Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
Mené sur 400 patients atteints d'un carcinome hépatocellulaire de stade avancé, cet essai de phase III évalue l'efficacité, du point de vue de la survie globale, et la toxicité de l'apatinib en traitement de deuxième ligne ou au-delà, après l'échec d'une ou plusieurs lignes de chimiothérapie ou de thérapie ciblée
Background : Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumouractivity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitorshave been done in populations with a high prevalence of hepatitis B virus infection.The aim of this study was to evaluate the efficacy and safety of apatinib in patientswith pretreated advanced hepatocellular carcinoma. Methods : AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinomawho had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receiveapatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocationwas done with a central randomisation system, with a block size of six, and was stratifiedby Eastern Cooperative Oncology Group performance status, previous sorafenib treatment,and presence of vascular invasion or extrahepatic metastasis. The primary endpointwas overall survival, which was defined as time from randomisation to death from anycause, and was analysed in patients who were randomly assigned and received at leastone dose of the study drug. Safety analyses were done in patients who received atleast one dose of the study treatment and had post-dose safety assessments. This trialis registered with ClinicalTrials.gov, NCT02329860. Findings : Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinibgroup and one in the placebo group) did not receive study treatment and were excludedfrom efficacy analyses. Overall survival was significantly improved in the apatinibgroup compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients(257 in the apatinib group and 130 in the placebo group) had a safety assessment afterstudy treatment and were included in safety analyses. The most common treatment-relatedadverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinibgroup vs three [2%] in the placebo group), hand–foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo groupdied due to adverse events, but none of these deaths were deemed to be related totreatment by investigators. Interpretation : Apatinib significantly improved overall survival in patients with pretreated advancedhepatocellular carcinoma compared with placebo, with a manageable safety profile.