A Randomized Study of Lenvatinib 18 mg vs 24 mg in Patients With Radioiodine-Refractory Differentiated Thyroid Cancer

Abstract

Background: Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity.

Methods: Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded.

Results: The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of -4.2% (95% CI -19.8, 11.4).

Conclusion: A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary.

Trial registration: ClinicalTrials.gov NCT02702388.

Keywords: RR-DTC; lenvatinib; starting dose; tyrosine kinase inhibitor.

Figure 1.

Patient enrollment, randomization, and treatment. ^aOf the 2 patients who failed screening due to an adverse event, both had serious adverse events requiring hospitalization (dyspnea and increasing cancer bone pain; pathologic femoral shaft fracture and a traumatic radius fracture). ^bOther reasons for failing screening were exceeding the screening window (n = 9) and patient decision (n = 1). ^cOther reasons for treatment discontinuation were clinical disease progression (n = 2). ^dOther reasons for treatment discontinuation were clinical disease progression (n = 1), sponsor decision (n = 1), and prohibited anticancer treatment (n = 1).

Figure 2.

Forest plot of objective response rate by baseline characteristics (investigator assessment per RECIST v1.1) as of week 24 (A) and overall (B). Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; NE, not estimable; ORR, objective response rate; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1; TSH, thyroid-stimulating hormone; VEGF, vascular endothelial growth factor.

Figure 3.

Kaplan-Meier plot of PFS as assessed by investigator using RECIST v1.1. Abbreviations: HR, hazard ratio; NE, not estimable; PFS, progression-free survival; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1.

Figure 4.

Percentage changes in the sums of diameters of target lesions from baseline to postbaseline nadir (by investigator using RECIST v1.1). Abbreviation: RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1. ^aPatients to the right of the arrow achieved at least a 30% reduction of target lesions.