The Lynx Group

SELECT: Lenvatinib Improves Outcomes as First-Line Treatment in Older Patients with Thyroid Cancer

September 2015, Vol 6, No 8

Chicago, IL—Lenvatinib (Lenvima) was approved by the FDA in February 2015 for the treatment of patients with advanced radioactive iodine (131I)-refractory differentiated thyroid cancer based on the SELECT trial results. Investigators looked at which patients will preferentially benefit from this oral tyrosine kinase inhibitor (TKI). At the 2015 American Society of Clinical Oncology meeting, 2 subgroup analyses of SELECT shed light on patient selection for treatment with lenvatinib.

SELECT was a randomized, double-blind, multicenter phase 3 study of 392 patients with advanced 131I-refractory differentiated thyroid cancer who received lenvatinib or placebo.

The primary analysis showed that patients who received lenvatinib had significantly longer progression-free survival (PFS); in fact, PFS was prolonged by an absolute difference of 14.7 months favoring lenvatinib (P <.001). This translated to a 79% reduced risk for disease progression in the group receiving lenvatinib. However, no difference in overall survival (OS) was found between the lenvatinib and placebo cohorts. After disease progression in the placebo arm, 83% of the patients crossed over to the lenvatinib arm.

A subanalysis of this study evaluated the impact of age on OS, dividing patients into 2 age-groups. In the ?65-year age-group, 155 patients were randomized to lenvatinib and 81 received placebo. Of the older group (>65 years), 106 patients were in the lenvatinib group and 50 in the placebo group.

The duration of exposure to lenvatinib was similar in both age-groups (approximately 13.5 months). The patients aged >65 years had a substantially shorter time to first dose reduction than the younger patients, which likely led to the significantly lower median lenvatinib dose intensity observed in older versus younger patients, noted lead investigator Marcia S. Brose, MD, PhD, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

At a median follow-up of 17.1 months, the median OS was not reached in any group, with the exception of older patients who were randomized to placebo and achieved a median OS of 18.4 months. In older patients, a significant OS difference was observed favoring lenvatinib over placebo (P = .02). No significant PFS differences were seen between older and younger patients who were assigned to lenvatinib.

Dr Brose said that crossover probably confounded survival differences, and no TKIs have increased OS in any single study. She also noted that these findings suggest that lenvatinib may be used as first-line therapy in older patients.

Potential Lenvatinib Biomarkers in Thyroid Cancer

A second study focused on the pharmacodynamic biomarkers in the SELECT trial in an attempt to explain the biology underlying the PFS results, and perhaps to identify the biomarkers that are predictive of improved response. Blood samples were collected from patients at baseline, on day 15 of the first cycle, on day 1 of subsequent cycles, and at the end of treatment.

The changes in thyroglobulin levels were associated with tumor shrinkage and overall response, whereas elevated fibroblast growth factor (FGF) 23 was associated with longer PFS.

“Our analysis provided further data suggesting that lenvatinib is targeting both VEGF [vascular endothelial growth factor] and FGF receptor signaling networks in patients, which is consistent with preclinical studies, and, of note, indicated that lenvatinib is effective in inhibiting the FGF receptor, an emerging target for thyroid cancer progression and escape mechanisms against VEGF-targeted therapies,” said lead investigator Makoto Tahara, MD, PhD, Chief, Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Dr Tahara said that the evidence from the pharmacodynamic subanalysis of SELECT suggests that changes in thyroglobulin levels may be helpful in monitoring responses to treatment, and that additional guidance may emerge as to how VEGF and angiopoietin-2 can be used to monitor response.

Previous VEGF Treatment

A prespecified analysis of SELECT showed no significant difference in PFS or overall response rates between the patients who had not received previous VEGF-targeted treatment (treatment-naïve) and those who had. However, PFS was numerically longer in the VEGF-naïve population, suggesting that this may be a preferred first-line agent.

“Lenvatinib may provide better outcomes when used first line,” noted lead investigator Kate Newbold, MD, MBChB, MRCP, Consultant Clinical Oncologist, the Royal Marsden National Health Service Foundation Trust, London, England.

In SELECT, 195 patients who received lenvatinib and 104 patients who received placebo were treatment-naïve; 66 and 27 patients, respectively, had received previous VEGF-targeted therapy.

The median PFS was statistically similar regardless of VEGF treatment status, at 18.7 months for the VEGF-naïve group versus 15.1 months for VEGF-treated patients.

The overall response rates were 65.6% for VEGF-naïve patients and 62.1% for VEGF-treated patients.

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