SELECT Subanalyses Provide Patient Selection Insight for Lenvatinib

Two subgroup analyses of the SELECT trial, testing the multi-kinase inhibitor (MKI) lenvatinib in differentiated thyroid carcinoma, provide clinicians with increased knowledge about which patients will benefit most from the drug. Results of these analyses were presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.

SELECT was a randomized, double-blind, multicenter phase III study of patients with differentiated thyroid cancer who were randomly assigned to treatment with lenvatinib or placebo. Results of the primary analysis showed that lenvatinib significantly prolonged progression-free survival by 14.7 months compared with placebo (hazard ratio [HR] = 0.21; 99% CI, 0.14–0.31; P < .001). However, no difference in overall survival was found between the study arms.

The first subanalysis was a poster presentation by Marcia S. Brose, MD, PhD, associate professor of otorhinolaryngology: head and neck surgery at the Hospital of the University of Pennsylvania, and colleagues, that looked at the effect of age on overall survival, separating patients into subgroups of 65 years or younger and those aged older than 65 (abstract 6048).

The researchers found that duration of lenvatinib exposure was similar in both age groups (13.9 vs 13.5 months for young and older patients, respectively). However, patients aged older than 65 had a substantially shorter time to first dose reduction than younger patients, which the researchers said “likely contributed to the significantly lower median lenvatinib dose intensity observed in older vs younger patients.”

No significant differences in progression-free survival were found between the older and younger patients assigned lenvatinib.

At a median follow-up of 17.1 months, overall survival was significantly improved in the older patient group assigned lenvatinib compared with those assigned placebo (HR = 0.53; 95% CI, 0.31–0.91; P = .02). The median overall survival for the younger group of patients had not yet been reached.

“MKIs have not been shown to increase overall survival in a single trial due to sequential therapies and crossover designs,” Brose told Cancer Network. “ This finding is in the older population, a population that some physicians have been hesitant about treating. As there are now two FDA approved agents it may justify lenvatinib being used first in this population.”

No substantial different in treatment-emergent adverse events of treatment discontinuation due to reasons other than progressive disease were noted between the two age groups.

The second poster presentation (abstract 6014) by Makoto Tahara, MD, PhD, of the National Cancer Center Hospital East, Japan, studied the pharmacodynamics biomarkers from the SELECT trial in an attempt to help clinicians understand the biology underlying the robust progression-free survival results and possibly discover markers suggestive of a better response.

For this analysis, blood samples were collected from patients at baseline, on day 15 of the first cycle, day 1 of subsequent cycles, and at treatment end.

The researchers found that changes in the levels of certain markers were correlated with different outcomes. Specifically, changes in thyroglobulin levels were correlated with tumor shrinkage and overall response, and elevated FGF23 was associated with longer progression-free survival.

“This analysis also provided further data suggesting that lenvatinib is indeed targeting both VEGF and FGFR signaling networks in patients, which is consistent with preclinical studies and, of note, indicates that lenvatinib is effective in inhibiting the FGF receptor, an emerging target for thyroid cancer progression and escape mechanisms against VEGF-targeted therapies,” Tahara told Cancer Network. “Additionally, identification of the Ang2/Tie2 axis for potential future biomarker analyses may help researchers focus on a particular system that may provide guidance on the use and monitoring of lenvatinib treatment.”

Based on these results, Tahara said that changes in thyroglobulin levels may be useful in monitoring responses to treatment and that additional guidance on how VEGF and Ang2 can be used to monitor response may be forthcoming.