Abstract PO1-12-09: Doublet or triplet antiemetic prophylaxis for trastuzumab deruxtecan-induced nausea and vomiting: An open-label, randomized, multicenter, exploratory phase 2 study

Abstract Background: Trastuzumab deruxtecan (T-DXd) is classified as an anticancer agent that poses a moderate emetic risk according to international guidelines for antiemetic therapy, which recommend emesis prophylaxis using a two-drug combination therapy comprising 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA) and dexamethasone (DEX). The incidence rates of nausea and vomiting in patients in DESTINY BREAST01 and DESTINY BREAST03 were 77.7%, 45.7%, 72.8%, and 44%, respectively. However, no effective antiemetic therapy was observed. The high nausea and vomiting incidence associated with T-DXd is problematic. Hence, this exploratory phase 2 study aimed to assess the efficacy and safety of treatment with 5-HT3RA and DEX, with or without a neurokinin-1 receptor antagonist (NK1RA), in preventing T-DXd-induced nausea and vomiting. Methods: We conducted an open-label, randomized exploratory phase 2 study at 14 centers in Japan. Patients with breast cancer scheduled to receive T-DXd were enrolled in this study. Patients were randomly assigned to receive granisetron and dexamethasone (arm GD) or granisetron, dexamethasone, and aprepitant (fosaprepitant; arm GDA). Patients in both treatment arms were administered granisetron (1 mg i.v. 30 min before T-DXd on day 1). Those in the GD arm were administered DEX (6.6 mg i.v. 30 min before T-DXd on day 1 and 8 mg p.o. on days 2–3). The patients in the GDA arm were administered DEX (9.9 mg i.v. 30 min before T-DXd on day 1) and NK1-RA (125 mg of aprepitant p.o. 60 min before chemotherapy on day 1 and 80 mg p.o. on days 2 and 3, or 150 mg fosaprepitant i.v. 60 min before T-DXd on day 1). The primary endpoint was complete response (CR; no emesis or rescue therapy) during the overall phase (0–120 h after the start of T-DXd). The primary endpoint was estimated using the CR rate and 95% confidence intervals (CIs) following the Pearson–Clopper method. The Cochran–Mantel–Haenszel test was used to compare the exploratory results between the two treatment arms with age strata and previous experience with chemotherapy-induced nausea and vomiting. Logistic regression analyses were performed to determine the risk factors associated with the non-achievement of CR, non-achievement of complete control (CC), and non-achievement of total control (TC) in the overall and long-overall phases. Results: Between September 2020 and March 2023, 40 patients were enrolled and randomly assigned to either the GD (n = 19) or GDA (n = 21) arm. In the GDA group, one patient who did not complete the rescue medication listed in the diary was excluded from the efficacy analysis, including rescue medication use. The CR rates during the overall phase were 36.8% and 70.0% in the GD and GDA groups, respectively (odds ratio OR, 0.1334; 95% confidence interval CI, 0.0232–0.7672; P = 0.0190), with a difference of 33.2%. The CR rates during the long-overall phase were 31.6% in the GD arm and 70.0% in the GDA arm (OR, 0.1073; 95% CI, 0.0185–0.6239; P = 0.0087), a difference of 38.4%. NK1RA use was associated with a significant decrease in the non-achievement of CR, CC, and TC in the overall and long-overall phases. Only patients in the GDA arm (33.3%) reported being “very satisfied” with the treatment. No grade 3 or 4 toxicities related to antiemetic therapy were observed. Conclusions: Breast cancer patients receiving T-DXd require triple therapy, including mandatory NK1RA administration, for antiemetic prophylaxis. Further investigation is needed to explore the development of more appropriate combination therapies for T-DXd-induced nausea and vomiting. Citation Format: Manabu Futamura, Hirotoshi Iihara, Hiroko Bando, Yoshihiro Kawaguchi, Yutaka Mizuno, Akari Murakami, Masaaki Kawai, Tomokazu Iyoda, Kazshige Ishida, Kazuhiro Ishihara, Takumi Nakada, Makoto Takeuchi, Mika Kitahora, Yoshihisa Tokumaru, Mototsugu Shimokawa, Nobuhisa Matsuhashi. Doublet or triplet antiemetic prophylaxis for trastuzumab deruxtecan-induced nausea and vomiting: An open-label, randomized, multicenter, exploratory phase 2 study abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-09.