Lenvatinib Starting Dose Confirmed for Refractory RAI-Refractory DTC Indication

A phase 2 clinical trial of radioactive iodine–refractory differentiated thyroid cancer demonstrated that the lenvatinib starting dose of 24 mg is superior to the lower dose of 18 mg, missing the noninferiority primary end point of the study.

A phase 2 clinical trial (Study 221, NCT02702388) of radioactive iodine (RAI)–refractory differentiated thyroid cancer (DTC) demonstrated that the lenvatinib (Lenvima) starting dose of 24 mg is superior to the lower dose of 18 mg, missing the noninferiority primary end point of the study, Eisai Inc, announced in a press release.1

The proper starting dose for lenvatinib in the study was determined based on the objective response rate (ORR) at week 24 in addition to the incidences of grade 3 or higher treatment-emergent adverse events. Reportedly, these toxicities were similar between the 2 treatment arms.

"These findings help reinforce the efficacy and safety of Lenvima for patients living with RAI-refractory differentiated thyroid cancer while supporting the appropriate starting dose for these patients," said Takashi Owa, PhD, chief medicine creation and chief discovery officer, Oncology Business Group at Eisai, in a statement. "Studies like this post-marketing trial represent Eisai's continued commitment to prioritizing patients' needs and safety through the ongoing examination of our medicines. We would like to thank the patients, their families, and clinical investigators for their participation in Study 211, and we look forward to presenting the full results of this study at an upcoming medical meeting."

Study 211 is a multicenter, randomized, double-blind trial that sought to determine whether a lower starting dose could provide comparable efficacy with a better safety profile. The coprimary end points are ORR between the 2 starting dose levels and the percentage of treatment-emergent adverse events (AEs). The secondary end points include progression-free survival (PFS), PFS after next-line therapy (PFS2), the number of participants with AEs, time to treatment discontinuation due to an AE, the number of dose reductions, the time to first dose reduction, area under the curve of lenvatinib, presence/absence of biomarkers, and health-related quality of life.

Inclusion criteria note that patients must have had histologically or cytologically confirmed diagnosis of DTC, which includes subtypes like papillary and follicular thyroid cancer subtypes. Patients were also required to have measurable disease confirmed by central radiographic review, evidence of disease progression within 12 months prior to enrolling, iodine-131 refractory/resistant disease, an ECOG performance status of 0 to 2, an adequately controlled blood pressure, as well as adequate blood coagulation function and liver function. Patients with brain metastasis were allowed if their condition was clinically stable, asymptomatic, and off steroids for a month prior to joining the study.

A total of 152 patients were enrolled in the study and randomized 1:1 to received either 24 mg of lenvatinib or an 18-mg dose. At the higher dose level, lenvatinib was administered once daily, with dose reduction carried out based upon the prior dose (24, 20, 14, 10, or 8 mg), which is also administered once daily. The 18-mg arm followed the same dosing schedule.

Study 211 findings meet a post-marketing commitment to the FDA and European Medicines Agency following approval and Priority Review designations in more than 50 countries as treatment of patients with locally recurrent or metastatic, progressive, RAI-refractory DTC.1,2

Lenvatinib is a kinase inhibitor with indications as treatment of patients with locally recurrent or metastatic, progressive, RAI-refractory DTC; as first-line treatment of patients with unresectable hepatocellular carcinoma; as well as in combination with pembrolizumab (Keytruda) for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, who have disease progression following prior systemic therapy, and are not candidates for curative surgery or radiation.

Toxicities mentioned on the lenvatinib drug label that can occur in patients with DTC include hypertension, cardiac dysfunction, arterial thromboembolic events, renal failure or impairment, proteinuria (6%), diarrhea, fistula formation, and gastrointestinal perforation, QT interval prolongation (9%), hypocalcemia, hemorrhagic events, and thyroid-stimulating hormone suppression/thyroid dysfunction.

The drug label also notes that AEs are observed in ≥30% of patients. The most common are hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%).

In terms of serious AEs, which only occur in about 2% of patients, the most common include pneumonia (4%), hypertension (3%), and dehydration (3%). Data shows that dose reductions are necessary for about 68% of patients with DTC who receive lenvatinib. Most commonly, dose reductions were caused by hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%). Hypertension (1%) and asthenia (1%) were the most common AEs leading to treatment discontinuation.


1. Eisai announces topline results from study 211 supporting 24 mg as the appropriate starting dose for Lenvima® (lenvatinib) in patients with differentiated thyroid cancer. News release. Eisai, Inc. August 11, 2020. Accessed August 11, 2020. https://bit.ly/3ixG6Jn

2. Hayato S, Shumaker R, Ferry J, Binder T, Dutcus CE, Hussein Z. Exposure–response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer. Cancer Chemother Pharmacol. 2018;82:971-978. doi:10.1007/s00280-018-3687-4