Background: The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up., Methods: COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791., Findings: Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths 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%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation)., Interpretation: First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals., Funding: Exelixis and Ipsen., Competing Interests: Declaration of interests TY reports a consulting or advisory role with Bristol Myers Squibb, MSD, AstraZeneca, Eisai, and Ipsen; research funding from Bristol Myers Squibb, MSD, Exelixis, Eli Lilly, AstraZeneca, Roche, and Taiho; travel, accommodations, or expenses from Roche and Bayer; stock and other ownership interests in Moderna; and other financial or non-financial interests with Taiho and Ipsen. AK reports honoraria from Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai; a consulting or advisory role with Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai; research funding from Exelixis, Roche, Merck, Bristol Myers Squibb, AdaptImmune, and Tvardi; and travel, accommodations, or expenses from Exelixis, Bristol Myers Squibb, Merck, Roche, and Eisai. A-LC reports honoraria from Merck Sharp Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Ipsen Innovation, BeiGene, and Exelixis; a consulting or advisory role with Merck Sharp Dohme, Bristol Myers Squibb, Bayer Healthcare, AstraZeneca, Genentech/Roche, Ipsen Innovation, BeiGene, and Exelixis; and participation on a data safety monitoring board or advisory board for Abbisko Therapeutics Co. AXZ reports employment and leadership with I-Mab Biopharma; a consulting or advisory role with Lilly, Sanofi, Merck, Exelixis, Roche, Eisai, and Bayer; and stock and other ownership interests in I-Mab Biopharma. SLC reports honoraria from MSD, AstraZeneca, Eisai, Roche, and Bristol Myers Squibb; a consulting or advisory role with MSD, AstraZeneca, Eisai, Roche, and Bayer; and travel, accommodations, or expenses from Ipsen and Novartis. VB reports honoraria from AstraZeneca, Roche, Novartis, Eisai, Bristol Myers Squibb, and Pfizer; and participation on a data safety monitoring board or advisory board with AstraZeneca, Roche, Novartis, Eisai, Bristol Myers Squibb, and Pfizer. GV reports travel, accommodations, and expenses from Roche, Bayer, Terumo, and Ipsen; and participation on a data safety monitoring board or advisory board with Roche, Eisai, and AstraZeneca. EG reports participation on a data safety monitoring board or advisory board with Gilead, Janssen, and Aligos. IB reports honoraria from Roche, Servier, Ipsen, Eisai, and AstraZeneca; travel, accommodations, and expenses with Ipsen and Roche; and participation on a data safety monitoring board or advisory board with AstraZeneca. PM reports a consulting or advisory role with Roche, AstraZeneca, MSD, Bayer, and Ipsen; research funding from Ipsen; travel, accommodations, and expenses from Ipsen, Roche, MSD, and AstraZeneca; and participation on a data safety monitoring board or advisory board with Roche, MSD, Bayer, Ipsen, and AstraZeneca. FB reports employment and stock or other ownership interests with Ipsen. SM reports employment with Exelixis; and stock and other ownership interests in Exelixis, Amgen, and Fibrogen. ZW reports employment and stock and other ownership interests with Exelixis. DC reports employment and stock and other ownership interests with Exelixis. RKK reports a consulting or advisory role with Agios (paid to institution), AstraZeneca (paid to institution), Exelixis (paid to institution), Ipsen (paid to institution), Merck (paid to institution), Kinnate, Regeneron, Tyra Biosciences, and Compass Therapeutics; research funding from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech/Roche, Loxo Oncology, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho, all paid to institution; travel, accommodations, and expenses from AstraZeneca and Merck; and participation on a data safety monitoring board or advisory board with Genentech/Roche, Merck, and Relay Therapeutics. LR reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte, Ipsen, Merck Serono, Roche, and Servier; a consulting or advisory role or participation on a data safety monitoring board with AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, and Zymeworks; research funding from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks, all paid to institution; a leadership or fiduciary role with the International Liver Cancer Association and the European Organisation for Research and Treatment of Cancer; and travel, accommodations, expenses from AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)