50th Annual Meeting of the American Society of Clinical Oncology (ASCO):
Lenvatinib Extends Progression-Free Survival in Iodine-Refractory Thyroid Cancer
The investigational small-molecule kinase inhibitor lenvatinib significantly extends progression-free survival (PFS) in patients with radioiodine-refractory differentiated thyroid cancer (DTC), according to results presented in a late-breaking abstract session at the 50th Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.
Lenvatinib is an oral inhibitor of multiple tyrosine kinases including vascular endothelial growth factor receptor (VEGFR)-1-3, fibroblast growth factor receptor (FGFR)-1-4, platelet-derived growth factor receptor (PDGFR)-alpha, RET, and KIT. After a phase 2 study demonstrated the clinical activity of lenvatinib in patients with radioiodine-refractory DTC, the phase 3 SELECT (Study of (E7080) Lenvatinib in differentiated Cancer of the Thyroid) trial was undertaken.
Phase III SELECT Trial
The randomized, double-blind, placebo-controlled phase III SELECT trial presented by Martin Schlumberger, MD, enrolled 392 patients with radioactive refractory DTC with evidence of progression within the last 13 months; up to 1 prior VEGF or VEGFR-targeted therapy was allowed.
Patients were randomly assigned 2:1 to lenvatinib 24 mg (261 patients) or placebo (131 patients) each administered daily. Treatment was continued until disease progression and crossover to open-label lenvatinib was permitted upon disease progression in the placebo group.
In his presentation, Dr. Schlumberger, of the Institut Gustave Roussy in Paris, France, noted that baseline characteristics were well balanced between arms. In the lenvatinib group, 25% of patients had received a prior VEGF-targeted therapy, compared with 21% in the placebo group. Pulmonary metastases were present in 87% and 95% of patients in the lenvatinib and placebo arms, respectively.
The study met its primary endpoint, with lenvatinib demonstrating a significant improvement in median PFS of 18.3 months versus 3.6 months with placebo (hazard ratio, 0.21; 95% confidence interval, 0.14-0.31; P < .0001). Similar improvements in PFS were observed regardless of prior use of VEGF-targeted therapy and across key subgroups, including tumor burden at baseline, histology, and presence of bone or lung metastases. A. Dimitrios Colevas, MD, of Stanford University, who was not involved with the study, called the results “truly an amazing extension of progression free survival”.
Lenvatinib was also associated with a high objective response rate of 65% versus 2% with placebo (P < .0001). Four patients receiving lenvatinib (2%) attained a complete response. The median time to response was 2.0 months and the median duration of response had not been reached at the time of analysis. “The objective response rate is amazing for this drug in a randomized, controlled trial,” commented Dr. Colevas, who noted that he was, and the audience should be, “blown away” by this degree of antitumor activity.
Despite this substantial difference in PFS between the two arms, lenvatinib was not associated with a significant improvement in overall survival. Dr. Schlumberger suggested that this was expected, given the crossover study design. The median overall survival was not reached in either arm.
The most common adverse events associated with lenvatinib were hypertension (68%), diarrhea (60%), fatigue (64%), diarrhea (59%), and decreased appetite (50%), nausea/vomiting (46%) and decreased weight (46%). The most common grade 3 or higher adverse events in the lenvatinib arm included hypertension (42%), decreased weight (10%), and proteinuria (10%).
Treatment-emergent adverse events led to dose reductions in 68% of patients and discontinuation in 14%. Of 20 treatment-emergent deaths in the lenvatinib arm, 6 were considered treatment-related, including 4 patients with general health deterioration, 1 patient with pulmonary embolism, and 1 patient with hemorrhagic stroke.
Quality of Life Not Assessed
Quality-of-life is an important consideration for these patients, Dr. Colevas noted in his discussion. Although the SELECT trial did not assess quality-of-life, Dr. Colevas commented on quality-of-life outcomes reported in the DECISION trial of sorafenib in radioactive iodine-refractory DTC to generally address the issue of quality-of-life in patients receiving tyrosine kinase inhibitors. In the DECISION trial, sorafenib was associated with a reduction in health-related quality of life. Dr. Colevas emphasized that even oral therapies are associated with toxicities that should be considered. He called the changes in quality-of-life associated with TKIs “different enough to give us pause about whom we should treat and when we should treat them.”
Dr. Colevas also presented a cross-trial comparison of outcomes in the SELECT and DECISION trials in which he called lenvatinib “clinically superiority to placebo and sorafenib” to the extent that a randomized, controlled trial of lenvatinib versus sorafenib is not warranted. However, he cautioned that both the SELECT and DECISION trials may have started treatment too early in the disease process.