Gender Impact on Safety and Efficacy in Lenvatinib treated patients with radioiodine-refractory Differentiated Thyroid Cancer (GISEL study)

Introduction: little is known about sex differences in lenvatinib treatment safety and efficacy. Methods: real-word retrospective Italian multicenter study enrolling patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib. Results: 138 patients (64 females) were included, with a median follow-up of 26 months (2-72). More men performed physical activities (34%vs17%, p=0.024). The frequency of smoking and alcohol consumption was higher in men (58%vs33%, p=0.003; 45%vs17%, p=0.001). We did not find sex differences in lenvatinib dose reduction due to adverse events, AE (78% of females vs 85% of males). 99% of patients developed at least one AE, with no sex difference in their number and the time to first AE. Severe AEs occurred in 74% of males and 66% of females (p=0.398), with a mean dose of 18.2 mg (±5.7), and a median time at the first severe AE of 9 weeks (1-154). Stomatitis/mucositis and hematological disorders were more frequent in females (48%vs30%, p=0.016; 17%vs4%, p=0.011). Gastrointestinal disorders were higher in males (15%vs2%, p=0.010). Eighty-seven patients interrupted lenvatinib due to AEs (median time: 3 months (0-48), mean dose: 17 mg ±5.5). Discontinuation occurred in 21 patients, 5 for severe AEs. No sex differences were found in progression-free survival, overall survival and disease control rate. Liver metastases were associated with disease progression (HR 3.73, 95%CI 1.06-13.12, p= 0.040) or death (HR 4.82, 95%CI 1.75-13.25, p= 0.002) only in females. Conclusions: lenvatinib is effective in both sexes and exhibits a good safety profile, with a sex difference in the frequencies of some adverse events.