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TKIs May Overcome Age-Related Survival Disparity in Refractory Thyroid Cancer

Published Online: 10:20 AM, Sun May 31, 2015
 Marcia S. Brose, MD, PhD

Marcia S. Brose, MD, PhD

Patients of all ages with iodine-refractory thyroid cancer lived significantly longer when treated with the targeted agent lenvatinib, a new analysis of a randomized trial showed.
 
After a median follow-up of 17.1 months, median overall survival (OS) had yet to be reached in any patient subgroup except older patients randomized to placebo, who had a median OS of 18.4 months. Patients older than 65 years had a 47% reduction in the survival hazard when treated with lenvatinib instead of placebo.
 
In the lenvatinib arm, OS did not differ significantly between older and younger patients, Marcia S. Brose, MD, PhD, reported at the American Society of Clinical Oncology Annual Meeting in Chicago.
 
“Overall, people who are over 65 do significantly worse, but with lenvatinib, the effect of age on survival is totally abrogated,” said Brose, an associate professor of otorhinolaryngology at the University of Pennsylvania in Philadelphia. “The confidence intervals are not overlapping, and at this point, I think the difference in survival [between lenvatinib- and placebo-treated older patients] is about 4 months.”
 
The findings came from a prespecified analysis of SELECT (Study of [E7080] Lenvatinib in Differentiated Cancer of the Thyroid) trial, a phase III randomized (2:1), placebo-controlled trial involving patients with iodine-refractory differentiated thyroid cancer. The trial had a primary endpoint of progression-free survival (PFS), and the results showed a 14.7-month improvement (HR = 0.21, P <.001) in median PFS with lenvatinib, a multitargeted inhibitor of vascular endothelial growth factor (VEGF).
 
Median overall survival, a secondary endpoint, did not differ significantly between the lenvatinib and placebo arms of the trial, although 83% of patients in the placebo arm crossed over to lenvatinib at progression. Median survival had yet to be reached in either arm at the time of the primary analysis.
 
Thyroid cancer tends to be more aggressive in older patients, who are more likely to have radioactive iodine-refractory differentiated disease at diagnosis. The SELECT trial included a prespecified analysis of efficacy and safety profiles of lenvatinib by age group (65 years or younger versus older).
 
The lenvatinib arm included 155 younger patients and 106 older patients, whereas the age breakdown in the placebo arm was 81 younger and 50 older patients. In the lenvatinib group, younger patients had a median age of 56 years versus 71 years in the older subgroup.
 
Duration of lenvatinib treatment was similar among younger (13.9 months) and older patients (13.5 months), but older patients had a shorter time to first dose reduction, Brose reported. The frequency of treatment-emergent adverse events did not differ by age in either treatment arm.
 
The most common reasons for dose reduction in the lenvatinib group were hypertension, proteinuria, decreased appetite, diarrhea, asthenia, and fatigue. A similar proportion of younger and older lenvatinib-treated patients discontinued for reasons other than disease progression (18 of 155 versus 16 of 106), whereas substantially more discontinuations occurred among older patients (9 of 50) in the placebo group (4 of 81 younger patients).
 
In the overall analysis, lenvatinib-treated patients had a higher objective response rate (secondary endpoint) than placebo-treated patients. In the lenvatinib arm, younger patients had a higher response rate versus the older subgroup (71.6% versus 54.7%).
 
The improvement in PFS with lenvatinib was observed in younger patients (20.2 versus 3.2 months, HR = 0.19, P <.0001) and older patients (16.7 versus 3.7 months, HR = 0.27, P <.0001). PFS did not differ significantly between younger and older patients in either treatment group.
 
The survival analysis revealed a significant improvement in survival among older patients treated with lenvatinib versus older patients in the placebo group (P = .02). Median OS had yet to be reached in either age group in the lenvatinib arm (95% CI, 22 months to not evaluable in both age groups). In contrast, older patients in the placebo arm had a significantly shorter survival compared with younger patients (P  = .0104).
 
Examination of potential contributors to the age-associated survival disparity in the placebo arm showed no significant differences in the number of prior therapies targeting VEGF, performance status, body mass index, or baseline comorbidities. A similar proportion of older and younger patients in the placebo group crossed over to lenvatinib at progression.
 
Importantly, the age-associated difference in survival in the placebo group could not be explained by post-SELECT therapies that patients received, which was similar between the older and younger subgroups.
 
“Some people might say that you shouldn’t treat older patients because they are too frail, but on the basis of these results, I would argue that you should treat them, because they are frail,” said Brose.

Brose MS, Schlumberger M, Tahara M, et al. Effect of age and lenvatinib treatment on overall survival for patients with 131I-refractory differentiated thyroid cancer in SELECT. J Clin Oncol 33, 2015 (suppl; abstr 6048).
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