Latest Developments in the Treatment of Hepatocellular Carcinoma

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1 Latest Developments in the Treatment of Hepatocellular Carcinoma Roniel Cabrera, MD MS Associate Professor of Medicine Director of Hepatology and Medical Director of Liver Transplantation Division of Gastroenterology, Hepatology and Nutrition University of Florida Gainesville, Florida

2 Objectives Discuss epidemiology, risk factors, and screening in hepatocellular carcinoma (HCC) Review diagnosis, tumor staging and importance of cirrhosis assessment in the complete staging of HCC Early and Intermediate Stage HCC Current Best Practices Advanced HCC Latest developments in treatment Importance of early referral and multidisciplinary care

3 Hepatocellular Carcinoma (HCC) Common malignancy worldwide 5th most common cancer worldwide 2nd leading cause of cancer death ~600,000 deaths annually US incidence has more than tripled over the last three decades Estimated new cases: ~40,000 new cases annually Fastest rising cause of cancer related death in US, Dismal 5-year survival <15% 85%-95% of HCC cases occur in cirrhotic livers Leading cause of death in cirrhosis Complex malignancy Heterogeneous etiologies - HCV, HBV, NAFLD, Alcohol Complex molecular carcinogenesis Mittal S, et al. J Clin Gastroenterol. 2013;47:S2-S6. Weledji EP, et al. Ann Med Surg (Lond). 2014;3: Ferlay J, et al. Int J Cancer. 2010;127: Siegel R, et al. CA Cancer J Clin. 2014;64:

4 Natural History of Untreated HCC in a US VA Cohort with HCV as the Predominant Etiology Mortality by BCLC Stage (n=518) Khalaf N et al. Clin Gastroenterol Hepatol 2016.

5 Risk of HCC in HCV Patients Treated with DAAs De Novo HCC risk unlikely to be increased by HCV therapy, risk likely relates to underlying disease state Small percentage may have undetected HCC Residual risk for HCC after SVR/cure in a VA Cohort (n=22,500) Recurrent HCC, particularly after noncurative treatment is more controversial Mechanism unclear reduced immune response to HCC and/or regeneration post HCV clearance promotes HCC growth Some transplant centers wait until HCC controlled for 6-12 months prior to initiating HCV therapy Needs more study HCC Recurrence after Successful HCC Treatment and DAA Therapy Kanwal F et al Gastroenterology Conti et al EASL Reig M et al EASL 2017.

6 HCC Surveillance: Guideline Recommendations Cirrhosis (any cause) HCV F4 and F3 with SVR HBV Asian males > 40 years Asian females > 50 years Africans > 20 years Family history of HCC Ultrasound with AFP every 6 months Strategies to improve US: Abbreviated MRI T2 weighted and DWI AFP Normal in 40% of patients with HC Normal in small HCC Values >200 ng/ml high PPV in cirrhotic patients with a mass Strategies to improve Rate of change over 6-12 months and combining with Age, PLT, ALT Majority of patients (~80%) with cirrhosis are not receiving HCC surveillance as recommended by guidelines. AASLD website. Available at: EASL Website. Available at:

7 Normal Liver Ultrasound but AFP >15,000

8 AASLD Diagnostic Criteria for HCC: Liver Nodule on Surveillance Ultrasound or High AFP in a Cirrhotic Liver Small nodule <1 cm >1 cm Repeat US at 3 months 4-phase MDCT / dynamic contrast enhanced MRI Growing/changing character Stable Arterial hypervascularity AND venous or delayed phase washout Investigate according to size Yes Other contrast enhanced study (CT or MRI) No HCC Arterial hypervascularity AND venous or delayed phase washout Biopsy Yes No Bruix J, et al. Hepatology. 2011;53: Available at

9 Radiologic Diagnosis of HCC in Cirrhosis Arterial phase enhancement Venous phase washout Cabrera R, Nelson DR. Aliment Pharmacol Ther ;31(4):

10 Liver Imaging Reporting and Data System (LI-RADS) Standardize Classification of Liver Nodules on Contrast Enhanced Cross-Sectional Imaging

11 Diagnosis of HCC: To Biopsy or Not? Yes Imaging is inconsistent with HCC Distinguish HCC from Intrahepatic Cholangiocarcinoma (CCA) Poor prognosis 5 year overall survival 8-50% High recurrence rates 30-40% Avoids inappropriate treatment and misleading cure May be required for experimental treatments May permit personalized therapy No Not always feasible Not needed if high diagnostic certainty based on imaging Risk Hemorrhage Tumor seeding (2.7% overall incidence) Risk of False negatives up to 1/3 of biopsies may delay treatment continue to monitor lesion with imaging **Biopsy is based on clinical picture** No high risk factors, Normal AFP, Non-classic radiographic features Heuman DM, et al. Eur J Intern Med. 2012;23: Rana A et al. Curr Opin Gastroenterol. 2012;28(3): Lee et al Liver Transpl 2018.

12 Survival by Child Pugh Class Natural History of Cirrhosis Impact HCC Outcome Observational HCC Treatment Study (GIDEON) Advanced HCC Child-Pugh B experienced more liver-associated AEs Time To Progression (TTP) Child-Pugh A, 4.2 months Child-Pugh B, 3.6 months Median Overall Survival (OS): Child-Pugh A, 10.3 months Child-Pugh B, 4.9 months Lencioni Int J Clin Pract 2012; Venook. ASCO GI (abstr 157); Marrero ASCO (abstr 4001). Pooled analysis on prognosis from 118 studies (n=23,797) Stage Clinical Criteria 1-yr Mortality 1 No Varices 1% 2 Presence of Varices 3% 3 Presence of Ascites 20% 4 GI bleeding 54% 5 Renal failure, Infection 67% D Amico G et al. Journal of Hepatology 44 (2006)

13 BCLC Staging and Treatment Strategy HCC PS 0, Child-Pugh A Okuda 1-2, PS 0-2, Child-Pugh A-B Okuda 3, PS > 2, Child-Pugh C Very early stage (0) Single < 2 cm Carcinoma in situ Early stage (A) Single or 3 nodules < 3 cm, PS 0 Intermediate stage (B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) Single Portal pressure/bilirubin Increased 3 nodules 3 cm Associated diseases Normal No Yes Resection Liver transplantation RFA/PEI Curative treatments (30%); 5-yr survival: 40%-70% TACE Sorafenib RCTs (50%); 3-yr survival: 10%-40% Symptomatic (20%); survival <3 mos MWA Llovet JM, et al. Journal of the National Cancer Institute. 2008;100: TARE (Y90) Lenvatinib, Regorafenib, Cabozantinib, Nivolumab

14 67 year old white male with HBV cirrhosis on antiviral therapy with good viral control. Abnormal US on surveillance. AFP = 5. Cirrhotic liver, stigmata of portal hypertension. Single 2.5 cm arterially enhancing lesion in the left lobe of the liver. Single Liver Mass

15 Multidisciplinary Care of Patients with HCC Palliative care Medical oncology Hepatology Tumor Registry Radiology Nursing Primary care provider Clinical research Interventional radiology Surgery Radiation oncology Pt

16 Very Early Stage and Early-Stage HCC: Current Best Practices Very early stage (0) Single < 2 cm (T1) Early stage (A) Single <5 cm or 3 < 3 cm (T2)

17 What is the best treatment option? C U R A T I V E Surgery: Liver Transplantation Resection Thermal Ablation: Microwave (MWA) Radiofrequency (RFA) P a l l i a t i v e Transarterial: Chemoembolization 90 Y microspheres Systemic Therapies: Sorafenib,?Lenvatinib Regorafenib, Nivo, Cabozantinib Clinical Trials

18 Liver Transplantation for HCC Accounts >20% of all liver transplants 5-year survival of > 70% Automated MELD exception if meets all three criteria: 1) Lesion must be >2 cm and <5cm (T2) 2) Arterial enhancement 3) Washout on venous phase or Capsule enhacement Growth by > 50% 6 month waiting period MELD Score begins at 28 after a 6 month waiting period Increases every 3 months if within criteria then caps at 34 Applying AFP as exclusion criterion Patients with AFP >1,000 ng/ml need to show a decrease to <500 ng/ml Milan Criteria Remains the Standard Criteria UCSF Down Staging Criteria Mazzaferro et al. NEJM Yo FY et al Hepatology UNOS HCC Policy.

19 Curative Treatments Resection Ablation Transplant Noncirrhotics Choice of therapy Cirrhotics Reserved for CTP A Avoid R hepatectomy Best for solitary HCC < 30% eligible Survival 5 yrs: 50-60% Effective when < 3 cm Multiple modalities Thermal, Combo for > 3cm Y90/Radiation Segmentectomy Stereotactic radiation Minimally invasive Survival 5 yrs: 50-60% Cures both MELD exception Milan criteria Downsizing Demand > supply Survival 5 yrs: 70% Recurrence 5 yrs: 70% Recurrence 5 yrs: 70% Recurrence 5 yrs: 15% *No proven adjuvant therapy to decrease recurrence* Belghiti J, et al. HPB (Oxford). 2005;7: Bruix J, et al. Hepatology. 2011;53: Feng Q, et al. J Cancer Res Clin Oncol. 2015;141:1-9. Sapisochin G, et al. at Rev Gastroenterol Hepatol. 2017;14: Thuluvath PJ, et al. Liver Transpl. 2009;15:

20 Radiation Segmentectomy Above 3 cm efficacy of RFA is diminished Y90 radiation segmentectomy is Y90 infusion limited to 2 hepatic segments allows accurate tumor targeting while sparing surrounding parenchyma (A) MRI a surface segment 4 HCC adjacent to the gallbladder, falciform ligament, and liver capsule (B) Angiography of segment 4 lesion 300 Gy (C) Complete mrecist tumor necrosis at 18 months follow-up. No viable tumor found at explant.

21 Y90 Radiation Lobectomy in Preparation for Resection Contra-lateral hypertrophy

22 Multifocal HCC, Large Bi-Lobar 70 year old white male with HCV cirrhosis noted with abnormal ultrasound. AFP =11. Cirrhotic liver multiple arterially enhancing lesions in the right and left hepatic lobes. 2 large enhancing lesion in the superior right hepatic lobe which measure 5.6 x 4.9 cm and 5.7 x 5.6 cm.

23 Intermediate Stage HCC: Current Best Practices

24 Probability of Survival (%) Palliative TACE Prolongs Survival in Unresectable HCC Chemoembolization (n = 40) Control (n = 35) OR (95% CI) Log-rank P < Mos Since Randomization Pts at Risk, n Author, Journal Yr Pts Lin, Gastroenterology GETCH, NEJM Bruix, Hepatology Pelletier, Hepatol Lo, Hepatology Llovet, Lancet Overall 503 Median survival: ~ 20 months z = 2.3 P =.017 Llovet J, et al. Lancet. 2002;359: Llovet J, et al. Hepatology. 2003;37:

25 Liver Directed Therapies: Embolotherapy Techniques Technique Mechanism Pros Cons TAE Conventional TACE (ctace) DEB-TACE Radioembolization Ischemic necrosis induced at arteriolar level via permanent embolic (eg, small particles) Intrahepatic chemotherapy with embolization by ethiodized oil Intrahepatic chemotherapy + embolization with slowrelease drug-eluting beads Radiation necrosis induced by beta-emitting Yttrium-90 microspheres Low cost, no chemotherapy adverse events Strongest evidence supporting benefit from RCT data More standardized than ctace, less systemic release of chemotherapy May improve TTP Fewer sessions required No postembolization syndrome May be safer in adv disease with PVT Radiation segmentectomy may be curative FLR hypertrophy from radiation lobectomy can provide tumor control and facilitate resection Postembolization syndrome may cause PEs Intra-operator technical variation (ctace) Systemic release of chemotherapy (ctace) Postembolization syndrome More expensive than ctace Postembolization syndrome Cost: 2-3x more expensive Requires multidisciplinary coordination Nontarget delivery may cause severe ulceration Potential biliary toxicity Radiation-induced liver disease Kishore S, et al. Curr Oncol Rep. 2017;19:40.

26 Radioembolization Using Yttrium-90 Single institution cohort study, Glass microsphere (Therasphere) Endpoints: Response rate,* TTP,* survival, toxicity 273/291 (94%) of patients had follow-up imaging 58% Downstaged, 32 transplanted Response rate 42% (WHO) and 57% (EASL) No GI ulcers Stage B 83 (28%) Stage C 152 (52%) TTP 13.3 months 6 months Overall Survival 17.2 months Child A = 17.3 months Child B = 13.5 months 7.3 months Child A = 13.8 months Child B = 6.4 months Salem R et al. Gastroenterology. 2010;138(1):52-64.

27 Randomized Study of ctace vs Radioembolization Overall Survival Time To Progression Single center phase 2 RCT. Primary endpoint: TTP 45 patients randomized 1:1 to TACE vs. Y90 Child-Pugh: 76% vs. 42% (P=0.08). BCLC stage A/B 81%/19% vs 75%/25% (P=0.73) Similar overall survival (17.7 vs 18.6 mon) but significantly longer TTP with Y90. Salem R et al. Gastro 2016;151:

28 Case: Progression After TACE A 57-yr-old male is diagnosed with BCLC stage B HCC based on compensated cirrhosis (Child-Pugh A), liver-only disease, and ECOG PS 0 After 2 TACE sessions, angiography revealed obstructed hepatic artery blood flow to the tumor and surrounding sites with disseminated disease

29 Case: Advanced HCC Arterial phase Venous phase Delayed phase

30 Management of Advanced HCC

31 Probability of Survival Probability of Radiologic Progression Palliation of Advanced HCC: Sorafenib Prior to 2007, no therapy was of benefit in advanced HCC SHARP trial: CTP A pts with advanced HCC randomized to sorafenib 400 BID vs placebo Sorafenib delayed progression and prolonged survival from 7.9 to 10.7 mos Led to approval by the FDA in 2007 for palliation of advanced-stage HCC It remains the only approved first-line systemic therapy for unresectable/advanced HCC Pts at Risk, n Sorafenib Placebo Pts at Risk. n Sorafenib Placebo 0 Time to Radiologic Progression P <.001 Sorafenib Placebo Mos Since Randomization P <.001 OS Sorafenib Placebo Mos Since Randomization Llovet JM, et al. N Engl J Med. 2008;359: Desai JR, et al. J Gastrointest Oncol. 2017;8:

32 Y90 vs Sorafenib in locally advanced HCC + PVT (Stage B and C) Phase 3 SARAH, Europe/France Vilgrain V, et al. Lancet Oncology Dec Phase 3 SIRveNIB, Asia-Pacific Chow et al. Journal Clinical Onc July Median Overall Survival Y90 /SIRT 8.0 months Sorafenib 9.9 months HR 1.15 (95% CI: ; P=.18) Median Overall Survival Y90 /SIRT 8.8 moths Sorafenib 10.0 months HR 1.12 (95% CI: ; P=.36) *Y90 versus Sor: Radioembolization has no clinical benefit versus sorafenib in advanced HCC. *SORAMIC Trial: Y90 plus Sorafenib (n=216) versus Sorafenib (n=208) alone did not improve OS -SIRT + Sor, 12.1 months versus Sor alone 11.5 months (Presented EASL 2018, SORAMIC Trial)

33 Lenvatinib vs Sorafenib in 1L Treatment in Advanced HCC Lenvatinib targets VEGFR axis as well as FGFR 1-3 Compared lenvatinib to sorafenib in the front line setting with a non-inferiority design (Phase 3 REFLECT) Patients with unresectable HCC randomized 1:1 Len (n=478: <60kg 8mg, >60kg 12 mg) Sor (n=476) Excluded patients with Main PV BCLC Stage B/C Len 22% / 78% Sor 19% / 81% Lenvatinib is noninferior to sorafenib in OS Statistically significant improvements in PFS, TTP, and ORR for lenvatinib vs sorafenib First phase 3 trial in HCC to be positive since sorafenib 2007 (SHARP trial) Outcome mos, mos (95% CI) mpfs, mos (95% CI) mttp, mos (95% CI) Lenvatinib (n = 478) 13.6 ( ) 7.4 ( )* 8.9 ( )* ORR, n (%) 115 (24.1)* Sorafenib (n = 476) 12.3 ( ) 3.7 ( ) 3.7 ( ) 44 (9.2) HR 0.92 ( ) 0.66 ( ) 0.63 ( ) Kudo M et al. Lancet Mar L= 1 st Line

34 RESORCE Phase 3: Regorafenib vs Placebo in 2L Advanced HCC Pts with HCC with documented radiologic progression on sorafenib (N= 573) Randomized 2:1 to Rego (n=379) vs Placebo (n=194). Tolerated sorafenib > 400 mg/day for at least 20 of the last 28 days of treatment Rego 160 mg PO QD, Days 1-21 of 28-day cycle Approved by FDA on April 2017 for HCC previously treated with sorafenib (2L) Probability of Survival (%)100 Placebo Regorafenib (n = 379) Placebo (n = 194) mos, mos (HR: 0.63; 95% CI: ; 1-sided P <.0001) Regorafenib Mos From Randomization 33 Outcomes of the Sequence of Sorafenib Followed by Regorafenib or Placebo Outcomes From start of sorafenib Regorafenib (n=374) Placebo (n=193) Median survival, months Estimated survival, at 3 yrs 31% 20% Estimated survival, at 5 yrs 16% 3% 2L=2nd line. Bruix J, et al. Lancet. 2017;389: Finn RS et al J hepatol 2018.

35 CELESTIAL Phase 3: Cabozantinib vs Placebo in 2L Advanced HCC Cabozantinib targets VEGFR axis and MET. Pts with advanced HCC radiologic progression on sorafenib No more than 2 prior systemic therapies Randomized 2:1 to Cabo 60 mg qd (n=470) vs Placebo (n=237) BCLC Stage C: 85% and 84% Cabozantinib significantly prolonged OS in patients with previously treated advanced HCC. Corresponding to this survival benefit, a longer duration of PFS was also observed Positive Phase 3 in 2L setting for advanced HCC with OS and PFS benefit Abou-Alfa GK et al. NEJM July L = second line

36 Nivolumab in Advanced HCC - Phase 1/2 CheckMate 040 FDA approval in September 2017 in 2L Advanced HCC for patients previously treated with sorafenib Approval contingent on additional confirmatory/phase 3 studies. El-Khoueiry et al Lancet 2017.

37 Conclusions Burden of HCC is increasing Screen your at risk patients with cirrhosis for HCC with ultrasound and AFP every 6 months for early detection Early-stage HCC (BCLC A) may be cured with - Thermal ablation, Resection and/or Liver transplantation Intermediate stage HCC (BCLC B) palliated with TACE and Y90 Local measures often fail in tumors with aggressive biology Advanced stage HCC (BCLC C) palliated with Sorafenib New 1L (Lenvatinib) and 2L therapies (Regorafenib, Cabozantinib, Nivolumab) Application of therapies may be limited by severity of cirrhosis Multidisciplinary teams are important for optimal outcome

38 Thank You!