The investigational tyrosine kinase inhibitor lenvatinib reduced disease progression by 79%, as compared to placebo, in patients with metastatic differentiated thyroid cancer that is refractory to radioactive iodine in the phase III SELECT trial. These findings were presented at the 2014 ASCO Annual Meeting by Martin Schlumberger, MD, Professor of Oncology at the University of Paris Sud in France.1
Limited Treatment Options
“Based on our findings, we are confident that lenvatinib will eventually become a standard treatment for [radioiodine-refractory differentiated thyroid cancer],” Dr. Schlumberger said at a media briefing during the meeting.
“Patients with progressive radioiodine-refractory differentiated thyroid cancer typically have a 10-year survival rate of only 10% from the time of metastatic disease. Until recently, treatment options for these patients have been limited,” he noted.
In November 2013, sorafenib (Nexavar) was approved by the U.S. Food and Drug Administration for radioiodine-refractory differentiated thyroid cancer. Vandetinib (Caprelsa) and cabozantinib (Cometriq) are now approved for metastatic medullary thyroid cancer.
Vascular endothelial growth factor (VEGF)-signaling networks have been implicated in tumor angiogenesis and are associated with the aggressiveness and metastasis of thyroid tumors. Lenvatinib is an oral tyrosine kinase inhibitor that binds not only to VEGFR1-3, but to multiple other sites involved in angiogenesis and proliferation. This may be important, since other molecular drivers of tumor growth and maintenance beyond VEGF-driven angiogenesis contribute to the pathogenesis of thyroid cancer, Dr. Schlumberger added.
Primary Endpoint Robustly Met
SELECT (Study of E7080 Lenvatinib in Differentiated Cancer of the Thyroid) included 392 patients with advanced radioiodine-refractory differentiated thyroid cancer, three-fourths of whom had received prior treatment with a VEGF-targeted agent. Patients were randomly assigned to receive lenvatinib (24 mg/d on a 28-day cycle) or placebo, with crossover allowed upon progression.
Median progression-free survival, the primary endpoint, was 18.3 months with lenvatinib vs 3.6 months with placebo—approximately a 14-month absolute benefit and a 79% reduction in risk that was highly significant (P < .0001) and is “an extraordinary improvement,” Dr. Schlumberger reported.
Progression at 2 years was observed in only 41% of the lenvatinib arm, vs 86% of the placebo arm. Receipt of prior anti-VEGF therapy did not adversely affect outcomes; previously treated patients had the same magnitude of risk reduction, and all other subgroups similarly benefited.
Similarly, response rates were 65% with lenvatinib, including four complete responses (2%), vs an overall 2% response rate with placebo (P < .0001). Time to response was prompt—about 2 months. Median duration of response has not been reached. Median tumor shrinkage for responders was 52%.
Median overall survival has not been reached in either arm, and due to expected crossover upon progression, this endpoint may be hard to interpret, the researchers noted.
In an interview with The ASCO Post, U.S. co-investigator Lori J. Wirth, MD, Assistant Professor of Medicine at Harvard Medical School, Boston, commented on the robust responses and prolonged remission time. “We don’t see numbers that high in oncology very often,” she said.
The median progression-free survival with sorafenib in the DECISION trial was 10.8 months, vs 5.8 months with placebo.2
Major Adverse Events
Treatment-emergent adverse events “reported as treatment-related” were observed in virtually all patients treated with lenvatinib (97%), compared with 60% of those receiving placebo. The most frequent events with lenvatinib were hypertension, diarrhea, fatigue, weight loss, and decreased appetite. These were grade ≥ 3 in 42%, 8%, 9%, 10%, and 5% of lenvatinib recipients, respectively. Proteinuria grade ≥ 3 was reported in 10%. Dose reductions were necessary for 68%, and dose interruptions, for 82%; 14% of lenvatinib-treated patients discontinued the drug due to toxicity.
A total of 20 patients (8%) in the lenvatinib group died, compared to 6 (5%) in the placebo group. Of these 20 deaths, 6 (2%) were considered by the investigators to be treatment-related, Dr. Schlumberger said. One patient died due to a pulmonary embolism, one died due to hemorrhagic stroke, and four others died as a result of general health deterioration, he explained. “Of course this is significant,” Dr. Schlumberger said, in response to questions from the media.
While treatment-related deaths are higher than seen in studies of the other agents used in differentiated thyroid cancer, general toxicity is not worse, he indicated, suggesting the risk/benefit ratio is positive.
ASCO press briefing moderator Gregory A. Masters, MD, FASCO, Attending Physician at the Helen F. Graham Cancer Center & Research Institute, Newark, Delaware, agreed, noting that the absolute improvement in progression-free survival shown with sorafenib vs placebo was less than 6 months, compared to almost 15 months with lenvatinib. “While it can be dangerous to compare two different trials, the numbers from this trial certainly show higher response rates and longer prolongation of progression-free survival,” he said.
Toxicities in Perspective
“There’s always a trade-off,” Dr. Masters acknowledged. “We are still trying to understand the toxicities of these new therapies. We must use new therapies with caution, and in deciding which patients to treat, we must balance the risks that go along with any cancer therapy…. But it is really rewarding to see another active drug in this disease, where a year ago we really had no active therapies.”
Dr. Wirth added, “We have to think about the toxicities of these drugs in perspective. Many patients with [radioiodine-refractory differentiated thyroid cancer] have a low burden of disease that is growing slowly, and watchful waiting can be appropriate for them. Patients in the SELECT study had a median progression-free survival of only 3.6 months on placebo. These are patients with rapidly progressive disease, and they need effective treatment.”
In her experience, lenvatinib has not been much harder to tolerate than the other tyrosine kinase inhibitors. “I have patients who have remained on lenvatinib for up to 2 years, but we are very active in managing them,” she said. “With active symptom management, supportive care, dose holds, and dose reductions, these drugs are very useful, and the risk/benefit ratio is favorable.” ■
Disclosure: The study was funded by Eisai. Dr. Schlumberger has consulted or received research support from Eisai, AstraZeneca, Bayer, and Genzyme/Sanofi, and honoraria from these companies and from Sobi. Drs. Wirth and Masters reported no potential conflicts of interest. For full disclosures of all study authors, visit meetinglibrary.asco.org.
References
1. Schlumberger M, Tahara M, Wirth LJ, et al: A phase 3, multicenter, randomized, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT). ASCO Annual Meeting. Abstract LBA6008. Presented June 2, 2014.
2. Brose MS, Nutting C, Jarzab B, et al: Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. ASCO Annual Meeting. Abstract 4. Presented June 2, 2013.
