Bernhard Scheiner1, Katharina Pomej1, Martha M Kirstein2, Florian Hucke3, Fabian Finkelmeier4, Oliver Waidmann4, Vera Himmelsbach4, Kornelius Schulze5, Johann von Felden5, Thorben W Fründt5, Marc Stadler6, Harald Heinzl7, Kateryna Shmanko8, Stephan Spahn9, Pompilia Radu10, Alexander R Siebenhüner11, Joachim C Mertens12, Nuh N Rahbari13, Fabian Kütting14, Dirk-Thomas Waldschmidt14, Matthias P Ebert15, Andreas Teufel16, Sara De Dosso17, David J Pinato18, Tiziana Pressiani19, Tobias Meischl1, Lorenz Balcar1, Christian Müller1, Mattias Mandorfer20, Thomas Reiberger21, Michael Trauner20, Nicola Personeni22, Lorenza Rimassa22, Michael Bitzer9, Jörg Trojan4, Arndt Weinmann8, Henning Wege23, Jean-François Dufour10, Markus Peck-Radosavljevic3, Arndt Vogel24, Matthias Pinter25. 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria. 2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Medicine I, University Medical Center Schleswig-Holstein, Lübeck, Germany. 3. Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology including Centralized Emergency Department (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria. 4. Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany. 5. 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria; Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria. 7. Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria. 8. Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 9. Department of Internal Medicine I, Eberhard-Karls University, Tuebingen, Germany. 10. Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland; University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland. 11. Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Zurich, Switzerland; Department of Medical Oncology and Hematology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland. 12. Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland. 13. Department of Surgery at University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 14. Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany. 15. Department of Internal Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 16. Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Internal Medicine II, Division of Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. 17. Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland. 18. Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK; Department of Translational Medicine, Università degli Studi del Piemonte Orientale, Novara, Italy. 19. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy. 20. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. 21. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. 22. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy. 23. 1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cancer Center Esslingen, Klinikum Esslingen, 73730 Esslingen am Neckar, Germany. 24. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 25. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria. Electronic address: matthias.pinter@meduniwien.ac.at.
Abstract
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.
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.
Authors: Maria Reig; Alejandro Forner; Jordi Rimola; Joana Ferrer-Fàbrega; Marta Burrel; Ángeles Garcia-Criado; Robin K Kelley; Peter R Galle; Vincenzo Mazzaferro; Riad Salem; Bruno Sangro; Amit G Singal; Arndt Vogel; Josep Fuster; Carmen Ayuso; Jordi Bruix Journal: J Hepatol Date: 2021-11-19 Impact factor: 30.083