Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial.

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 progression-free 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 PRO-evaluable 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.

FUNDING

F Hoffmann-La Roche and Genentech.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests PRG has had a consulting or advisory role and received honoraria from AdaptImmune, AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Eisai, Lilly, Ipsen, Roche, and Sirtex; has been on a speakers' bureau for AstraZeneca, Bayer, Bristol Myers Squibb, MSD, Eisai, Lilly, Ipsen, Roche, and Sirtex; has received research funding from Bayer and Roche; has provided expert testimony for Lilly; and has received travel or accommodation expenses from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Lilly, Ipsen, and F Hoffmann-La Roche. RSF has had a consulting or advisory role and received consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, F Hoffmann-La Roche and Genentech, Lilly, Merck, Novartis, and Pfizer; has received institutional research funding from Bayer, Bristol Myers Squibb, Eisai, Lilly, Merck, Novartis, Pfizer, and F Hoffmann-La Roche and Genentech, and has provided expert testimony for Novartis. MI has received institutional grant support from Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, AstraZeneca, MSD, Novartis, Bristol Myers Squibb, and Merck Serono; honoraria from Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, and Sumitomo Dainippon Pharma; and has had a consulting or advisory role for Bayer, Eisai, Eli Lilly Japan, Chugai Pharmaceutical, and Takeda. AXZ has had a consulting or advisory role with F Hoffmann La-Roche, Meck Lilly, Bayer, Sanofi, Eisai, and Exelixis. MK has received honoraria from Lilly, Bayer, Eisai, Merck Sharp & Dohme, Bristol-Myers Squibb, and EA Pharma; had a consulting or advisory role for Eisai, Ono, MSD, Bristol Myers Squibb, and F Hoffmann-La Roche; and received research funding from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, and Eisai. VB has received advisory or consultancy fees and travel and accommodation expenses from F Hoffmann-La Roche, MSD, Eisai, and Bristol-Myers Squibb; advisory or consultancy fees from Ipsen; and travel and accommodation expenses from Bayer. PM is on advisory boards for Bayer, Eisai, Exelixis, Ipsen, Lilly, Roche, AstraZeneca, Bristol Myers Squibb, MSD, Merck, and Onxeo. AK has received research support from F Hoffmann-La Roche, Bristol Myers Squibb, Exelixis, Bayer, AdaptImmune, Immatics, Merck, and Eisai. DL has had a consulting or advisory role and received honoraria from Lexicon, Ipsen, Bayer, Eisai, Exelixis, F Hoffmann-La Roche and Genentech, Taiho, Advanced Accelerator Applications, and QED; has been on a speaker's bureau for Lexicon, Ipsen, Eisai, Exelixis, Advanced Accelerator Applications, Coherus, and Sun Pharma; and has received institutional research funding from Brooklyn Immunotherapeutics. SM is a full-time employee of, and owns stock in, F Hoffmann-La Roche. WV is a full-time employee of Genentech. D-ZX is a full-time employee of F Hoffmann-La Roche. SH is a full-time employee of Genentech. BD is a full-time employee of Genentech. JL is a full-time employee of Shanghai Roche Pharmaceuticals. CH is a full-time employee of Shanghai Roche Pharmaceuticals. HYL has received advisory or consulting fees from Bayer, Eisai, Bristol-Myers Squibb, Ono, AstraZeneca, and F Hoffmann-La Roche. A-LC has received honoraria from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, MSD, F Hoffmann-La Roche and Genentech, BeiGene, CSR Pharma Group, and IQVIA; advisory or consulting fees from AstraZeneca, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix, IPSEN Innovation, Bayer Healthcare, MSD, Roche and Genentech, BeiGene, CSR Pharma Group, F Hoffmann-La Roche, and IQVIA; speaker bureau fees from Bayer Yakuhin, Novartis, Eisai, Oxal, and Amgen Taiwan; and travel and accommodation expenses from Bayer Yakuhin, F Hoffmann-La Roche and Genentech, and IQVIA. MD has received honoraria and advisory or consultancy fees from F Hoffmann-La Roche, Merck Serono, Bayer, Ipsen, Servier, Amgen, MSD, and Pierre Fabre; research funding from F Hoffmann-La Roche, Merck Serono, and Bayer; and travel and accommodation expenses from F Hoffmann-La Roche, MSD, and Servier. All other authors declare no competing interests.