advancing the multidisciplinary management of ...cio+iss... · advancing the multidisciplinary...

Advancing the Multidisciplinary Management of Hepatocellular Carcinoma

Supported by an educational grant from Bristol-Myers Squibb.

Faculty

Riad Salem, MD, MBA, FSIR Santiago Aparo, MD, MSProfessor of Radiology, Medicine and Surgery Oncology Attending Physician Vice-Chair, Image-Guided Therapy Miami Cancer InstituteChief, Vascular and Interventional Radiology Miami, FloridaRobert H Lurie Comprehensive Cancer CenterNorthwestern UniversityChicago, Illinois

Faculty DisclosuresRiad Salem, MD, MBA: Consultant—BSc, BTG, Eisai, Merit, Terumo; Grant/Research Support—BTG

Santiago Aparo, MD, MS has nothing to disclose.

Riad Salem, MD, MBA and Santiago Aparo, MD, MS have disclosed that no off-label/unapproved use(s) of drugs and/or devices will be discussed.

Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred.

Learning Objectives• Discuss the relative benefits and limitations of loco-regional or systemic therapies for

HCC with respect to patient impact and clinical outcomes across disease stages and severity

• Outline the scientific evidence supporting the use of immunotherapy in HCC, including the mechanisms of action and targeted signaling pathways under clinical investigation

• Evaluate the efficacy, safety, tolerability, and indications of available and emerging systemic therapies for the management of HCC

• Integrate the latest evidence-based guidelines and clinical data into individualized HCC therapeutic decisions informed by the staging and etiology of disease

• Implement multidisciplinary HCC management plans that facilitate a continuity of care over the course of disease and transition between loco-regional and systemic therapy as appropriate

Locoregional Therapy for Hepatocellular Carcinoma

Riad Salem, MD, MBA, FSIRProfessor of Radiology, Medicine and Surgery

Vice-Chair, Image-Guided TherapyChief, Vascular and Interventional Radiology

Robert H Lurie Comprehensive Cancer CenterNorthwestern University

Chicago, Illinois

Barcelona Clinic Liver Cancer (BCLC) Staging System and Therapeutic Strategy

Adapted from Llovet JM, et al. Nat Rev Dis Primers. 2016;2:16018. doi:10.1038/nrdp.2016.18.

Studies Reporting 5-Year Survival in Early-Stage HCC after RFA as the First-Line Nonsurgical Treatment

Adapted from Breen DJ, Lencioni R. Nat Rev Clin Oncol. 2015;12:175-186.

Study Number of PatientsOverall Survival Rate (%)

At 1 Year At 3 Years At 5 Years

Lencioni et al. (2005)48 Child-Pugh A: 144Child Pugh B: 43

Child-Pugh A: 100Child Pugh B: 89



Tateishi et al. (2005)49 Child-Pugh A: 221Child Pugh B–C*: 98

Child-Pugh A: 96Child Pugh B–C: 90



Choi et al. (2007)50 Child-Pugh A: 359Child Pugh B: 160

Child-Pugh A: NRChild Pugh B: NR



N’Kontchou et al. (2009)51 Resectableǂ: 67Unresectableǂ: 168

Resectable: NRUnresectable: NR

Resectable: 82Unresectable: 49

Resectable: 76Unresectable: 27

*Only 4 of 98 patients had Child-Pugh C cirrhosis. ǂBased on BCLC criteria for resection: single tumor, normal billrubin level (<1.5 mg/dL), and absence of significant portal hypertension. Abbreviations: BCLC, Barcelona Clinic for Liver Cancer; HCC, hepatocellular carcinoma; NR, not reported; RFA, radiofrequency ablation.

Early-Stage HCC: RCTs of RFA vs Surgical Resection

StudyNumber of Patients 1-Year OS (%) 3-Year OS (%) 5-Year OS (%) P Value *

RFA Resection RFA Resection RFA Resection RFA Resection

Chen et al. (2006)64 90 90 96 93 71 73 NR NR NS

Huang et al. (2010)65 115 115 87 98 70 92 55 76 0.001

Feng et al. (2012)66 84 84 93 96 67 75 NR NR NS

*The OS curves were compared using the log-rank test and the prognostic significance of the variables in predicting OS was assessed by univariate and multivariant Cox proportional hazards regression models. Abbreviations: HCC, hepatocellular carcinoma; NR, not reported; NS, not significant; OS, overall survival, RFA, radiofrequency ablation.

Adapted from Breen DJ, Lencioni R. Nat Rev Clin Oncol. 2015;12:175-186.

Efficacy of Resection and Ablation: Complementary, Not Competitive

Adapted from Mazzaferro V, et al. Semin Liver Dis. 2014;34:415-426.

Adapted from Lencioni R, et al. Liver Cancer. 2015;4:208-214.

Weighing Energy-Based AblationTechnology Potential Advantages Potential Disadvantages

RFA • High rates of local control in tumors 3 cm or smaller• Established safety profile• Known limitations• Experience in combination treatments (HCC)• Widely available

• High rates of incomplete ablation in tumors larger than 3 cm• Heat sink effect in perivascular tumors• Potential risk of thermal injury to critical structures• Variability in RFA devices

MWA • Potential to treat tumors larger than 3 cm more effectively

• Less impacted by heat sink effect• Ability to activate multiple probes at the same time• No grounding pads required

• Limited efficacy data (predictability and reproducibility)• Limited safety data• Potential risk of thermal injury to critical structures

(and vessels?)• Variability in MWA devices

CRYO • Ability to activate multiple probes at the same time• Ability to image the ice-ball formation

• Insufficient clinical data• Risk of bleeding• Risk of cryoshock

IRE • Potential to treat tumors located in the vicinity of critical structures

• Heat sink effect not relevant

• Insufficient clinical data• Neuromuscular blockage and cardiac gating required

• Resection and RFA are equally effective for stage 0 (very early) HCC tumors− Complementary vs competitive: location does matter!

• Ablation is recommended for stage A (early) HCC in patients who are not optimal surgical candidates− Novel technologies (MWA, IRE) may overcome some of the limitations of RFA

• The high rate of tumor recurrence after local ablation remains a major unmet medical need− Research on novel drugs /new carriers is a top priority

Key Points: Image-Guided Ablation in the Treatment of HCC

Conventional ChemoembolizationAdvantages/Rationale1. Cut off blood supply to tumor2. Lipiodol®/drug injection3. Endpoint drug injection/tumor saturation4. Lobar/segmental5. Inpatient treatment6. Survival advantage compared with best supportive care

FDA [website]. Drugs@FDA: FDA Approved Drug Products. Lipiodol. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=009190. Accessed January 25, 2018.

• Prospective randomized trial, TACE vs TAE vs conservative Rx• 112 patients, 1996-2000, majority BCLC B (80%), aged 61-68 years• Trial stopped early: TACE found to have survival benefit over conservative therapy (P=.009)

• Objective response sustained for 6 months: TAE 43%, TACE 35%• TACE significantly lowered probability of PVT (P=.005)

• Conclusion: TACE improved survival of selected patients with unresectable HCC

Llovet JM, et al. Lancet. 2002;359:1734-1739.

Survival 1 Year 2 Years 3 Years

TACE 82% 63% 29%

TAE 75% 50% 29%

Conservative Rx 63% 27% 17%

Bland EmbolizationAdvantages/Rationale1. Cut off blood supply to tumor2. Simple, reproducible, not confounded by drug (dose, ability to

deliver)3. Endpoint of complete stasis is clear4. Lobar/segmental5. Inpatient treatment 6. No survival advantage demonstrated

• 322 patients received 766 embolizations– Intent was terminal blockade– Repeated if viable disease on FU

• Median survival: 21 months• In patients with no mets/pvt, 1, 2, and 3-year survival rates were 84%, 66%, and 51% • 90 complications (11.9%) in 75 patients• 8 deaths within 30 days (2.5%)• Promising survival outcomes

Maluccio MA, et al. J Vasc Interv Radiol. 2008;19(6):862-869.

Maluccio MA, et al. J Vasc Interv Radiol. 2008;19(6):862-869.

Drug-Eluting Microspheres

Advantages/Rationale1. Standardized dose prescription2. Endpoint of substasis advocated3. Controlled drug delivery4. Lobar/segmental5. Inpatient treatment6. No survival advantage demonstrated

Lammer J, et al. PRECISION V Investigators. Cardiovasc Intervent Radiol. 2010;33(1):41-52.

• RCT of DEB-TACE vs cTACE• N=212

− Child-Pugh A/B cirrhosis − Large and/or multinodular, unresectable, N0, M0 HCC

• Stratified by ECOG, CP, prior curative therapy and uni/bilobar • Patients with at least one follow-up were studied• Endpoint: EASL response at 6 months

− 51.6% vs 43.5% DEB-TACE vs cTACE; P=.11• Higher response with DEB-TACE in CP B, ECOG 1, bilobar and recurrent

disease

Prospective Randomized Study of Doxorubicin-Eluting-Bead Embolization in the Treatment of Hepatocellular Carcinoma: Results of the PRECISION V Study

Patient Subgroups

Lammer J, et al. PRECISION V Investigators. Cardiovasc Intervent Radiol. 2010;33(1):41-52.

DEB-TACEInvestigator Level of

Evidence# Patients BCLC Child-Pugh-

ScoreCR/PR Survival

Reyes (2009) 2DIII 20 A - 6B - 2C - 12

A (75%)B (25%)

CR: (5%)PR: (35%)(RECIST)

26 mo

Recchia (2012) 2DIII 35 N/A A (12)B (23)

CR/PR:(63%)(EASL)

18.4 mo

Burrel (2012) 2A 104 N/A A (95)B (5)

N/A 47.7 mo(after censor)

Malagari(2012)

3A 173 A – 38B – 135

A (59%)B (41%)

A (38.2%)B (30.9%)after TACE1

A (29.4%)B (12.8%)(5-yr OS)

Reyes D, et al. Cancer J. 2009;15:526-532. Recchia F, et al. Oncol Rep. 2012;27(5):1377-1383. Burrel M, et al. J Hepatol. 2012;56:1330-1335. Malagari K, et al. 2012.

• Exploratory phase 2 trial • Efficacy and safety of DEB-TACE plus sorafenib • N=307 patients with intermediate-stage multinodular HCC without

macrovascular invasion (MVI) or extrahepatic spread (EHS) • Randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg bid

or placebo• Primary endpoint: TTP • Secondary endpoints

− Time to MVI/EHS − OS − Overall response rate (ORR, modified RECIST criteria) − Disease control rate (DCR)− Time to unTACEable progression (TTUP) − Safety

Sorafenib or Placebo plus TACE with Doxorubicin-eluding Beads forIntermediate-Stage HCC: The SPACE Trial

Lencioni R, et al. J Hepatol. 2016;64(5):1090-1098.

Endpoint Sorafenib (n=154)

Placebo (n=153) HR Significance

Median TTP 169 days 166 days 0.797 P=.072

Median time to MVI/EHS Not reached Not reached 0.621 P=.076

Median OS Not reached Not reached 0.898 P=.29

ORR 55.9% 41.3%

DCR 89.2% 76.1%

Median TTUP 95 days 224 days 1.586 95% CI, 1.200-2.096

No unexpected AEs related to sorafenib were observedLencioni R, et al. J Hepatol. 2016;64(5):1090-1098.

Sorafenib or Placebo plus TACE with Doxorubicin-eluding Beads forIntermediate-Stage HCC: The SPACE Trial

• Randomized phase 2 study, 2007-2012• 101 patients, TAE vs DEB-TACE• No difference

– Adverse events– Initial RECIST and EASL response– RECIST response rate and disease control at 3, 6, 9, and 12 months– Progression-free survival (6.9 mo TAE v 8.9 mo DEB TACE, P=.59)– Overall survival (14 months TAE v 16 months DEB TACE, P=.7)

• Conclusions–TAE and DEB-TACE have no difference in survival, adverse events or response–TAE may be preferable to DEB-TACE

Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-eluting Microspheres Compared with Embolization with

Microspheres Alone

Brown KT, et al. J Clin Oncol. 2016;34(17):2046-2053.

Brown KT, et al. J Clin Oncol. 2016;34(17):2046-2053.

Randomized Trial of Hepatic Artery Embolization for Hepatocellular Carcinoma Using Doxorubicin-eluting Microspheres Compared with Embolization with

Microspheres Alone

Radioembolization

Advantages/Rationale1. Non-embolic–microembolic2. Simple, reproducible, ability to infuse entire dose3. No endpoint of stasis4. Lobar/segmental/whole liver5. Outpatient treatment6. No survival advantage demonstrated

Radioembolization

Salem R, et al. Gastroenterology. 2010;138:52-64, Hilgard P, et al. Hepatology. 2010;52:1741-1749, Sangro B, et al. Hepatology. 2011;54:868-878. Mazzaferro V, et al. Hepatology. 2013.

Vouche M, et al. Hepatology. 2014;60:192-201.

• 102 patients (NU, Mt. Sinai) were included in this study• CR was seen in 47/99 (47%), PR in 39/99 (39%), and SD in 12/99 (12%) according to mRECIST

criteria • Median time-to-disease-progression was 33.1 months• 33/102 (32%) patients were transplanted with a median (IQR) time to transplantation of

6.3 months (3.6-9.7)• Pathology revealed 14/30 (47%) CPN, 16/30 (53%) PN• Median OS was 53.4 months

Fernández-Ros N, et al. HPB (Oxford). 2014;16(3):243-249. Edeline, et al. ASO. 2013.

Salem R, et al. Gastroenterology. 2016;151(6):1155-1163.e2.

Clinical trial number: NCT00956930Start date: August 8, 2009Closed date: July 15, 2016Study design and rationale

• Prospective randomized phase 2 controlled trial, open-label• Unresectable HCC not suitable for ablation per tumor board• Control arm: cTACE with Dox in Lipiodol (75 mg/m2)• Test arm: Glass Y90 microspheres (120 Gy)

Outcomes• Primary: Time-to-progression (TTP) from randomization• Secondary

• Response by primary index lesion (EASL, WHO)• Safety (CTCAE v4)• Overall survival


CONSORT Study Flowchart

cTACE: 6.8 mo

Y90: >26 mo

P=.0012

Hazard RatioKM: 0.12 CI: 0.027–0.557 P=.007CR: 0.13 CI: 0.03–0.57 P=.006IPCW: 0.07 CI: 0.008–0.645 P=.019

}88%-93% risk reduction progressionPost hoc power analysis: 97%


Primary Endpoint: TTP

Secondary Endpoint: OS

cTACE: 17.7 mo

Y90: 18.6 mo

P=.99Salem R, et al. Gastroenterology. 2016;151(6):1155-1163.e2.

Intermediate-Stage HCC

Progression

DEB- TACE

Y90

Sorafenib

Intermediate-Stage HCC

OLT

Resection

Y90 DEB-TACE SorafenibOLT Resection

Overall Survival

TACE – DEB TACE – Y90 -BSC

TACE – DEBs- DEBs - BSC

TACE – DEBs- Sorafenib -BSC

TACE – DEBs- OLT – TACE / Y90 – BSC

TACE – Resection – OLT – TACE / Y90 Sorafenib -BSC

Progression

Y90 DEB-TACE SorafenibOLT Resection

TACE- Y90- Y90- Sorafenib -BSC

TACE- Y90- DEBS – Sorafenib -BSC

TACE - Y90- Sorafenib -BSC

TACE - Y90- OLT- TACE – Sorafenib -BSC

OLT - Y90- TACE – Sorafenib -BSC

Y90 DEB-TACE Another DrugOLT Resection

TACE – Sorafenib- Y90 -BSC

TACE- Sorafenib- DEBs- BSC

TACE – Sorafenib – Another Drug- BSC

TACE – Sorafenib – OLT- TACE / Y90- BSC

TACE - Sorafenib - Resection – OLT- Y90 / TACE- Sorafenib –BSC

Y90 DEB-TACE Sorafenib

TACE – OLT - Y90 / TACE – Sorafenib -BSC

TACE – OLT - Y90 / TACE – Sorafenib - BSC

TACE – OLT- DEBs -Y90 / TACE – Sorafenib -BSC

Y90 DEB-TACE SorafenibOLT

TACE – Resection - Y90 / TACE – Sorafenib -BSC

TACE – Resection- DEBs – Sorafenib - BSC

TACE – Resection - Sorafenib -BSC

TACE – Resection – OLT - Y90- TACE –Sorafenib -BSC

Progression

TACE

• 1000 HCC patient, 15 year experience• Overall Survival data, both censored and intention-

to-treat• Comprehensive review of data, AEs

Salem et al Hepatology 2018

Salem et al Hepatology 2018

Summary: Locoregional Therapies• Technical variability

− Different ablation issues depending on location lesion− Angiographic endpoint, dose, drug, sequelae of embolization− Standardization is a work in progress

• Imaging and response assessment− EASL, qEASL, RECIST, WHO, RECIST 1.1, mRECIST, RECICL

• Comparative studies lacking− Ablation vs surgery− Survival studies difficult-LARGE SAMPLE SIZES− Importance of response controversial− Limited QOL studies− Econometrics− Positive data Y90 vs cTACE

• Overall applications− Bland embolization: Used in some centers− cTACE: SOC with survival improvement c/w BSC− DEB-TACE: Safe in more advanced patients, with sorafenib− Y90: Safe in PVT, improved TTP c/w cTACE by PREMIERE, SARAH/SIRvenIB

Systemic Therapy for Advanced Hepatocellular Carcinoma

Santiago Aparo, MD, MS

Faculty Disclosures

Santiago Aparo, MD, MS, has nothing to disclose.

Brand names are included in this presentation for participant clarification purposes only. No product promotion should be inferred.

BCLC Criteria

Bruix J et al, Hepatology, 2011...

Systemic Therapy for HCC• 2007: Sorafenib (SHARP trial)• 2017-2018: 4 new drugs

• 3 biologic agent (TKIs) – Regorafenib (2nd line): FDA approved 2017– Lenvatinib (1st line)– Cabozantinib (2nd line)

• 1 immunologic agent (ICI)– Nivolumab (2nd line): FDA approved 2017

Outline • RESORCE trial: Phase 3 (regorafenib vs placebo)

• Immunotherapy in HCC

• CheckMate 040 trial: Phase 1/2 (nivolumab)

• REFLECT trial, phase 3, non-inferiority (lenvatinib vs sorafenib)

• CELESTIAL trial: Phase 3 (cabozantinib vs placebo)

• Future trials/directions

RESORCE Trial

• Randomized 573 patients

• Placebo-controlled

• HCC that progressed on sorafenib, Child-Pugh A

• Primary endpoint: Overall survivalBruix J, et al. Lancet. 2017;389:56-66.

Study Schema

Bruix J, et al. Lancet. 2017;389:56-66.

Patient Characteristics


Primary Endpoint: OS

OSRegorafenib Placebo

Median OS

10.6 m 7.8 m

HR 0.63 (95% CI: 0.50–0.79)P<.0001


Secondary Endpoint: PFS by mRECIST

Regorafenib Placebo

Median PFS

3.1 m 1.5 m

HR 0.46 (95% CI: 0.37–0.56)P<.0001


RESORCE TrialResponses Toxicity


Conclusions of RESORCE Study • Regorafenib significantly improves OS vs placebo in patients with unresectable HCC

who have progressed on sorafenib

• The safety was acceptable with the main toxicity being Hand-Foot Reaction in 53% of patients

• Based on these results, the FDA approved regorafenib on April 2017 for patients with HCC who have progressed on prior sorafenib therapy

Immunotherapy in HCC

Dranoff G, et al. Nav Rev Cancer. 2004.

Immunosuppressive State in HCC• Upregulation of inhibitory CTLA-4, LAG-3 and PD1/PD-L1• Downregulation of stimulatory CD28 and IL7Ra• Increased frequency of regulatory T cells• Elevated production of immunosuppressive cytokines:

IL10, TGF-B• Higher prevalence of invariant natural killer T cells capable of

inhibiting expansion of tumor Ag specific CD8 T cells• Impaired function of antigen-presenting cells

Peng G, et al. Mol Immunol. Ormandy LA, et al. Cancer Res. 2005;65:2457-2464. Huang A, et al. J Immunol. 2014. Cariani E, et al. Plos One. 2012. Matsui M, et al. J Gastroenterol Hepatol. 2002.

Targeting Checkpoints in Cancer

Pardoll DM, et al. Nat Rev Cancer. 2012;12(4):252-264. Mellman I, et al. Nature. 2011;480(7378):480-489.

CheckMate 040

• Phase 1/2 • Child-Pugh 7 or less, ECOG PS 0-1• Patients with hepatitis B: Antiviral therapy• Progressed, refused, or intolerant to sorafenib

El-Khouery AB, et al. Lancet. 2017;389(10088):2492-2502.

Study Schema


Patient Characteristics


CheckMate 040

• Asthenia 10%• Nausea 10%• Diarrhea 10%• Skin rash 10%• Transaminitis 10%-20%

Responses Toxicity


Responses by HCV/HBV andSorafenib Exposure


Responses by PD-L1 Expression

El-Khouery AB, et al. Lancet. 2017;389(10088):2492-2502. Presented by Ignacio Melero. Gastrointestinal Cancers Symposium. 2017.

Conclusions of ChekMate 040 Study • Nivolumab safety profile was manageable and consistent across cohorts

• Nivolumab demonstrated objective response rates and long-term survival in both sorafenib-experienced and -naïve patients with advanced HCC

• Based on these results, FDA granted accelerated approval in September 2017

A Phase 3 Trial of Lenvatinib vs Sorafenib in First-Line Treatment of Patients with Unresectable

Hepatocellular Carcinoma (REFLECT Study)

Cheng, et al. ASCO Meeting. 2017.


Study Schema

Most Frequent AEsAdverse Event, n (%) Lenvatinib (n=476) Sorafenib (n=475)

Any grade Grade 3/4 Any Grade Grade 3/4

Hypertension 201 (42) 111 (24) 144 (30) 68 (14)

Diarrhea 184 (39) 20 (4) 220 (42) 20 (4)

Decreased appetite 162 (34) 22 (5) 127 (27) 6 (1)

Decreased weight 147 (31) 36 (8) 106 (22) 14 (3)

Fatigue 141 (30) 18 (4) 119 (25) 17 (4)

Palmar-Plantar erythrodysesthesia 128 (27) 14 (3) 249 (52) 54 (11)


Conclusions of REFLECT Study • Lenvatinib demonstrated non-inferiority vs sorafenib in OS in patients with

unresectable HCC

• The safety of lenvatinib and sorafenib in this study appeared consistent with that previously reported in patients with HCC

• Based on these results, lenvatinib may be a potential treatment option for patients with advanced HCC (Sept 2017, FDA accepted new drug application)

Randomized Phase 3 Trial of Cabozantinib vs Placebo in Patients with Advanced Hepatocellular Carcinoma Who

Have Received Prior Sorafenib (CELESTIAL Trial)

• Randomized 760 patients• Placebo controlled• HCC that progressed on sorafenib, Child-Pugh A• Primary endpoint: OS

Abou-Alfa, et al. GI ASCO Symposium. 2018.

Study Schema


Most Frequent Grade 3 or 4 AEsAdverse Event ( %) Cabozantinib (n=467) Placebo (n=237)

Any gradeGrade 3/4

Any GradeGrade 3/4

Palmar-Plantar erythrodysesthesia 17 0

Hypertension 16 2

Elevation in AST 12 7

Fatigue 10 4

Diarrhea 10 2

Asthenia 7 2

Anorexia 6 <1

Anemia 4 5


Conclusions of CELESTIAL Study • Cabozantinib significantly improves OS vs placebo in patients with

advanced HCC after prior systemic therapy

• The safety was acceptable

• Based on these results, the company will likely file an FDA application in the first quarter of 2018

Summary: First Line

Summary: Second Line

Future Trials• CheckMate 459: Phase 3, nivolumab vs sorafenib, phase 3,

front-line

• KeyNote 224: Phase 2, pembrolizumab monotherapy, previously treated HCC

• KeyNote 240: Phase 3, pembrolizumab vs placebo, previously treated HCC

• Combinational studies: Immunotherapy + locoregional therapies

Thank You

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