Clinical trialPhase 3Liver cancer

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

Lancet · 2018954 patients (478 lenvatinib, 476 sorafenib)

Kudo M, Finn RS, Qin S, et al. Lancet. 2018. 391:1163-1173

Study type: Clinical trial
Study name: REFLECT
Phase: Phase 3
Design: Randomised (1:1), open-label, non-inferiority, multicentre trial (154 centres in 20 countries)
Sample size: 954 patients (478 lenvatinib, 476 sorafenib)
Source: Lancet · 2018
Trial registration: NCT01761266

In plain words

This study compared lenvatinib tablets with sorafenib tablets, which was the only standard drug at the time for advanced liver cancer. Lenvatinib kept patients alive at least as well as sorafenib and had a different pattern of side effects: high blood pressure was more common with lenvatinib, and a skin reaction on the hands and feet was more common with sorafenib. Today, lenvatinib is an option for patients who cannot receive immunotherapy.

Key results

13.6 vs 12.3 months

Median overall survival

HR 0.92 (95% CI 0.79–1.06); non-inferiority criterion met (margin 1.08)

7.3 vs 3.6 months

Median progression-free survival (mRECIST)

HR 0.64 (95% CI 0.55–0.75); p<0.001; FDA label

41% vs 12%

Objective response rate (mRECIST)

Complete response 2.1% vs 0.8%; p<0.001; FDA label

Drugs in this study:Lenvatinib (Lenvima)Sorafenib (Nexavar)

Dose and schedule cards

Lenvatinib (REFLECT)

Unresectable HCC, first-line, particularly when immunotherapy is not suitable; in the trial: Child-Pugh A, ECOG 0–1Cycle length: ContinuousOn the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Unresectable HCC, first-line, particularly when immunotherapy is not suitable; in the trial: Child-Pugh A, ECOG 0–1

Drug	Dose	Route	Schedule
Lenvatinib	Body weight 60 kg or more: 12 mg; body weight less than 60 kg: 8 mg (based on actual body weight)	Oral, with or without food	Once daily, continuous

Cycle length: Continuous
Duration: Until progression or intolerable toxicity

Dose-reduction levels: body weight 60 kg or more: 8 mg daily, then 4 mg daily, then 4 mg every other day; body weight less than 60 kg: 4 mg daily, then 4 mg every other day, then discontinue.

Monitoring: control blood pressure before starting, then measure it after 1 week, every 2 weeks for the first 2 months and at least monthly thereafter; proteinuria and liver tests before starting and periodically; monitor and correct electrolyte disturbances, and withhold for QTc greater than 500 ms. For proteinuria of 2 g or more per 24 hours, withhold and resume at a lower dose; for nephrotic syndrome, gastrointestinal perforation or an arterial thromboembolic event, discontinue permanently. In REFLECT, hepatic encephalopathy occurred in 8% of patients on lenvatinib (grade 3 to 5: 5%).

On the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Lenvatinib

Lenvatinib capsules orally once daily based on baseline weight: 12 mg for weight 60 kg or more and 8 mg for weight below 60 kg, in continuous 28-day cycles until documented disease progression, unacceptable toxicity or patient request.

Dose reduction levels per the FDA label (HCC): weight 60 kg or more: 8 mg daily, then 4 mg daily, then 4 mg every other day; weight below 60 kg: 4 mg daily, then 4 mg every other day, then discontinue. Blood pressure should be controlled before starting and monitored after 1 week, then every 2 weeks for the first 2 months and then at least monthly (FDA label).

2Sorafenib

Sorafenib 400 mg tablets orally twice daily, in continuous 28-day cycles until documented disease progression, unacceptable toxicity or patient request.

Source of the regimen details: Abstract of the paper (Lancet 2018); ClinicalTrials.gov NCT01761266 (arm descriptions: weight-based dose, 28-day cycle, treatment duration); FDA label for Lenvima (DailyMed, Dosage, Dose Reduction and REFLECT study sections)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with unresectable HCC without prior systemic therapy for advanced disease. Per ClinicalTrials.gov and the FDA label: BCLC stage B (unsuitable for TACE) or C, Child–Pugh A, ECOG 0 or 1 and at least one measurable target lesion by mRECIST; albumin 2.8 g/dL or more, bilirubin up to 3 mg/dL, AST, ALT and ALP up to 5 times the upper limit of normal, platelets at least 75,000 per microlitre, INR up to 2.3, creatinine clearance above 40 mL/min and controlled blood pressure (up to 150/90 on up to 3 drugs). Key exclusion criteria: 50% or more liver involvement, obvious bile duct invasion, invasion of the main portal vein trunk (Vp4), proteinuria of 1 g or more per 24 hours, varices requiring intervention in the previous 28 days, gastrointestinal bleeding in the previous 28 days and brain metastases.

Endpoints

Primary outcome: overall survival (from randomisation to death from any cause), with a non-inferiority margin of 1.08.

Other efficacy outcomes (FDA label): progression-free survival and objective response rate by mRECIST.

Safety and side effects

The most common adverse events (any grade) with lenvatinib: hypertension (42%), diarrhoea (39%), decreased appetite (34%) and weight loss (31%); with sorafenib: palmar–plantar erythrodysaesthesia (hand–foot syndrome; 52%), diarrhoea (46%), hypertension (30%) and decreased appetite (27%).

Grade 3–4 adverse events per the FDA label (lenvatinib versus sorafenib): hypertension 24% versus 15%, weight loss 8% versus 3%, fatigue 7% versus 6%, proteinuria 6% versus 2%, decreased appetite 5% versus 1%, haemorrhage 4% versus 4% and hand–foot syndrome 3% versus 11%. With lenvatinib, dose reduction or interruption occurred in 62% and discontinuation due to adverse events in 20% of patients; the most common serious adverse events were hepatic encephalopathy (5%), hepatic failure (3%) and ascites (3%).

Clinical significance and place in guidelines

Based on this study, the FDA approved lenvatinib in 2018 for first-line treatment of unresectable HCC. Since the arrival of immunotherapy combinations, lenvatinib and sorafenib are first-line options in the AASLD 2023 guidance for Child–Pugh A patients in whom immunotherapy combinations are contraindicated (Level 1, Strong) and preferred options after failure of first-line immunotherapy (Level 5, Weak).

Limitations

Open-label, non-inferiority design (survival superiority was not shown); the abstract does not report the percentage of grade 3 or higher adverse events or the full exclusion criteria (including extent of liver involvement and portal vein invasion), so the full text of the paper should be consulted for patient selection; the comparator was sorafenib, and there is no direct comparison with immunotherapy combinations.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.