The CRAFITY score: A promising prognostic predictor for patients with hepatocellular carcinoma treated with tyrosine kinase inhibitor and immunotherapy combinations

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy – development and validation of the CRAFITY scoreJournal of HepatologyVol. 76Issue 2PreviewImmunotherapy 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. Full-Text PDF Open AccessReply to: “The CRAFITY score: a promising prognostic predictor for patients with hepatocellular carcinoma treated with tyrosine kinase inhibitor and immunotherapy combinations”Journal of HepatologyVol. 77Issue 2PreviewWe read with great interest the letter by Dr. Yang and colleagues published in Journal of Hepatology. We thank the authors for sharing their interesting data1 regarding the performance of the CRAFITY score2 in 2 cohorts of patients with hepatocellular carcinoma (HCC) from 2 Chinese centers, one treated with lenvatinib monotherapy and the other cohort treated with the combination of lenvatinib plus immunotherapy.1 In both cohorts,1 the CRAFITY score nicely separated 3 prognostic subgroups, with C-statistics and discrimination being similar to those reported in the original publication which included only European centers. Full-Text PDF We read with interest the study by Scheiner et al.,[1]Scheiner B. Pomej K. Kirstein M.M. Hucke F. Finkelmeier F. Waidmann O. et al.Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - Development and validation of the CRAFITY score.J Hepatol. 2022; 76: 353-363Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar who developed a novel prognostic score named ‘‘CRAFITY” based on serum C-reactive protein and alpha-fetoprotein levels for patients with hepatocellular carcinoma (HCC) treated with anti-programmed death (ligand) 1 (PD-(L)1)-based immunotherapy. The CRAFITY score could easily discriminate patients with HCC into 3 prognostic stratifications (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). A lower CRAFITY score was associated with better tumour response and overall survival (OS). We appreciate this impressive work because the CRAFITY score is likely to be a promising predictive biomarker of immunotherapy for HCC.Lenvatinib and sorafenib, as multi-tyrosine kinase inhibitors (TKIs), are alternative first-line systemic options for HCC if the atezolizumab-bevacizumab combination is not indicated.[2]Bruix J. Chan S.L. Galle P.R. Rimassa L. Sangro B. Systemic treatment of hepatocellular carcinoma: an EASL position paper.J Hepatol. 2021; 75: 960-974Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Lenvatinib plus anti-PD-1-based immunotherapy has shown superior tumour response and survival benefits compared with lenvatinib alone in a phase Ib trial,[3]Finn R.S. Ikeda M. Zhu A.X. Sung M.W. Baron A.D. Kudo M. et al.Phase Ib study of lenvatinib plus Pembrolizumab in patients with unresectable hepatocellular carcinoma.J Clin Oncol. 2020; 38: 2960-2970Crossref PubMed Scopus (374) Google Scholar and a phase III trial is ongoing (NCT03713593). We found that only 4 (2%) and 7 (7%) patients treated with TKI plus immunotherapy were included in the training and validation sets, respectively, and the performance of the CRAFITY score was only investigated in a sorafenib-treated cohort. The predictive value of the CRAFITY score for TKI plus immunotherapy combinations and lenvatinib monotherapy warrants further validation. Therefore, we evaluated the applicability of the CRAFITY score in a lenvatinib-immunotherapy combination cohort of 108 patients with HCC (cohort 1, October 2019-June 2021) and a lenvatinib-treated cohort of 72 patients with HCC (cohort 2, November 2018-May 2020) from 2 cancer centres in China (Beijing and Zhengzhou).The median ages were 57 (interquartile range [IQR], 44–69) and 55 (IQR, 43–71) years, 96 (89%) and 63 (88%) patients were men in cohorts 1 and 2, respectively. The aetiology was mainly hepatitis B virus infection (cohorts 1 and 2, 88% and 86%, respectively). Furthermore, 26 patients (24%) and 82 patients (76%) in cohort 1 and 15 patients (21%) and 57 patients (79%) in cohort 2 were Barcelona Clinic Liver Cancer stage B and stage C, respectively. The median OS was 19.3 (95% CI, 15.9–not estimable [NE]) months and 12.3 (95% CI, 10.6–16.2) months in cohorts 1 and 2. The median OS was significantly different among the 3 groups according to the CRAFITY score (CRAFITY-low, CRAFITY-intermediate, and CRAFITY-high) in cohorts 1 (p = 0.007, Fig. 1A) and 2 (p = 0.002, Fig. 1B). The objective response rate (ORR) and disease control rate (DCR) evaluated using mRECIST were 41% and 89% in cohort 1 and 21% and 74% in cohort 2, respectively. For CRAFITY-low vs. CRAFITY-intermediate vs. CRAFITY-high, the ORR was 60% vs. 41% vs. 28% (p = 0.054) and 35% vs. 21% vs. 9% (p = 0.151), and the DCR was 96% vs. 87% vs. 79% (p = 0.191) and 88% vs. 74% vs. 62% (p = 0.187) in cohorts 1 and 2, respectively. The C-statistics for the CRAFITY score were 0.66 and 0.63 in cohorts 1 and 2, respectively. Time-dependent area under the receiver-operating characteristic curve showed that the discrimination was 0.70, 0.65, and 0.66 in cohort 1 (Fig. 1A) and 0.67, 0.65, and 0.69 in cohort 2 at 6, 12, and 18 months (Fig. 1B), respectively.The CRAFITY score successfully predicted OS in 3 stratifications in patients with HCC undergoing treatment with lenvatinib plus immunotherapy (p = 0.007) and Lenvatinib monotherapy (p = 0.002), which was similar to the training, validation, and sorafenib-treated cohorts. Higher CRAFITY scores showed a trend toward lower ORR and DCR in the combination (p = 0.054, p = 0.191) and lenvatinib-treated cohorts (p = 0.151, p = 0.187).The discovery and validation of predictive biomarkers are major challenges in HCC immunotherapy.[4]Sangro B. Sarobe P. Hervás-Stubbs S. Melero I. Advances in immunotherapy for hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol. 2021; 18: 525-543Crossref PubMed Scopus (181) Google Scholar Biomarkers for predicting the efficacy of HCC immunotherapy at the molecular, genomic, transcriptional, and gut microbiome levels have been explored in some studies; however, their clinical guidance still needs further validation.[5]Llovet J.M. Castet F. Heikenwalder M. Maini M.K. Mazzaferro V. Pinato D.J. et al.Immunotherapies for hepatocellular carcinoma.Nat Rev Clin Oncol. 2022; 19: 151-172Crossref PubMed Scopus (106) Google Scholar Tumour PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signature consisting of 4 genes (CD274, CD8A, LAG3, and STAT1) showed improved OS and tumour response in patients with HCC treated with anti-PD-1-based immunotherapy.[6]Sangro B. Melero I. Wadhawan S. Finn R.S. Abou-Alfa G.K. Cheng A.L. et al.Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.J Hepatol. 2020; 73: 1460-1469Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Novel immunovascular classifications may bring new perspectives from immune and angiogenic tumour microenvironments for predicting the therapeutic effect of antiangiogenic therapy, immunotherapy, and their combination.[7]Kurebayashi Y. Matsuda K. Ueno A. Tsujikawa H. Yamazaki K. Masugi Y. et al.Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments.Hepatology. 2021; https://doi.org/10.1002/hep.32201Crossref PubMed Scopus (6) Google ScholarOur validation cohorts were retrospective with limited sample size and included only Chinese patients. The predictive ability of the CRAFITY score in patients with HCC with different aetiologies requires further validation. Our team is conducting a study to predict the efficacy of HCC immunotherapy based on deep learning radiomics and transcriptional signatures. We believe that a multi-omics perspective will help bridge this gap.In conclusion, we thank Scheiner et al. for their well-designed study. The CRAFITY score helps predict the prognosis of patients with HCC treated with immunotherapy-based systematic therapy. In our TKI-based combination cohort and lenvatinib-treated cohort from China, the CRAFITY score has excellent prognostic efficacy in patients with HCC. The CRAFITY score will improve patient stratification and clinical decision making, leading to survival benefits for our patients.Financial supportThis study was supported by the National Natural Science Foundation of China (No. 81972311 , 82141127 ), the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-066 ), and the Non-profit Central Research Institution Fund of Chinese Academy of Medical Sciences (No. 2019PT310026 ).Authors’ contributionsDr. Yi Yang, MD, PhD; Dr. Jingzhong Ouyang, MD; and Dr. Yanzhao Zhou MD contributed equally to this work and shared co-first authorship. All authors contributed either to research design, and/or the data acquisition, analysis, or interpretation of data. Dr. Yi Yang, MD, PhD; Dr. Jingzhong Ouyang, MD; and Dr. Yanzhao Zhou MD drafted the manuscript, which was critically revised by all other authors. We read with interest the study by Scheiner et al.,[1]Scheiner B. Pomej K. Kirstein M.M. Hucke F. Finkelmeier F. Waidmann O. et al.Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - Development and validation of the CRAFITY score.J Hepatol. 2022; 76: 353-363Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar who developed a novel prognostic score named ‘‘CRAFITY” based on serum C-reactive protein and alpha-fetoprotein levels for patients with hepatocellular carcinoma (HCC) treated with anti-programmed death (ligand) 1 (PD-(L)1)-based immunotherapy. The CRAFITY score could easily discriminate patients with HCC into 3 prognostic stratifications (CRAFITY-low, 0 points; CRAFITY-intermediate, 1 point; and CRAFITY-high, 2 points). A lower CRAFITY score was associated with better tumour response and overall survival (OS). We appreciate this impressive work because the CRAFITY score is likely to be a promising predictive biomarker of immunotherapy for HCC. Lenvatinib and sorafenib, as multi-tyrosine kinase inhibitors (TKIs), are alternative first-line systemic options for HCC if the atezolizumab-bevacizumab combination is not indicated.[2]Bruix J. Chan S.L. Galle P.R. Rimassa L. Sangro B. Systemic treatment of hepatocellular carcinoma: an EASL position paper.J Hepatol. 2021; 75: 960-974Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Lenvatinib plus anti-PD-1-based immunotherapy has shown superior tumour response and survival benefits compared with lenvatinib alone in a phase Ib trial,[3]Finn R.S. Ikeda M. Zhu A.X. Sung M.W. Baron A.D. Kudo M. et al.Phase Ib study of lenvatinib plus Pembrolizumab in patients with unresectable hepatocellular carcinoma.J Clin Oncol. 2020; 38: 2960-2970Crossref PubMed Scopus (374) Google Scholar and a phase III trial is ongoing (NCT03713593). We found that only 4 (2%) and 7 (7%) patients treated with TKI plus immunotherapy were included in the training and validation sets, respectively, and the performance of the CRAFITY score was only investigated in a sorafenib-treated cohort. The predictive value of the CRAFITY score for TKI plus immunotherapy combinations and lenvatinib monotherapy warrants further validation. Therefore, we evaluated the applicability of the CRAFITY score in a lenvatinib-immunotherapy combination cohort of 108 patients with HCC (cohort 1, October 2019-June 2021) and a lenvatinib-treated cohort of 72 patients with HCC (cohort 2, November 2018-May 2020) from 2 cancer centres in China (Beijing and Zhengzhou). The median ages were 57 (interquartile range [IQR], 44–69) and 55 (IQR, 43–71) years, 96 (89%) and 63 (88%) patients were men in cohorts 1 and 2, respectively. The aetiology was mainly hepatitis B virus infection (cohorts 1 and 2, 88% and 86%, respectively). Furthermore, 26 patients (24%) and 82 patients (76%) in cohort 1 and 15 patients (21%) and 57 patients (79%) in cohort 2 were Barcelona Clinic Liver Cancer stage B and stage C, respectively. The median OS was 19.3 (95% CI, 15.9–not estimable [NE]) months and 12.3 (95% CI, 10.6–16.2) months in cohorts 1 and 2. The median OS was significantly different among the 3 groups according to the CRAFITY score (CRAFITY-low, CRAFITY-intermediate, and CRAFITY-high) in cohorts 1 (p = 0.007, Fig. 1A) and 2 (p = 0.002, Fig. 1B). The objective response rate (ORR) and disease control rate (DCR) evaluated using mRECIST were 41% and 89% in cohort 1 and 21% and 74% in cohort 2, respectively. For CRAFITY-low vs. CRAFITY-intermediate vs. CRAFITY-high, the ORR was 60% vs. 41% vs. 28% (p = 0.054) and 35% vs. 21% vs. 9% (p = 0.151), and the DCR was 96% vs. 87% vs. 79% (p = 0.191) and 88% vs. 74% vs. 62% (p = 0.187) in cohorts 1 and 2, respectively. The C-statistics for the CRAFITY score were 0.66 and 0.63 in cohorts 1 and 2, respectively. Time-dependent area under the receiver-operating characteristic curve showed that the discrimination was 0.70, 0.65, and 0.66 in cohort 1 (Fig. 1A) and 0.67, 0.65, and 0.69 in cohort 2 at 6, 12, and 18 months (Fig. 1B), respectively. The CRAFITY score successfully predicted OS in 3 stratifications in patients with HCC undergoing treatment with lenvatinib plus immunotherapy (p = 0.007) and Lenvatinib monotherapy (p = 0.002), which was similar to the training, validation, and sorafenib-treated cohorts. Higher CRAFITY scores showed a trend toward lower ORR and DCR in the combination (p = 0.054, p = 0.191) and lenvatinib-treated cohorts (p = 0.151, p = 0.187). The discovery and validation of predictive biomarkers are major challenges in HCC immunotherapy.[4]Sangro B. Sarobe P. Hervás-Stubbs S. Melero I. Advances in immunotherapy for hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol. 2021; 18: 525-543Crossref PubMed Scopus (181) Google Scholar Biomarkers for predicting the efficacy of HCC immunotherapy at the molecular, genomic, transcriptional, and gut microbiome levels have been explored in some studies; however, their clinical guidance still needs further validation.[5]Llovet J.M. Castet F. Heikenwalder M. Maini M.K. Mazzaferro V. Pinato D.J. et al.Immunotherapies for hepatocellular carcinoma.Nat Rev Clin Oncol. 2022; 19: 151-172Crossref PubMed Scopus (106) Google Scholar Tumour PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signature consisting of 4 genes (CD274, CD8A, LAG3, and STAT1) showed improved OS and tumour response in patients with HCC treated with anti-PD-1-based immunotherapy.[6]Sangro B. Melero I. Wadhawan S. Finn R.S. Abou-Alfa G.K. Cheng A.L. et al.Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.J Hepatol. 2020; 73: 1460-1469Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Novel immunovascular classifications may bring new perspectives from immune and angiogenic tumour microenvironments for predicting the therapeutic effect of antiangiogenic therapy, immunotherapy, and their combination.[7]Kurebayashi Y. Matsuda K. Ueno A. Tsujikawa H. Yamazaki K. Masugi Y. et al.Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments.Hepatology. 2021; https://doi.org/10.1002/hep.32201Crossref PubMed Scopus (6) Google Scholar Our validation cohorts were retrospective with limited sample size and included only Chinese patients. The predictive ability of the CRAFITY score in patients with HCC with different aetiologies requires further validation. Our team is conducting a study to predict the efficacy of HCC immunotherapy based on deep learning radiomics and transcriptional signatures. We believe that a multi-omics perspective will help bridge this gap. In conclusion, we thank Scheiner et al. for their well-designed study. The CRAFITY score helps predict the prognosis of patients with HCC treated with immunotherapy-based systematic therapy. In our TKI-based combination cohort and lenvatinib-treated cohort from China, the CRAFITY score has excellent prognostic efficacy in patients with HCC. The CRAFITY score will improve patient stratification and clinical decision making, leading to survival benefits for our patients. Financial supportThis study was supported by the National Natural Science Foundation of China (No. 81972311 , 82141127 ), the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-066 ), and the Non-profit Central Research Institution Fund of Chinese Academy of Medical Sciences (No. 2019PT310026 ). This study was supported by the National Natural Science Foundation of China (No. 81972311 , 82141127 ), the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-066 ), and the Non-profit Central Research Institution Fund of Chinese Academy of Medical Sciences (No. 2019PT310026 ). Authors’ contributionsDr. Yi Yang, MD, PhD; Dr. Jingzhong Ouyang, MD; and Dr. Yanzhao Zhou MD contributed equally to this work and shared co-first authorship. All authors contributed either to research design, and/or the data acquisition, analysis, or interpretation of data. Dr. Yi Yang, MD, PhD; Dr. Jingzhong Ouyang, MD; and Dr. Yanzhao Zhou MD drafted the manuscript, which was critically revised by all other authors. Dr. Yi Yang, MD, PhD; Dr. Jingzhong Ouyang, MD; and Dr. Yanzhao Zhou MD contributed equally to this work and shared co-first authorship. All authors contributed either to research design, and/or the data acquisition, analysis, or interpretation of data. Dr. Yi Yang, MD, PhD; Dr. Jingzhong Ouyang, MD; and Dr. Yanzhao Zhou MD drafted the manuscript, which was critically revised by all other authors. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The authors thank Prof. Jianqiang Cai, MD; Prof. Feng Ye, MD; Dr. Ying Xu, MD; Dr. Lu Li, MD; Dr. Hongcai Yang, MD, PhD; Dr. Qichen Chen, MD; Dr. Yiqiao Deng, PhD, from Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College; Dr. Zhiwen Luo, MD, PhD, from Technion-Israel Institute of Technology; Prof. Tongguo Si, MD, PhD; Prof. Xi Wei, MD, PhD; Dr. Yuwei Zhang, MD, from Tianjin Medical Cancer Institute and Hospital; and Dr. Fei Cao, MD, from The Cancer Hospital of the University of Chinese Academy of Sciences for their kind help and constant support. 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