In a phase III trial reported in The New England Journal of Medicine, Martin Schlumberger, MD, of Institut Gustave Roussy, and colleagues found that the multikinase inhibitor lenvatinib (Lenvima) produced a large improvement in progression-free survival vs placebo in patients with advanced radioiodine-refractory differentiated thyroid cancer.¹ Adverse events were more common with lenvatinib. The trial served as the basis for the recent U.S. Food and Drug Administration approval of lenvatinib in this setting.

Lenvatinib is an inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT.

Study Details

In this double-blind trial conducted in the Americas, Europe, Asia, and Australia, 392 patients with progressive thyroid cancer refractory to iodine-131 and disease progression within the prior 12 months were recruited between August 2011 and October 2012. Progression at baseline was confirmed by incidence rate ratio.

Patients were randomly assigned 2:1 to receive lenvatinib at 24 mg/d in 28-day cycles (n = 261) or placebo (n = 131). Patients in the placebo group could cross over to open-label lenvatinib at disease progression. The primary endpoint was progression-free survival using independent radiologic review.

The lenvatinib and placebo groups were generally balanced for age (median, 64 and 61 years), region (Europe for 50% and 49%, North America for 30% in both, other for 20% and 21%), Eastern Cooperative Oncology Group performance status of 0 or 1 (95% and 98%), one prior tyrosine kinase inhibitor therapy (25% and 21%), histologic subtype (papillary in 51% and 52%, poorly differentiated in 11% and 14%, follicular–non-Hürthle cell in 20% and 17%, Hürthle cell in 18% and 17%), and presence of bony metastases (40% and 37%) and pulmonary metastasis (87% and 95%). A greater proportion of placebo patients were male (57% vs 48%).

Progression-Free Survival

At the time of data cutoff (November 2013), the median duration of follow-up was 17.1 months in the lenvatinib group and 17.4 months in the placebo group; 130 patients were still receiving blinded treatment, including 122 in the lenvatinib group (47%) and 8 in the placebo group (6%). Among 114 eligible placebo patients with tumor progression, 109 (96%) elected to receive open-label lenvatinib. A total of 41 lenvatinib patients (16%) received additional therapy after disease progression.

Median progression-free survival was 18.3 months in the lenvatinib group vs 3.6 months in the placebo group (hazard ratio [HR] = 0.21, P < .001), with benefit of lenvatinib being observed in all prespecified subgroups. Progression-free survival was 63.0% vs 10.5% at 12 months and 44.3% vs not estimable at 24 months.

Response Rate, Overall Survival

The response rate was 64.8% in the lenvatinib group (including four complete responses) vs 1.5% in the placebo group (odds ratio [OR] = 28.87, P < .001). Stable disease was observed in 23.0% vs 54.2% of patients, and the disease control rate was 87.7% vs 55.7% (OR = 5.05, P < 001). The median time to response in the lenvatinib group was 2.0 months.

Median overall survival (using rank-preserving structural failure time to adjust for potential crossover bias) was not reached in either the lenvatinib group (95% confidence interval [CI] = 22.0 months to not estimable) or the placebo group (95% CI = 14.3 months to not estimable (HR = 0.62, P = .05). Overall survival was 81.6% vs 70.0% at 12 months and 58.2% vs not estimable at 24 months.

Similar benefits were achieved in both treatment-naive patients and those who had already been treated with one line of an antiangiogenic tyrosine kinase inhibitor.

Adverse Events

The median duration of treatment was 13.8 months in the lenvatinib group and 3.9 months in the placebo group. Treatment-related adverse events of any grade occurred in 97% vs 60%, with grade ≥ 3 events in 76% vs 10%. The most common treatment-related adverse effects of any grade in the lenvatinib group were hypertension (68% vs 9% in placebo group), diarrhea (59% vs 8%), fatigue or asthenia (59% vs 28%), and decreased appetite (50% vs 12%). The most common grade ≥ 3 adverse events were hypertension (42% vs 2%), proteinuria (10% vs 0%), decreased weight (10% vs 0%), and fatigue/asthenia (9% vs 2%).

In addition to hypertension and proteinuria, adverse events of special interest in the lenvatinib group consisted of arterial thromboembolic effects (5.4% any grade, 2.7% grade ≥ 3), venous thromboembolic effects (5.4%, 3.8%), renal failure including acute renal failure (4.2%, 1.9%), hepatic failure (0.4% grade ≥ 3), gastrointestinal fistula (1.5%, 0.8%), corrected QT prolongation (8%, 1.5%), and posterior reversible encephalopathy syndrome (0.4%, 0%).

Adverse events led to discontinuation of the study drug in 14.2% vs 2.3% of patients, with the most common causes in the lenvatinib group being hypertension and asthenia (both 1.1%). Adverse events led to dose interruption in 82.4% vs 18.3% and dose reduction in 67.8% vs 4.6%. The most common adverse events leading to dose interruption or reduction were diarrhea (22.6%), hypertension (19.9%), proteinuria (18.8%), and decreased appetite (18.0%).

Adverse events considered related to treatment led to death in six lenvatinib patients (2.3%), including pulmonary embolism, hemorrhagic stroke, and general deterioration of physical health in one patient each and three cases reported as death or sudden death (not otherwise specified).

The investigators concluded: “Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and response rate among patients with iodine-131–refractory thyroid cancer. Patients who received lenvatinib had more adverse effects.” ■

Disclosure: This study was funded by Eisai. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015.

Lori J. Wirth, MD, of Dana-Farber/Harvard Cancer Center, discusses treatment options for patients with radioiodine-refractory thyroid cancer.