July 2015, Special ASCO Edition

← Back to Issue

Clues to Patient Selection for Lenvatinib in Thyroid Cancer

Uncategorized

Lenvatinib was approved by the FDA in February of this year for the treatment of patients with advanced 131I-refractory differentiated thyroid cancer based on results from the SELECT trial. However, it is important to identify which patients will preferentially benefit from this oral tyrosine kinase inhibitor (TKI). At ASCO, 2 subgroup analyses of SELECT shed some 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 treated with either lenvatinib or placebo. Results of 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 of disease progression for the lenvatinib-treated group. However, no difference in overall survival (OS) was found between lenvatinib and placebo. After disease progression on the placebo arm, 83% of patients crossed over to lenvatinib.

A subanalysis of this study evaluated the effect of age on OS in the SELECT trial, according to age ?65 years or >65 years. In the ?65-year age group, 155 patients were randomized to lenvatinib and 81 to placebo. There were 106 older (>65 years) patients in the lenvatinib group and 50 in the placebo group.

Duration of exposure to lenvatinib was similar in both age groups—about 13.5 months. Patients >65 years had a substantially shorter time to first dose reduction compared with younger patients, which probably led to the significantly lower median lenvatinib dose intensity observed in older versus younger patients, noted lead author Marcia S. Brose, MD, PhD, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

At a median follow-up of 17.1 months, median OS was not reached in any group, with the exception of older patients randomized to placebo (18.4 months). In older patients, a significant difference was observed in OS favoring lenvatinib over placebo (P = .02). A related analysis found no OS difference in older and younger patients treated with lenvatinib, but there was a statistically significant difference in the placebo arm favoring younger patients (P = .010).

No significant differences in PFS were observed between older and younger age groups assigned to lenvatinib.

Brose noted that crossover probably confounded survival differences. She noted that no TKIs have increased OS in any single study. She also noted that 2 new drugs are now approved by the FDA for thyroid cancer, and these findings suggest that lenvatinib might be used first in older patients (Abstract 6014).

Pharmacodynamic Biomarkers

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

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 author Makoto Tahara, MD, National Cancer Center Hospital East, Kashiwa, Japan.

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 Ang2 can be used to monitor response (Abstract 6014).

Prior VEGF Treatment

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

“Lenvatinib may provide better outcomes when used first-line,” noted lead author Kate Newbold, MD, of the Royal Marsden NHS Foundation Trust in London, UK.

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

Median PFS was statistically similar regardless of VEGF treatment status: 18.7 months for the VEGF-naive group versus 15.1 months for VEGF-treated patients.

The overall response rate was 65.6% for VEGF-naive patients and 62.1% for VEGF-treated patients (Abstract 6013).

Immunotherapy - August 13, 2015

Encouraging Results for Pembrolizumab in Head and Neck Cancer

Pembrolizumab achieved “remarkable” results in a phase 1 study of previously treated, recurrent, squamous cell carcinoma of the head and neck. Tumor shrinkage was observed in 57% of these poor-prognosis, heavily pretreated patients, and 24.8% had partial or complete response on treatment with pembrolizumab in an expansion cohort of the [ Read More ]

Genetics - August 13, 2015

Genetic Abnormality Pinpointed for Intensive Therapy in Wilms Tumor

In children with favorable-risk Wilms tumor, the presence of a rare genetic abnormality identifies children who can have a survival benefit from the augmentation or intensification of therapy. The abnormality—loss of heterozygosity on chromosomes 1p and 16q (LOH 1p, 16q)—is associated with worse prognosis in children with Wilms tumor. Two [ Read More ]