Real-World Data for Lenvatinib Is Similar to Clinical Trials

Yael Celermajer, MD

Although lenvatinib (Lenvima) has shown antitumor effects in hepatocellular carcinoma (HCC), long-term safety data are lacking. In general, lenvatinib is associated with favorable efficacy, but it is also associated with adverse effects (AEs) that require monitoring and proactive management by the clinician.

Findings from a real-world safety and tolerability trial demonstrated that the agent’s safety profile was similar to that observed in initial clinical trials, according to a poster presented at The Liver Meeting Digital Experience, the American Association for the Study of Liver Diseases annual conference. Yael Celermajer, MD, and coinvestigators noted in their poster that hypothyroidism occurred more frequently in this real-world cohort (39%). This AE was independently associated with improved overall survival (OS) in lenvatinib-treated patients with HCC.

Fifty-one patients were treated with lenvatinib between December 2018 and June 2020, with 90% of patients experiencing an AE. Hypertension and hypothyroidism were the most common AEs, with 47% of patients reporting new or worsening hypertension and 39% reporting hypothyroidism (FIGURE see page 47).

Among patients reporting new or worsening hypertension, 88% required antihypertensive medication; 15 patients required 1 antihypertensive agent, 5 patients required 2 agents, and 2 patients required more than 2 agents. Among patients who developed hypothyroidism (thyroid stimulating hormone > 4.20 mIU/L), 75% required thyroid replacement therapy.

Severe AEs included duodenal ulcer (2%), malignant hypertension (2%), anaphylaxis (2%), and sudden unexplained death after starting therapy (2%). Investigators reported that 41% of patients had a dose reduction and that treatment was temporarily held in 35% of patients.

Patients who developed hypothyroidism while on therapy had a greater median OS than those who did not. The median OS for patients with normal thyroid function was 309 days; for those with hypothyroidism, the median OS was not reached (P = .033).

On univariable analysis, predictors of survival were hypothyroidism, and baseline albumin and bilirubin levels. On multivariable analysis, albumin and bilirubin levels remained significant.

The primary objectives of the study were to elucidate the type, rate, and severity of AEs. Secondary objectives were to determine rates of dose reduction, discontinuation, and OS.

Patients were a mean age of 64 years, 44 patients were male, and 43 patients had received prior treatment for HCC, specifically transarterial chemoembolization (57%), resection (31%), ablation (20%), sorafenib ([Nexavar], 20%), and selective internal radiation therapy (10%).

At a median follow-up of 216 days, 59% of patients had ceased treatment with lenvatinib. Investigators reported that reasons for stopping therapy were disease progression (31%), intolerance (20%), and death while on therapy (8%).

Forty-seven percent of patients had preexisting hypertension, and 90% had cirrhosis caused by hepatitis C (43%), hepatitis B (20%), and alcohol (16%). Regarding prognosis, 74% of patients were Child-Pugh A, 24% were Child-Pugh B, and 2% were Child-Pugh C.

Further, 63% of patients were Barcelona Clinic Liver Cancer (BCLC) stage C and 37% were BCLC stage B.

Lenvatinib gained its approval for the first-line treatment of patients with unresectable HCC based on the open-label, noninferiority REFLECT trial (NCT01761266).² The trial’s findings showed that lenvatinib was noninferior but not statistically superior to sorafenib (Nexavar) for OS (HR, 0.92; 95% CI, 0.79- 1.06). The most common AEs observed in the lenvatinib-treated patients with HCC in order of decreasing frequency were hypertension, fatigue, diarrhea, and decreased appetite.

_References:

_{1. Celermajer Y, Prince DS, Stratton E, et al. Real-world safety and tolerability data for lenvatinib use in unresectable hepatocellular cancer. Presented at: American Association for the Study of Liver Diseases The Liver Meeting Digital Experience; November 13-16, 2020; virtual. Abstract 1167. Accessed January 12, 2021. https://bit.ly/2LQJaFC}

_{2. FDA approves lenvatinib for unresectable hepatocellular carcinoma. FDA. Updated August 16, 2018. Accessed January 13, 2021. https://bit.ly/3i8l5Vw}