Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial
Mené sur 931 patients atteints d'un carcinome hépatocellulaire non résécable, cet essai de phase III compare l'intérêt, du point de vue du maintien de la qualité de vie, du lenvatinib et du sorafénib en traitement de première ligne
Background : Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide.Preservation of health-related quality of life (HRQOL) during treatment is an importanttherapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL. Methods : REFLECT was a previously published multicentre, randomised, open-label, non-inferiorityphase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib asa first-line systemic treatment for unresectable hepatocellular carcinoma. Eligiblepatients were aged 18 years or older with unresectable hepatocellular carcinoma andone or more measurable target lesion per modified Response Evaluation Criteria inSolid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation,Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of1 or lower, and adequate organ function. Patients were randomly assigned (1:1) viaan interactive voice–web response system; stratification factors for treatment allocationincluded region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOGperformance status; and bodyweight. Patient-reported outcomes (PROs), collected atbaseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluatedin post-hoc analyses of secondary and exploratory endpoints in the analysis population,which was the subpopulation of patients with a PRO assessment at baseline. A linearmixed-effects model evaluated change from baseline in PROs, including European Organisationfor Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30(QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpointsof the REFLECT trial). Time-to-definitive-deterioration analyses were done based onestablished thresholds for minimum differences for worsening in PROs. Responder analysesexplored associations between HRQOL and clinical response. This study is registeredwith ClinicalTrials.gov, NCT01761266. Findings : Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476)between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463for sorafenib) were included in this analysis. Baseline PRO scores reflected impairedHRQOL and functioning and considerable symptom burden relative to full HRQOL. Differencesin overall mean change from baseline estimates in most PRO scales generally favouredthe lenvatinib over the sorafenib group, although the differences were not nominallystatistically or clinically significant. Patients treated with lenvatinib experiencednominally statistically significant delays in definitive, meaningful deteriorationon the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69–0·99), pain (0·80, 0·66–0·96),and diarrhoea (0·52, 0·42–0·65) domains versus patients treated with sorafenib. Significantdifferences in time to definitive deterioration were not observed for other QLQ-C30domains, and there was no difference in time to definitive deterioration on the globalhealth status/QOL score (0·89, 0·73–1·09). For most PRO scales, differences in overallmean change from baseline estimates favoured responders versus non-responders. Acrossall scales, HRs for time to definitive deterioration were in favour of responders;median time to definitive deterioration for responders exceeded those for non-respondersby a range of 4·8 to 14·6 months. Interpretation : HRQOL for patients undergoing treatment for unresectable hepatocellular carcinomais an important therapeutic consideration. The evidence of HRQOL benefits in clinicallyrelevant domains support the use of lenvatinib compared with sorafenib to delay functionaldeterioration in advanced hepatocellular carcinoma.