Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes

PURPOSE In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, most patients experienced an adverse event. In this report, we examine common lenvatinib-emergent adverse events in this phase three, randomized, double-blind study. METHODS Adverse events were graded per Common Terminology Criteria for Adverse Events v4.0. 392 patients were enrolled (lenvatinib: 261, placebo: 131) and received lenvatinib 24 mg/day or placebo. The main outcome measures were: associations with progression-free survival and overall survival in exploratory univariate and multivariate analyses along with additional variables. RESULTS The most common any-grade adverse events (any grade; grade 3) in lenvatinib-treated patients included proteinuria (32%; 10%), diarrhea (67%; 9%), fatigue/asthenia/malaise (67%; 10%), rash (23%; 0.4%), and palmar-plantar erythrodysesthesia syndrome (33%; 3%). There were no grade 4 events for these adverse events. They generally occurred early (median time to first onset [weeks]: proteinuria [6.1], diarrhea [12.1], fatigue/asthenia/malaise [3.0], rash [7.3], and palmar-plantar erythrodysesthesia syndrome [5.9]), and were resolved primarily with dose modifications (median time to resolution [weeks]: proteinuria [8.8], diarrhea [18.1], fatigue/asthenia/malaise [16.3], rash [5.9], and palmar-plantar erythrodysesthesia syndrome [20.0]). Discontinuation due to these adverse events occurred in 2 (1%) patients with proteinuria and 4 (2%) with fatigue. Progression-free survival was not associated with any of the adverse events. Eastern Cooperative Oncology Group performance status (P = 0.001), follicular histology (P = 0.002), and diarrhea (P = 0.023) were associated with overall survival in multivariate analyses (median overall survival for patients with diarrhea: not reached; without: 17.1 months). CONCLUSIONS In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the most common adverse events typically occurred early and were primarily managed with dose modifications. Overall survival was significantly associated with diarrhea.