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Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma., Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509., Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related., Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks., Funding: Bristol Myers Squibb in collaboration with Ono Pharmaceutical., Competing Interests: Declaration of interests TY reports consulting fees from, honoraria from, and participation on a data safety monitoring board or advisory board for, AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, EMD Serono, Exelixis, H3 Biomedicine, Ipsen, Merck Sharp and Dohme, New B Innovation, Novartis, OrigiMed, Pfizer, Sillajen, Sirtex, and Taiho Pharmaceutical. J-WP reports consulting fees from AstraZeneca, Exelixis, Genentech, Ipsen, and Roche; honoraria from Bayer, Bristol Myers Squibb, and Ono Pharmaceutical; and research funding from Bristol Myers Squibb. RSF reports consulting fees for the present manuscript (to self) from Bristol Myers Squibb; other consulting fees from AstraZeneca, Bayer, C Stone, Eisai, Eli Lilly, Exelixis, Merck Sharp and Dohme, Novartis, Pfizer, and Roche–Genentech; research funding for the present manuscript (to institution) from Bristol Myers Squibb; research funding grants or contracts from Bayer, Eisai, Eli Lilly, Merck Sharp and Dohme, Pfizer, and Roche–Genentech; honoraria from Bayer, Bristol Myers Squibb, Eisai, Merck Sharp and Dohme, Pfizer, and Roche–Genentech; expert testimony for Bayer; meeting attendance for AstraZeneca, Bayer, Eisai, Exelixis, Merck Sharp and Dohme, Pfizer, and Roche–Genentech; and participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, C Stone, Eisai, Eli Lilly, Exelixis, Merck Sharp and Dohme, Novartis, Pfizer, and Roche–Genentech. A-LC reports consulting fees and honoraria from AstraZeneca, Bayer Healthcare, BeiGene, Bristol Myers Squibb, Eisai, Hoffman-LaRoche, IPSEN Innovation, IQVIA, Merck Sharp and Dohme, Ono Pharmaceutical, and Roche–Genentech; and meeting attendance for Bayer Yakuhin and Roche. PM reports consulting fees, honoraria, and research funding from AbbVie, Bristol Myers Squibb, Eisai, Gilead Sciences, and Ipsen; consulting fees and honoraria from Bayer; and participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Lilly, Merck Sharp and Dohme, and Roche. JE reports consulting fees from AstraZeneca, Basilea, Bayer, Boston Scientific, Bristol Myers Squibb, BTG, Eisai, Ipsen, Merck Sharp and Dohme, and Roche; meeting attendance for Amgen, Bristol Myers Squibb, Merck Sharp and Dohme, and Roche; and research funding (to institution) from BeiGene and Bristol Myers Squibb. MK reports consulting fees from Bristol Myers Squibb, Eisai, Merck Sharp and Dohme, Ono Pharmaceutical, and Roche; honoraria from Bayer, Bristol Myers Squibb, Chugai, EA Pharma, Eisai, Eli Lilly, and Merck Sharp and Dohme; and research funding (to institution) from AbbVie, Chugai, EA Pharma, Eisai, Gilead Sciences, Ono Pharmaceutical, Otsuka, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, and Takeda. JJH reports consulting fees from Adaptimmune, Bristol Myers Squibb, CytomX Therapeutics, Eisai, Exelexis, Lilly, Merck Sharp and Dohme, QED Therapeutics, and Zymeworks, and research funding from Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Incyte, Lilly, Novartis, Pfizer, Polaris, Yivivia, and Zymeworks. PM reports grants (to institution) from IPSEN and participation on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Lilly, Merck Sharp and Dohme, and Roche. OR reports participation on a data safety monitoring board or advisory board for Bayer, Eisai, and Sitrex. SPC reports a research grant from Bristol Myers Squibb; honoraria from AstraZeneca, Bristol Myers Squibb, Celgene, Eisai, Ipsen, Novartis, Roche, Shire, and Sirtex Medical; meeting attendance for Amgen, Bristol Myers Squibb, and Merck Sharp and Dohme; and stock or stock options from Bristol Myers Squibb. RKK reports research support (to institution) from Adaptimmune, Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech–Roche, MedImmune, Merck Sharp and Dohme, Novartis, Partner Therapeutics, QED Therapeutics, Relay Therapeutics, and Taiho Pharmaceutical; consulting fees (to institution) from Agios, AstraZeneca, Bristol Myers Squibb, Genentech–Roche, and Merck Sharp and Dohme; consulting fees (to self) from Exact Sciences, Genentech–Roche, and Gilead Sciences; participation on a data safety monitoring board or advisory board for Genentech–Roche (uncompensated after October 2020, formerly compensated to self), Merck Sharp and Dohme (uncompensated); and meeting attendance for Ipsen. JF reports consulting fees from Astellas Pharma, AstraZeneca, Bayer Yakuhin, Chugai Pharma, Eisai, Fujifilm, J-Pharma, Lilly Japan, Merck Sharp and Dohme, Novartis, Ono Pharmaceutical, Otsuka, Shire, Sumitomo Dainippon, Taiho Pharmaceutical, Takara Bio, and Yakult Honsha; honoraria from AbbVie, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Fujifilm, J-Pharma, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, Mochida Pharmaceutical, Merck Sharp and Dohme, Nihon Servier, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, Sawai Pharmaceutical, Shionogi, Shire, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult Honsha; and research funding (to institution) from Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Daiichi Sankyo, Eisai, J-Pharma, Kyowa Hakko Kirin, Lilly Japan, Mochida Pharmaceutical, Merck Sharp and Dohme, NanoCarrier, Ono Pharmaceutical, Pfizer, Sanofi, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, and Yakult Honsha. GKA-A reports research support to institution from Arcus, Agios, AstraZeneca, Bayer, BioNTech, Bristol Myers Squibb, Celgene, Flatiron, Genentech–Roche, Genoscience, Incyte, Polaris, Puma, QED Therapeutics, Sillajen, and Yiviva; and consulting support from Adicet, Agios, AstraZeneca, Alnylam, Autem, Bayer, BeiGene, Berry Genomics, Cend, Celgene, CytomX, Eisai, Eli Lilly, Exelixis, Flatiron, Genentech–Roche, Genoscience, Helio, Incyte, Ipsen, Legend Biotech, Loxo, Merck Sharp and Dohme, MiNA Therapeutics, QED Therapeutics, Rafael, Redhill, Silenseed, Sillajen, Sobi, Surface Oncology, Therabionics, twoXAR, Vector, and Yiviva. ABE-K reports grants or contracts from AstraZeneca, Astex, and Fulgent Genetics; consulting fees from ABL Bio, Agenus, AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck Sharp and Dohme, Pieris Pharmaceuticals, and Roche–Genentech; participation on a data safety monitoring board or advisory board for Agenus, AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck Sharp & Dohme, Pieris Pharmaceuticals, QED Therapeutics, and Roche–Genentech; and research funding from Astex Pharmaceuticals, AstraZeneca, and Merck Sharp and Dohme. IM reports consulting fees from AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, EMD Serono, F-Star, Genmab, Gossamer Bio, Lilly, Merck Sharp and Dohme, Numab, PharmaMar, Roche, and Tusk Therapeutics; honoraria from Alligator Biosciences, AstraZeneca–MedImmune, Bayer, Bristol Myers Squibb, Lilly, Roche–Genentech, and Tusk Therapeutics; meeting attendance for Bristol Myers Squibb, Incyte, Merck Sharp and Dohme, Roche–Genentech; and research grants (to institution) from Alligator Biosciences, Bristol Myers Squibb, Genmab, Pfizer, Roche–Genentech. DB, JN, TW, and MT reports employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. GC reports employment with Bristol Myers Squibb. BS reports grants or contracts (to institution) from Bristol Myers Squibb and Sirtex; consulting fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Eli Lilly, H3 Biomedicine, Incyte, Ipsen, Roche, Sirtex Medical, and Terumo; honoraria from and meeting attendance for Bayer, Bristol Myers Squibb, Incyte, Ipsen, Sirtex, and Terumo; and participation on a data safety monitoring board or advisory board for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, H3 Biomedicine, Incyte, Ipsen, Lilly, Roche, Sirtex, and Terumo. LW, ES, WS, EA, and RZ declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients., Methods: Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m 2 gemcitabine; 100 mg/m 2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate., Results: Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1-51); median number of GEMOX cycles was 7 (1-16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8-6.8) and 13.5 (7.5-16.2) months, and 4.6 (3.9-6.2) months and 14.8 (12.2-22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand-foot syndrome (5%/18)., Conclusions: Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned.

Background: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher., Methods: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433., Findings: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure)., Interpretation: REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma., Funding: Eli Lilly., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background & Aims: The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.78; p <0.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib., Methods: In RESORCE, 573 patients were randomized 2:1 to regorafenib 160 mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment., Results: HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day vs. <800 mg/day) were 52%, 11%, and 15% vs. 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6-28.1) for regorafenib and 19.2 months (16.3-22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45-0.96; Q1); 0.26 (0.17-0.40; Q2); 0.40 (0.27-0.60; Q3); and 0.54 (0.36-0.81; Q4)., Conclusions: These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose., Lay Summary: This analysis examined characteristics and outcomes of patients with hepatocellular carcinoma who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib treatment and regardless of their last sorafenib dose. The sequence of sorafenib followed by regorafenib for hepatocellular carcinoma may extend survival beyond what has been previously reported. ClinicalTrials.gov NCT01774344., (Copyright © 2018. Published by Elsevier B.V.)

ObjectiveIn the phase 3 CELESTIAL trial, cabozantinib improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). This subgroup analysis evaluated cabozantinib in patients who had received sorafenib as the only prior systemic therapy.MethodsCELESTIAL randomised (2:1) patients with advanced HCC and Child-Pugh class A liver function to treatment with cabozantinib (60 mg daily) or placebo. Eligibility required prior treatment with sorafenib, and patients could have received ≤2 prior systemic regimens. The primary endpoint was OS. Outcomes in patients who had received sorafenib as the only prior therapy were analysed by duration of prior sorafenib (

Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has proven its efficacy. Objectives: The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population. Methods: All patients with advanced HCC, treated in first-line setting by atezolizumab–bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study. Results: Patients were assigned to the regorafenib group (n = 29, 35.4%) or other TKI (sorafenib n = 41, lenvatinib n = 8, or cabozantinib n = 4) group (n = 53). PFS was not significantly different between the two groups [2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61–1.86), p = 0.818]. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group [15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20–0.79), p = 0.023]. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p = 0.019). OGS of patients who received regorafenib was improved compared to other TKI [18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22–0.84), p = 0.036]. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively. Conclusion: Efficacy of any TKI in the second-line setting was not affected by atezolizumab–bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies. [ABSTRACT FROM AUTHOR]

Introduction: The efficacy of systemic first-line treatments in older adults with unresectable hepatocellular carcinoma (HCC) has not been well-studied. We compared the safety and efficacy of atezolizumab plus bevacizumab versus sorafenib as a first-line treatment in younger versus older patients with unresectable HCC. Methods: This global, phase 3, open-label, randomized clinical trial (IMbrave150) recruited patients aged ≥18 years with locally advanced metastatic or unresectable HCC, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and Child-Pugh class A liver function who had not previously received systemic therapy for liver cancer. Patients received either 1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks or 400 mg sorafenib orally twice daily until loss of clinical benefit or unacceptable toxicity. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the incidence of adverse events and time to deterioration of patient-reported outcomes (PROs). This subgroup analysis evaluated safety and efficacy endpoints in patients <65 years, ≥65 to <75 years, and ≥75 years. Results: Of 501 patients, 165 patients were randomized to sorafenib and 336 were randomized to atezolizumab plus bevacizumab (175 patients <65 years; 106 patients ≥65 to <75 years; 55 patients ≥75 years). Across all age groups, patients receiving atezolizumab plus bevacizumab had longer median OS (<65: 18.0 vs. 12.2 months [HR, 0.57; 95% CI: 0.40–0.82]; ≥65 to <75: 19.4 vs. 14.9 months [HR, 0.80; 95% CI: 0.52–1.23]; ≥75: 24.0 vs. 18.0 months [HR, 0.72, 95% CI: 0.37–1.41]) and PFS than those receiving sorafenib. Time to deterioration for multiple PROs was delayed for patients receiving atezolizumab plus bevacizumab, including older adults. There were no clinically meaningful differences in toxicity between age groups. Conclusion: Atezolizumab plus bevacizumab is safe and effective in adults <65, ≥65 to <75, and ≥75. Treatment was well-tolerated even in elderly patients. [ABSTRACT FROM AUTHOR]

Background: Most phase 3 clinical trials of systemic therapy for first-line unresectable hepatocellular carcinoma (HCC) have failed, with the exception of SHARP, REFLECT, and IMbrave150. We conducted indirect comparisons of therapies evaluated for first-line HCC treatment. Summary: We conducted a systematic review and meta-analysis of treatments for adults with locally advanced or metastatic unresectable HCC and no prior systemic treatment, including atezolizu-mab plus bevacizumab, sorafenib, lenvatinib, nivolumab, selective internal radiotherapy (SIRT), transarterial chemoembolization, and placebo or best supportive care. Randomized controlled trials published from January 1, 2007, to March 12, 2020, were retrieved from MEDLINE and Embase. Qualitative assessment of heterogeneity evaluated study designs, populations, and outcomes. Indirect comparisons used generalized linear models with random effects within a Bayesian framework and informative priors. We calculated relative efficacy estimates with 95% credible intervals (CrIs) and Bayesian posterior probability estimates of atezolizumab-bevacizumab being superior to other treatments. Nine clinical studies with a total of 3,897 participants were identified from 8,783 records and used to build the all-trials evidence network. Indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus lenvatinib (odds ratio, 0.63 [95% CrI 0.39–1.04]; with 97% Bayesian posterior probability of being superior), nivolumab (0.68 [95% CrI 0.41–1.14]; 94%), sorafenib (0.59 [95% CrI 0.39–0.87]; 99%), SIRT (0.51 [95% CrI 0.32–0.82]; 100%), or placebo/best supportive care (0.40 [95% CrI 0.25–0.64]; 100%). Key Messages: Within the context of indirect comparisons, analyses of OS favored atezolizumab-bevacizumab versus other treatment options for patients with locally advanced or metastatic unresectable HCC. [ABSTRACT FROM AUTHOR]

Background: Health‐related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE‐240 (NCT02702401) assessed the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient‐reported outcomes. Methods: Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ‐C30) and its HCC supplement (EORTC QLQ‐HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30‐day safety follow‐up visit. Results: The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ‐HCC18 domains of abdominal swelling, fatigue, and pain. Conclusion: Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE‐240, these findings support a positive benefit/risk profile for pembrolizumab in a second‐line treatment setting for patients with HCC who previously received sorafenib. Pembrolizumab preserves health‐related quality of life during treatment in patients with advanced hepatocellular carcinoma (HCC) who had progression during or after or were intolerant to sorafenib. The results of this prespecified exploratory analysis combined with efficacy and safety data from KEYNOTE‐240 support a favorable risk–benefit profile for pembrolizumab in a second‐line treatment setting for patients with HCC who previously received sorafenib. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients' health-related quality of life. Fatigue, diarrhoea, hand-foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI-drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs. [ABSTRACT FROM AUTHOR]

Introduction Use of sorafenib remains debated in elderly patients treated for advanced hepatocellular carcinoma (HCC). Methods This was a bicentric retrospective study including all patients ≥75 years and treated with sorafenib for advanced HCC between January 2010 and March 2014. Results Of the 51 patients included (median age: 78 years, range: 75–92; performance status (PS) 0–1: 98%; cirrhosis: 88.2%; Child–Pugh A: 95.6%) all experienced at least one adverse event (AE). About 2/3 of them (66.7%) had grade 3–4 toxicities, including fatigue (43.1%), hand foot skin syndrome (11.8%), anorexia (9.8%) or diarrhea (9.8%). After adjustment for arterial hypertension, heart failure, other(s) cardiovascular history(ies), and sorafenib dose at baseline, only patients ≥80 years were associated with severe AE (OR: 13.3; p = 0.009). Discontinuation for toxicity was reported in 31 (60.8%) patients, mainly within the 3rd months, especially in those who had PS ≥1 at baseline (OR: 10.4; p = 0.01), or other cardiovascular histories (OR: 30.9; p = 0.016). In this setting, overall survival was significantly reduced (HR: 4.5; p < 0.0001). Conclusion Tolerance of Sorafenib seems to be low in elderly, especially for patients aged ≥80 years or with PS ≥1. Starting with reduced dose of sorafenib does not seem to impact results. Some of these patients may truly benefit from the treatment in terms of survival. [ABSTRACT FROM AUTHOR]

Background: There are no systemic treatments for patients with hepatocellular carcinoma (HCC) whose disease progresses during sorafenib treatment. We aimed to assess the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment.Methods: In this randomised, double-blind, parallel-group, phase 3 trial done at 152 sites in 21 countries, adults with HCC who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment), progressed on sorafenib, and had Child-Pugh A liver function were enrolled. Participants were randomly assigned (2:1) by a computer-generated randomisation list and interactive voice response system and stratified by geographical region, Eastern Cooperative Oncology Group performance status, macrovascular invasion, extrahepatic disease, and α-fetoprotein level to best supportive care plus oral regorafenib 160 mg or placebo once daily during weeks 1-3 of each 4-week cycle. Investigators, patients, and the funder were masked to treatment assignment. The primary endpoint was overall survival (defined as time from randomisation to death due to any cause) and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01774344.Findings: Between May 14, 2013, and Dec 31, 2015, 843 patients were screened, of whom 573 were enrolled and randomised (379 to regorafenib and 194 to placebo; population for efficacy analyses), and 567 initiated treatment (374 received regorafenib and 193 received placebo; population for safety analyses). Regorafenib improved overall survival with a hazard ratio of 0·63 (95% CI 0·50-0·79; one-sided p<0·0001); median survival was 10·6 months (95% CI 9·1-12·1) for regorafenib versus 7·8 months (6·3-8·8) for placebo. Adverse events were reported in all regorafenib recipients (374 [100%] of 374) and 179 (93%) of 193 placebo recipients. The most common clinically relevant grade 3 or 4 treatment-emergent events were hypertension (57 patients [15%] in the regorafenib group vs nine patients [5%] in the placebo group), hand-foot skin reaction (47 patients [13%] vs one [1%]), fatigue (34 patients [9%] vs nine patients [5%]), and diarrhoea (12 patients [3%] vs no patients). Of the 88 deaths (grade 5 adverse events) reported during the study (50 patients [13%] assigned to regorafenib and 38 [20%] assigned to placebo), seven (2%) were considered by the investigator to be related to study drug in the regorafenib group and two (1%) in the placebo group, including two patients (1%) with hepatic failure in the placebo group.Interpretation: Regorafenib is the only systemic treatment shown to provide survival benefit in HCC patients progressing on sorafenib treatment. Future trials should explore combinations of regorafenib with other systemic agents and third-line treatments for patients who fail or who do not tolerate the sequence of sorafenib and regorafenib.Funding: Bayer. [ABSTRACT FROM AUTHOR]

Background: Cabozantinib has shown clinical activity in combination with checkpoint inhibitors in solid tumours. The COSMIC-312 trial assessed cabozantinib plus atezolizumab versus sorafenib as first-line systemic treatment for advanced hepatocellular carcinoma.Methods: COSMIC-312 is an open-label, randomised, phase 3 trial that enrolled patients aged 18 years or older with advanced hepatocellular carcinoma not amenable to curative or locoregional therapy and previously untreated with systemic anticancer therapy at 178 centres in 32 countries. Patients with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were not eligible. Tumours involving major blood vessels, including the main portal vein, were permitted. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), Barcelona Clinic Liver Cancer stage B or C disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ and marrow function, and Child-Pugh class A. Previous resection, tumour ablation, radiotherapy, or arterial chemotherapy was allowed if more than 28 days before randomisation. Patients were randomly assigned (2:1:1) via a web-based interactive response system to cabozantinib 40 mg orally once daily plus atezolizumab 1200 mg intravenously every 3 weeks, sorafenib 400 mg orally twice daily, or single-agent cabozantinib 60 mg orally once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were progression-free survival per RECIST 1.1 as assessed by a blinded independent radiology committee in the first 372 patients randomly assigned to the combination treatment of cabozantinib plus atezolizumab or sorafenib (progression-free survival intention-to-treat [ITT] population), and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib (ITT population). Final progression-free survival and concurrent interim overall survival analyses are presented. This trial is registered with ClinicalTrials.gov, NCT03755791.Findings: Analyses at data cut-off (March 8, 2021) included the first 837 patients randomly assigned between Dec 7, 2018, and Aug 27, 2020, to combination treatment of cabozantinib plus atezolizumab (n=432), sorafenib (n=217), or single-agent cabozantinib (n=188). Median follow-up was 15·8 months (IQR 14·5-17·2) in the progression-free survival ITT population and 13·3 months (10·5-16·0) in the ITT population. Median progression-free survival was 6·8 months (99% CI 5·6-8·3) in the combination treatment group versus 4·2 months (2·8-7·0) in the sorafenib group (hazard ratio [HR] 0·63, 99% CI 0·44-0·91, p=0·0012). Median overall survival (interim analysis) was 15·4 months (96% CI 13·7-17·7) in the combination treatment group versus 15·5 months (12·1-not estimable) in the sorafenib group (HR 0·90, 96% CI 0·69-1·18; p=0·44). The most common grade 3 or 4 adverse events were alanine aminotransferase increase (38 [9%] of 429 patients in the combination treatment group vs six [3%] of 207 in the sorafenib group vs 12 [6%] of 188 in the single-agent cabozantinib group), hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), aspartate aminotransferase increase (37 [9%] vs eight [4%] vs 18 [10%]), and palmar-plantar erythrodysaesthesia (35 [8%] vs 17 [8%] vs 16 [9%]); serious treatment-related adverse events occurred in 78 (18%) patients in the combination treatment group, 16 (8%) patients in the sorafenib group, and 24 (13%) in the single-agent cabozantinib group. Treatment-related grade 5 events occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) patient in the sorafenib group (general physical health deterioration), and one (<1%) patient in the single-agent cabozantinib group (gastrointestinal haemorrhage).Interpretation: Cabozantinib plus atezolizumab might be a treatment option for select patients with advanced hepatocellular carcinoma, but additional studies are needed.Funding: Exelixis and Ipsen. [ABSTRACT FROM AUTHOR]

IMbrave150 demonstrated that atezolizumab plus bevacizumab led to significantly improved overall survival (OS) and progression-free survival (PFS) compared with sorafenib in patients with unresectable hepatocellular carcinoma at the primary analysis (after a median 8.6 months of follow-up). We present updated data after 12 months of additional follow-up. Patients with systemic treatment-naive, unresectable hepatocellular carcinoma were randomized 2:1 to receive 1,200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks or 400 mg sorafenib orally twice daily in this open-label, phase III study. Co-primary endpoints were OS and PFS by independently assessed RECIST 1.1 in the intention-to-treat population. Secondary efficacy endpoints included objective response rates and exploratory subgroup efficacy analyses. This is a post hoc updated analysis of efficacy and safety. From March 15, 2018, to January 30, 2019, 501 patients (intention-to-treat population) were randomly allocated to receive atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165). On August 31, 2020, after a median 15.6 (range, 0-28.6) months of follow-up, the median OS was 19.2 months (95% CI 17.0–23.7) with atezolizumab plus bevacizumab and 13.4 months (95% CI 11.4–16.9) with sorafenib (hazard ratio [HR] 0.66; 95% CI 0.52-0.85; descriptive p <0.001). The median PFS was 6.9 (95% CI 5.7-8.6) and 4.3 (95% CI 4.0-5.6) months in the respective treatment groups (HR 0.65; 95% CI 0.53-0.81; descriptive p < 0.001). Treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 and 72 (46%) of 156 safety-evaluable patients in the respective groups, and treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients. After longer follow-up, atezolizumab plus bevacizumab maintained clinically meaningful survival benefits over sorafenib and had a safety profile consistent with the primary analysis. NCT03434379. The primary analysis of IMbrave150 showed that atezolizumab plus bevacizumab had significantly greater benefits than sorafenib in patients with advanced hepatocellular carcinoma, but survival data were not yet mature. At this updated analysis done 12 months later, median overall survival was 5.8 months longer with atezolizumab plus bevacizumab than sorafenib, and the severity profile of treatment-related side effects remained similar. These updated results confirm atezolizumab plus bevacizumab as the first-line standard of care for advanced hepatocellular carcinoma. [Display omitted] • Atezolizumab plus bevacizumab or sorafenib were given for unresectable HCC. • This updated analysis was performed 12 months after the primary analysis of IMbrave150. • Median OS was 5.8 months longer with atezolizumab plus bevacizumab than sorafenib. • ORR was 30% with atezolizumab plus bevacizumab (median duration of 18.1 months). • The safety profile was similar to the findings of the primary analysis. [ABSTRACT FROM AUTHOR]

The article discusses the need to conduct patient level and trial level to treat hepatocellular carcinoma (HCC) to provide overall survival (OS) during surrogacy. Particular focus is given to topics including the failure in improvement of OS with increase in overall response rates (ORR), treatment with drugs sorafenib and the benefit of mRECIST on RECIST.