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Background & Aims: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need., Methods: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204)., Results: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response., Conclusions: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation., Lay Summary: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers., Competing Interests: Conflict of interest B.S. received travel support from AbbVie, Ipsen and Gilead. K.P. nothing to disclose. M.K. received honoraria from BMS and AstraZeneca as consultant and is an investigator for AstraZeneca. F.H. received travel support from Bayer, Abbvie, and Gilead. F.F. received travel support from Abbvie and Novartis, and speaker fees from Abbvie and MSD. O.W. served as consultant for Amgen, Bayer, BMS, Celgene, Eisai, Merck, Novartis, Roche, Servier, and Shire. He served as a speaker for Abbvie, Bayer, BMS, Celgene, Falk, Ipsen, Novartis, Roche, and Shire. He received travel support from Abbvie, BMS, Ipsen, Novartis, and Servier. V.H. has nothing to disclose. K.S. Served as consultant for Ipsen and Bayer, and conducts studies for Bayer, Roche, Lilly, MSD, and BMS. J.v.F. has received advisory board fees from Roche. T.W.F. has nothing to disclose. M.S. has nothing to disclose. H.H. received compensations as a member of a scientific advisory board of Lilly. K.S. has nothing to disclose. S.S. has nothing to disclose. P.R. has nothing to disclose. A.R.S. has served at advisory boards and received consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier. J.C.M. has received consulting honoraria from Abbvie, Astra Zeneca, Bayer, BMS, Eisai, Gilead, Incyte, Intercept, MSD, Sanofi, Vifor for work performed outside the current study. N.N.R. has nothing to disclose. F.K. received speakers' fees from Bayer, Ipsen, MSD, Eisai, Shire, Sirtex and has received travel grants from Eisai, Janssen, Ipsen and Novartis. D.T.W. served as speaker/expert testimony for AstraZeneca, Eisai, BMS, Celgene, Incyte, Ipsen, Falk, Novartis, Roche Pharma AG, Servier, Shire Baxelta, and Sirtex; he received travel support from Bayer Health Pharma, Celgene, Ipsen, Novartis, and SIRTEX, and research grants/funding from Servier. M.P.E. received consulting honoraria from BMS and MSD. A.T. received consulting honoraria and /or lecture fees from Bayer, IPSEN, Lilly, BMS, Eisai Novartis, Roche, Intercept, Falk, AbbVie, and Gilead. He received and travel grants from IPSEN, AbbVie, and Gilead. He is an investigator for IPSEN and GILEAD. S.D.D. received consulting honoraria from Amgen, Bayer, BMS, IPSEN, Lilly, Merck, BMS, Novartis, Pfizer, Roche, Sanofi, and Servier, and travel grants from Amgen, BMS, IPSEN, Roche, and Servier. D.J.P. received lecture fees from ViiV Healthcare, Bayer Healthcare, Falk, BMS, EISAI and Roche; travel expenses from BMS, MSD and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, H3B, Roche, Astra Zeneca, and DaVolterra; research funding (to institution) from MSD, BMS. T.P. received consulting fees from IQVIA and Bayer; and institutional research funding from Lilly, Roche, Bayer. T.M. has nothing to disclose. L.B. has nothing to disclose. C.M. has nothing to disclose. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Collective Acumen, Gilead, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. T.R. received speaker fees from Boehringer Ingelheim, Roche, W.L. Gore and MSD, grant support from Boehringer Ingelheim, Boston Scientific, Cook Medical, Gilead, Guerbet, Abbvie, Phenex Pharmaceuticals, Philips, W.L. Gore, and MSD, served as a consultant for Abbvie, Bayer, Boehringer Ingelheim, Gilead, Intercept and MSD and received travel support from Gilead, Roche, MSD, and Gore. M.T. received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz. N.P. received consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly; travel fees from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. L.R. has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. M.B. received compensations as a member of scientific advisory boards of Bayer, Bristol–Meyers Squibb, EISAI, IPSEN, and MSD. J.T. served as consultant for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche, received travel support from BMS and Ipsen, and speaking fees from Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. He is also an investigator for Amgen, Bayer, BMS, Eisai, Lilly, Merck Serono, MSD, Ipsen, and Roche. A.W. received compensations as a member of scientific advisory boards for BMS, Wako, Sanofi and. He served as a speaker for Leo Pharma, Eisai, Ipsen and Roche and received travel support from Merck and Servier. H.W. served as speaker for Bayer, Eisai, Ipsen, and Roche, and as a consultant for Bayer, Eisai, Lilly, BMS, Roche, and Ipsen. He conducts studies for Bayer, Roche, Lilly, MSD, and BMS. J.F.D. received compensations as a member of scientific advisory boards of Abbvie, Bayer, Bristol-Myers Squibb, Falk, Galapagos, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis. M.P.R. is advisor/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eisai, Ipsen, Lilly, and Roche; he is an investigator for Bayer, BMS, Eisai, Exelixis, Lilly, and Roche. A.V. served as consultant for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen, and received speaking fees form Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. He is also an investigator for Roche, Bayer, Lilly, BMS, Eisai, and Ipsen. M.P. is an investigator for Bayer, BMS, Lilly, and Roche, he received speaker honoraria from Bayer, BMS, Eisai, and MSD, he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, Roche, and MSD, and he received travel support from Bayer, BMS, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)