Lenvatinib Significantly Extends OS in Older Patients With Thyroid Cancer

Marcia Brose, MD, PhD

Lenvatinib (Lenvima) significantly improved overall survival (OS) in patients older than 65 years with radioiodine-refractory differentiated thyroid cancer, according to findings from the SELECT trial published in the Journal of Clinical Oncology.

Compared with placebo, lenvatinib was associated with a significant improvement in OS in older patients (HR, 0.53; 95% CI, 0.31-0.91; P = .020).

The FDA approved lenvatinib in 2015 as a treatment for patients with progressive, radioactive iodine-refractory differentiated thyroid cancer based on initial progression-free survival (PFS) results from SELECT, which showed that the drug reduced progression by 79% (HR, 0.21; 99% CI, 0.14-0.31; P <.0001) compared with placebo. Lead author Marcia Brose, MD, PhD, an associate professor of otorhinolaryngology at the University of Pennsylvania Perelman School of Medicine and a member of Abramson Cancer Center, said in a press release that SELECT is the first study to demonstrate that lenvatinib can improve OS.

“Due to limitations of study design, it has been hard to prove that multikinase inhibitors improve overall survival, although we have suspected it,” she said. “These findings put that doubt to rest for the group of patients over 65 treated with lenvatinib.”

When stratified by age, only older patients in the placebo arm achieved the median OS of 18.4 months (95% CI, 13.3-20). Survival data were not mature for younger patients. Investigators noted a statistically significant longer OS in patients younger than 65 years compared with older patients in the placebo arm (HR, 0.48; 95% CI, 0.27-0.85; P = .010). OS was not significantly different between age groups in the lenvatinib arm (HR, 0.78; 95% CI, 0.49-0.26; P = .30).

Median follow-up was 17.1 months.

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of VEGFR 1 to 3, FGFR 1 to 4, PDGFR-alpha, and RET and KIT proto-oncogenes.

SELECT was an international, phase III, randomized trial. Enrollment ran from August 2011 to October 2012, and adults with measurable, histologically confirmed radioiodine refractory differentiated thyroid cancer and independently reviewed radiologic evidence of progression during the previous 13 months were eligible.

Patients were stratified by age (≤65 or >65 years), geographic region (Europe, North America, or other), and whether they had prior VEGF-targeted treatment. They were then randomly assigned to 24 mg of oral lenvatinib once daily (n = 261) or placebo (n = 131) in 28-day cycles until disease progression was confirmed. Roughly 40% of the cohort was older than 65.

Dose interruptions and incremental dose reductions to 20 mg, 14 mg, or 10 mg per day were permitted. Patients whose disease progressed while they were receiving placebo were offered treatment with open-label lenvatinib.

Median age in the younger age group was 56 years for both the lenvatinib and placebo arms. For the older age group, the median age was 71 years for both arms. Other baseline characteristics were generally similar across all groups.

PFS with lenvatinib versus placebo was 20.2 versus 3.2 months (HR, 0.19; 95% CI, 0.13-0.27; P <.001) for younger patients and 16.7 versus 3.7 months (HR, 0.27; 95% CI, 0.17-0.43; P <.001) in the older group.

Lenvatinib improved objective response rate (ORR) compared with placebo in both younger (odds ratio [OR], 45.7; 95% CI, 14.8-141.0; P <.001) and older (OR, 16.8; 95% CI, 4.7-60.0; P <.001) patients. Median time to objective response was 2.0 months in both age groups. Median duration of response was 17.0 months (95% CI, 14.6—not evaluable) in older patients and not reachable (95% CI, 12.9–not evaluable) in younger patients.

Median duration of treatment was similar in the age cohorts, but older patients had a shorter time to first dose reduction and more older patients required that their dose be reduced to 10 mg/day compared with younger patients. As a result, median dose intensity was 16.0 mg per day in older patients versus 17.5 mg per day in younger patients (P = .007).

Common adverse events (AEs) leading to lenvatinib dose reduction included hypertension, proteinuria, decreased appetite, diarrhea, asthenia, and fatigue. Older patients were more likely to experience AEs that required dose modifications.

The most common treatment-related AE was hypertension, which occurred in 67% to 69% of lenvatinib-treated patients in both age groups. More than half of older patients experienced diarrhea, decreased appetite, and weight loss, but those AEs were rarely severe.

“There’s a belief that these drugs should be withheld from older patients due to concerns about toxicity and other medical concerns, but our results show just the opposite,” Brose said. “Not only do older patients benefit from these drugs, but they generally tolerate them well.”

Incidence of grade ≥3 treatment-related AEs in patients receiving lenvatinib was significantly higher in older patients versus younger patients (89% vs 67%, P <.001). Half of older patients experienced serious hypertension compared with 37% of younger patients, and 13% of older patients experienced grade ≥3 proteinuria.

The rate of serious treatment-emergent AEs was similar in younger (48%) and older (55%) lenvatinib-treated patients. The incidence of fatal treatment-emergent AEs was slightly higher in older patients (9.4% vs 6.5%). Causes of death in the older group included pulmonary embolism, hemorrhagic stroke, sudden death, and general physical health deterioration.

Brose MS, Worden FP, Newbold KL, Guo M, Hurria A. Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial [published online June 14, 2017]. J Clin Oncol. doi: 10.1200/JCO.2016.71.6472.