Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial.
OBJECTIVE
The Sorafenib Hepatocellular Carcinoma (HCC) Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC. In this trial, 602 patients with well-preserved liver function (>95% Child-Pugh A) were randomized to receive either sorafenib 400mg or matching placebo orally b.i.d. on a continuous basis. Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment. In a comprehensive series of exploratory subgroup analyses, data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib.


METHODS
Five subgroup domains were assessed: disease etiology, tumor burden, performance status, tumor stage, and prior therapy. Overall survival (OS), time to progression (TTP), disease control rate (DCR), and safety were assessed for subgroups within each domain.


RESULTS
Subgroup analyses showed that sorafenib consistently improved median OS compared with placebo, as reflected by hazard ratios (HRs) of 0.50-0.85, similar to the complete cohort (HR=0.69). Sorafenib also consistently improved median TTP (HR, 0.40-0.64), except in HBV-positive patients (HR, 1.03), and DCR. Results are limited by small patient numbers in some subsets. The most common grade 3/4 adverse events included diarrhea, hand-foot skin reaction, and fatigue; the incidence of which did not differ appreciably among subgroups.


CONCLUSIONS
These exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy.
Barcelona Clínic Liver Cancer Group, Liver Unit, CIBERehd, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Barcelona, Spain. jbruix@clinic.ub.es
Jordi
J
Bruix
Jean-Luc
JL
Raoul
Morris
M
Sherman
Vincenzo
V
Mazzaferro
Luigi
L
Bolondi
Antonio
A
Craxi
Peter R
PR
Galle
Armando
A
Santoro
Michel
M
Beaugrand
Angelo
A
Sangiovanni
Camillo
C
Porta
Guido
G
Gerken
Jorge A
JA
Marrero
Andrea
A
Nadel
Michael
M
Shan
Marius
M
Moscovici
Dimitris
D
Voliotis
Josep M
JM
Llovet
D000368:Aged; D000437:Alcoholism / Q000150:complications; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology* / Q000628:therapy; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D060831:Hand-Foot Syndrome / Q000209:etiology; D019694:Hepatitis B, Chronic / Q000150:complications; D019698:Hepatitis C, Chronic / Q000150:complications; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D012720:Severity of Illness Index; D000077157:Sorafenib; D013997:Time Factors; D047368:Tumor Burden
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib