REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

Abstract

Background: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported.

Methods: The intent-to-treat population enrolled in Japan was analyzed.

Results: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm.

Conclusions: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.

Trial registration id: ClinicalTrials.gov. No. NCT01761266.

Keywords: Hepatocellular carcinoma; Japanese population; Lenvatinib; REFLECT trial; Sorafenib.

Fig. 1

Kaplan–Meier analysis of overall survival (a) and progression-free survival (b) in the lenvatinib arm and the sorafenib arm of the Japanese unresectable HCC population

Fig. 2

Waterfall plot showing maximum changes in tumor size in the Japanese patients by lenvatinib and sorafenib. Target regions of tumors were examined in the individual patients and assessed for tumor size by local investigators (a, b) and by masked independent imaging review (c, d) according to mRECIST. The waterfall plot represents maximum changes in tumor size of each patient receiving lenvatinib (a, c) and sorafenib (b, d)

Fig. 3

Box plot of lenvatinib AUC predicted in the Japanese population. A population pharmacokinetic analysis was performed in the Japanese population receiving lenvatinib. The box plot represents predicted lenvatinib exposure (AUC) by starting dose (8 mg/day or 12 mg/day). Bar in the box, median value; uppermost and lowermost sides of the box, first and third quartiles, respectively; brackets, range of individual AUCs excluding the outliers denoted by open circles