An Update on Hepatocellular Carcinoma. Ed Gane NZ Liver Transplant Unit

Transcription

1 An Update on Hepatocellular Carcinoma Ed Gane NZ Liver Transplant Unit

2 Hepatocellular Carcinoma has a High Burden of Disease APSCVIR March 2018 Lung Liver Colon/Rectal Stomach Breast Cervix Uteri Esophagus Bladder Non-Hodgkin's Lymphoma Oral Cavity Ovary Corpus Uteri Global Deaths from Cancer 204, , , , , , , , , , ,000 1,690, , , , ,000 1,000,000 1,200,000 1,400,000 1,600,000 1,800,000 HCC is 3 rd most common cancer HCC is 2 nd most common cancer-related death 1. Parkin DM, et al. CA Cancer J Clin. 2005;55: Pons-Renedo F, et al. Med Gen Med. 2003;5:11. iacentre/factsheets/fs297/en/. Accessed 16 April

3 # HCCs per annum Aetiology of HCC in New Zealand 2315 new HCC cases referred to the NZLTU HCC MDM HCV HBV NASH ALD Other Nov 2017-Nov 2018 APSCVIR March

4 # HCCs per annum Current trend due to aging untreated HCV cohort 100 HCV APSCVIR March Nov 2017-Nov

5 Pan-genotypic DAAs will reverse this trend 60,000 50,000 40,000 30,000 20,000 10,000 - Total Total Infected Cases Cases (Viremic) (Viremic) New Zealand New Zealand Liver Related Deaths New Zealand Baseline IFN Baseline DAAs IFN G1 only DAAs all all Genotypes Baseline IFN DAAs Baseline G1 IFN only DAAs all Genotypes HCC New Zealand Decompensated Cirrhosis New Zealand , Baseline IFN DAAs Baseline G1 only IFN DAAs all all Genotypes Baseline IFN Baseline DAAs G1 IFN only DAAs all Genotypes APSCVIR March 2018

6 # HCCs per annum Future trend will be due to the obesity epidemic 40 NASH % increase in NAFLD-HCC cases over the last decade 6

7 Liver cancer from HBV neonatal vaccination HBV remains the leadiing case of HCC in NZ despite universal neonatal vaccination since Trans-Tasman Lecture AGW 2018

8 ...reflecting increasing migration to New Zealand from countries with endemic HBV infection 30% 20% Chinese, SE Asian Pacific Islander 10% Within 20 years, 40% New Zealand population with be either Asian or Polynesian Trans-Tasman Lecture AGW % Source:

9 Current diagnosis of HCC

10 Updated Radiological Diagnostic Criteria for HCC (LiRADS) 10

11 Updated Radiological Diagnostic Criteria for HCC (LiRADS)

12 Management of HCC

13 EASL Updated BCLC Clinical Staging Criteria 13

14 EASL Updated BCLC Clinical Staging Criteria How to evaluate suitability for resection EASL Clinical Practice Guidelines

15 EASL Updated BCLC Clinical Staging Criteria Ablation is first line for small HCCs 1. Meta-analysis of 17 studies 3996 patients underwent resection 4424 patients underwent RFA OS Overall survival, DFS, disease free survival RFA has similar quality-adjusted life-expectancy but at lower cost than resection for patients with up to three nodules 3 cm Cucchetti et al, JHep

16 EASL Updated BCLC Clinical Staging Criteria Ablation is first line for small HCCs 2. NZLTU Data 1 year 3 year 5 year OLT (n = 145) 88% 77 % 73% Resection (n = 190) 88% 64% 54% Ablation (n = 109) 95% 72% 50% Wu L, et al. HPB 2018; 20:

17 Screening for HCC in patients infected with HBV Treatment determines Recurrence Rate at NZLTU 1 year 3 year 5 year OLT (n = 121) 97% 89% 84% Resection (n = 190) 66% 43% 35% Ablation (n = 109) 73% 33% 19% Wu L, et al. HPB 2018; 20:

18 Transplant Criteria for HCC

19 Overall Survival (%) Changing Criteria for Transplant for HCC 1. Milan Criteria ( ) - (i) Single tumour 5 cm or (ii) 2 or 3 tumours 3cm Based on small single centre study at National Cancer Institute, Milan - 48 patients with HBV or HCV cirrhosis transplanted for small HCC 100 Criteria Met Mazzafero, et al, NEJM Criteria Not Limitations 60 Met of Milan Criteria Too P< restrictive Excludes 20 patients with reasonable survival P=0.01 by the Log-Rank Test Within Milan Outside Milan Months After Transplantation Within Milan Outside Milan Sensitivity of pre-operative imaging improved 3 3

20 Survival Distribution Function Changing Criteria for Transplant for HCC 1. Milan Criteria ( ) - (i) Single tumour 5 cm or (ii) 2 or 3 tumours 3cm 2. UCSF Criteria ( ) - (i) Single tumour 6.5 cm or (ii) 2 or 3 tumours 4.5 cm (total diameter <8) Based at UCSF between patients transplanted for HCC 0.8 Within Milan (46) 0.6 Within UCSF (60) Outside UCSF (10) 0.0 Yao, et al, Liver Transpl 2002; 8: Year After Liver Transplantation Meeting New UCSF Staging Criteria Yes: No:

21 Changing Criteria for Transplant for HCC 1. Milan Criteria ( ) - (i) Single tumour 5 cm or (ii) 2 or 3 tumours 3 cm 2. UCSF Criteria ( ) - (i) Single tumour 6.5 cm or (ii) 2 or 3 tumours 4.5 cm (total diameter <8) 3. Extended Criteria with Downstaging Protocol (2018) Entry Criteria (before loco-regional therapy) (i) 1 tumour 8 cm or (ii) 2 or 3 tumours 5 cm or (iii) 4 or 5 tumours 3cm (total diameter <8) Listing Criteria (after loco-regional therapy) (i) Within UCSF or (ii) Milan Criteria (centre-dependent) - Wait 3 months prior to listing - Wait 6 months until provide MELD Exception points - DELIST if progresses outside Milan Criteria

22 Downstaging of HCC before Liver Transplant 118 patients down-staged to within UCSF criteria compared to 488 patients not down-staged and within Milan criteria (i) Post-transplant Survival (HCC Recurrence) (ii) Pre-transplant Drop-out (HCC progression) Within Milan P=0.04 P=0.69 Within Milan Yao F, et al. Hepatology 2015; 61:

23 Cumulative Survival (%) Downstaging of HCC before Liver Transplant Impact on response to downstaging on outcomes 543 outside UCSF criteria underwent downstaging pretransplant HCC down-staged to within UCSF in 422 pts ( UNOS-DS ) HCC remained outside UCSF in 121 pts ( AC-DS ) AFP predicted survival in down-staged patients Mehtra N, et al. AASLD 2018 Abstract # Months Post-transplant

24 NZLTU Downstaging Protocol Outside UCSF Within entry criteria* TACE Downstaged within Milan Observed 3 months Listed Observed 3 months +22 MELD points +2 points q3 mthly Entry Criteria 1 8cm or 2-3 5cm or 4-5 3cm AND Total 8cm 3 monthly restaging with CT/MRI + AFP DELIST if exceeds Milan or if AFP >400?

25 Any there any new systemic treatments for Advanced HCC?

26 Emerging Therapies for Advanced HCC 1. Small molecules targeting tumour pathways Anti-proliferative Anti-angiogenic 2. Immune checkpoint inhibitors 3. Oncolytic viruses APSCVIR March 2018 WHAD, July 28th

27 Landscape of Systemic Treatment 2008 Agent Class Line of Treatment Status Result Sorafenib TKI First line FDA Approved 2005 Median OS 10.7 mos 27

28 Survival Probability ( %) Sorafenib: the first approved therapy for Advanced HCC SHARP study of sorafenib, an oral tyrosine kinase inhibitor 602 patients with advanced HCC (28 from Auckland) 100 Sorafenib (n=299) Median: 10.8 mo (95% CI: ) 75 Placebo (n=303) Median: 7.9 mo (95% CI: ) 50 APSCVIR March Patients at Risk Sorafenib Placebo HR (95% CI): 0.69 ( ) P= * Months Llovet JM, et al. N Engl J Med Jul 24;359(4):

29 APSCVIR March 2018 Currently $9,000 per month, unfunded

30 Landscape of Systemic Treatment Agent Class Line of Treatment Status Result Sorafenib TKI First line Lenvatinib TKI First line Nivolumab Anti-PD-1 Second line Regorafenib TKI Second line Cabozantinib Anti-MET Second line Ramucirumab Anti-VEGFR2 Second line FDA Approved 2005 FDA Approved 2012 FDA Approved 2017 FDA Approved 2017 Currently under FDA Review Currently under FDA Review Median OS 10.7 mos Median OS 13.6 mos Median OS 13.2 mos phase 1/2 Median OS 10.6 mos Median OS 10.2 mos Press Release POSITIVE 30

31 Phase III REFLECT study of Lenvatinib a Multikinase Inhibitor in Advanced HCC Probability of PFS APSCVIR March patients with advanced HCC were randomized 2:1 to sorafenib or lenvatinib 8 mg (< 60 kg)/12 mg ( 60 kg) In patients with advanced HR: 0.66 (95% HCC, CI: ) Log-rank test: P < Lenvatinib 0.3 improved progression- 0.2 free 0.1 survival compared to Sorafenib Mos Pts at Risk, n Median, mos (95% CI) Lenvatinib: 7.4 ( ) Sorafenib: 3.7 ( ) Cheng AL, et al. ASCO Abstract

32 Phase III CELESTIAL study of Carbozantinib a MET Inhibitor in Advanced HCC 760 patients with advanced HCC who had failed sorafenib were randomized 2:1 to 60 mg of cabozantinib or placebo APSCVIR March In patients who failed Sorafenib, Carbozantinib improved survival Median survival 15 months Hazard Ratio 0.44; P < Median survival 8 months Abou-Alfa G, et al, ASCO-GI;

33 Immunotherapy with Checkpoint inhibitors Phase II CheckMate study of Nivolumab (anti-pd1) 311 compensated cirrhotic patients with advanced HCC received Nivolumab 0.3mg/kg IV every 2 weeks Sorafenib failures APSCVIR March decompensated cirrhotics Tumour response in 55% Median survival 8 months Similar safety profile Kudo M, et al AASLD Abstract LB#2 Disease response in 68% Median survival 15 months (cf 6 months historical) 4% discontinued, no treatment-related deaths El-Khoueiry A, et al Lancet 2017; 389:

34 Check-point inhibitor combined with other agents 1. Anti PD-1 + Isatuximab (anti-cd38 mab) 2. Anti PD-1 + Cabozantinib (multi-tyrosine kinase inhibitor) 3. Anti-PD-1 + Ipilimumab 4. Anti-PD-1 + Ipilimumab + cabozantinib 5. Anti PD-1 + CBT-101 (c-met inhibitor) 6. Anti PD-1 + Lenvatanib (VEGFR and FGFR inhibitor) 7. Anti-PD-L1 + Bevacizumab (anti-vegf) 8. Anti-PD-L1 + Ramucirumab (anti-vegf-r2 Ab 9. Anti-PD-L1 plus tremelimumab (anti-ctla-4 mab) 10. Anti PD-1 + NC280 (c-met inhibitor) 11. Anti PD-1 + galunisertib (TGF-b inhibitor) 12. Anti PD-1 + NIS793 (anti TGF-b mab) 13. Anti-CTLA-4 mab + MGN1703 (TLR agonist) 14. Anti-PD-L1 + AZD4635 (adenosine A2A receptor antagonist) 34

35 Immunotherapy with an Oncolytic Virus Pexa-Vec: genetically modified vaccinia virus APSCVIR March 2018 A frozen viral suspension Administered IV and/or IT 35 35

36 Immunotherapy with an Oncolytic Virus Pexa-Vec: genetically modified vaccinia virus 8wks 20mth s Infects and destroys distant HCC mets 12 wks 6 cm APSCVIR March 2018 Park et al, Lancet Oncol

37 Screening for HCC in patients infected with HBV Most patients receive palliative therapy NZLTU (n=2161) TACE 12% 51% Palliative 11% 11% 15% Ablation Transplant Resection APSCVIR March

38 Nothing About Us Without Us to improve the way we manage our patients with advanced HCC NAUWOU Workshops

39 NAUWOS output Unmet needs Emotional impact of diagnosis and short survival Language/cultural barriers Social/financial impact (sole income in large whanau) Changes New clinic (not Friday afternoon) Closer community follow up Early palliative care APSCVIR March

40 Management of Hepatocellular Carcinoma requires a Multidisciplinary Approach Interventional radiology Diagnostic Radiology Hepatology Hepatobiliary and Transplant Surgery Patient with HCC Medical Oncology Pathology Radiation Oncology Primary care Provider Palliative Care

41 Hepatocellular Carcinoma in Asia-Pacific Current Problems Huge disease burden in Asia Pacific Region Due to endemic HBV infection Increasing 10% per annum from HCV and obesity epidemic Unmet medical need >90% patients have cirrhosis Transplant is limited resource Most are detected late, no curative options Sorafenib is expensive and has poor safety/efficacy profile APSCVIR March

42 Hepatocellular Carcinoma in Asia-Pacific Future Solutions 1. Earlier detection identification of those at-risk populations uptake of HCC surveillance 2. Safer, more effective therapy Local ablation for early HCC Funded systemic therapy for advanced HCC 3. Better prevention HBV vaccination Wide access to HCV treatment Government strategies to reduce obesity APSCVIR March

43 Thank you! John McCall, Adam Bartlett Lucy Modhal, Andrew Holden Oonagh Lithgow, Veronica Henderson Anne Callaghan, Palliative Care Team The NAUWOU working group