Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trialстатья
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Аннотация:Background Understanding patients’ experience of cancer treatment is important. We aimed to evaluate patient-reported
outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular
carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival
benefits with this combination therapy.
Methods We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or
regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or
clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or
progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted
block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or
both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus
15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical
benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment
allocation. Previously reported coprimary endpoints were overall survival and independently assessed progressionfree survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses
descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per
the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer
(QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed
deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PROevaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The
trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379.
Findings Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and
randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab
plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population.
At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2–10·8). EORTC QLQ-C30 completion
rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88–100% in the atezolizumab plus
bevacizumab group and 80–100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or
greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88–100%) and 21 of 24 cycles in the
sorafenib group (range 89–100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of
deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite
loss [hazard ratio (HR) 0·57, 95% CI 0·40–0·81], diarrhoea [0·23, 0·16–0·34], fatigue [0·61, 0·46–0·81], pain [0·46,
0·34–0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for
analysis (fatigue [0·60, 0·45–0·80] and pain [0·65, 0·46–0·92], but not jaundice [0·76, 0·55–1·07]). At day 1 of
treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30
score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: –3·29 (SD 17·56)
versus –5·83 (20·63) for quality of life, –4·02 (19·42) versus –9·76 (21·33) for role functioning, and –3·77 (12·82)
versus –7·60 (15·54) for physical functioning.
Interpretation Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported
quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib,
strengthening the combination therapy’s positive benefit–risk profile versus that of sorafenib in patients with
unresectable hepatocellular carcinoma.