Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma.

BACKGROUND: Proteinuria monitoring is required in patients receiving lenvatinib, however, current methodology involves burdensome overnight urine collection. METHODS: To determine whether the simpler urine protein:creatinine ratio (UPCR) calculated from spot urine samples could be accurately used for proteinuria monitoring in patients receiving lenvatinib, we evaluated the correlation between UPCR and 24-hour urine protein results from the phase 3 REFLECT study. Paired data (323 tests, 154 patients) were analysed. RESULTS: Regression analysis showed a statistically significant correlation between UPCR and 24-hour urine protein (R2: 0.75; P < 2 × 10-16). A UPCR cut-off value of 2.4 had 96.9% sensitivity, 82.5% specificity for delineating between grade 2 and 3 proteinuria. Using this UPCR cut-off value to determine the need for further testing could reduce the need for 24-hour urine collection in ~74% of patients. CONCLUSION: Incorporation of UPCR into the current algorithm for proteinuria management can enable optimisation of lenvatinib treatment, while minimising patient inconvenience. CLINICAL TRIAL REGISTRATION: NCT01761266.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.

BACKGROUND: In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS: This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS: Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING: Eisai Inc.