Lenvatinib: beneficial for thyroid cancer patients or not?12 Feb 2015
In a phase-3 randomized trial, lenvatinib was associated with improved progression-free survival but also more serious adverse effects, compared with placebo when treating radioiodine-refractory thyroid cancer. This innovative study enrolled patients from 21 countries and all patients had independently verified progressive disease at the time of enrollment.
Lenvatinib is an oral drug, medically characterized as a "multitargeted tyrosine kinase inhibitor (TKI)".
Study design and details
The randomized trial included nearly 400 patients, who were assigned to receive lenvatinib or placebo at a 2:1 ratio. Patients in the placebo group who showed disease progression during the study could opt immediately to receive open-label lenvatinib.
Overall, 77 of 152 patients with baseline bone lesions had progressive disease at the start of the trial. Median duration of treatment was 13.8 months for patients on lenvatinib, and 3.9 months for patients on a placebo. Among the patients on placebo who had progression, 95.6% chose to receive open-label lenvatinib.
According to Martin Schlumberger, MD, at the Institute Gustave Roussy in France, and his colleagues:
- the overall response rate was 64.8% in the lenvatinib group, with 4 complete responses and 165 partial ones versus 1.5% in the placebo group,
- Median progression-free survival, the primary endpoint of the study, was 18.3 months for patients in the lenvatinib group versus 3.6 months for the placebo group,
- Median progression-free survival for patients who had not received previous treatment with a similar inhibitor was 18.7 months, and among those who had received similar treatment, 15.1 months,
- Median overall survival was not reached in the trial, which had up to 26 months of follow-up.
"This improvement in progression-free survival is longer than that observed in other placebo-controlled clinical patients with this disease" the researchers wrote in the Feb. 12 issue of “The New England Journal of Medicine”, adding that "one distinguishing feature of lenvatinib that may underlie this observation is the inhibition of unique targets."
"This efficacy after prior treatment with a tyrosine kinase inhibitor is a key clinical consideration given the likely increased use of these therapies in patients with thyroid cancer," commented the authors.
Significant adverse events and limitations of the study
97% of those on lenvatinib experienced adverse effects judged to be treatment-related versus 60% of those in the placebo group. Adverse events affecting many patients in the lenvatinib group included:
- hypertension (67.8%)
- diarrhea (59.4%)
- fatigue or asthenia (59.0%)
- decreased appetite (50.2%)
- decreased weight (46.4%)
- and nausea (41%).
In the lenvatinib group, the rate of discontinuation of the drug because of adverse effects was 14.2%, versus 2.3% in the placebo group. A total of 118 deaths occurred before the study was completed: 71 in the experimental group (27.2%) and 47 in the placebo group (35.9%). In both groups, about three-quarters of those deaths were due to disease progression.
Six of 20 deaths that occurred during the treatment period were considered to be related to lenvatinib, said the authors: one case of pulmonary embolism, one of hemorrhagic stroke, one of deterioration of physical health, and three unspecified. "In patients who receive lenvatinib, serum thyrotropin levels should be measured on a regular basis, and the daily dose of levothyroxine should be increased accordingly if the level rises," wrote the authors.
Limitations of the study included the possibility that the survival analysis could have been confounded because of the crossover from placebo to lenvatinib. The researchers also wrote that they lacked information on patients' quality of life.
Source: MedPage Today