1. May, Brandon

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Nearly 90 percent of thyroid carcinomas are classified as differentiated thyroid cancers (DTCs) and feature follicular, Hurthle, or papillary cell morphology. Approximately 15 percent of these DTCs eventually become refractory to radioiodine treatment. In previous research, investigators observed a median rate of survival of 3-6 years in patients with metastatic refractory DTC, indicating the significant poor prognosis in this patient population (Expert Review of Endocrinology & Metabolism 2012;7(5):541-554, J Clin Endocrinol Metab 2006;91(8):2892-2899).

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Lenvatinib, a multi-targeted tyrosine kinase inhibitor directed against vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 as well as platelet- and fibroblast-derived growth receptors, is currently indicated for radioiodine-refractory DTC. Approval for lenvatinib use in refractory DTC was primarily based on the randomized Study of Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) phase III study, which demonstrated significant improvement in median progression-free survival (PFS) compared with placebo in radioiodine-refractory DTC patents (N Engl J Med 2015;372(7):621-630).


Benefit Among Older DTC Patients

Results from a recent subanalysis of the SELECT study published in the Journal of Clinical Oncology found that, despite higher rates of toxicities observed in older DTC patients refractory to radioiodine therapy, there is an improvement in PFS regardless of age (2017;35(23):2692-2699). Although therapy-related toxicities aren't uncommon in this population, the coordination and communication between patient and physician, as well as the timely management of symptoms, is key for optimizing overall outcomes in older patients prescribed lenvatinib.


"The patients and physicians who work closely together to manage the toxicities well will have the best results overall," explained the lead study author, Marcia S. Brose, MD, PhD, Associate Professor at the University Of Pennsylvania School Of Medicine, Philadelphia, in the Departments of Otorhinolaryngology: Head and Neck Surgery, and Medicine, Division of Hematology/Oncology.



In this substudy, investigators stratified patients by age (<= 65 or > 65 years), whether or not they had a history of VEGF-targeted treatment, and geographic location (Europe, North America, or other). Patients were then randomized to receive either 24 mg lenvatinib once a day (n = 261) or placebo in cycles of 28 days until confirmation of disease progression (n = 131). Open-label lenvatinib was offered to patients in the placebo group if disease progressed. Patients >65 years old comprised 39.8 percent of the entire cohort (n = 156). As expected from the findings in the original SELECT study, researchers observed similar baseline characteristics among both the lenvatinib and placebo groups.


Progression-Free Survival

Primary endpoint for this study was the intent-to-treat population's PFS, whereas secondary endpoints included overall survival (OS) and safety outcomes. Safety was assessed via the recording of vital signs and symptoms, urinalysis, electrocardiography, echocardiography, and hematologic and biochemical testing. The NCI Common Terminology Criteria for Adverse Events version 4.0 was used for assessing adverse events (AEs).


Among patients <=65 years in the lenvatinib versus placebo groups, the median PFS was 20.2 months versus 3.2 months, respectively (HR, 0.19; 95% CI, 0.13-0.27; P <.001). Median PFS in patients >65 years was 16.7 months versus 3.7 months (HR, 0.27; 95% CI, 0.17-0.43; P <.001). Researchers concluded that there was no significant difference between older and younger patients in in the placebo (HR, 1.12; 95% CI, 0.74-1.71; unstratified log-rank P =.74) or lenvatinib (HR, 0.80; 95% CI, 0.54-1.18; unstratified log-rank P =.24) arms in regard to PFS.


According to initial exploratory analyses, investigators saw no significant difference between older and younger patients in regard to Eastern Cooperative Oncology Group (ECOG) performance status at baseline (lenvatinib: P =.56 vs. placebo: P =.46). Older patients did have a numerically higher mean baseline tumor burden as represented by total target lesion diameters (74.7 mm vs. 67.4 mm; P =.11). In the placebo group, older patients had a higher number of median target lesions versus younger participants in the placebo group and both age groups in the lenvatinib arm (3 vs. 2, respectively).


Overall Survival

The median OS at a median follow-up period of 18.4 months occurred only in older patients treated with placebo (95% CI, 13.3-20.3). There was a significant improvement in OS among older patients receiving lenvatinib compared to placebo (HR, 0.53; 95% CI, 0.31-0.91; P =.020).


Among patients receiving placebo, a longer OS was observed in patients <=65 years versus >65 years (HR, 0.48; 95% CI, 0.27-0.85; P =.010). In the lenvatinib arm, there was no significant difference in OS between age groups (HR, 0.78; 95% CI, 0.49-1.26; P =.30). Analyzed as a continuous variable, researchers observed a significant correlation between age and shorter OS in the placebo group (P =.018), but not the lenvatinib group (P =.082).


Since no significant differences in patient characteristics were observed at baseline, differences were assessed following the study to determine potential contributing factors or underlying confounders that might provide more clarity on the OS improvement among older patients in the lenvatinib arm. There was no significant difference in the number of placebo patients who later received open-label lenvatinib following disease progression (placebo: younger, 85% vs. older, 80%; P =.44), nor were there any differences between the number of younger and older patients receiving post-study anticancer therapy in either the lenvatinib or placebo arms.


Adverse Events

There were significantly higher rates of severe treatment-related AEs (grade >=3) in older versus younger patients (89% vs. 67%, respectively; P < .001). Hypertension was the most common AE related to treatment, occurring in 67-69 percent of all patents in the lenvatinib group. Younger and older patients demonstrated similar rates of fatal AEs (7% and 9%, respectively).



Although lenvatinib is approved for use in patients with RAI refractory to DTC, there is some concern among clinicians in prescribing this medication in older population groups due to these patients' greater number of comorbidities. Also, few data currently demonstrate a clear survival benefit of lenvatinib in this patient group. The findings generated by Brose's team, however, aimed to challenge conventional wisdom as it relates to lenvatinib use, particularly in elderly patients. According to Brose, "Our work shows that the older patients clearly benefit with an improved survival and tolerate it with close attention to side effect management."


Older patients tend to experience greater levels of mortality across disease types, especially in cancer. Perhaps the most surprising finding of this study, noted Brose, was that "the older patients showed a clear benefit in overall survival." This significant benefit provides greater hope in the field of cancer and will perhaps facilitate improved survival in patients with RAI refractory thyroid cancer overall.


The investigators urge readers to interpret the results with caution due to the fact that the SELECT study's OS data was not mature enough at the primary data cutoff time. Additionally, authors note that patients with an ECOG performance status of <=2 were the only participants in SELECT; therefore, the "preselected population...may not be completely representative of older patients in the clinical setting."


Impact on Current Practice

Brose doesn't believe there are any foreseeable challenges or roadblocks related to this study and its ability to sway clinicians toward prescribing lenvatinib for radioiodine-refractory thyroid cancer in older patients. "If anything," said Brose, "our data removes a concern for physicians in prescribing this medication in the older population." The findings of this study, therefore, challenge conventional practice that advises against prescribing lenvatinib in patients >65 years in order to avoid treatment-related toxicities.


Brose hopes this study will facilitate further research into older patient populations, particularly studies demonstrating efficacy and safety outcomes associated with lenvatinib therapy in refractory DTC.


"Many times, research studies overlook the population of patients over 65 and make assumptions that they will not do as well," stated Brose.


While these assumptions may have held true in the past with some traditional chemotherapy treatments, she added, oral agents may behave differently and require additional study in older patients. Ultimately, researchers hope these findings will eventually impact oncology care and improve prognosis for older radioiodine-refractory DTC patients.


Brandon May is a contributing writer.