September 18, 2024
By Catlin Nalley
A new analysis suggests that olanzapine (5 mg for 6 days) coupled with 5-hydroxytryptamine type 3-receptor antagonist (5-HT3RA) and dexamethasone is an effective approach to reduce delayed and persistent nausea and vomiting among metastatic breast cancer patients treated with trastuzumab deruxtecan (T-DXd). These findings were recently presented during ESMO 2024 in Barcelona (Abstract 1816O) and simultaneously published in the Annals of Oncology (2024; doi:10.1016/j.annonc.2024.09.001).
“Nausea and vomiting are among the most common adverse events reported with trastuzumab deruxtecan,” noted study author Hitomi Sakai, DMSc, Associate Professor at the Advanced Cancer Translational Research Institute in Showa University, Tokyo, Japan. “The incidence of nausea and vomiting is often highest in the first cycle and decreases in subsequent cycles, and patients may experience long-lasting or persistent symptoms during T-DXd treatment.
“The DESTINY clinical trial program did not define specific antiemetic therapy in the protocol and have not evaluated the use, type, or efficacy of antiemetic therapy. Therefore, the emetogenic risk of T-DXd has not been fully described, even in recent guidelines,” she stated, while also noting that trastuzumab deruxtecan is classified as a high emetogenic risk anticancer agent by NCCN Guidelines and at the high end of moderate risk by MASCC/ESMO guidelines. As a result, a triplet or even quadruplet is recommended as prophylactic anti-emetic treatment.
“Olanzapine, a multiple neurotransmitter receptor blocker, has been shown to be effective in relieving refractory nausea and vomiting. When used in combination with 5-HT3RA and dexamethasone, it is more effective than NK1RA in preventing delayed nausea,” Sakai said.
In the ERICA study, researchers evaluated the efficacy of an olanzapine-based triplet antiemetic therapy for the prevention of nausea and vomiting among patients with HER2-positive or HER2-low metastatic breast cancer.
A randomized, double-blind, placebo-controlled, Phase II study, ERICA included patients with HER2-positive or HER2-low metastatic breast cancer who were scheduled to receive trastuzumab deruxtecan. Study participants were randomized 1:1 to receive olanzapine 5mg or placebo (once daily) from Day 1-6 in combination with 5-HT3RA and dexamethasone (6.6 mg intravenously or 8 mg orally on Day 1), according to Sakai and colleagues.
The observation period was 504 hours (21 days) from the first T-DXd administration. An electronic symptom diary was used to assess patients daily (Day 1-22) for symptoms of nausea and vomiting, as well as confirmation of additional anti-nausea medications.
The primary endpoint of this analysis was complete response (CR), defined as no emetic events and no rescue drugs, in the delayed phase (24-120 hours post-T-DXd). Secondary endpoints included the following: CR rate during the acute, persistent phase; complete control (no emetic events, no rescue drugs, and no/mild nausea) rate during the acute, delayed, and persistent phase; total control (no emetic events, no rescue drugs, and no nausea) rate during the acute, delayed, and persistent phase; no nausea rate during the acute, delayed, and persistent phase; CR per day; no nausea per day; other symptoms assessed by PRO-CTCAE; and safety.
A total of 168 patients were enrolled in ERICA at 43 sites in Japan between November 2021 and September 2023. Of these individuals, 162 patients—80 olanzapine and 82 placebo—were included in the per protocol set.
Sakai reported that the complete response rate in the delayed phase was significantly higher among patients in the olanzapine group when compared to the placebo group (70.0% vs. 56.1%), and the primary endpoint of the study was met. The efficacy of olanzapine was maintained in the persistent phase (63.9% vs. 44.4%). Data showed that, across all endpoints, the olanzapine group was consistently higher in the delayed and persistent phase, Sakai noted during her ESMO presentation.
“The no nausea rate was also significantly greater with olanzapine than placebo (delayed phase: 57.5% vs. 37.8%; persistent phase: 51.4% vs. 31.9%),” according to Sakai and colleagues. “Complete response rates in the delayed phase favored olanzapine over placebo across subgroups. Total days with nausea in the first cycle were fewer for olanzapine than placebo (4.0 vs. 8.0 days). Appetite loss was less with olanzapine than placebo (any grade: 60.0% vs. 80.7%).
Diarrhea was also less frequent in the olanzapine group compared with the placebo group, noted Sakai, while also highlighting that somnolence and hyperglycemia were more frequent in the olanzapine group compared with the placebo group; however, they were mostly low-grade.
“In conclusion, complete response rate in the delayed phase was significantly higher in the olanzapine group than in the placebo group, indicating that the primary endpoint was met,” Sakai said. “Continued efficacy of olanzapine was observed throughout the 21-day observation period, and the efficacy of olanzapine was most apparent in the first 10 days. The adverse events were similar to those previously reported for olanzapine and there were no new safety signals in both groups.
“Olanzapine-based triplet therapy appears to be an effective antiemetic therapy to prevent delayed and persistent nausea and vomiting induced by trastuzumab deruxtecan treatment,” Sakai concluded.
Catlin Nalley is a contributing writer.