 mg vs 10 mg for the prophylaxis of chemotherapy-induced nausea and vomiting: a network meta-analysis. Support Care Cancer. 2022;30(2):1015-1018.
[11] Yanai T, Iwasa S, Hashimoto H, et al. A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy. Int J Clin Oncol. 2018;23(2):382-388.
[12] 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(2):242-249.
(Source: Editorial Department of Oncology Outlook)
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