INTERMEDIATE HEPATOCELLULAR CARCINOMA MANAGEMENT

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1 INTERMEDIATE HEPATOCELLULAR CARCINOMA MANAGEMENT GI Preceptorship Nov 2018 Dr Choo Su Pin Senior Consultant and Deputy Head, Medical Oncology Co-Chair, Comprehensive Liver Cancer Centre National Cancer Centre Singapore esmo.org

2 Disclosures Advisory role and honoraria: Bayer, Sirtex, Bristol-Myers Squibb, Shire, Eisai, Ipsen, Norvatis, Celgene Speaker fees: Lilly Oncology, Sirtex. BMS Research funding: BMS, Sirtex 2

3 Liver cancer is a common and deadly disease Very common Exceptionally lethal Heterogeneous Disease 782,000 global new cases of liver cancer in Men Women 6 th most common form of cancer worldwide more prominent in male Around 50% of HCC are diagnosed at advanced stage globally Second only to lung cancer in terms of mortality 2,3 Only 20% of diagnosed UK patients live longer than a year after diagnosis 1 Liver Cancer mortality in the US is growing at a higher rate than other cancers HBV is leading cause of HCC in Asia and China 594 Mio cases in Asia 2 HCV and life style is the leading cause of HCC in western population 96 Mio cases in Nothern America and Europe 1. Gravitz L, Nature 2014:516(7529):S1. 2. GloboCan US National Cancer Institute Surveillance, Epidemiology, and End Results Program. 4. Ahmed, F. et al. Prev. Chronic Dis. 2008; 5:A Scudellari N. Nature 2014; 2014:516(7529):S4; 6.Nature Outlook 12/14. Before 2017: estimated median survival for advanced HCC < 12 months 3

4 BCLC staging and treatment outcomes Median OS 20 m Median OS 6.5 to 10.7m 4

5 ESMO guidelines 5

6 The problem with intermediate HCC High heterogeneity Clinical decisions differ from centre to centre coz of lack of clear scientific evidence for many therapies Thus, there are treatment discrepancies between guidelines 6

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8 LOCOREGIONAL THERAPIES FOR INTERMEDIATE HCC: - NOT AMENABLE TO RESECTION/ TRANSPLANT OR ABLATION - Transarterial Chemoembolisation ( TACE ) - Selective Internal radiotherapy (SIRT) - Sorafenib

9 TACE Is there survival benefit What are the factors that affect TACE outcomes? What is the best method for TACE How often should we TACE / what is deemed TACE failure?

10 TAE/TACE vs Best Supportive Care: 2-year Survival Author, journal year Patients Random effects model (DerSimonian and Laird) Odds ratio (95% CI) Lin, Gastroenterology GETCH, NEJM Bruix, Hepatology Pelletier, J Hepatol Lo, Hepatology Llovet, Lancet Overall 503 z= 2.3 p= Heterogeneity p=0.14 Favours treatment Favours control Meta-analysis of 7 RCTs showed survival benefit with TACE, OR 0.53, RR35% Llovet JM, et al. Lancet. 2003;362: Der Simonian R, Laird N. Controlled Clin Trials. 1986;7: Llovet et al Hepatology 2003

11 Overall survival in RCTs with TACE : TACE is better than best supportive care TACE: Long-term survival outcomes Llovet JM, et al. 1 Lo C-M, et al. 2 Chemoembolization (n = 40) HR: 0.47 [95% CI ] P=0.025 Control (n = 35) Chemoembolization (n = 40) P=0.002 Control (n = 39) 1. Llovet JM, et al. Lancet 2002;359: Lo C-M, et al. Hepatology 2002;35: Relative risk of death, 0.49; 95% CI, ; P=

12 Factors affecting TACE outcomes: Prognostic scores in patients undergoing TACE Child-Pugh score/ Albumin-bilirubin HAP score ART Score ABCR score Albumin <35g/L Bilirubin > 17mmol/L Child-Pugh increase following TACE : +1, +2 points) Hucke et al 2014; Adhoute 2015; Kadalayi 2013 Child-Pugh increased following TACE ( >2 points) Tumor stage Tumor diameter > 7vm BCLC stage (B,C) AFP AFP> 400ng/dL AFP> 200ng/ml AST Radiological response AST> 25% from baseline Lack of radiological response Presence of radiological response

13 Contraindications to TACE Absolute contraindications Thrombus in the main portal vein and portal vein obstruction (high risk liver failure) Encephalopathy Biliary obstruction Child-Pugh C cirrhosis Renal failure Extensive tumour burden Technical Relative contraindications include a variety of other factors including, but not limited to: Bile duct occlusion or incompetent papilla Reduced PS Impaired liver function (CP B) High risk oesophageal varices Branch portal vein thrombosis Vogel ESMO guidelines 13

14 Complications of TACE Post-embolization syndrome (60 80%) Ischaemic damage with consequent liver failure Hepatic abscess, biliary duct injury, cholecystitis (2%) Gastroduodenal ulceration (3-5%) Renal dysfunction (2%) Pulmonary and cerebral lipiodol embolization (rare but can be fatal) Mortality approx. 2-3% 14

15 Conventional TACE vs DCBeads TACE PRECISION V Trial : Phase 2 randomised, Europe, n=200 Arm 1: TACE with doxorubicin Arm 2: DC Beads with doxorubicin (150mg) Up to 3 times at 0,2,4mths Primary endpoint was = RR at 6 months Results: DC Bead ctace Response rate 52% 44% p not sig Disease Control Rate 63% 52% p not sig Less liver toxicity (p<0.001) and less doxorubicin toxicity (p=0.0001)with DC Beads. 15

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17 Courtesy Dr Huang 17

18 OPTIMIS: patients not indicated for TACE given TACE M Peck-Radosavlijevic

19 OPTIMIS: Variation in Timing to TACE Unsuitability Across Regions Timing After Initial TACE Treatment Median days (SD) EU & CANADA n=148 ASIA* n=156 JAPAN n=91 CHINA n=80 Total n=475 Median time to TACE unsuitability 79.5 (n=20) (n=20) (n=17) 42.0 (n=5) 92.0 (n=62) Mean (SD) time between 1 st & 2 nd TACE 84.7 (70.9) (n=87) 83.5 (61.3) (n=75) (101.7) (n=51) 80.8 (61.9) (n=37) 90.6 (75.4) (n=250) TACE to initiation of other treatment (69.0) (n=13) (96.6) (n=20) (73.3) (n=11) 72.0(66.2) (n=7) (82.9) (n=46) There is a need to initiate treatment sooner following TACE unsuitability *Excludes Japan and China. Data on file. Bayer HealthCare. Whippany, New Jersey. M Peck-Radosavlijevic

20 OPTIMIS: Liver Dysfunction Observed After TACE Treatment After TACE, changes in liver laboratory values are documented It is essential to preserve liver function in order to maximize the treatment potential for systemic therapy Worsening of Lab AE Grade Relevant to the Liver Summary Deterioration EUROPE N=148 (100%) ASIA* N=156 (100%) CHINA N=80 (100%) JAPAN N=91 (100%) Total N=475 (100%) Any Parameter 38 (25.7%) 66 (42.3%) 28 (35.0%) 38 (41.8%) 170 (35.8%) Alanine Aminotransferase 13 (8.8%) 16 (10.3%) 7 (8.8%) 10 (11.0%) 46 (9.7%) Albumin 20 (13.5%) 25 (16.0%) 16 (20.0%) 24 (26.4%) 85 (17.9%) Aspartate Aminotransferase 17 (11.5%) 35 (22.4%) 14 (17.5%) 15 (16.5%) 81 (17.1%) Bilirubin 12 (8.1%) 26 (16.7%) 13 (16.3%) 2 (2.2%) 53 (11.2%) Prothrombin INR 9 (6.1%) 18 (11.5%) 9 (11.3%) 11 (12.1%) 47 (9.9%) M Peck-Radosavlijevic

21 What is TACE failure? Proposed algorithm based on ART score Raoul

22 WILL ADDING SYSTEMIC THERAPY TO TACE IMPROVE OUTCOMES? Median OS with TACE alone about 20 months ---At least 5 negative trials Rationale for combining TACE with sorafenib: TACE is not curative and repeated TACE compromises the liver function TACE recurrence is associated with upregulation of VEGF and angiogenesis which sorafenib can inhibit. BRISK-TA (TACE +/- brivanib)and ORIENTAL (TACE +/- orantinib) trials negative

23 COMPARISON OF TACE COMBINATION TRIALS Post-TACE Phase 3 (n=458) SPACE Rand ph2 (n=307) TACE-2 Phase 3 ( n=399) TACTICS Rand ph 2 ( n=156) Sites Japan/Korea Global (excl Japan) UK ( terminated early) Japan only CP score A A A A to B7 Inclusion criteria <7cm; < 10 tumors Responded totace Unresectable TACE used ctace, on demand DEB-TACE, at3,7 and 13m and then 6mthly Primary end point TTP 5.4m vs 3.7m, HR 0.87, p=0.252 TTP 5.6 vs 5.5m HR 0.797, p=0.072 Not for resection or transplant DEB-TACE,on demand PFS 7.8m vs 7.7m HR 0.99, p=0.94 <10cm < 10 tumors ctace, on demand PFS 25.2m vs 13.5m HR 0.59, p=0.006 Secondary endpoint OS 29.7 m, HR1.06 p=0.79 OS not reached, HR 0.898, p =0.295 OS 21.1m vs 19.7m HR0.97, p=0.57 Not reached yet Definition of PD RECICL2014 mrecist RECIST1.1 untace-able progression Sorafenib duration 17 weeks 21 weeks 17.1 weeks 38.7 weeks Adapted from Kudo, Oncology 2017

24 4. TACTICS trial Study Schema Stratification: sites, within Milan, No of prior TACE Inclusion criteria Unresectable HCC Child-Pugh score;<7 Prior TACE; 0-2 Viable tumor (<10 nodules, <10cm) Adequate organ function Exclusion criteria EHS/MVI n=156 Randomization (1:1) TACE Sorafenib 400mg daily was started 2-3 weeks before 1 st TACE to check the tolerability and to block the VEGF receptors after TACE followed by 800mg daily Sorafenib was interrupted 2days before and 3 days after each TACE session as long as organ function is maintained within TACE re-starting 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 Sorafenib arm (n=80) Control arm (n=76) Sorafenib (400mg od 400 mg bid) Co-Primary Endpoint Slides courtesy of: Masatoshi Kudo, MD, PhD UnTACEable progression/ Progression to TACE failure PFS/OS (Gatekeeping strategy) Secondary Endpoint TTUP, TTP, ORR Safety

25 Definition of Progression Free Survival (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 )* 2) Deterioration of liver function to Child-Pugh C 3) Appearance of extrahepatic spread 4) Appearance of major vascular invasion (*Note: In this trial new lesion is not regarded as Tumor progression since it is not the treatment failure nor suggesting next line of treatment) Progression that meets the TACE failure/refractoriness criteria by JSH definition 2 2. Any cause of death RECICL: Response Evaluation Criteria In Cancer of the Liver JSH: Japan Society of Hepatology 1 Kudo M, et al, HepatolRes. 2010;40: Kudo M, et al. Dig Dis 2011;29: Presented by: Masatoshi Kudo, MD, PhD

26 Definition of TACE failure/refractoriness (JSH Criteria) 1 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 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 3 months after having adequately performed selective TACE 1 Kudo M, et al. TACE Failure criteria JSH guideline. Dig Dis 2011;29: Presented by: Masatoshi Kudo, MD, PhD

27 Main inclusion criteria Main inclusion / exclusion 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 M before) ECOG Performance Status (PS) score of 0 or 1 Child-Pugh score of 7 points or less Main exclusion criteria Macrovascular invasion (MVI) Extrahepatic spread (EHS) Presented by: Masatoshi Kudo, MD, PhD

28 Baseline Patient Characteristics Characteristics Category TACE with Sorafenib (n=80) TACE alone (n=76) Median Age at enrollment (range) 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) 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) 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) Presented by: Masatoshi Kudo, MD, PhD

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30 POSSIBLE REASONS WHY THESE TRIALS FAILED OR SUCCEEDED Post-TACE SPACE TACE-2 TACTICS Mean daily dose of sorafenib was only 386mg/ day ( 73% dose reductions and 91% interruptions) Three were significant differences in TTP between Korean and Japan cohorts - Korean patents had longer duration of treatment - Japanese patients had more lesions and were more elderly Scheduled TACE- could this have resulted in unnecessary compromise of liver function or inadequate TACE in some? E.g. One-third of those in sorafenib arm received only 1 x TACE Asians had better HR than non- Asians and were also on longer duration of sorafenib (30 weeks vs 17.4 weeks) and more TACE - More non-asians had untaceable progression due to liver function deterioration rather than lack of response these trials suggest that the duration of sorafenib ( +/- TACE duration) results in better outcomes As RECIST 1.1 used for determining progression, new intrahepatic lesionsin non-taced areas were considered PD - Does this mean treatment is not working and do TACE trials require a different definition of PD - Should time to TACE progression ( TTTP) be used instead? Different definition of PFS and what is considered TTTP 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 wks, SPACE; 21.0 wks, TACE 2; 17.1 wks).

31 UNANSWERED QUESTIONS ABOUT TACE What is optimal duration and frequency of TACE What is best method and chemotherapy for TACE Do the results of TACTICS apply to everyone else?

32 SIRT (SELECTIVE INTERNAL RADIATION THERAPY)

33 SIRT Selective Internal Radiotherapy HCC is radio-sensitive But external beam radiation risks significant collateral damage and toxicity to liver. However HCCs are almost exclusively supplied by the artery used to deliver local radiation therapy - brachytherapy Ytrium-90 tagged glass or resin microspheres Yttrium-90: delivers radiation; penetration avg 2.5 mm, max 11.0 mm Microsphere: delivers Yttrium-90 to HCC Needs pretreatment technetium-00m scan to ensure limited radiation exposure to lung/gi tract Safe for those with branch portal vein thrombosis

34 90 Y microspheres in Patients with HCC and PVT

35 SIRT vs TACE No randomized phase 3 trials comparing both modalities Zhang Y, 2015 Meta-analysis N=8 trials Better OS and TTP with SIRT vs TACE Salem R 2016 Randomised phase 2 trial SIRT vs ctace in BCLC A and B HCC TTP 26m vs 6.8 m 35

36 Slide 14 Courtesy of E Kim 36 Presented By Edward Kim at 2018 Gastrointestinal Cancers Symposium

37 Slide 15 Courtesy of E Kim 37 Presented By Edward Kim at 2018 Gastrointestinal Cancers Symposium

38 SARAH trial: a randomized controlled trial comparing efficacy and safety of SIRT (with yttrium-90 microspheres) and sorafenib in patients with locally advanced hepatocellular carcinoma 25 centres in France Co-investigators: hepatologists, oncologists, radiologists and nuclear medicine MDs V. Vilgrainet al

39 SIRveNIB trial: Phase II multi-centre, open label randomized controlled trial of SIRT versus sorafenib in locally advanced HCC Study Design and Assessments 39 Presented By Pierce Chow at 2017 ASCO Annual Meeting

40 SARAH vs SIRveNIB: trial endpoints and criteria SARAH SIRveNIB Primary Endpoint OS OS Secondary endpoints Inclusion criteria Safety and tolerability QOL PFS at 6 months Unresectable HCC - BCLC C - BCLC A/B if new lesions or unsuitable for further radical therapy or no response after TACEx2 - CP A to B7 - ECOG Fit for sorafenib or SIRT % did not get SIRT and 7.2% did not get sorafenib Safety and tolerability QOL PFS at 6 months Unresectable HCC with or without PVT - BCLC B or C without extrahepatic metastases - CP A to B7 - ECOG Fit for sorafenib or SIRT - Not more than 2 prior hepatic artery directed therapies % did get SIRT and 9% did not get sorafenib 40

41 SARAH Sample size Main PVT 32% 30% Etiology Alcohol. 68% HCV. 25% NASH. 23% SIRveNIB HBV 51% HCV 14.3% Both HBV+HCV 2.2% BCLC stage A/B/C 3.8/ 27.8/ 68.4% 0/ 54.9/ 44.5% OS SIRT 8m vs sorafenib 9.9m HR 1.15, p=0.18 PFS/ TTP PFS 4.3 vs 3.7m HR0.97, p=0.77 SIRT 8.9m vs soraf 10m HR1.12, p=0.36 TTP 6.08 vs 5.36m HR 0.88, p=0.287 ORR ( CR + PR) 19% vs 11.6%, p= % vs 1.7%, p<

42 In SARAH: Better QOL with SIRT compared to sorafenib In SIRveNIB: Better safety profile with SIRT Intention-To-Treat population N=459 42

43 SORAMIC Trial: Schema European Trial SCREENING Imaging Sub-Study NEGATIVE trial 1⁰ endpoint Non-inferiority (1 st step) or superiority (2 nd step) of Primovist-MRI vs. CE-CT MICRO-Tx SYSTEMIC Tx Local Ablation Group 1⁰ endpoint (<4 tumours; <5 cm each) sorafeni Randomise RFA 1:1 b SIRT + sorafenib vs sorafenib: OS Time to Recurrence n = 290 Contrastenhanced CT Assign to placebo 12.1m vs 11.5m Primovist - study arm enhanced MRI Off Study BCLC 0 BCLC D Palliative Group Randomise 11:10 n = 375 SIR- Spheres sorafeni b Overall Survival sorafeni b

44 ROLE of SIRT in ESMO guidelines SIRT is not recommended as first-line therapy for patients in intermediate or advancedstage[i,e] ESMO guidelines 44

45 SORAFENIB IN INTERMEDIATE HCC When TACE fails or not suitable for further locoregional therapy BCLC-B patients Number of patients SHARP subgroup analysis N=54 sorafenib N=51 placebo GIDEON N=311 N=74 OS 14.5 m (+ 39%) 12.6m 20.6m TTP 6.9m ( +113%) Safety Similar to BCLC C Italian SOFIA BruixJ, et al. J Hepatol2009; 50: S28 S29. Lencioni R. ESMO-ECCO oncology meeting Stockholm; avaronem, et al Hepatology 2011; 54(6):

46 ESMO GUIDELINES FOR HCC

47 FUTURE FOR INTERMEDIATE HCC - Combining A Multicenter locoregional Pilot Study of Nivolumab therapy With Drug with Cohort newer 1:TACE TKIs nivolumab or immuno-oncology 2 weeks later agents NCT Eluting Bead Transarterial Chemoembolization in Patients With Advanced Hepatocellular Carcinoma Cohort 2: nivolumab 4 weeks before TACE then nivo continued x 1 year (No dosing on TACE day) Cohort 3: nivolumab 4 weeks before TACE then nivo - Starting systemic therapy earlier in the continued treatment x 1 year ( Dosing algorithm on TACE day) with increasing evidence Phase of I/Ib good Study of outcomes Nivolumab in Combination with newer With Therasphere systemic nivolumab therapies 4 weeks later and limits of USA Therasphere (Yttrium-90) in Patients With TACE Advanced Hepatocellular Carcinoma NCT NCT NCT NCT NCT A Pilot Study of Pembrolizumab in Combination With Y90 Radioembolization in Subjects With Poor Prognosis Hepatocellular Carcinoma With Preserved Liver Function Phase I Study of Stereotactic Body Radiotherapy (SBRT) Followed by Nivolumab or Ipilimumab With Nivolumab in Unresectable Hepatocellular Carcinoma A Pilot Study of Combined Immune Checkpoint Inhibition in Combination With Ablative Therapies in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC) Pembrolizumab and Stereotactic Radiotherapy Combined in Subjects With Advanced Hepatocellular Carcinoma - A Phase II Study SIRspheres pembrolizumab 1 week later 40Gy nivolumab or nivolumab + ipilumumab 2 weeks later Tremelimumab + Durvalumab with RFA or TACe or cryoablation Pembrlizumab SBRT from day 2 USA USA USA USA Canada

48 A Phase II Open-Label, Single Centre, Non-Randomized Trial Of Y90- Radioembolization In Combination With Nivolumab In Asian Patients With Hepatocellular Carcinoma: An interim analysis MAA hepatic angiogram: Suitable for Y90 N=40 Enrolled into trial Y90 Radioembolization (RE) followed by IV Nivolumab 240mg flat doseover 30 minutes administered 21 days (±3 days) after RE and every 2 weeks thereafter Day 1: Y90- radioembolisation Day 21: i.v nivolumab 240mg over 1 hour, every 2 weeks Liver biopsy In collaboration with Prof Evan Newell (SiGN) and Dr Zhai Weiwei ( GIS) Main aims of study: 1) To evaluate the efficacy of combining Y90 radioembolisation with nivolumab 2) To evaluated the safety and tolerability of combining Y90 radioembolisation with nivolumab 3) Exploratory studies to assess immune markers and response to therapy Liver biopsy Choo SP et al ; AASLD Nov

49 SHOULD WE BE STARTING SYSTEMIC THERAPY EARLIER IN INTERMEDIATE HCC? Potentail new therapeutic options as other therapies prove to be more efficacious Galle 2017

50 CONCLUSION TACE is still the standard of care for intermediate HCC with good liver function In patients with TACE failure, PVT or poorer liver function, systemic therapy should be given While SIRT resulted in better ORR, it did not result in better OS compared to sorafenib. Thus role of SIRT is largely for very selected patients who are not suitable for TACE or sorafenib ( not everyone agrees with this) Treatment of intermediate HCC will evolve as results from combination trials become available

51 THANK YOU For fellows and junior consultants interested in clinical research: SSO-ACORD Trial Concept Development Workshop 4 th July Look out for submission date for 1-page study proposals - Check out Singapore Society of Oncology website and facebook