Table 6.

Food and Drug Administration benefit‐risk summary

Dimension	Evidence and uncertainties	Conclusions and reasons
Analysis of condition	Approximately 42,220 new cases and approximately 30,200 deaths due to HCC estimated in the U.S. in 2018. a Estimated 5‐year survival rate is 17.7%. The 5‐year survival rates are 11% with regional (nodal) involvement and 2% with metastatic disease.	Unresectable HCC is a serious and life‐threatening condition with unmet medical needs.
Current treatment options	Available therapy for untreated unresectable or metastatic Child‐Pugh A HCC is sorafenib. Sorafenib approval based on a single (1:1) placebo‐controlled international trial demonstrating a significant improvement in OS (HR, 0.69; 95% CI, 0.55–0.87) and PFS (HR, 0.58; 95% CI, 0.45–0.74).	One FDA‐approved drug for the first‐line treatment of unresectable HCC.
Benefit	Lenvatinib's effectiveness is based on results of a single adequate and well‐controlled trial, Study 304 (REFLECT), randomizing 954 patients to lenvatinib (n = 478) or sorafenib (n = 476). REFLECT demonstrated that lenvatinib is NI to sorafenib for OS (HR, 0.92; 95% CI, 0.79–1.06) according to prespecified NI margin (≤1.08); median OS was 13.6 months (95% CI, 12.1–14.9) and 12.3 months (95% CI, 10.4–13.9) in lenvatinib and sorafenib arms, respectively. REFLECT also demonstrated a significant improvement in investigator‐assessed PFS according to mRECIST. Similar treatment effects on PFS (HR,0.65; 95% CI, 0.56–0.77) were observed by IRF‐assessed per RECISTv1.1 and mRECIST. REFLECT demonstrated a significant improvement in investigator‐assessed ORR per mRECIST (24.1% vs. 9.2%) for lenvatinib. Similar effects on ORR assessed by IRF were observed. The magnitude of ORR was greater when assessed using mRECIST than with RECISTv1.1 in both treatment arms.	REFLECT demonstrated that lenvatinib has an effect on OS that is noninferior to sorafenib and demonstrated superior investigator‐assessed PFS and ORR. PFS and ORR effects supported by IRF assessment.
Risk and risk management	The single‐agent lenvatinib safety profile was previously established in 1,421 patients with advanced cancers across multiple clinical trials. The safety profile in lenvatinib‐treated patients in REFLECT identified no new or unexpected adverse reactions.	Product labeling adequately conveys risks of lenvatinib and mitigates risks of serious toxicities to facilitate a choice between lenvantinib or sorafenib treatment.

^aClinicalTrials.gov [10].

Abbreviations: CI, confidence interval; FDA, Food and Drug Administration; HCC, hepatocellular carcinoma; HR, hazard ratio; IRF, independent radiology facility; mRECIST, modified RECIST for HCC; NI, noninferiority; ORR, overall response rate; OS, overall survival; PFS, progression‐free survival.