Meta-analysis: Lenvatinib boosts survival in refractory thyroid carcinoma with caveat

In the treatment of patients with radioiodine-refractory thyroid carcinoma, lenvatinib may improve their chances of survival but at the cost of a high adverse event (AE) rate, according to the results of a meta-analysis.

Pooled data from 14 studies showed that compared with placebo, lenvatinib prolonged progression-free survival (PFS; hazard ratio [HR], 0.24, 95 percent confidence interval [CI], 0.19–0.31; p<0.001) and overall survival (OS; HR, 0.65, 95 percent CI, 0.52–0.81; p<0.001). [Clin Endocrinol 2021;doi:10.1111/cen.14479 ]

“However, [the drug] was associated with significant grade 3 or above AEs (risk ratio, 8.25, 95 percent CI, 6.50–10.46; p<0.001),” the investigators said.

Treatment-emergent hypertension (TE-HTN) was the most common AE, followed by proteinuria (median time to onset, 6.1 weeks). The former is said to be the outcome of an accumulated high-dose exposure to lenvatinib. As such, TE-HTN may be resolved upon dose interruptions and/or reductions, the investigators pointed out.

“[Meanwhile], proteinuria is considered to be a class effect of antiangiogenic treatments. Decision to interrupt medication or modification of dosage should be done on case-by-case analysis within the period of proteinuria,” they added. 

The pooled study population comprised 3,997 patients (mean age 62.5 years). All studies consistently showed that the median PFS was longer with lenvatinib (7.3–33.1 months) than with placebo (3–12.9 months). The former also showed a promising effect on objective response rate (ORR; risk ratio, 35.41, 95 percent CI, 19.42–64.58; p<0.001).

“With a high ORR, lenvatinib significantly reduce[d] tumour size. In a study by Robinson [and colleagues] on the characterization of tumour size changes over time in 392 patients, the mean maximum change in tumour was significantly higher in the four categories of metastasis (lung, liver, lymph node, and bone). The tumour reduction occurred in two phases, with the first 8 weeks of rapid reduction by an average of 25.2 percent, followed by a slower, continuous average rate of reduction by 1.3 percent per month,” the investigators noted. [J Clin Endocrinol Metab 2016;101:4103‐4109]

Subgroup analyses showed that lenvatinib conferred survival benefits for all patients with radioiodine-refractory thyroid carcinoma, regardless of age, histological subtypes, radiological subtypes, and mutation status.

“All studies included are clinical trials with high evidence values. One limitation of the study is [that] the numerical value of median PFS and OS could not be obtained, since many patients did not reach the primary endpoints during the follow-up period,” according to the investigators.

A multi-kinase inhibitor for the treatment of several types of cancers, lenvatinib has been approved as a treatment for radioiodine-refractory thyroid carcinoma since 2015. In light of the elevated incidence of AEs, the investigators recommended close clinical monitoring during treatment. [Clin Cancer Res 2015;21:5205‐5208]

In case of treatment failure, combining lenvatinib with another drug may be considered to achieve a higher efficacy, they added. Combinations that have been explored so far include those with anti-PD-1/PD-L1, pembrolizumab, and immune checkpoint inhibitor.

More studies are needed to explore the lenvatinib-based combination of treating treatment-resistant thyroid carcinoma, the investigators said.