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Lenvatinib versus placebo in radioiodine-refractory thyroid cancer
Martin Schlumberger1, Makoto Tahara, Lori J Wirth
1The authors' affiliations are listed in the Appendix.
Background:
Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131).
Methods:
In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety.
Results:
The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.
Conclusions:
Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).
Insights
Lenvatinib significantly improved progression-free survival and response rates in patients with radioiodine-refractory differentiated thyroid cancer. However, lenvatinib use was associated with increased adverse effects compared to placebo.
Area of Science:
- Oncology
- Pharmacology
Background:
- Differentiated thyroid cancer (DTC) refractory to radioiodine (iodine-131) presents a therapeutic challenge.
- Lenvatinib, a multi-targeted tyrosine kinase inhibitor, demonstrated prior clinical activity in this patient population.
Purpose of the Study:
- To evaluate the efficacy and safety of lenvatinib compared to placebo in patients with progressive iodine-131-refractory differentiated thyroid cancer.
Main Methods:
- A phase 3, randomized, double-blind, multicenter study assigned 261 patients to lenvatinib (24 mg/day) and 131 to placebo.
- The primary endpoint was progression-free survival (PFS); secondary endpoints included response rate, overall survival, and safety.
- Placebo patients could receive open-label lenvatinib upon disease progression.
Main Results:
- Median PFS was 18.3 months with lenvatinib versus 3.6 months with placebo (HR 0.21, P<0.001).
- Objective response rate was 64.8% for lenvatinib vs. 1.5% for placebo (P<0.001).
- Common adverse events with lenvatinib included hypertension, diarrhea, fatigue, decreased appetite, weight loss, and nausea.
Conclusions:
- Lenvatinib significantly improves PFS and response rates in patients with iodine-131-refractory differentiated thyroid cancer.
- The observed benefits of lenvatinib come with an increased incidence of adverse effects.
