Clinical trialPhase 3Thyroid cancer

Lenvatinib versus placebo in radioiodine-refractory thyroid cancer

N Engl J Med · 2015392 patients (261 lenvatinib, 131 placebo)

Schlumberger M, Tahara M, Wirth LJ, et al. N Engl J Med. 2015. 372:621-630

Study type: Clinical trial
Study name: SELECT
Phase: Phase 3
Design: Randomised, double-blind, multicentre, placebo-controlled trial (2:1 randomisation); open-label lenvatinib available to the placebo group after disease progression
Sample size: 392 patients (261 lenvatinib, 131 placebo)
Source: N Engl J Med · 2015
Trial registration: NCT01321554

In plain words

In some patients, differentiated thyroid cancer stops responding to radioactive iodine and keeps growing. In this large trial, lenvatinib tablets, which block pathways the tumour uses to grow and to form new blood vessels, were compared with a placebo (dummy pill). Lenvatinib greatly lengthened the time the disease was kept under control (a median of about 18 months versus under 4 months), and the tumour shrank in about two thirds of patients. On the other hand, side effects such as high blood pressure, diarrhoea, tiredness and loss of appetite were common and need close monitoring and sometimes a lower dose; when to start this drug should be decided with a specialist.

Key results

18.3 months vs 3.6 months

Median progression-free survival

HR 0.21; 99% CI 0.14-0.31; P<0.001 (FDA label: 95% CI 0.16-0.28)

64.8% vs 1.5%

Response rate

4 complete and 165 partial responses in the lenvatinib group; P<0.001

Not reached in either group

Median overall survival

Placebo patients could receive lenvatinib after progression

14.2% vs 2.3%

Discontinuation due to adverse events

37 lenvatinib patients vs 3 placebo patients

Drugs in this study:Lenvatinib (Lenvima)

Dose and schedule cards

Lenvatinib (SELECT)

Locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer; in the absence of a biomarker with an approved first-line therapy (preferred over sorafenib)On the page “Thyroid cancer” · Radioactive iodine-refractory differentiated thyroid cancer: systemic therapy

Locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer; in the absence of a biomarker with an approved first-line therapy (preferred over sorafenib)

Drug	Dose	Route	Schedule
Lenvatinib	24 mg	Oral, with or without food	Once daily, continuously

Cycle length: Continuous (28-day cycles in SELECT)
Duration: Until disease progression or unacceptable toxicity

Source: FDA label; SELECT. Dose reduction levels: 20 mg, then 14 mg, then 10 mg daily. CrCl less than 30 mL/min or severe hepatic impairment (Child-Pugh C): 14 mg daily. Control blood pressure before starting and monitor it during treatment (grade 3 despite optimal therapy → withhold; grade 4 → permanently discontinue). Check for proteinuria before starting and periodically (≥2 g/24 hours → withhold; nephrotic syndrome → permanently discontinue).

On the page “Thyroid cancer” · Radioactive iodine-refractory differentiated thyroid cancer: systemic therapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Lenvatinib

Oral lenvatinib 24 mg once daily (two 10 mg capsules and one 4 mg capsule), continuously in 28-day cycles, until disease progression (confirmed by independent review), unacceptable toxicity or withdrawal. Dose interruption or reduction for treatment-related toxicity was allowed.

FDA label points for this regimen: dose-reduction levels in DTC are 20, 14 and 10 mg once daily in turn; in severe renal impairment (CrCl below 30 mL/min) or severe hepatic impairment (Child-Pugh C) the dose is 14 mg once daily; capsules are swallowed whole (with or without food). Blood pressure should be controlled before starting and monitored after 1 week, then every 2 weeks for the first 2 months and at least monthly thereafter; for proteinuria of 2 g or more per 24 hours, withhold until 2 g or less and resume at a reduced dose; an arterial thromboembolic event or gastrointestinal perforation of any grade, and grade 3 or 4 fistula, require permanent discontinuation.

2Placebo

Matching placebo (same number of capsules) once daily, continuously. After progression confirmed by independent review, patients could receive open-label lenvatinib (the starting dose in this phase was 24 mg daily until 15 February 2013, then reduced to 20 mg daily at the request of the data monitoring committee). According to the FDA label, 83% of placebo patients crossed over to lenvatinib after progression.

Source of the regimen details: ClinicalTrials.gov NCT01321554 (arms and interventions: 24 mg orally daily, continuously; 28-day cycles per the abstract) and the FDA label for lenvatinib (LENVIMA, DailyMed) for dose-reduction levels, dose adjustment in renal and hepatic impairment and monitoring. The full text of the NEJM paper was not available in PMC.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with locally recurrent or metastatic, radioiodine (iodine-131)-refractory differentiated thyroid cancer (papillary or follicular, including Hürthle cell and clear cell subtypes), with measurable disease per RECIST 1.1 (confirmed by central review) and radiological evidence of progression within the 12 months before enrolment (confirmed by independent review). Radioiodine refractoriness was defined as at least one measurable lesion without iodine uptake on iodine scan, or iodine uptake with progression within 12 months of iodine-131 therapy, or a cumulative activity above 600 mCi (22 GBq) with the last dose at least 6 months before enrolment. Zero or one prior VEGF/VEGFR-targeted therapy was allowed (24% of patients had one prior therapy), and adequate renal, hepatic, bone marrow and coagulation function was required. Exclusion criteria: anaplastic or medullary carcinoma, two or more prior VEGF/VEGFR-targeted therapies, and any anticancer therapy within 21 days (or an investigational drug within 30 days) before starting. 54% of patients had ECOG 0 and 99% had metastases (lung 89%, lymph nodes 52%, bone 39%).

Endpoints

Primary outcome: progression-free survival by independent radiological review (RECIST 1.1). Secondary outcomes: objective response rate, overall survival and safety.

Safety and side effects

Treatment-related adverse events (any grade) occurring in more than 40% of the lenvatinib group: hypertension (67.8%), diarrhoea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), weight loss (46.4%) and nausea (41.0%). According to the abstract, 14.2% of lenvatinib patients and 2.3% of placebo patients discontinued the drug because of adverse events, and in the lenvatinib group 6 of the 20 deaths during the treatment period were considered drug-related.

According to the FDA label (SELECT adverse event table), grade 3 to 4 adverse events with lenvatinib versus placebo: hypertension 44% versus 4%, weight loss 13% versus 1%, proteinuria 11% versus 0%, fatigue 11% versus 4%, diarrhoea 9% versus 0%, decreased appetite 7% versus 1%, stomatitis 5% and arthralgia/myalgia 5% versus 3%. Adverse events led to dose reduction in 68% and to lenvatinib discontinuation in 18% of patients. Other important adverse events: renal impairment or failure 14% (grade 3 to 5: 3%), arterial thromboembolic events 5%, QTc prolongation 9% (grade 3 to 4: 2%), pulmonary embolism 3% and osteonecrosis of the jaw 0.4%. Median time to onset of hypertension was 16 days.

Clinical significance and place in guidelines

Based on this trial, the US Food and Drug Administration (FDA) approved lenvatinib (LENVIMA) on 13 February 2015 for progressive, radioiodine-refractory differentiated thyroid cancer. The 2025 American Thyroid Association (ATA) guideline recommends multikinase inhibitor therapy (lenvatinib or sorafenib) for patients with progressive radioiodine-refractory differentiated thyroid cancer who lack a biomarker-driven first-line therapy, and in most cases considers lenvatinib the preferred first-line multikinase inhibitor (strong recommendation, high-certainty evidence).

Limitations

At the time of this report, median overall survival had not been reached, and the option for placebo patients to receive lenvatinib after progression makes it difficult to assess the effect on overall survival. Toxicity was substantial, and 6 drug-related deaths were reported. The comparison was with placebo, not with another active treatment.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.