Study Objective and Design

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Randomized, Open Label, Multicenter, Phase II Trial of Transcatheter Arterial Chemoembolization (TACE) Therapy in Combination with Sorafenib as Compared With TACE Alone in Patients with

1 Randomized, Open Label, Multicenter, Phase II Trial of Transcatheter Arterial Chemoembolization (TACE) Therapy in Combination with Sorafenib as Compared With TACE Alone in Patients with Hepatocellular Carcinoma: TACTICS Trial Abstract 4017 Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, Hino K, Tsumura H, Kuzuya T, Isoda N, Yasui K, Yoshimura K, Okusaka T, Furuse J, Kokudo N, Okita K, Arai Y, and TACTICS Study Group

2 Background Because transarterial chemoembolization (TACE) has been shown to lead to a spike in the intratumoral concentration of VEGF, blockade of VEGF receptors may prevent the effects of a surge in proangiogenic factors 1-3 Since TACE and sorafenib have been shown to prolong survival in patients with unresectable hepatocellular carcinoma (HCC), 4-7 their combination may improve clinical outcomes 8 although 3 previous randomized clinical trials failed to show its benefit Several single arm trials have shown that the combination of sorafenib plus TACE is safe, effective, and feasible in patients with unresectable HCC 9-11 Subgroup analyses of Japan-Korea Post TACE trial and SPACE trial suggested that longer duration of treatment with sorafenib in combination with TACE may improve clinical outcome 12,13 This trial was conducted to assess whether combination of sorafenib and TACE improves outcomes as compared with TACE alone using a new end point, ie, time to untreatable (untaceable) progression and/or progression to TACE refractoriness (NCT # ) In this trial, intrahepatic new lesions were NOT regarded as progressive disease since it is natural tumor biology of HCC and does not imply treatment failure/moving to the next line of treatment 1. Lo CM, et al. Hepatology. 2002;35(5): Wang B, et al. Acta Radiol. 2008;49(5): Xiao EH, et al. World J Gastroenterol. 2009;15(36): Bruix J, et al. Hepatology. 2011;53(3): Llovet JM, et al. J. Hepatology. 2003;37(2): Llovet JM, et al. N Engl J Med. 2008;359(4): Cheng AL, et al. J Clin Oncol. 2013;31(32): Pawlik TM, et al. J Clin Oncol. 2011;29(30): Cabrera R, et al. Aliment Pharmacol Ther. 2011;34(2): Sieghalt W, et al. Eur Radiol. 2012;22(6): Park JW, et al. J Hepatol. 2012;56(6): Kudo M, et al. Eur J Cancer. 2011;47(14): Lencioni R, et al. J Hepatol. 2016;64(5):

3 Objective To evaluate the safety and efficacy of the combination therapy with conventional Lipiodol TACE and sorafenib compared to ctace alone in patients with unresectable HCC who are not candidates for resection or ablation Design Randomized, open label, multicenter, phase II trial conducted at 33 institutions in Japan Per protocol, the two treatment groups were compared using a stratified 1-sided log-rank test with an alpha of 0.15 (80% power) Efficacy assessments were performed on the ITT population (all randomized patients) Safety assessments were performed on all patients who received at least one dose of sorafenib or TACE procedure Stratification factors Study Objective and Design Study site Within Milan criteria ( 5 cm single or 3 cm 3 nodules): Yes vs No Prior TACE number: 0 vs 1-2 ctace, conventional TACE; ITT, intention-to-treat

Study Schema Stratification: Sites, within Milan, number of prior TACE Inclusion criteria Unresectable HCC Child-Pugh score: 7 Prior TACE: 0-2 Viable tumor ( 10 nodules, 10 cm) Adequate organ

4 Study Schema Stratification: Sites, within Milan, number of prior TACE Inclusion criteria Unresectable HCC Child-Pugh score: 7 Prior TACE: 0-2 Viable tumor ( 10 nodules, 10 cm) Adequate organ function Exclusion criteria EHS/MVI N = 156 Randomization (1:1) TACE Sorafenib arm (n = 80) Control arm (n = 76) Sorafenib (400 mg od 400 mg bid) UnTACEable progression/ Progression to TACE failure Sorafenib 400 mg daily was started 2 to 3 weeks before 1 st TACE to check the tolerability and to block the VEGF receptors after TACE followed by 800 mg daily Sorafenib was interrupted 2 days before and 3 days after each TACE session as long as organ function is maintained within TACE restarting criteria Repeated TACE is recommended on demand when viable lesion is more than 50% compared with baseline tumor volume or in the investigator s discretion Radiological assessment was done every 8 weeks by investigators Co-Primary Endpoint PFS/OS (Gatekeeping strategy) Secondary Endpoints TTUP, TTP, ORR, Safety EHS/MVI, extrahepatic spread/macroscopic vascular invasion; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TTP, time to progression; TTUP, time to untraceable progression

5 Statistical Considerations Gatekeeping strategy* for multiplicity adjustments (preplanned) Hierarchical statistical testing: Performed in prespecified sequential order PFS Targeted number of events: % power to detect HR = 0.71; 1-sided alpha 0.15 Only if the result of PFS is statistically significant, OS is to be tested OS Targeted number of events: % power to detect HR = 0.71; 1-sided alpha 0.15 *Statistical method to deal with clinical trials with co-primary endpoints, which efficiently solves the multiplicity issues. Dmitrienko A, et al. Stat Med. 2003;22(15):

6 Definition of Events for PFS, TTP, and TTUP Progression-free survival Untreatable (UnTACEable) progression Progression to TACE failure/refractory by JSH Death Progression Untreatable (UnTACEable) progression Progression to TACE failure/refractory by JSH untaceable progression Untreatable (UnTACEable) progression JSH, Japan Society of Hematology

7 Definition of PFS Time from the randomization day to the following events: 1. Progression: Untreatable (UnTACEable) progression (Defined as inability of a patient to further receive or benefit from TACE) 1) Intrahepatic tumor progression (25% growth, RECICL JSH 20091)* 2) Deterioration of liver function to Child-Pugh C 3) Appearance of extrahepatic spread 4) Appearance of major vascular invasion (*Note: In this trial, a new lesion is not regarded as tumor progression since it is neither the treatment failure nor suggesting next line of treatment) Progression that meets the TACE failure/refractoriness criteria by JSH definition 2. Any cause of death RECICL: Response Evaluation Criteria In Cancer of the Liver 1. Kudo M, et al, Hepatol Res. 2010;40(7): Kudo M, et al. Dig Dis. 2011;29(3):

8 Definition of TACE Failure/Refractoriness (JSH Criteria) Intrahepatic lesion I. Two or more consecutive insufficient responses of the treated tumor (viable lesion >50%) even after changing the chemotherapeutic agents and/or reanalysis of the feeding artery seen on response evaluation CT/MRI at 1 to 3 months after having adequately performed selective TACE II. Two or more consecutive progressions in the liver (tumor number increases as compared to tumor number before the previous TACE procedure) even after having changed the chemotherapeutic agents and/or reanalysis of the feeding artery seen on response evaluation CT/MRI at 1 to 3 months after having adequately performed selective TACE CT/MRI, computed tomography/magnetic resonance imaging 1. Kudo M, et al. Dig Dis. 2011;29(3):

9 Main Inclusion/Exclusion Criteria Main inclusion criteria Patients aged 20 years or over Life expectancy more than 12 weeks Typical HCC by histology, cytology, or diagnostic imaging such as dynamic CT (MRI) Unresectable HCC: The maximum diameter 10 cm, and the maximum number 10 No or 1-2 prior history of TACE therapy before enrollment (prior TACE must be >4 months before) ECOG PS score of 0 or 1 Child-Pugh score of 7 points or less Main exclusion criteria Macrovascular invasion (MVI) Extrahepatic spread (EHS) ECOG PS, Eastern Cooperative Oncology Group performance status

10 CONSORT Diagram of Patient Disposition Randomized patient (1:1 randomization) n = 156 TACE with sorafenib n = 80 ITT Population TACE alone n = 76 Did not receive protocol treatment (n = 3) Did not receive protocol treatment (n = 5) TACE with sorafenib n = 77 Safety Population TACE alone n = 71 Enrollment was halted after 156 patients had been randomized from Feb 2011 to Mar 2016

11 Baseline Patient Characteristics Characteristics Median age at enrollment, years (range) Category TACE With Sorafenib (n = 80) TACE Alone (n = 76) 72.0 (36-85) 73.0 (53-86) Male, n (%) Male 63 (78.8) 55 (72.4) Female 17 (21.2) 21 (27.6) Performance status, n (%) 0 71 (88.8) 67 (88.2) 1 9 (11.3) 9 (11.8) Etiology, n (%) Hepatitis B 10 (12.5) 2 (2.6) Hepatitis C 38 (47.5) 53 (69.7) Child-Pugh score, n (%) 5 64 (80.0) 54 (71.1) 6 15 (18.8) 17 (22.4) Characteristics Category TACE With Sorafenib (n = 80) TACE Alone (n = 76) Tumor burden, n (%) Within Milan 26 (32.5) 31 (40.8) Over Milan 54 (67.5) 45 (59.2) BCLC stage, n (%) A 25 (31.3) 30 (39.5) B 46 (57.5) 37 (48.7) C 9 (11.3) 9 (11.8) Prior TACE, n (%) 0 45 (56.3) 48 (63.2) (43.8) 28 (36.8) 7 1 (1.3) 5 (6.6) AFP, n (%) <200 ng/ml 64 (80.0) 60 (78.9) 200 ng/ml 16 (20.0) 16 (21.1) AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer Kudo M, et al. Dig Dis. 2011;29(3):

12 Primary Endpoint: PFS 1.0 HR % CI: 0.41,0.87 P =.006 PFS, Proportion 0.5 TACE alone TACE with sorafenib TACE with sorafenib Median: 25.2 months TACE alone Median: 13.5 months Patients at Risk TACE With Sorafenib TACE Alone Months

13 Co-Primary Endpoint: OS (Preliminary) 1 Observed/targeted number of events = 92/125 (73.6%) TACE with Sorafenib TACE alone Maturity 73.6% OS, Proportion 0.5 OS results will be presented in the future meeting when events reach the targeted number. Patients at Risk TACE With Sorafenib TACE Alone Months

14 Forest Plot of PFS in Subgroup Analyses Subgroup No. of Patients (%) Hazard Ratio (95%CI) Overall 156 (100%) 0.59 ( ) Age <65 27 (17%) 0.48 ( ) (83%) 0.61 ( ) Gender Men 118 (76%) 0.59 ( ) Women 38 (24%) 0.60 ( ) ECOG-PS (88%) 0.59 ( ) 1 18 (12%) 0.33 ( ) AFP 200 ng/ml 32 (21%) 0.65 ( ) <200 ng/ml 124 (79%) 0.55 ( ) Etiology HBV 12 (8%) 0.24 ( ) HCV 91 (58%) 0.80 ( ) nonbnonc 54 (35%) 0.43 ( ) BCLC stage Stage A 51 (33%) 0.77 ( ) Stage B 103 (66%) 0.53 ( ) Milan Criteria IN 57 (37%) 0.71 ( ) OUT 99 (63%) 0.54 ( ) Up-to-7 IN 104 (68%) 0.64 ( ) OUT 50 (32%) 0.51 ( ) Child-Pugh score (76%) 0.62 ( ) 6 32 (21%) 0.82 ( ) Prior TACE None 93 (60%) 0.66 ( ) (40%) 0.51 ( ) TACE with sorafenib arm better TACE alone arm better

15 Pattern of Progression TACE With Sorafenib TACE Alone No progression Progression Intrahepatic lesion Vascular invasion 11 8 Extrahepatic metastases 13 8 Deterioration of liver function 2 2 Total 80 76

16 Secondary Endpoint: Tumor Response DCR, disease control rate 1. Kudo M, et al, Hepatol Res. 2010;40(7): TACE With Sorafenib (n = 80) TACE Alone (n = 76) Best response, n(%) Complete response 23 (28.8) 21 (27.6) Partial response 34 (42.5) 26 (34.2) Stable disease 10 (12.5) 12 (15.8) Progression disease 2 (2.5) 3 (3.9) Not evaluable 11 (13.8) 14 (18.4) P value* P =.77 ORR, n(%) 57 (71.3) 47 (61.8) P value* P =.23 DCR, n(%) 67 (83.8) 59 (77.6) P value* P =.42 Evaluated at 4week after 1 st TACE According to RECICL update *Fisher exact test 2-sided

17 Treatment-Emergent Adverse Events Selected all-grade AEs with frequency 10% in either group, corresponding grade 3/4 AEs TACE With Sorafenib (n = 77) TACE Alone (n = 71) n (%) Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 AST increased 72 (92.3) 17 (21.8) 5 (6.4) 65 (91.5) 14 (19.7) 1 (1.4) ALT increased 69 (88.5) 18 (23.1) 1 (1.3) 55 (77.5) 13 (18.3) 0 (0.0) Thrombocytopenia 67 (85.9) 10 (12.8) 0 (0.0) 53 (74.6) 2 (2.8) 0 (0.0) Bilirubin increased 55 (70.5) 1 (1.3) 0 (0.0) 39 (54.9) 2 (2.8) 0 (0.0) Hemoglobin 50 (64.1) 1 (1.3) 0 (0.0) 35 (49.3) 1 (1.4) 0 (0.0) HFSR 41 (52.6) 4 (5.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Hypertension 40 (51.3) 8 (10.3) 0 (0.0) 28 (39.4) 3 (4.2) 0 (0.0) Lipase increased 38 (48.7) 11 (14.1) 1 (1.3) 18 (25.4) 2 (2.8) 0 (0.0) Amylase increased 32 (41.0) 6 (7.7) 0 (0.0) 19 (26.8) 1 (1.4) 0 (0.0) Neutropenia 29 (37.2) 4 (5.1) 0 (0.0) 29 (40.8) 0 (0.0) 0 (0.0) WBC decreased 29 (37.2) 1 (1.3) 0 (0.0) 26 (36.6) 0 (0.0) 0 (0.0) Malaise 20 (25.6) 0 (0.0) 0 (0.0) 9 (12.7) 0 (0.0) 0 (0.0) Fatigue 19 (24.4) 2 (2.6) 0 (0.0) 7 (9.9) 0 (0.0) 0 (0.0) Fever 15 (19.2) 1 (1.3) 0 (0.0) 18 (25.4) 0 (0.0) 0 (0.0) Anorexia 11 (14.1) 2 (2.6) 0 (0.0) 8 (11.3) 1 (1.4) 0 (0.0) Diarrhea 11 (14.1) 2 (2.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Erythema multiforme 9 (11.5) 2 (2.6) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Weight loss 9 (11.5) 0 (0.0) 0 (0.0) 2 (2.8) 0 (0.0) 0 (0.0) Hoarseness 9 (11.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) (within 4 weeks after TACE) AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; HFSR, hand-foot skin reaction; WBC, white blood cell count

18 Study Drug and TACE Administration TACE With Sorafenib (n = 80) TACE Alone (n = 76) Duration of sorafenib (week) Mean (SD) 57.1 (53.3) NA Median (range) 38.7 ( ) NA Actual daily dose of sorafenib (mg) Mean (SD) (172.0) NA Median (range) ( ) NA Interval between each TACE session, weeks (median, IQR) 21.1( ) 16.9 ( ) P =.018* * Mann-Whitney U test Median follow up period: weeks Data cut-off for analysis 31.Oct 2017

19 Time to Vascular Invasion and Extrahepatic Spread Time to Vascular Invasion Time to Extrahepatic Spread Proportion of Patients With Vascular Invasion HR % CI: 0.09,0.75 P =.008 TACE with sorafenib Median: 31.3 months TACE alone Median: 4.0 months Proportion of Patients With Extrahepatic Spread HR % CI: 0.06,0.70 P =.006 TACE with sorafenib Median: 15.7 months TACE alone Median: 6.9 months Time to Vascular Invasion, Months Time to Extrahepatic Spread, Months 60.0

20 Time to Stage Progression (Time to Vascular Invasion and/or Extrahepatic Spread) Proportion of Patients With Stage Progression HR % CI: 0.15, 0.63 P =.001 TACE with sorafenib Median: 22.5 months TACE alone Median: 6.3 months Time to Stage Progression, Months

21 TACE Combination Trials With Sorafenib Trial Phase III Post-TACE Phase II SPACE Phase III TACE-2 Phase II TACTICS Author Kudo M, et al Eur J Cancer 2011 Lencioni R, et al J Hepatol 2016 Tim Meyer, et al Lancet GH 2017 Kudo M, et al ASCO-GI 2018 Child-Pugh A A (No ascites) A A5-B7 ECOG-PS Tumor burden 7 cm 10 tumors Unresectable multinodular Not a candidate for resection or transplantation 10 cm 10 tumors TACE procedure ctace on demand DEB-TACE scheduled DEB-TACE on demand ctace on demand Endpoint TTP (5.4 M) TTP (5.6 M) PFS (8.5 M) PFS (25.2M) Criteria of progression RECICL 2004 mrecist RECIST 1.1 UnTACEable progression/tace Failure New lesion: not PD Sorafenib duration (weeks) Median f/u period (weeks) NA DOT, duration of treatment; PD, progressive disease; UP, UnTACEable progression Kudo M, et al. Eur J Cancer. 2011;47(14): Lencioni R, et al. J Hepatol. 2016;64(5): Meyer T, et al. Lancet Gastroenterol Hepatol. 2017;2(8):

22 Conclusions TACE in combination with sorafenib significantly improved PFS compared with TACE alone (25.2 months vs 13.5 months) TACE in combination with sorafenib significantly prolonged time to VI/EHS and stage progression (22.5 months vs 6.3 months) as well as interval between each TACE session Longer sorafenib treatment duration (38.7 weeks) may be the key of success of this trial as compared with previous failed trials (Post TACE; 17.0 weeks, SPACE; 21.0 weeks, TACE 2; 17.1 weeks) New intrahepatic lesions should not be regarded as progressive disease/stopping rule of the study in TACE combination trial The TACTICS trial clearly showed TACE in combination with sorafenib is a treatment option to improve clinical outcome and may be a standard of care in patients with intermediate stage HCC

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