Advances in percutaneous ablation and systemic therapies for hepatocellular carcinoma

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1 Advances in percutaneous ablation and systemic therapies for hepatocellular carcinoma Paris Hepatology Congress 2019 Pierre Nahon Service d Hépatologie Hôpital Jean Verdier Bondy Université Paris 13 INSERM Paris 5 Génomique fonctionnelle des tumeurs solides

2 Conflicts of interest Speaker for Abbvie, Bayer, BMS, Gilead, Ipsen Advisory board for Abbvie, Astra Zeneca, Bayer, BMS, Ipsen

3 Technological innovation New molecules Increase the rates of patients who will benefit from curative procedures Increase overall survival in palliative setting Bruix et al, Gastroenterology 2016

4 First case o 71 years old male o Child-Pugh A6 HBV related cirrhosis (treated) o Grade II esophageal varices o Platelets count: / mm3 o Bilirubin: 9 mg/l o Albumin: 34 g/l o Prothrombin time: 77% o Liver stiffness: 22 Kpa o Alpha-fetoprotein: 478 ng/ml o PS 0, ECOG 0

5 Pretherapeutic imaging 5 cm

6 Which treatment? 1. Transplantation 2. Resection 3. Ablation 4. TACE 5. Other

7 Which treatment? 1. Transplantation 2. Resection 3. Ablation 4. TACE 5. Other

8 BCLC staging CURATIVE PALLIATIVE

9 Gastroenterology 2006 Cuchetti et al, J Hepatol 2016 Boslelawski et al, Br J Surg 2012

10 Portal hypertension (CSPH): Resection? 1108 patients (386 with vs 722 without HP) in 8 studies Berzigotti, Bruix, Hepatology 2015 Odds Ration, CI95% Liver decompensation HVPG: 10 mm Hg PVP: 20 cm H2O 2.48 Surrogate: GEV or Plt.< 105/ml or Spleen > 12 cm 2.56 Pooled

11 Ablation or resection? Ablation Resection Distant Same segment Deep Superficial Gooda Excellentb Portal Hypertension Yes No Mortality 0.3% 1% 76% in patients 75% 2 or 3 nodules Localization Liver function 5-yrs survival eligible for resection a Malades appartenant principalement à la classe A ou B de Child-Pugh b Malades appartenant principalement à la classe A de Child-Pugh.avec bilirubine normale et sans hypertension portale

12 BCLC (AASLD/EASLD)

13 Percutanous ablation US control Radiofrequency ablation

14 Principles for large ablations Monopolar RFA Multibipolar «no touch»

15 Principles for large ablations Monopolar RFA Multibipolar «no touch»

16 Principles for large ablations Monopolar RFA Multibipolar «no touch»

17 Principles for large ablations Monopolar RFA Multibipolar «no touch»

18 Principles for large ablations Monopolar RFA Multibipolar «no touch»

19 No touch multibipolar RFA for HCC Seror et al, Radiology 2012

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21 On October 2009 : o Near no touch RFA consisting in inserting 7 straight electrodes with 4 cm active tips: 6 in square configuration at periphery of the tumor and 1 in its center. o 200 kj in 42 minute of application time has been delivered o 2 days of hospital stay

22 One month later AFP: 2 ng/ml

23 5 years later 0 recurrence

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25 Second case o 69 years old male o Child-Pugh A6 alcohol-related cirrhosis o Grade I esophageal varices o Platelets count: / mm3 o Bilirubin: 7 mg/l o Albumin: 45 g/l o Prothrombin time: 97% o Liver stiffness: 62 Kpa o Alpha-fetoprotein: 5ng/ml o PS 0, ECOG 0

26 Imaging findings

27 Which treatment? 1. TACE 2. Radio-embolization 3. Sorafenib 4. Lenvatinib 5. Other systemic therapy

28 Which treatment? 1. TACE 2. Radio-embolization 3. Sorafenib 4. Lenvatinib 5. Other systemic therapy

29 Radioembolization : negative trials SARAH trial (West) Vilgrain et al, Lancet Oncol 2017 SIRveNIB trial (East) Chow et al, JCO 2018

30 New molecules: where do we stand? Llovet et al, Nature Reviews 2016

31 New molecules: where do we stand? Llovet et al, Nature Reviews 2016

32 EASL 2018: recommandations for HCC management L.FR.MA European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol (2018),

33 Lenvatinib: an alternative to sorafenib in first line SHARP trial Llovet et al, NEJM 2008 Non-inferiority trial Kudo et al, Lancet 2018

34 Second case (continued) o The patient received sorafenib full dose o Tolerance OK except asthenia grade I o CT scan every 2 months: stable disease for 8 months o Progression at month 9 with new hepatic lesions and one lung metastasis o Liver function preserved

35 Which treatment? 1. Lenvatinib 2. Regorafenib 3. Cabozantinib 4. Nivolumab 5. Other

36 Which treatment? 1. Lenvatinib 2. Regorafenib 3. Cabozantinib 4. Nivolumab 5. Other

37 Regorafenib : first approved systemic therapy in second line RESORCE (NCT ) a multinational,* randomized, double-blind, placebo-controlled phase III study that will evaluate the efficacy and safety of regorafenib in patients with advanced liver cancer who have progressed on prior sorafenib PATIENTS (N = 573) HCC patients with documented radiologic progression during sorafenib treatment R 2:1 Regorafenib 160 mg orally once daily (3 weeks on, 1 week off) + best supportive care (4 weeks/cycle, n = 379) Placebo matching tablets orally once daily (3 weeks on, 1 week off) + best supportive care (4 weeks/cycle, n = 194) Disease progression Stratification L.FR.MA Geographic region (Asia vs ROW) Macrovascular invasion Extrahepatic disease ECOG PS (0 vs 1) AFP (<400 ng/ml vs 400 ng/ml) *152 centers in 21 countries in North and South America, Europe, Australia, and Asia. Including clinical progression, unacceptable toxicity, withdrawal of patient consent, or discontinuation of therapy by the treating physician. AFP, alpha-fetoprotein; ECOG PS, Eastern Cooperative Oncology Group performance status; ROW, rest of world. Adapted from Bruix J, et al. Lancet. 2017;389: Death

38 Probability of survival (%) Regorafenib and OS Benefit Compared With Placebo in patients with HCC Who Have Progressed on Sorafenib Regorafenib (n = 379) Placebo (n = 194) Events 233 (61%) 140 (72%) Censored 147 (39%) 54 (28%) 10.6 mo ( ) 7.8 mo ( ) Median OS (95% CI) HR = 0.63 (95% CI: ) P <.0001 (one-sided) Months from randomization L.FR.MA Number at risk Regorafenib Placebo Bruix J, et al. Lancet. 2017;389:56-66.

39 Improvement in OS With Regorafenib Was Maintained in All Preplanned Subgroups Subgroup n/event s L.FR.MA Age group <65 years 65 years Sex Male Female Geographical region Asia ROW ECOG score 0 1 AFP <400 ng/ml 400 ng/ml Child-Pugh score A5 A6 Extrahepatic disease No Yes Macrovascular invasion No Yes Extrahepatic disease, or macrovascular invasion, or both No Yes Hepatitis B No Yes Hepatitis C No Yes Alcohol use No Yes Bruix J, et al. Lancet. 2017;389: Favors regorafenib Favors placebo 2.0 Hazard ratio (95% CI) 315/ / ( ) 0.74 ( ) 504/327 69/ ( ) 0.88 ( ) 216/ / ( ) 0.68 ( ) 377/ / ( ) 0.78 ( ) 324/ / ( ) 0.68 ( ) 362/ / ( ) 0.80 ( ) 161/ / ( ) 0.60 ( ) 409/ / ( ) 0.67 ( ) 107/68 466/ ( ) 0.63 ( ) 357/ / ( ) 0.58 ( ) 454/ / ( ) 0.79 ( ) 428/ / ( ) 0.92 ( )

40 Sequential treatment with sorafenib and regorafenib: effet on survival Death Progression n= 374 Sorafenib 26 months Regorafenib ( ) 7,1 7,1 n= 193 Sorafenib 0,9 0,9 10,6 7,8 Placebo Δ 2,8 months Δ 6,8 months 19,2 months ( ) L.FR.MA Adapted from Finn R, et al. ASCO GI Abstract 344.

41 Cabozantinib : another option in second line (and beyond?) Abou-Alfa et al, NEJM 2018

42 Towards new recommandations? First line Sorafenib Lenvatinib Intolerance/progression Second line Cabozantinib Regorafenib Ramucirumab AFP>400 ng/ml

43 Survival Benefits of immunotherapy for cancer treatment? Time Chemotherapy Targeted therapy Immunotherapy Combo or sequential with immuno

44 Check-point inhibitors NIVOLUMAB PD1-PDL1 pathway Pardoll DM, Nat Rev Cancer 2012

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46 Tumour reduction: 45% patients Reduction at least 30%: 22% patients El-Khoueiry et al, Lancet 2017 AEs 3-4: 18% patients

47 Translation into survival benefit? Meyer et al, EASL 2018

48 Summary Advances in ablative techniques offer new aggressive therapeutic managements for large and locally advanced tumors which can be treated in a curative approach. Several systemic therapies are now available and allow management of patients in first and second lines. However, no biomarkers are available to predict response and select the optimal candidates for a given molecule. Immunotherapy is emerging and might become the backbone for combined therapy.

49 French phase 2 trial Academic trial supported by BMS Coordinating investigator: Pr Pierre Nahon Nivolep trial ClinicalTrials.gov ID: NCT (Every 30 days) n=50 5 centres «Curative intent» Primary Endpoint: local recurrence-free survival