Clinical trialPhase 3Liver cancer

Sorafenib in advanced hepatocellular carcinoma

N Engl J Med · 2008602 patients

Llovet JM, Ricci S, Mazzaferro V, et al. N Engl J Med. 2008. 359:378-390

Study type: Clinical trial
Study name: SHARP
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled, multicentre trial
Sample size: 602 patients
Source: N Engl J Med · 2008
Trial registration: NCT00105443

In plain words

SHARP was the first study to show that a drug taken by mouth (sorafenib) can help people with advanced liver cancer live longer — by about 3 months on average compared with a placebo (dummy pill). For more than a decade this drug was the mainstay of drug treatment for liver cancer. Today, immunotherapy combinations have replaced it for most patients, but sorafenib is still an option for patients who cannot receive immunotherapy.

Key results

10.7 vs 7.9 months

Median overall survival

HR 0.69 (95% CI 0.55 to 0.87); P<0.001; the study was stopped at the second interim analysis (321 deaths)

5.5 vs 2.8 months

Median time to radiological progression

P<0.001

4.1 vs 4.9 months

Median time to symptomatic progression

P=0.77 — difference not significant

2% vs 1%

Partial response

7 vs 2 patients; no complete responses were seen

Drugs in this study:Sorafenib (Nexavar)

Dose and schedule cards

Sorafenib (SHARP)

Advanced HCC, first-line, when immunotherapy is not suitableCycle length: ContinuousOn the page “Liver cancer” · Advanced hepatocellular carcinoma: first-line

Advanced HCC, first-line, when immunotherapy is not suitable

Drug	Dose	Route	Schedule
Sorafenib	400 mg	Oral, on an empty stomach (1 h before or 2 h after a meal)	Twice daily, continuous

Cycle length: Continuous
Duration: As long as the patient derives clinical benefit, or until intolerable toxicity

Dose-reduction levels: 400 mg once daily, then 200 mg once daily or 400 mg every other day; if more than 2 dose reductions are needed, discontinue permanently.

Monitoring and discontinuation: regular liver tests; discontinue permanently for unexplained transaminase elevation (ALT grade 3 or higher, or AST/ALT more than 3 times the upper limit of normal with bilirubin more than 2 times), grade 2 or higher cardiac ischemia or infarction, bleeding requiring intervention, and gastrointestinal perforation; for QTc greater than 500 ms, withhold and correct electrolytes.

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

1Sorafenib

Sorafenib 400 mg orally (2 × 200 mg tablets) twice daily. Two prespecified dose-reduction levels were allowed for treatment-related adverse events: 400 mg once daily, then 400 mg every other day.

According to the FDA label, sorafenib is taken without food (at least 1 hour before or 2 hours after a meal) for as long as the patient derives clinical benefit or until unacceptable toxicity.

2Placebo

Placebo tablets matching sorafenib, orally twice daily. In the open-label follow-up phase, patients in the placebo group could cross over to sorafenib 400 mg twice daily.

Source of the regimen details: ClinicalTrials.gov NCT00105443 (arm descriptions: dose and dose-reduction levels); abstract of the paper (NEJM 2008); FDA label for Nexavar (DailyMed/openFDA, dosing and SHARP 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

Patients with advanced HCC and no prior systemic therapy. According to ClinicalTrials.gov: age 18 years or older, histologically or cytologically confirmed HCC, at least one measurable lesion per RECIST not previously treated locally, ECOG performance status 0 to 2 and life expectancy of at least 12 weeks; renal failure requiring dialysis, history of cardiac disease, brain metastases and clinically significant gastrointestinal bleeding within the last 30 days were exclusion criteria. According to the FDA label, 95% of patients in the sorafenib group were Child-Pugh A and 5% Child-Pugh B, and 81.6% were BCLC stage C.

Endpoints

Primary outcomes: overall survival and time to symptomatic progression.

Secondary outcomes: time to radiological progression and safety.

Safety and side effects

According to the FDA label (SHARP data): grade 3 adverse events in 39% and grade 4 in 6% of the sorafenib group, versus 24% and 8% in the placebo group. Important grade 3 events with sorafenib: diarrhoea 10%, fatigue 9%, abdominal pain 9%, hand-foot skin reaction 8% and hypertension 4%. Grade 3 (3% versus 5%) and grade 4 (2% versus 4%) haemorrhage was more frequent with placebo; oesophageal variceal bleeding 2.4% versus 4%. Permanent discontinuation due to adverse events (including those associated with disease progression): 32% versus 35%.

According to the abstract, diarrhoea, weight loss, hand-foot skin reaction and hypophosphataemia were more common in the sorafenib group.

Clinical significance and place in guidelines

This study was the basis for FDA and EMA approval of sorafenib for unresectable HCC in 2007 and made sorafenib the first standard systemic therapy for advanced HCC. Sorafenib was the comparator in most later first-line trials (REFLECT, IMbrave150, HIMALAYA, CheckMate 9DW). The 2023 AASLD guidance recommends sorafenib or lenvatinib for Child-Pugh A patients in whom immunotherapy combinations are contraindicated (Level 1, Strong).

Limitations

The absolute survival benefit was modest (about 3 months) and tumour responses were rare; the study was stopped early at an interim analysis; most patients were from Europe and the Americas and had preserved liver function; time to symptomatic progression was not improved.

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.