- Email: [email protected]
Patterns and challenges of treatment sequencing in patients with hepatocellular carcinoma
POSTER PRESENTATIONS Liver Disease/Nonalcoholic Steatohepatitis) patients with or without Hepatocellular Carcinoma (HCC). Methods: Peripheral blood lymphocytes isolated from 5 healthy donors, 8 cases with mild NASH determined by F0-F2 (in the Fibroscan or biopsy), 10 NASH cirrhosis patients without HCC and 8 NASH cirrhosis with HCC cases. NLG4 receptor expressions and NK activation marker (CD107, LAMP1) were determined by flow cytomerty. Results: Compared to healthy controls, the NLG4 expressions significantly increased in NK cells from NASH cirrhosis (without and with HCC), suggesting NK impairment. However, HCC cirrhosis cases had higher NLG4 expressions as compared to non-HCC cirrhotic cases. The NK activation marker CD107a increased in mild NASH cases and both cirrhosis groups showed a further increase. Activator ratio (CD107a:NLG4) significantly increased in all sick cases. The mild NASH cases had the highest activation ratio. The NK activation ratio becomes weaker gradually in the cirrhosis groups, with prominent decrease in CD107a in the HCC group. Hep3B (human HCC cell line) highly express the NLG4-ligand b-neuroxin (NLG4 ligand). Cocultures of Hep3B with human healthy NK cells showed increase Hep3B killing in case of NLG4 siRNA knockdown. Co-cultures of Hep3B with human NK cell line (YTS) or healthy NK cells decreased their aFP secretions indicating less tumor activity (P < 0.001) however, NK cell from HCC patients failed to modulate aFP levels.
Conclusions: The NLG4 is a novel inhibitory NK cell receptor over expressed in advanced fibrosis and HCC, causing NK impairment. CD107a:NLG4 ratio is a better marker for NK killing than CD107a. FRI-086 Patterns and challenges of treatment sequencing in patients with hepatocellular carcinoma M.M. Kirstein1, N. Schweitzer2, T. Winter2, K. Lappas2, N. Graen2, I. Kunstmann2, T. Voigtländer2, T. Reineke-Plaaß2, M.P. Manns2, T. Rodt2, F. Lehner2, A. Vogel2. 1Gastroenterology, Hepatology and Endocrinology; 2Hannover Medical School, Hannover, Germany E-mail: [email protected] Background and Aims: Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Several local and sytemic therapies are available for patients with HCC depending on the stage of the disease. In clinical practice, treatment decision-making and sequencing may be very heterogeneous. Methods: In this study, we retrospectively analyzed treatment algorithms in 2,101 patients with HCC treated from 2000 to 2015 at Hannover Medical School. Treatment lines were defined as the switch from one to another treatment modality after recurrent or progressive disease. Results: Transarterial chemoembolization (TACE) was the most common initial treatment (n = 545; 25.9%), followed by resection (n = 435, 20.7%), localablative procedures (n = 283, 13.5%), systemic therapies (n = 275, 13.1%) and liver transplantation (LT, n = 52; 2.5%). Among patients receiving any treatment, most patients were treated only once (n = 960; 59.6%). 433 (26.9%) and 160 (9.9%) patients received a 2nd line and 3rd line treatment after recurrent or progressive disease, whereas only a minority was treated in 4th/5th line. Using binary logistic regression, AFP ≤ 200 μg/L, albumin >36 g/L and small tumor size (≤50 mm) were identified as predictors of achieving more than one treatment line. Subsequent treatment stage migration to a therapy suggested for the next, advanced stage occurred only in 56.9%, whereas 43.1% received treatments suggested for earlier disease stages. Only 16% of all treated patients received systemic therapy in the salvage setting.
Conclusions: In clinical practice, most patients were treated only once and only a minority of patients received systemic treatment. The high drop out rate for subsequent therapies needs to be considered within therapy decision-making. Potential treatment sequencing may be individually estimated by means of tumor burden and hepatic function. FRI-087 Comparison of modified (m)RECIST and RECIST 1.1 assessments in the phase 3 RESORCE trial comparing regorafenib and placebo in patients with hepatocellular carcinoma who progressed during sorafenib treatment J. Bruix1, P. Merle2, A. Granito3, Y.-H. Huang4, G. Bodoky5, M. Pracht6, O. Yokosuka7, O. Rosmorduc8, V. Breder9, R. Gerolami10, G. Masi11, P.J. Ross12, S. Qin13, T. Song14, J.-P. Bronowicki15, I. Ollivier-Hourmand16, M. Kudo17, A. Baumhauer18, M.-A. LeBerre19, G. Meinhardt20, G. Han21 and on behalf of the RESORCE Investigators. 1 BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain; 2Hepatology Unit, Groupement Hospitalier Lyon Nord, Lyon, France; 3University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; 4Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 5St Laszlo Teaching Hospital, Budapest, Hungary; 6Service d’Oncologie ̀ e Marquis, Rennes, France; 7Chiba University, Médicale, Centre Eugen Chiba, Japan; 8Hôpital de la Pitié-Salpétrier̀ e, Assistance PubliqueHôpitaux de Paris and Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; 9Russian Cancer Research Center n.a.N. Blokhin, Moscow, Russia; 10CHU Timone, Université de la Méditerranée, Marseille, France; 11Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 12King’s College Hospital NHS Foundation Trust, London, United Kingdom; 13Chinese People’s Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing; 14Tianjin Medical University Cancer Hospital, Tianjin, China; 15INSERM 954, CHU de Nancy, Université de Lorraine, Nancy; 16Service d’hépatogastroentérologie, CHU, Caen, France; 17Kindai University Faculty of Medicine, Osaka, Japan; 18Bayer Pharmaceuticals, Bayer Vital GmbH, Leverkusen, Germany; 19Bayer HealthCare SAS, Loos, France; 20Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States; 21The First Affiliated Hospital (Xijing Hospital) of the Fourth Military Medical University, Xi’an, China E-mail: [email protected] Background and Aims: In the RESORCE trial, regorafenib improved overall survival (OS) in patients with hepatocellular carcinoma (HCC) who progressed during sorafenib treatment, with a HR of 0.63 (95% CI 0.50–0.79; one-sided p < 0.0001) and an improvement in median OS to 10.6 months from 7.8 months with placebo. We present a prospective comparison of investigator-assessed tumor response and progression by the HCC-specific mRECIST and by RECIST 1.1. mRECIST Regorafenib (n = 379) Disease control rate, n (%) Complete response (CR), n (%) Partial response (PR), n (%) Stable disease, n (%) Response rate (CR + PR), n (%) Progressive disease, n (%) Median PFS (95% CI), months Median TTP (95% CI), months
Placebo (n = 194)
RECIST 1.1 Regorafenib (n = 379)
Placebo (n = 194)
247 (65) 2 (1)
70 (36) 0
249 (66) 0
67 (35) 0
38 (10)
8 (4)
25 (7)
5 (3)
206 (54) 40 (11)
62 (32) 8 (4)
223 (59) 25 (7)
62 (32) 5 (3)
86 (23) 108 (56) 3.1 (2.8, 4.2) 1.5 (1.4, 1.6)
85 (22) 111 (57) 3.4 (2.9, 4.2) 1.5 (1.4, 1.5)
3.2 (2.9, 4.2) 1.5 (1.4, 1.6)
3.9 (2.9, 4.2) 1.5 (1.4, 1.6)
Methods: Adults with HCC Barcelona Clinic Liver Cancer (BCLC) stage B or C who had radiological progression during sorafenib treatment, Child-Pugh A liver function, and ECOG performance status 0–1 were randomized 2:1 to regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. Treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint
Journal of Hepatology 2017 vol. 66 | S333–S542
S451
Conclusions: The NLG4 is a novel inhibitory NK cell receptor over expressed in advanced fibrosis and HCC, causing NK impairment. CD107a:NLG4 ratio is a better marker for NK killing than CD107a. FRI-086 Patterns and challenges of treatment sequencing in patients with hepatocellular carcinoma M.M. Kirstein1, N. Schweitzer2, T. Winter2, K. Lappas2, N. Graen2, I. Kunstmann2, T. Voigtländer2, T. Reineke-Plaaß2, M.P. Manns2, T. Rodt2, F. Lehner2, A. Vogel2. 1Gastroenterology, Hepatology and Endocrinology; 2Hannover Medical School, Hannover, Germany E-mail: [email protected] Background and Aims: Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Several local and sytemic therapies are available for patients with HCC depending on the stage of the disease. In clinical practice, treatment decision-making and sequencing may be very heterogeneous. Methods: In this study, we retrospectively analyzed treatment algorithms in 2,101 patients with HCC treated from 2000 to 2015 at Hannover Medical School. Treatment lines were defined as the switch from one to another treatment modality after recurrent or progressive disease. Results: Transarterial chemoembolization (TACE) was the most common initial treatment (n = 545; 25.9%), followed by resection (n = 435, 20.7%), localablative procedures (n = 283, 13.5%), systemic therapies (n = 275, 13.1%) and liver transplantation (LT, n = 52; 2.5%). Among patients receiving any treatment, most patients were treated only once (n = 960; 59.6%). 433 (26.9%) and 160 (9.9%) patients received a 2nd line and 3rd line treatment after recurrent or progressive disease, whereas only a minority was treated in 4th/5th line. Using binary logistic regression, AFP ≤ 200 μg/L, albumin >36 g/L and small tumor size (≤50 mm) were identified as predictors of achieving more than one treatment line. Subsequent treatment stage migration to a therapy suggested for the next, advanced stage occurred only in 56.9%, whereas 43.1% received treatments suggested for earlier disease stages. Only 16% of all treated patients received systemic therapy in the salvage setting.
Conclusions: In clinical practice, most patients were treated only once and only a minority of patients received systemic treatment. The high drop out rate for subsequent therapies needs to be considered within therapy decision-making. Potential treatment sequencing may be individually estimated by means of tumor burden and hepatic function. FRI-087 Comparison of modified (m)RECIST and RECIST 1.1 assessments in the phase 3 RESORCE trial comparing regorafenib and placebo in patients with hepatocellular carcinoma who progressed during sorafenib treatment J. Bruix1, P. Merle2, A. Granito3, Y.-H. Huang4, G. Bodoky5, M. Pracht6, O. Yokosuka7, O. Rosmorduc8, V. Breder9, R. Gerolami10, G. Masi11, P.J. Ross12, S. Qin13, T. Song14, J.-P. Bronowicki15, I. Ollivier-Hourmand16, M. Kudo17, A. Baumhauer18, M.-A. LeBerre19, G. Meinhardt20, G. Han21 and on behalf of the RESORCE Investigators. 1 BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain; 2Hepatology Unit, Groupement Hospitalier Lyon Nord, Lyon, France; 3University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy; 4Taipei Veterans General Hospital, Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 5St Laszlo Teaching Hospital, Budapest, Hungary; 6Service d’Oncologie ̀ e Marquis, Rennes, France; 7Chiba University, Médicale, Centre Eugen Chiba, Japan; 8Hôpital de la Pitié-Salpétrier̀ e, Assistance PubliqueHôpitaux de Paris and Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; 9Russian Cancer Research Center n.a.N. Blokhin, Moscow, Russia; 10CHU Timone, Université de la Méditerranée, Marseille, France; 11Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 12King’s College Hospital NHS Foundation Trust, London, United Kingdom; 13Chinese People’s Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing; 14Tianjin Medical University Cancer Hospital, Tianjin, China; 15INSERM 954, CHU de Nancy, Université de Lorraine, Nancy; 16Service d’hépatogastroentérologie, CHU, Caen, France; 17Kindai University Faculty of Medicine, Osaka, Japan; 18Bayer Pharmaceuticals, Bayer Vital GmbH, Leverkusen, Germany; 19Bayer HealthCare SAS, Loos, France; 20Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States; 21The First Affiliated Hospital (Xijing Hospital) of the Fourth Military Medical University, Xi’an, China E-mail: [email protected] Background and Aims: In the RESORCE trial, regorafenib improved overall survival (OS) in patients with hepatocellular carcinoma (HCC) who progressed during sorafenib treatment, with a HR of 0.63 (95% CI 0.50–0.79; one-sided p < 0.0001) and an improvement in median OS to 10.6 months from 7.8 months with placebo. We present a prospective comparison of investigator-assessed tumor response and progression by the HCC-specific mRECIST and by RECIST 1.1. mRECIST Regorafenib (n = 379) Disease control rate, n (%) Complete response (CR), n (%) Partial response (PR), n (%) Stable disease, n (%) Response rate (CR + PR), n (%) Progressive disease, n (%) Median PFS (95% CI), months Median TTP (95% CI), months
Placebo (n = 194)
RECIST 1.1 Regorafenib (n = 379)
Placebo (n = 194)
247 (65) 2 (1)
70 (36) 0
249 (66) 0
67 (35) 0
38 (10)
8 (4)
25 (7)
5 (3)
206 (54) 40 (11)
62 (32) 8 (4)
223 (59) 25 (7)
62 (32) 5 (3)
86 (23) 108 (56) 3.1 (2.8, 4.2) 1.5 (1.4, 1.6)
85 (22) 111 (57) 3.4 (2.9, 4.2) 1.5 (1.4, 1.5)
3.2 (2.9, 4.2) 1.5 (1.4, 1.6)
3.9 (2.9, 4.2) 1.5 (1.4, 1.6)
Methods: Adults with HCC Barcelona Clinic Liver Cancer (BCLC) stage B or C who had radiological progression during sorafenib treatment, Child-Pugh A liver function, and ECOG performance status 0–1 were randomized 2:1 to regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. Treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint
Journal of Hepatology 2017 vol. 66 | S333–S542
S451