OA02.04 Phase II Trial of Antiemetic Oral Granisetron Plus Dexamethasone for Nausea and Vomiting Caused by Crizotinib in ALK or ROS1 Fusion-Positive NSCLC

Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases ALK, ROS1, and C-Met, that show marked antitumor activity for ALK/ROS 1 fusion or MET exon 14 skipping mutation-positive NSCLC. However, crizotinib is associated with a high incidence of certain adverse effects, such as grade-1 or greater nausea (52%–58%) and vomiting (39%–44%) with median time to first onset of 2 d that frequently leads to treatment interruption. Further, crizotinib caused nausea and vomiting in 73% and 65% of the Japanese population, respectively. The optimal prophylactic regimen for crizotinib has not been established. We conducted this phase II trial to evaluate the efficacy and safety of a double combination antiemetic therapy with oral granisetron plus dexamethasone for nausea and vomiting caused by crizotinib in patients with ALK or ROS1 fusion-positive NSCLC. Patients with ALK or ROS1 fusion-positive NSCLC who were scheduled to recieve crizotinib were enrolled. Patients received oral granisetron at a dose of 2 mg (day 1–5) plus oral dexamethasone at a dose of 8 mg (day 1) with crizotinib treatment. The events of nausea, vomiting, and using rescue treatment were recorded in each phase [acute (first 24 h), delayed (24–120 h), overall (0–120 h), and long term (day 1–day 14)]. The primary end point was the complete response (CR; no emetic events and no rescue medication) rate in the overall phase. The secondary endpoints were CR in long term phase, complete control (CC) in each phase, total control (TC) in each phase, and safety. A CR rate of 65% would indicate potential usefulness, while a rate of 40% would be the lower limit of interest, with one sided α = 0.05 and ß = 0.20. From September 2015 and March 2020, 25 patients were enrolled from 7 institutions. Patients characteristics were as follows: median age (range): 66 (41–88) y; women, n = 15 (60%); ROS1 fusion, n = 4 (16%), and history of motion sickness, n = 2 (8.0%). The CR rate in overall phase was 80.0% (90%CI, 62.5–91.8); the lower limit of 90% confidence interval exceeded the predefined threshold. Further, the CR rate in long term phase was 60% (95%CI, 38.7–78.9), suggesting that short-term oral administration of granisetron plus dexamethasone achieved long-lasting control of nausea and vomiting caused by crizotinib. The CC rate and TC rate in overall phase were 80.0% (95%CI, 59.3–93.2) and 76.0% (95%CI, 54.9–90.6), respectively. The most common adverse event (AE) of any grade was constipation (76.0%) followed by visual disorder (28.0%) and insomnia (24.0%). No grade-4 AEs and treatment-related deaths were observed. The double combination of oral granisetron plus dexamethasone is the valid prophylactic regimen for nausea and vomiting caused by crizotinib in patients with ALK or ROS1-positive NSCLC. Clinical trial information: jRCTs031180378.