Personalized Management of HCC

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1 Personalized Management of HCC Josep M. Llovet, MD, FAASLD Professor of Medicine. Director, Liver Cancer Program, ISM at Mount Sinai, NYC. Professor of Research-ICREA. BCLC Group-IDIBAPS. Liver Unit. Hospital Clínic Barcelona. Postgraduate Course: Challenges in Management of Common Liver Diseases 526 1

2 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 527 FOR THE STUDY OF LIVER DISEASES 2

3 Case description 69- yr old man, with compensated HCV-cirrhosis 2012: Single HCC 5cm, no macrovascular invasion (MVI) or extrahepatic spread (EHS) Child-Pugh A, ECOG 0, Bilirubin: 1 mg/dl and no portal hypertension Segmental resection: R0, no satellites, microvascular invasion 2014: Multinodular HCC recurrence: 3 nodules (max: 4cm) Child-Pugh A, ECOG 0, no MVI- EHS, AFP: 100 ng/ml Chemoembolization (TACE x3): partial response 2016: Progression main HCC nodule : 6cm, satellites and branch portal vein thrombosis Child-Pugh A, ECOG 1, Bilirubin 1.5 mg/dl, AFP: 600 ng/ml. Treatment strategy? a) TACE b) Sorafenib c) TARE (Y-90) d) Radiotherapy 528

4 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 529 FOR THE STUDY OF LIVER DISEASES 4

5 BCLC staging system Scientific societies endorsing BCLC EASL Guidelines. Management of HCC. 2001, 2012; EORTC 2012 AASLD guidelines. Management of HCC, 2005,

6 BCLC Staging and treatment schedule Unresectable HCC 531 Llovet JM et al. Nat Rev Dis Primers 2016

7 Intermediate-advanced HCC Redefining unresectable HCC: NATURAL HISTORY -BCLC B and C Survival BCLC B stage (n=370) Median survival: Placebo 15.8m Seocalcitol 15.1m Survival BCLC C stage (n=376) Median survival : Placebo 5.7m Seocalcitol 5.6m p=0.76 p= % 23% 11% 10% RCT seocalcitol vs placebo (n=746) 532 Llovet et al, Hepatology 1998; Beaugrand M, et al. J Hepatol, 2005A.

8 BCLC Staging and treatment schedule 533 Llovet JM et al. Nat Rev Dis Primers 2016

9 Evidence and recommendations for HCC therapies 534 EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012

N=602 Sorafenib (n=299) 400 mg po bid continuous dosing Placebo (n=303) 2 tablets po bid

10 Systemic therapies: sorafenib Sorafenib Stratification: * Macroscopic vascular invasion (portal vein) and/or extrahepatic spread * ECOG PS * Geographical region Randomization N=602 Sorafenib (n=299) 400 mg po bid continuous dosing Placebo (n=303) 2 tablets po bid continuous dosing EASL-EORTC Guidelines, J Hep Llovet JM et al, NEJM 2008;359:378-90

11 BCLC Staging and treatment schedule Endorsed by AASLD, EASL, EORTC, ESMO 536 Llovet JM et al. Nat Rev Dis Primers 2016

12 Phase III SHARP Trial Subgroup analysis: portal vein invasion 537 Bruix et al, J Hepatol 2012.

13 Alternative therapies for macrovascular invasion in HCC Author (n) Survival Surgical resection Roayaie S ; Ann Surg Oncol mo Restrospective studies Underpowered, selection bias Hypothesis generating 538

Alternative therapies for macrovascular invasion in HCC Loco-regional therapies: TACE and TARE, Radiotherapy Author Treatment (n) Survival Xue, BMC Gastro 2013 TACE (160) Meta-analysis Gorodeski, Eur

14 Alternative therapies for macrovascular invasion in HCC Loco-regional therapies: TACE and TARE, Radiotherapy Author Treatment (n) Survival Xue, BMC Gastro 2013 TACE (160) Meta-analysis Gorodeski, Eur Rad 2016 TACE (95) 5 mo TACE-DEB (38) 3.3 mo Zhu K, Radiology 2014 TACE+S (46) 13mo TACE 6 mo Memon K, J Hep 2013 Y mo (Child A) 6 mo (Child B) Nakazawa, BMC Gastro 2014 Sorafenib (40) 4.3 mo Radiotherapy (57) 5.9mo Restrospective studies Underpowered, selection bias Hypothesis generating 539

15 Radioembolization for portal vein invasion in HCC Prospective/retrospective studies Hypothesis generating Completed Completed Recruiting Completed 540 Salem R et al, Hepatology 2013

16 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 541 FOR THE STUDY OF LIVER DISEASES 16

17 Landscape of mutations in HCC Genome sequencing in HCC (n=250) Undruggable mutations Zucman-Rossi and Llovet groups, Nat Genetics 2015 Vogelstein et al, Science

18 Landscape of mutations in HCC (meta-analysis, n= 928) Untargetable drivers Targetable drivers 543 Llovet JM et al, Nat Rev Clin Oncol 2015

19 Molecular targets for HCC Signaling pathways: molecular targets for new therapies. Signaling pathways (mut): Telomerase maintenance: 60% Cell cycle gene: 49% Wnt-B-Catenin: 54% Epigenetic modifier: 32% Akt/mTOR: 51% MAPK: 43% Signaling pathways (other): NOTCH: 30% TGF-Beta: 17% MET: 50% IGF Signaling : 15% (IGF2 epi-driver) 544 Zucman-Rossi, Nat Genetics 2015 Villanueva, Gastrotenterology 2012; Coulouarn et al, Hepatology 2008

20 Molecular classification of HCC 545 Zucman J, et al Gastroenterology 2015

21 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 546 FOR THE STUDY OF LIVER DISEASES 21

Poor survival OK 1,2 Down-regulation mir-26a Poor survival OK 1,2 Signature from adjacent tissue Poor-survival signature

22 Modeling prognosis in HCC Gene signatures/ biomarkers with prognostic power Level II-C Molecular alteration Clinical significance REMARK recommendations Status Signatures from HCC 5-gene signature Poor survival OK 1,2 (3) EpCAM signature Poor survival OK 1,2 Down-regulation mir-26a Poor survival OK 1,2 Signature from adjacent tissue Poor-survival signature Poor survival OK 1,2 (3) Biomarkers AFP ( ng/ml; Ang2, VEGF) Poor survival Ok 1,2 (3) mrna based (gene signatures) 547

23 Modeling Prognosis- molecular outcome in HCC Outcome approach-survival 5-gene survival signature (HN1,RAN,RAMP3,CK19,TAF9) Training: 189, Validation : 125 External Validation: Western Cohort: 213 Asian Cohort: Nault et al. Gastroenterology

Inflammation 2. NF-KB signaling 3. interferon-related immune response 4.

24 Molecular prognosis of HCC Relevance of microenvironment Training set (n=82) p<0.01 Gene signature-poor prognosis: # 186 genes Gene Set Enrichment : 1. Inflammation 2. NF-KB signaling 3. interferon-related immune response 4. Oxidative stress and 5. Proliferative signals (IL6, EGF) 549 Hoshida et al, NEJM 2008

25 Modeling Prognosis- molecular outcome in HCC Outcome approach-survival 550 Nault et al. Gastroenterology

26 Modeling prognosis in HCC Gene signatures/ biomarkers with prognostic power 551 Llovet JM et al, Nat Rev Clin Oncol 2015

27 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 552 FOR THE STUDY OF LIVER DISEASES 27

Phase III SHARP Trial Sorafenib vs placebo in advanced HCC Stratification: * Macroscopic vascular invasion (portal vein) and/or extrahepatic spread * ECOG PS * Geographical region Randomization N=602

28 Phase III SHARP Trial Sorafenib vs placebo in advanced HCC Stratification: * Macroscopic vascular invasion (portal vein) and/or extrahepatic spread * ECOG PS * Geographical region Randomization N=602 Sorafenib (n=299) 400 mg po bid continuous dosing Placebo (n=303) 2 tablets po bid continuous dosing Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.87). P= * 553 Llovet JM et al, NEJM 2008;359:378-90

29 Phase III SHARP and AP Trials Predictors of response to sorafenib (n=827 pts) Number of patients Hazard Ratio a (sorafenib/placebo) Treatment Interaction Baseline Covariate EHS HCV Neutrophyl to lymphocyte ratio No Yes No Yes median >median Sorafenib Placebo HR (95% CI) P Value [ ] [ ] [ ] [ ] [ ] [ ] 554 Bruix J, Hepatol Int 2016 (suppl 1).

30 Predictors of Survival All patients (multivariate analysis) Sorafenib Cohort Multivariate Analysis Variable P-value HR Macrovascular invasion Extrahepatic spread Baseline AFP Baseline alkaline phosphatase Baseline c-kit Baseline HGF Placebo Cohort Baseline AFP Macroscopic vascular invasion < Baseline alkaline phosphatase Baseline Ang Baseline VEGF Llovet et al, CCR 2012.

31 Predictors of response to sorafenib Predictors of survival: C-KIT Status Patients with high c-kit showed a trend of better OS benefit from sorafenib (interaction P-value=0.081). 556 Llovet et al, CCR 2012.

32 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 557 FOR THE STUDY OF LIVER DISEASES 32

33 Molecular therapies tested for HCC in Phase III (2016) Targeted population Phase III comparison Adjuvant Prevent recurrences 1. Sorafenib vs placebo (STORM)* 2. Retinoids vs placebo* Intermediate HCC Improve TACE 1. RF vs RF-Dox 2. TACE+/- sorafenib* 3. TACE +/- brivanib* Advanced HCC First line: 1. Sorafenib + /- erlotinib* 2. Sorafenib vs brivanib* 3. Sorafenib vs sunitinib* 4. Sorafenib vs linifanib* 5. Sorafenib +/- Doxorubicin* 6. Sorafenib +/- Y90 7. Sorafenib vs lenvatinib 8. Sorafenib vs nivolumab Second line: 1. Brivanib vs placebo* 2. Everolimus vs placebo* 3. Ramucirumab vs placebo* 4. Regorafenib vs placebo 5. Tivantinib vs placebo 6. Cabozantinib vs placebo 7. Pembrolizumab vs placebo 558

34 Why these RCT are negative in HCC? 1. Limited understanding of molecular drivers 2. Lack of translation of knowledge into trial design 3. Two diseases: HCC and cirrhosis - Balance between efficacy and toxicity (sunitinib, linifanib) - Difficult trial design: Non-inferiority concept (Brivanib, linifanib) Surrogate end-points of survival? TTP (contradictory data), ORR 4. Moving to phase III without clear signals. (Sunitinib, erlotinib) 5. Drugs are not powerful enough (brivanib, linifanib, erlotinib, everolimus, ramucirumab, doxo). 559 Llovet JM et al, Clin Can Res 2014

35 Strategies to overcome failures 1. Targeting all comers with more effective drugs Multikinase inhibitors: regorafenib, lenvatinib Immunotherapy: nivolumab Combination. 2. Selective targeting of drivers: precision medicine Oncogenic loops: FGF19, IGF2, CTNNB1 Signaling pathways: TGF-Beta, MET, Akt/mTOR, 560

36 Phase I-III studies in HCC: targeting all comers Drug Phase Target(s) Trial enrichment Primary end point NCT Antiangiogenic agents Lenvatinib III VEGFR2/3 No OS NCT Ramucirumab III VEGFR2 αfp>400 OS NCT Regorafenib III VEGFR2/TIE2 No OS NCT Apatinib III VEGFR2 No OS NCT Axitinib II VEGFR/C-KIT/PDGFR No DCR NCT Tivozanib I-II VEGFR No PFS NCT TRC Sorafenib I-II Endoglin No MTD/TTP NCT Cell-cycle inhibitors and antiproliferative agents Tivantinib III Tubulin inhibitor/met MET+ OS NCT Cabozantinib III MET; VEGFR No OS NCT INC280 II MET MET pathway deregulation TTP NCT MSC J I-II MET MET+ DLT/TTP NCT LY Ramucirumab I-II MET/VEGFR2 No DLT/ORR NCT Galunisertib +/- Sorafenib II TGFβR1 No OS NCT Galunisertib + Nivolumab I-II TGFβR1/anti-PD-1 No MTD NCT Temsirolimus + Sorafenib II mtor No TTP NCT Donafenib I-II RAF No DLT NCT FGF401 I-II FGFR4 FGFR4 and KLB+ expression DLT/TTP/ORR NCT TKM I-II PLK1 No MTD NCT BLU-554 I-II FGFR4 FGF19 amplification/overexpression MTD NCT Immune-modulators Nivolumab II; III anti-pd-1 No ORR; OS MEDI tremelimumab I-II anti-pd-l1/ctla-4 No DLT NCT Miscellaneous CF102 II Adenosine receptor A3 No OS NCT Enzalutamide II Androgen receptor No OS NCT LEE011 II CDK4/6 No PFS NCT BBI503 II Nanog No DCR NCT BBI608/503 + Sorafenib I-II STAT3/Nanog No DLT NCT DCR-MYC I-II MYC No DCR NCT Resminostat I-II HDAC No DLT NCT Llovet JM et al, Nature Review Disease Primers 2015

37 Regorafenib: phase II study in 2n line SETTING N REGORAFENIB DOSE EFFICACY SAFETY 2nd line mg PO QD 21d on/7d off DCR: 72% PR: 3% SD: 69% Median TTP: 4.3 mo Median OS: 13.8 mo All Grade/Grade >3 /Drug-related Aes: HFSR: 53% 14% Diarrhea: 53% 6% Fatigue: 53% 17% Hypothyroidism:42% 0% Hypertension: 36% 3% 562 Bruix J, et al. Eur J Cancer 2013

Phase III studies in HCC: Regorafenib 2nd line HCC patients with documented

(Asia vs ROW) Macrovascular invasion Extrahepatic disease ECOG PS (0 vs 1) AFP (<400

(4-week cycle) (n=379) N= 573 Placebo (n=194) 152 centers in 21 countries in North and

until progression, unacceptable toxicity, or withdrawal ROW, rest of the world; ECOG

38 Phase III studies in HCC: Regorafenib 2nd line HCC patients with documented radiological progression during sorafenib treatment Stratified by: Geographic region (Asia vs ROW) Macrovascular invasion Extrahepatic disease ECOG PS (0 vs 1) AFP (<400 ng/ml vs 400 ng/ml) R 2:1 Regorafenib 160 mg po once daily 3 weeks on / 1 week off (4-week cycle) (n=379) N= 573 Placebo (n=194) 152 centers in 21 countries in North and South America, Europe, Australia, Asia All patients received best supportive care Treat until progression, unacceptable toxicity, or withdrawal ROW, rest of the world; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein 563 Bruix J-RESORCE, WCGC 2016.

39 Phase III studies in HCC: Regorafenib 2nd line Regorafenib vs placebo Probability of Survival (%) Overall survival Regorafenib N=379 Placebo N=194 Events 232 (61%) 140 (72%) Censored 147 (39%) 54 (28%) Median OS 10.6 months 7.8 months HR 0.62 (95% CI: 0.50, 0.78) P <0.001 Time to Progression Regorafenib N=379 Placebo N=194 Events 273 (72%) 173 (89%) Censored 106 (28%) 21 (11%) Median TTP 3.2 months 1.5 months HR 0.44 (95% CI: 0.36, 0.55) P <0.001 Regorafenib 1. Positive results in terms of OS vs placebo in patients progressing to sorafenib 2. Magnitud of benefit is clinical significant: will become standard of care 564 Bruix J-RESORCE, WCGC 2016.

40 Nivolumab (anti-pd-1) in Phase I/II in HCC Herbst et al, Nature, 2014 ORR OS n=42 19% 62%- 1yr n~200 16% 14 mo 565 El-Khoueriry al, ASCO 2015 Sangro, ASCO 2016

41 Molecular classification of HCC Anti-TGF-Beta Anti-FGFR4 Anti-CTNNB1 Anti-IGF2 AktmTOR/ MET inhibitors RAS inhibitors 566 Zucman J et al, Gastroenterology 2015

42 Linking targets and therapies in HCC 567 Llovet JM et al. Nat Rev Dis Primers 2016

Proof of concept trial FGF19 is a molecular driver in

IHC FGF19 RNA expression FGF19 amplification: 7%

Log 2 fold change 1 Chromosome X Sawey Cancer Cell

43 Proof of concept trial FGF19 is a molecular driver in HCC FGF19 gene amplification FGF19 up-regulation FISH IHC FGF19 RNA expression FGF19 amplification: 7% Amplicon freq. Log 2 fold change 1 Chromosome X Sawey Cancer Cell 2011; Hagel Cancer Discovery 2015; Schulze 568 Nature Genetics 2015; Totoki Nature Genetics 2015.

44 FGFR4 inhibitors in FGF19-positive PDX Models FGF19 amplification FGF19 overexpression Phase I-II: FGFR4 inhibitor assessing response in patients with amplification/overexpression FGF Hagel M, et al. Cancer Discovery. 2015

45 Biomarker-based Trial enrichment Tivantinib vs placebo in 2nd line: Phase II studies Tivantinib (n=71; OS= 6.6 mo) vs placebo (n=36; OS= 6.2 mo) Subgroup analysis-enrichment for c-met +: Tivantinib 7.2mo vs placebo 3.8 mo Phase III: tivantinib vs placebo in 2 nd line in MET+ patients 570 Santoro et al, Lancet Oncol 2013

46 Ramucirumab for advanced HCC: Phase III, 2nd line Phase III: ramucirumab vs placebo in 2 nd line in HCC-AFP>400 ng/ml 571 Zhu et al, Lancet Oncol 2015

47 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 572 FOR THE STUDY OF LIVER DISEASES 47

48 Questions & Answers (I) Q1- Personalized treatment for HCC Defining tumor stage according to AASLD/ EASL Clinical Practice Guidelines BCLC staging system: defines prognostic stages and allocates the best treatment according to evidence Defines standard of care Other staging systems( i.e Hong Kong): Describes treatment schedules according to practice Defines standard of practice Defining treatment for multinodular tumors with macrovascular invasion Sorafenib: standard of care according to level #1 evidence in AASLD, EASL-EORTC guidelines Other treatments (i.e TARE-Y90): have reported promising results in cohort studies (level #2 evidence) and thus require randomized studies prior of being adopted by Clinical Practice Guidelines 2016 AMERICAN ASSOCIATION 573 FOR THE STUDY OF LIVER DISEASES 48

49 Questions & Answers (II) Q2- Role of biomarkers Defining biology and molecular classes Oncodrivers: Mutations of TERT promoter p53, CTNNB1, ARID1, Amplification VEGFA, FGF19 Impact: Few are targetable. Trial enrichment for oncogenes (i.e FGF19)/ signaling cascades (MET, TGF-B) Molecular classes: 1. Tumor profiling : a)proliferation-tgf-b, b) Proliferation-progenitor, c)ctnnb1 2. Adjacent tissue profiling Impact: Biologically meaningful, not yet translated into clinical setting Predicting prognosis Prognosis: AFP > 200 or 400 ng/ml, 5-gene signature, 186 adjacent tissue signature. Impact: So far used to define patients with poor outcome and for stratification of HCC trials Predicting response to sorafenib Predictors: Sorafenib benefits all subgroup of patients. HCV-patients have better outcome than non-hcv There are no biological markers predicting response to sorafenib Impact: HCV can be considered for stratification of trials testing sorafenib 2016 AMERICAN ASSOCIATION 574 FOR THE STUDY OF LIVER DISEASES 49

50 Questions & Answers (III) Q3- New targeted therapies and precision medicine for HCC 1. Regorafenib: as only second line therapy in patients progressing to sorafenib Impact: Pending FDA approval for clinical use Will change CP Guidelines for management of HCC 2. Emerging molecular therapies for all comers : Potent/non-toxic TKI: lenvatinib. Alternative drugs: check-point inhibitors (nivolumab: pembrolizumab) Impact: If positive might change standard of care (CP Guidelines) 3. Proof of concept and trial enrichment for a) Oncogenic loops (i.e FGF19/FGFR4 ) b) Signaling cascades MET: tivantinib, VEGF/MET: cabozantinib c) Biomarkers (AFP: ramucirumab) Impact: If positive might become the first biomarker-driven standard of care in HCC 2016 AMERICAN ASSOCIATION 575 FOR THE STUDY OF LIVER DISEASES 50

51 Personalized management of HCC 1. Case description 2. Q1- Personalized treatment of HCC 3. Q2- Role of biomarkers Defining biology and molecular classes Predicting prognosis Predicting response to sorafenib 4. Q3- New target therapies: precision medicine for HCC 5. Question & Answer 6. Conclusion 2016 AMERICAN ASSOCIATION 576 FOR THE STUDY OF LIVER DISEASES 51

52 Conclusions & recommendations 1. Personalized management (case): as per AASLD-EASL Guidelines (evidence, standard of care) Treatment 1 st : sorafenib alternative therapies (i.e Y90, lenvatinib) require level #1 evidence Prognosis: median survival 8-9 mo; AFP >600 ng/ml biomarker predictor of poor outcome 2. Biomarkers: a) Define molecular subclasses : proliferation, progenitor cell, Wnt-CTNNB1 b) Predict prognosis : 5-gene signature, 186-signature adjacent tissue, AFP c) Predict better response to sorafenib: HCV Waiting for translational trials to be incorporated in CP Guidelines 3. Precision medicine: a) Sorafenib is the standarad of care for advanced HCC b) Regorafenib will become the standard of care for patients progressing to sorafenib c) Trials with proof-of-concept (FGF19) or trial enrichment (MET+, AFP+, etc..) are needed in HCC If positive, they will incorporate biomarkers in the clinical decision-making 2016 AMERICAN ASSOCIATION 577 FOR THE STUDY OF LIVER DISEASES 52

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