Revolutionizing Hepatocellular Carcinoma Treatment at the Cutting-Edge of Medicine

Size: px

Start display at page:

Download "Revolutionizing Hepatocellular Carcinoma Treatment at the Cutting-Edge of Medicine"

Bruno Morgan
5 years ago
Views:

1 Revolutionizing Hepatocellular Carcinoma Treatment at the Cutting-Edge of Medicine - The First Half Year Since the Debut of a New Medicine - Masatoshi Kudo Kindai University, Faculty of Medicine Department of Gastroenterology and Hepatology 0 This English presentation was translated from the original Japanese version presented at the Hepatocellular Carcinoma Latest Trends in Diagnostics and Treatment Media/Investor Conference held on September 18, 2018 in Tokyo, Japan. In the event of any inconsistency between the statements in the two versions, the statements in the Japanese version shall prevail.

2 Epidemiology of Hepatocellular Carcinoma and the Transition from Hepatitis to Hepatocellular Carcinoma 1

Epidemiology of Hepatocellular Carcinoma Hepatocellular carcinoma is the 5 th most common cancer worldwide, and is the 3 rd leading cause of cancer-related deaths annually after lung cancer and colon

3 Epidemiology of Hepatocellular Carcinoma Hepatocellular carcinoma is the 5 th most common cancer worldwide, and is the 3 rd leading cause of cancer-related deaths annually after lung cancer and colon cancer (5 th highest in Japan). 750,000 people die each year from hepatocellular carcinoma. According to reports, over 80% of hepatocellular carcinoma patients are in Asia and Africa, and China accounts for 50% worldwide. Over 360,000 people die of hepatocellular carcinoma each year in East Asia (including China, Japan, South Korea and Taiwan). Approximately 42,000 patients are newly diagnosed with hepatocellular carcinoma in Japan, and approximately 27,000 patients die each year. Area Prevalence /100,000 <4.0 <5.8 <8.7 <17.7 < GASTROENTEROLOGY 2007;132;

4 Incidence of Liver Cancer in Japan Annual number of deaths from liver cancer: approx. 27,000 Forecast number of cancer deaths by organ (2017) Site Total No. of deaths All cancers 378,000 Lung 78,000 Colon 53,000 Stomach 47,400 Pancreas 34,100 Liver 27,500 Gall bladder / bile duct 18,900 Men Site No. of deaths All cancers 222,000 Lung 55,600 Colon 31,000 Stomach 28,300 Liver 17,900 Pancreas 17,100 Prostate 12,200 Women Site No. of deaths All cancers 156,000 Colon 24,700 Lung 22,400 Pancreas 16,900 Stomach 16,400 Breast 14,400 Liver 9, /19 Journal of Health and Welfare Statistics Trends in Civilian Health Center for Cancer Control and Information Services, National Cancer Center, Japan(

5 (per 100,000) Number of Deaths from Hepatocellular Carcinoma in Japan 1950~2012 Total Men Women No. of deaths (total) (people) No. of deaths 60, , Number of deaths peaked between and has been on a decreasing trend since ICD6 ICD7 ICD8 ICD9 ICD Created based on by J. Tanaka et al, Demographic Statistics April 2014

6 Trends in Disease Background for Hepatocellular Carcinoma 100% 90% 80% 70% 60% 50% 40% BC HBV HCV NBNC 30% 20% 10% 0% In Japan, the most common cause of hepatocellular carcinoma is HBC, however in recent years, the number of cases of hepatocellular carcinoma derived from neither HBV or HBC (NBNC) is increasing 5 *BC: Hepatitis B and C, HBV(hepatitis B), HCV (hepatitis C), NBNC (non-b, non-c hepatitis) Tateishi R et al.: J Gastroenterol 2015; 50:

7 Key Message 1 While viral hepatitis is being steadily overcome, hepatocellular carcinoma caused by NBNC* such as non alcoholic steatohepatitis (NASH) is on the rise due to changes in dietary habits. Hepatic carcinogenesis from NASH is increasing which is now an issue, and it is particularly necessary to watch for cases in elderly people with progressive fibrosis 6 * NBNC: non-b, non-c hepatitis

Inhibition of viral nucleic acid synthesis Inhibition of protein synthesis Inhibition of RNA polymerase TH1

8 Treatment of Hepatitis C Interferon(IFN) Mechanism of action Induction of anti-viral proteins Induction of immunity nm E1 E2 HCV Core protein HCV RNA Envelope proteins Ribavirin(RBV) Mechanism of action Inhibition of viral nucleic acid synthesis Inhibition of protein synthesis Inhibition of RNA polymerase TH1 cytokines TH2 cytokines Direct acting antivirals (DAAs) Mechanism of action Viral protein functions are directly inhibited

9 Issues to be Solved for Hepatitis C Treatment Hepatitis C treatment takes a long period of time The main age group of patients is getting older Reducing adverse effects is important Due to various physiological factors accompanying aging, medicines with better safety profile are desired Existence of patients who are unable to take interferon Interferon-free treatment 8

interferon-free treatment DAA(2014~) Peg-IFN+RBV+DAA(2011~) IFN(1992) HCV discovered (1989) Peg-IFN+RBV(2004) Peg-IFN(2003) IFN+RBV(2001)

10 History of Hepatitis C Treatment 1989 Discovery of hepatitis C virus From 1992 Treatment with interferon had low efficacy and only around 20% of patients were cured From 2004 Improved cure rate to over 50% by combining interferon with ribavirin From 2014 Toward the era of interferon-free treatment DAA(2014~) Peg-IFN+RBV+DAA(2011~) IFN(1992) HCV discovered (1989) Peg-IFN+RBV(2004) Peg-IFN(2003) IFN+RBV(2001) Interferon based treatment Peg-Interferon based treatment Interferon-free treatment Peg-IFN: Peg-Interferon, RBV: Ribavirin

Transition of Sustained Virological Response (SVR) Rates to Hepatitis C by Treatment (Initial treatment at type 1b/high viral load) 100% 90% 80% 73% 88% 83% 89% 100% 95% 96% 96% 99% 70% 60% 50% 50%

11 Transition of Sustained Virological Response (SVR) Rates to Hepatitis C by Treatment (Initial treatment at type 1b/high viral load) 100% 90% 80% 73% 88% 83% 89% 100% 95% 96% 96% 99% 70% 60% 50% 50% 40% 30% 20% 16% 25% 10% 5% 0% IFN Peg-IFN IFN Ribavirin Peg-IFN Ribavirin Telaprevir Peg-IFN Ribavirin Simeprevir Peg-IFN Ribavirin Vaniprevir Peg-IFN Ribavirin Daclatasvir Ledipasvir Ombitasvir Asunaprevir Sofosbuvir Paritaprevir Ritonavir Elbasvir Grazoprevir Daclatasvir Glecaprevir Asunaprevir Pibrentasvir Beclabuvir 10 2 Mainly interferon Interferon+DAA nd, 3 rd generation DAA (Interferon-free) SVR: sustained virological response, a condition in which the virus has been completely removed Peg-IF: Peg-interferon Created based on various interview forms

12 Key Message 2 Great progress has been made in improving the cure rates for hepatitis C, but onset of cancer following SVR remains an issue. 11 SVR: sustained virological response

Risk of Cancer Onset Following SVR 1.00 Rate of cancer onset following SVR with DAA treatment 0.95 0.90 0.

13 Risk of Cancer Onset Following SVR 1.00 Rate of cancer onset following SVR with DAA treatment No cirrhosis, SVR achieved No cirrhosis, SVR not yet achieved Liver cirrhosis, SVR achieved Liver cirrhosis, SVR not yet achieved Time elapsed since commencing HCV treatment (years) Greater proportion of onset of hepatocellular carcinoma According to the results of large scale studies conducted overseas, there are cases of hepatocellular carcinoma occurring even after SVR with DAA. Careful monitoring is required even after SVR. In particular, it is essential to note that patients with complication of cirrhosis show higher liver cancer incidence even after SVR. 12 Created in reference to Ioannou G, et al., AASLD 2017 Abstract 142

14 Japan Society of Hepatology Guidelines for the Management of Hepatitis C (Version 6.1, March 2018) Onset of liver cancer after sustained virological response (SVR) Recommendation: Interferon-free treatment with direct acting anti-viral agents (DAA) There is an increasing number of reports indicating that elimination of HCV by IFN-free DAA therapy inhibits the onset of hepatocellular carcinoma at a similar level to IFN treatment (Level 2b). IFN-free therapy may not completely prevent the onset of hepatocellular carcinoma. Careful screening for hepatocellular carcinoma is needed. In particular, rigorous follow-up is recommended for the population with high carcinogenic risk, namely elderly patients in whom fibrosis has progressed (Level 2b, Grade A). Even after elimination of hepatitis C virus, careful screening should be conducted Level means evidence level: 1 is highest, Grade means degree of recommendation: A is highest 13 Japan Society of Hepatology. Guidelines for the Management of Hepatitis C Virus Infection (Version 6.1, March 2018) P8 (accessed in September 2018)

15 Key Message 3 Great progress has been made in the treatment of hepatitis C. The next issue is establishing a new method of treatment for hepatocellular carcinoma accompanying the increase in hepatocellular carcinoma following SVR with DAA treatment and cases of NBNC such as NASH. 14

16 Rapid Transformation of Systemic Therapy for Hepatocellular Carcinoma - Debut of the New Medicine Lenvatinib - 15

17 Conventional Standard Therapy for Each Stage of Hepatocellular Carcinoma Treatment modalities Based on tumor progression, treatment is selected from among hepatectomy, local therapy, embolic therapy, transplantation, and chemotherapy. Only sorafenib has significantly prolonged survival as first-line systemic chemotherapy. Early Moderate Advanced End-stage Solitary, or 3 cm, or <3 tumors Large tumor Multiple ( 5 cm) ( 4) Extrahepatic metastasis, intravascular invasion (portal vein) Decreased hepatic reserve (Child-Pugh C) 16 Resection Radiofrequency Microwave Transcatheter Arterial Chemo- Embolization (TACE) Sorafenib Palliative care

Molecular-targeting Therapy Molecular-targeting drugs provide systemic therapy to

1-3 Randomized controlled trials have demonstrated prolongation of survival in patients

1-3 The indication is patients in Child-Pugh A with unresectable advanced HCC, who have

transplantation, local therapy, or TACE.

(second-line therapy) have been approved.

Cancer cells 17 1) Llovet JM et al. N Engl J Med.

18 Molecular-targeting Therapy Molecular-targeting drugs provide systemic therapy to inhibit the growth of tumor cells or angiogenesis, resulting in inhibition of cancer. 1-3 Randomized controlled trials have demonstrated prolongation of survival in patients with advanced hepatocellular carcinoma. 1-3 The indication is patients in Child-Pugh A with unresectable advanced HCC, who have a good performance status (PS 0/1) and are unsuitable for surgical resection, liver transplantation, local therapy, or TACE. 4 Lenvatinib (first-line therapy), sorafenib (first-line therapy), and regorafenib (second-line therapy) have been approved. Molecular-targeting drugs Inhibition of cancer cell growth Inhibition of angiogenesis Cancer cells 17 1) Llovet JM et al. N Engl J Med Jul 24;359(4):378-90; 2) Cheng AL et al. Lancet Oncol Jan;10(1):25-34; 3) Bruix J et al. Lancet Jan 7;389(10064):56-66; 4) Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 edited by The Japan Society of Hepatology, KANEHARA & Co., Ltd, p

19 Unmet Needs: Drugs with fewer adverse reactions than current drugs Drugs that are more effective than current drugs Prolongation of overall survival (OS) *1 OS non-inferiority with fewer adverse reactions Clinically meaningful improvement in objective response rate (ORR) *2 and progression-free survival (PFS) *3, and time to progression (TTP) *4, etc. 18 *1: OS (Overall survival) : time period from the commencement of cancer treatment up until death by any cause *2: ORR (objective response rate) : proportion of patients whose tumor was reduced *3: PFS (Progression-free survival) : objectively confirmed time from the commencement of cancer treatment to the date of disease progression, or date of death from any cause, whichever occurs first *4: TTP (Time to progression) : objectively confirmed time from the commencement of cancer treatment to the date of disease progression

Lenvima (Generic Name: Lenvatinib mesylate) Chemical structure of lenvatinib H 3 C H 2 N O N O O Cl N H O N H Molecular weight 427 Angiogenesis inhibitor discovered at Eisai Tsukuba Research

20 Lenvima (Generic Name: Lenvatinib mesylate) Chemical structure of lenvatinib H 3 C H 2 N O N O O Cl N H O N H Molecular weight 427 Angiogenesis inhibitor discovered at Eisai Tsukuba Research Laboratories Inhibits RTKs of VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRα Approved for differentiated thyroid cancer in Japan*, the US, and EU in Also approved for renal cell carcinoma (2 nd line, in combination with everolimus) in the US and EU in Approved for unresectable hepatocellular carcinoma in Japan, the US, EU, China and Asia in RTK: receptor tyrosine kinase, RET: rearranged during transfection, KIT: KIT proto-oncogene product *Approved for unresectable thyroid cancer in Japan.

Mechanism of Action of Lenvatinib Lenvatinib simultaneously

carcinoma, suppressing tumor angiogenesis as well as tumor

7 VEGF P VEGFR2 FGFs P FGFR1 FGFs P FGFR1-3 FGF19 P FGFR4

3 FGFR1 61 FGFR2 27 FGFR3 52 Lenvatinib Tumor angiogenesis

21 Mechanism of Action of Lenvatinib Lenvatinib simultaneously inhibits VEGFR and FGFR signaling in hepatocellular carcinoma, suppressing tumor angiogenesis as well as tumor survival and proliferation TKR IC 50 (nmol/l) LEN VEGFR VEGF P VEGFR2 FGFs P FGFR1 FGFs P FGFR1-3 FGF19 P FGFR4 VEGFR-2 3 VEGFR FGFR1 61 FGFR2 27 FGFR3 52 Lenvatinib Tumor angiogenesis Lenvatinib Tumor survival / growth FGFR4 43 Endothelial cells Hepatocellular carcinoma cells 20 J Thyroid Res. 2014;2014:

22 Change versus baseline (%) Progression -free rate (%) Phase 2 Study Results Waterfall plot: Response rate = 37 % (mrecist, Independent Image Adjudication Committee) mttp: 7.4 months (mrecist, Independent Image Adjudication Committee) 80 Best response 60 PR (Partial response) n=17 SD (Stable disease) n= Lenvatinib PD (Progressive disease) n=6 NE (Not evaluable) n=3 80 Censored 0 * TTP (months) 43 Japanese and 3 Korean patients were enrolled. The response rate was 37% and the median time to progression was 7.4 months. Favorable efficacy was demonstrated. 21 Ikeda.K,Kudo M et al, J Gastroenterol. 2017,52(4):

23 Body weight (kg) Phase 2 Study Results The body weight and blood concentration of lenvatinib were suggested to be related to early dose reduction or discontinuation C1D15Ctrough (ng/ml) Dose reduction / Discontinuation (+) Dose reduction / Discontinuation ( ) 0 Dose reduction / Discontinuation (+) Dose reduction / Discontinuation ( ) Patients requiring dose reduction or discontinuation within 30 days after initiation of lenvatinib had a significantly lower body weight and a significantly higher minimum blood concentration of lenvatinib (trough value). 22 Ikeda.K,Kudo M et al, J Gastroenterol. 2017,52(4):

24 Background to Body Weight-adjusted Dosing of Lenvatinib To explore the starting dose for low-weight patients, the effects of lenvatinib at 12 mg or 8 mg were projected in those over the body weight range from 40 to 120 kg. It was determined that the dose should be 12 mg for a body weight 60 kg and 8 mg for <60 kg. When the dose of an anticancer agent is determined, the recommended dose based on the MTD (maximum tolerated dose) may not always optimize efficacy. It is reported that oral drugs tend to show stronger toxicity in patients with a small physique. Accordingly, body-weight adjusted dosing of lenvatinib seemed to be a reasonable approach. Dose adjustment based on the body weight This approach was based on the suggestion from Prof. Hiromitsu Kumada of Toranomon Hospital, after each patient in the Phase II study was reviewed on December 14,

25 Dosage of Lenvatinib in the Phase 3 Study Recommended dose of lenvatinib <60 kg: 8 mg 60 kg: 12 mg 24

REFLECT Study Phase 3, global, randomized, open-label, non-inferiority study Randomized (1:1) 954 patients with nonresectable hepatocellular carcinoma (20 countries, 154 clinical sites) No prior

Western countries) Macroscopic portal invasion and/or extrahepatic metastasis (Yes/No) ECOG PS (0 vs. 1) Body weight (<60 kg vs.

cirrhosis with 3- stage (A, B and C) classification. Class C indicating most severe status.

26 REFLECT Study Phase 3, global, randomized, open-label, non-inferiority study Randomized (1:1) 954 patients with nonresectable hepatocellular carcinoma (20 countries, 154 clinical sites) No prior systemic chemotherapy Measurable lesions 1 BCLC: B or C Child-Pugh A ECOG PS: 0 1 Exclusion criteria: Vp4 Biliary invasion Tumor occupancy 50% Stratification Region (Asia/Pacific vs. Western countries) Macroscopic portal invasion and/or extrahepatic metastasis (Yes/No) ECOG PS (0 vs. 1) Body weight (<60 kg vs. 60 kg) BCLC (Barcelona Clinic Liver Cancer): Staging classification commonly used worldwide for hepatocellular carcinoma Child-Pugh: Assessment for the prognosis of chronic liver disease and cirrhosis with 3- stage (A, B and C) classification. Class C indicating most severe status. ECOG PS (Performance Status): Indicator for general status developed by the Eastern Cooperative Oncology Group (ECOG) OS: Overall survival, PFS: Progression free survival, TTP: Time to progression, ORR: Objective response rate mrecist: Assessment criteria used to evaluate effects on solid cancers EORTC QLQ-C30 and QLQ-HCC18: Evaluation scale to measure QoL Primary endpoint: - OS Secondary endpoints: - PFS, TTP, ORR (mrecist) Lenvatinib Group 12 mg/day (BW 60 kg) 8 mg/day (BW <60 kg) Once daily (n = 478) Sorafenib Group 400 mg/dose Twice daily (n = 476) - QoL: EORTC QLQ-C30, QLQ-HCC18 - Safety and tolerability - PK and PK/PD assessment 25 Kudo M et al., Lancet Mar 24;391(10126):

27 REFLECT Study: Statistical Analysis Plan (Non-inferiority study with strict margin set for non-inferiority) Target sample size: 940 patients Target no. of events: 700 events Hypothesis for the primary endpoint: Median OS with sorafenib: 10 months Median OS with lenvatinib: 12.5 months HR: 0.8 Power for detection of non-inferiority: 97% (Non-inferiority margin: 1.08) Hypothesized scenario Upper limit of non-inferiority Non-inferior Estimated HR lenvatinib superior sorafenib superior 26 Kudo M et al., Lancet Mar 24;391(10126):

28 Patient Demographics 27 Characteristic Category Lenvatinib (n = 476) Sorafenib (n = 475) Age (years) Mean Sex Male 85% 84% Female 15% 16% Region Asia / Pacific 67% 67% Body weight (kg) < 60 32% 31% 60 68% 69% ECOG PS 0 64% 63% 1 36% 37% Macroscopic portal invasion and/or extrahepatic metastasis Yes No 69% 31% 71% 29% Child-Pugh A 99% 99% B 1% 1% BCLC stage B (Intermediate) 22% 19% C (Advanced) 78% 81% Hepatitis B 53% 48% Cause of hepatocellular carcinoma Baseline AFP (ng/ml) Hepatitis C Alcohol Others Unknown < % 8% 8% 13% 53% 46% 27% 4% 7% 15% 60% 39% Kudo M et al., Lancet Mar 24;391(10126):

29 OS rate Primary Endpoint: Overall Survival (OS) Median OS was 13.6 months in the lenvatinib group and 12.3 months in the sorafenib group (HR: 0.92, 95% CI: ). The primary endpoint of the study, noninferiority of lenvatinib vs. sorafenib in OS, was achieved Patients at risk lenvatinib group sorafenib group Median (Mo) 95% CI lenvatinib group sorafenib group HR:0.92(95%CI: ) Observation period (months) Kudo M et al., Lancet Mar 24;391(10126):

30 PFS rate Secondary Endpoint: Progression-free Survival (PFS) Based on investigator assessment using mrecist, median PFS was 7.4 months in the lenvatinib group and 3.7 months in the sorafenib group (HR: 0.66, 95% CI: , P < by stratified log-rank test). The lenvatinib group was significantly better Patients at risk lenvatinib group sorafenib group Median (Mo) Observation period (months) %CI lenvatinib group sorafenib group HR: 0.66 (95% CI: ) Log-rank test: P < Kudo M et al., Lancet Mar 24;391(10126):

31 Response Rate: Independent Imaging Review Parameter Lenvatinib (n = 478) Sorafenib (n = 476) Complete Response (CR) 2.1% 0.8% Partial Response (PR) 38.5% 11.6% Stable Disease (SD) 33.3% 46.0% Durable Stable Disease 17.6% 18.9% Progressive Disease (PD) 16.5% 31.9% Unknown/Not Evaluable 9.6% 9.7% Response Rate (CR + PR) 40.6% 12.4% Odds Ratio (95% CI); P-value 5.01 (3.59, 7.01); < Disease control rate (CR + PR + SD) 73.8% 58.4% 30 *Durable SD: SD period greater than or equal to 23 weeks Significant tumor reduction and tumor necrosis was observed with lenvatinib, marking the first time a response rate of over 40% was achieved with a molecular targeted therapy Kudo M et al., Lancet Mar 24;391(10126):

32 Max. reduction rate (%) of contrast-enhanced lesions or viable residual tumor Max. reduction rate (%) of contrast-enhanced lesions or viable residual tumor Waterfall Plot of the Maximum Rate of Change in Target Lesion Diameter vs. Baseline Lenvatinib group (n=433) Sorafenib group (n=436) Rate of change in tumor diameter based on mrecist: nadir vs. baseline (increase was cut at 100%) Kudo M et al., Lancet Mar 24;391(10126):

33 32 Incidence of Treatment Emergent Adverse Events in the Study Common adverse events in the lenvatinib group: hypertension, diarrhea, decreased appetite, and weight loss. Common adverse events in the sorafenib group: palmarplantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Lenvatinib group (n=476) Sorafenib group (n=475) TEAE with an incidence 15% in either group All Grades Grade 3 All Grades Grade 3 Palmar-plantar erythrodysesthesia 128(26.9) 14(2.9) 249(52.4) 54(11.4) Diarrhea 184(38.7) 20(4.2) 220(46.3) 20(4.2) Hypertension 201(42.2) 111(23.3) 144(30.3) 68(14.3) Decreased appetite 162(34.0) 22(4.6) 127(26.7) 6(1.3) Decreased weight 147(30.9) 36(7.6) 106(22.3) 14(2.9) Fatigue 141(29.6) 18(3.8) 119(25.1) 17(3.6) Alopecia 14(2.9) 0(0) 119(25.1) 0(0) Proteinuria 117(24.6) 27(5.7) 54(11.4) 8(1.7) Dysphonia 113(23.7) 1(0.2) 57(12.0) 0(0) Nausea 93(19.5) 4(0.8) 68(14.3) 4(0.8) Abdominal pain 81(17.0) 8(1.7) 87(18.3) 13(2.7) Decreased platelet count 87(18.3) 26(5.5) 58(12.2) 16(3.4) Elevated aspartate aminotransferase 65(13.7) 24(5.0) 80(16.8) 38(8.0) Hypothyroidism 78(16.4) 0(0) 8(1.7) 0(0) Vomiting 77(16.2) 6(1.3) 36(7.6) 5(1.1) Constipation 76(16.0) 3(0.6) 52(10.9) 0(0) Rash 46(9.7) 0(0) 76(16.0) 2(0.4) Based on CTCAE version 4.0. Data are n (%). Kudo M et al., Lancet Mar 24;391(10126):

34 Palmar-plantar Erythrodysesthesia by Grade Grade 1 Grade 2 Grade 3 33 Created based on presentation materials of Kindai University

35 HRQoL: Analysis of Time to Clinically Significant Worsening Worsening of role function (P = ), pain (P = ), diarrhea (P <0.0001), nutrition (P = ), and physical image (P = ) occurred earlier in the sorafenib group. EORTC QLQ-C30 EORTC QLQ-HCC18 HR LCL UCL P-value HR LCL UCL P-value Physical function Role function Psychological function Cognitive function Social function Fatigue Nausea Pain Abdominal distension Sexual life Fever Pain Respiratory distress Sleep disorder Anorexia Constipation Diarrhea Financial difficulty Nutrition Physical image Jaundice General health/qol Summary score < Fatigue Lenvatinib group is better Sorafenib group is better Lenvatinib group is better Sorafenib group is better Kudo M et al., Lancet. 2018

36 Key Factors in Success of the REFLECT Study: My Thoughts Study design (1) Dose adjustment based on body weight (12 mg or 8 mg) (2) Non-inferiority study design Efficacy: Excellent antitumor effect Toxicity:Acceptable range with good QoL Tolerability:Palmar-plantar erythrodysesthesia was comparatively less common and longterm treatment was feasible 35

37 Key Message 4 While there was only one effective first-line therapy for hepatocellular carcinoma, efficacy was confirmed for the new medicine lenvatinib First Phase 3 clinical study of a first-line treatment for hepatocellular carcinoma to succeed in approximately 10 years 36

First Successful Phase III Study in a Decade Clinical studies after sorafenib Emergence of lenvatinib 2008 2016 2017 Success in REFLECT study 2007

In a global study of patients with unresectable hepatocellular carcinoma at 154 clinical sites in 20 countries, lenvatinib successfully

survival (OS) treatment effect by the statistical confirmation of non-inferiority compared to sorafenib.

38 First Successful Phase III Study in a Decade Clinical studies after sorafenib Emergence of lenvatinib Success in REFLECT study drug candidates vs. sorafenib did not achieve primary endpoints. Sorafenib achieved prolongation of OS for the first time. In a global study of patients with unresectable hepatocellular carcinoma at 154 clinical sites in 20 countries, lenvatinib successfully demonstrated efficacy and safety with regards to improvement of prognosis* 37 * lenvatinib met the primary endpoint and demonstrated an overall survival (OS) treatment effect by the statistical confirmation of non-inferiority compared to sorafenib. Additionally, lenvatinib showed highly statistically significant and clinically meaningful improvements in the secondary endpoints of Progression Free Survival (PFS), Time To Progression (TTP), and Objective Response Rate (ORR).

39 THE LANCET 38 Impact Factor: Kudo M et al., Lancet Mar 24;391(10126):

Clinical trial Lenvatinib was developed mainly in Japan, approved for

for the first time in the world 2002 Lenvatinib mesylate was

2013 2014 2015 2016 2017 2018 Study 202 Ph1 part (2 sites in Japan)

December 13, 2011 First body weightadjusted dose setting in the world

countries including 23 sites in Japan) ASCO oral presentation 39

40 Clinical trial Lenvatinib was developed mainly in Japan, approved for indication of unresectable hepatocellular carcinoma (HCC) in Japan, for the first time in the world 2002 Lenvatinib mesylate was developed at Eisai Tsukuba Research Laboratories Study 202 Ph1 part (2 sites in Japan) Study 202 Ph2 part (12 sites in Japan and 2 sites in South Korea) December 13, 2011 First body weightadjusted dose setting in the world as oral molecular-targeted agent REFLECT Study Ph3 (154 sites in 20 countries including 23 sites in Japan) ASCO oral presentation 39 March 23, 2018 Additional indication of unresectable HCC in Japan, first approval in the world

41 Treatment Algorithm from the JSH HCC Guidelines 2017 Hepatocellular carcinoma Hepatic functional reserve Child-Pugh A, B *1 Child-Pugh C Extrahepatic metastasis No Yes Vascular invasion No No. of tumors or more Yes Meet the Milan criteria Nontransplantable Tumor diameter 3 cm >3 cm Treatment Resection and ablation *2 *3 *4 Resection and embolism Embolism, Arterial infusion / Moleculartargeting drugs Embolism/ Resection/ Arterial infusion/ Moleculartargeting drugs Moleculartargeting drugs Transplant Palliative care *1: Before hepatectomy, the severity of hepatic dysfunction should be assessed. *2: If there is a solitary tumor: [1] Resection, [2] Ablation. *3: Child-Pugh class A only *4: Age 65 years. Ablation:Radiofrequency ablation (RFA) Embolism: Transarterial chemoembolization (TACE) Arterial infusion: Hepatic arterial infusion chemotherapy (HAIC) Child-Pugh: Assessment for the prognosis of chronic liver disease and cirrhosis with 3-stage (A, B and C) classification. (Class C indicating most severe status) 40 Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 edited by The Japan Society of Hepatology, KANEHARA & Co., Ltd P68

42 Treatment Algorithm from the JSH HCC Guidelines 2017 Hepatocellular carcinoma Hepatic functional reserve Child-Pugh A, B *1 Child-Pugh C Extrahepatic metastasis No Yes Vascular invasion No No. of tumors or more Yes Meet the Milan criteria Nontransplantable Tumor diameter 3 cm >3 cm Treatment Resection and ablation *2 *3 *4 Resection and embolism Embolism, Arterial infusion / Moleculartargeting drugs Embolism/ Resection/ Arterial infusion/ Moleculartargeting drugs Moleculartargeting drugs Transplant Palliative care *1: Before hepatectomy, the severity of hepatic dysfunction should be assessed. *2: If there is a solitary tumor: [1] Resection, [2] Ablation. *3: Child-Pugh class A only *4: Age 65 years. Ablation:Radiofrequency ablation (RFA) Embolism: Transarterial chemoembolization (TACE) Arterial infusion: Hepatic arterial infusion chemotherapy (HAIC) Child-Pugh: Assessment for the prognosis of chronic liver disease and cirrhosis with 3-stage (A, B and C) classification. (Class C indicating most severe status) 41 Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 edited by The Japan Society of Hepatology, KANEHARA & Co., Ltd P68

43 Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 CQ43 CQ43 Whether to have patients with progressive unresectable hepatocellular carcinoma undergo molecular-targeted therapy? Recommendation: Treatment with sorafenib (or lenvatinib * ) is recommended as first-line therapy for patients with progressive unresectable hepatocellular carcinoma that are not indicated for surgical resection, liver transplantation, percutaneous ablation therapy or TACE, as well as for patients with Child Pugh A who have good performance status (PS) and have good hepatic functional reserve (Strong recommendation) Treatment with regorafenib is recommended as second-line therapy for patients with Child-Pugh A, who are diagnosed with disease progression by the imaging after treatment with sorafenib and demonstrated tolerance to sorafenib (Strong recommendation) * Hepatocellular carcinoma did not approved for reimbursement in Japan as of September 2017 Patients who demonstrated tolerance to sorafenib: In the RESORCE Study, defined as patients who were treated with sorafenib at 400mg/day (once daily) as minimum dose during the 28 days before discontinuation of the treatment, as well as treated with sorafenib for 20 days and more 42 Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 edited by The Japan Society of Hepatology, KANEHARA & Co., Ltd P

Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 CQ43 CQ43 Whether to have patients with progressive unresectable hepatocellular carcinoma undergo molecular-targeted therapy?

44 Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 CQ43 CQ43 Whether to have patients with progressive unresectable hepatocellular carcinoma undergo molecular-targeted therapy? Recommendation: Treatment with sorafenib or lenvatinib is recommended as first-line therapy for patients with progressive unresectable hepatocellular carcinoma that are not indicated for surgical resection, liver transplantation, percutaneous ablation therapy or TACE, as well as for patients with Child Pugh A who have good performance status (PS) and have good hepatic functional reserve (Strong recommendation) Treatment with regorafenib is recommended as second-line therapy for patients with Child-Pugh A, who are diagnosed with disease progression by the imaging after treatment with sorafenib and demonstrated tolerance to sorafenib (Strong recommendation) Patients who demonstrated tolerance to sorafenib: In the RESORCE Study, defined as patients who were treated with sorafenib at 400mg/day (once daily) as minimum dose during the 28 days before discontinuation of the treatment, as well as treated with sorafenib for 20 days and more 43 Lenvatinib was approved in March 2018 and recommended as a first-line therapy for hepatocellular carcinoma. Clinical Practice Guidelines for Hepatocellular Carcinoma 2017 edited by The Japan Society of Hepatology, KANEHARA & Co., Ltd P

45 Reproduction of REFLECT Study Results in Real World Clinical site n ORR Japanese subjects in the REFLECT study n= % Teikyo University Chiba General Medical Center n=16 40% Nagoya University n=10 50% RELPEC Group n= % Hokkaido University n= % Musashino Red Cross Hospital n=5 100% Kindai University n=34 38% 44 The response rate of over 40% observed in the REFLECT study was reproduced in real world, suggesting high usefulness in clinical practice Japan Association of Molecular-targeting Therapy for HCC, Kan-Tan-Sui August, Arc Media

70s, Male, NBNC, PS0, CP score= 5, BCLC-B Due to the large tumor burden, lenvatinib

PIVKA-II AFP Proteinuria 8 mg/day 4 mg/day Intrahepatic multiple mass lesions

lenvatinib AFP 100 90 80 6000 5000 4000 3000 2000 1000 Best response: PR (clinical

4 years 70 60 50 40 30 20 10 45 0 2014/8/26 2014/11/26 2015/2/26 2015/5/26

46 70s, Male, NBNC, PS0, CP score= 5, BCLC-B Due to the large tumor burden, lenvatinib was initiated without TACE Rash PIVKA-II Lenvatinib 12 mg/day PIVKA-II AFP Proteinuria 8 mg/day 4 mg/day Intrahepatic multiple mass lesions Complete response was observed (turned black) after the administration of lenvatinib AFP Best response: PR (clinical study) CR (post-cutoff) 2014/9/1 Tx start 2018/9/17 Tx ongoing Dosing period: over 4 years /8/ /11/ /2/ /5/ /8/ /11/ /2/ /5/ /8/ /11/ /2/ /5/ /8/ /11/ /2/26 0

70s, Male, HCV, PS0, CP score=5, BCLC-C AFP 3000 2500 2000

of hepatocellular carcinoma following SVR for hepatitis C

tumor reduction Rate of tumor reduction 0-10 -20-30 -40-50 0

markers promptly decreased, partial response achieved at 8

47 70s, Male, HCV, PS0, CP score=5, BCLC-C AFP Started treatment with lenvatinib after onset of hepatocellular carcinoma following SVR for hepatitis C lenvatinib 12mg/day lenvatinib 8mg/day AFP値腫瘍縮小率 Rate of tumor reduction Rate of tumor reduction Baseline 4W 8W 16W 24W 32W 40W 48W 56W 64W 72W -60 Tumor markers promptly decreased, partial response achieved at 8 weeks, and treatment effect continued over a long-term period, more than one year 46

48 Key Message 5 High response rate with lenvatinib would be clinically significant in following aspects: i) high responses will lead to an extended prognosis, ii) both healthcare professionals and patients will realize the efficacy of treatment, and iii) feeling positive about treatment will increase further motivation and compliance 47 Kudo M., Liver Cancer 2018;7: (DOI: / )

49 Kinki Criteria (Treatment strategy for BCLC stage B at Kindai University ) BCLC subclass B1 B2 B3 B4 Child-Pugh score Out of Milan criteria and Up-to-7 IN OUT Subclass ーー B3-a B3-b Tx strategy First-line Alternative Tx Curative Hepatectomy Ablation Ultra-selective ctace DEB-TACE (large nodules, CP-7) B-TACE Non-curative Palliative DEB-TACE (>6cm) HAIC (>6) Sorafenib (CP-A*) ctace IN Curative (up-to-7) Liver transplant Ablation Ultra-selective ctace DEB-TACE B-TACE, HAIC ANY OUT Palliative No Tx HAIC Selective DEB- TACE Lenvatinib and sorafenib are recommended for patients with a Child-Pugh score of 5/6. *CP-A : Child-Pugh A DEB-TACE (Drug-eluting beads transcatheter arterial chemoembolization) is recommended for large tumors >6 cm. HAIC (hepatic arterial infusion chemotherapy) is recommended for >6 tumors. B-TACE (balloon-occluded transarterial chemoembolization) is recommended for a few tumor nodules. 48 Kudo M, et al. Dig Dis Oct;33(6): BSC

50 Kindai Criteria:Updated Kinki Criteria (Treatment strategy for BCLC stage B at Kindai University) BCLC subclass B1 B2 B3 B4 Child-Pugh score Out of Milan criteria and Up-to-7 IN Subclass B3-a B3-b OUT IN ANY OUT Tx strategy Curative Non-curative Palliative Curative (up-to-7) Palliative No Tx First-line Alternative Tx Hepatectomy Ablation Ultra-selective ctace DEB-TACE (large nodules, CP-7) B-TACE Lenvatinib (CP-A*) Sorafenib-regolafenib sequential Tx TACE + sorafenib DEB-TACE (>6cm) Liver transplantation Ablation Ultra-selective ctace DEB-TACE B-TACE, HAIC HAIC Selective DEB-TACE Lenvatinib and sorafenib are recommended for patients with a Child-Pugh score of 5/6. *CP-A : Child-Pugh A DEB-TACE (Drug-eluting beads transcatheter arterial chemoembolization) is recommended for large tumors >6 cm. HAIC (hepatic arterial infusion chemotherapy) is recommended for >6 tumors. B-TACE (balloon-occluded transarterial chemoembolization) is recommended for a few tumor nodules. 49 Kudo M., Liver Cancer 2018;7: (DOI: / ) BSC

51 Debut of a Medicine Showing Potential as First-Line Therapy This was the first successful clinical study of first-line systemic therapy for hepatocellular carcinoma in the decade since sorafenib was approved as first-line therapy. This is a remarkable achievement. Less frequent subjective adverse reactions and good QoL with lenvatinib. Superior antitumor effect (response rate and progression free survival). Higher response (tumor reduction effect) raises the possibility of curative treatment (resection, ablation, or embolization therapy) becoming feasible after down-staging. In particular, embolization therapy may be switched to lenvatinib treatment. Good cost effectiveness is expected. Key Message 6 Lenvatinib could potentially become the first-line systemic therapy for hepatocellular carcinoma. 50

52 Future Outlook on Hepatocellular Carcinoma Treatment 51

53 Scientific Rationale for Combining Molecular Targeted Therapy and Immunotherapy (4Rs) Create the optimal environment for removing tumors Recognize, Recruit, Reprogram, and Restore VEGF impedes the maturation of dendritic cells, but VEGF inhibitors have an important function in the priming and activation of T-cells (Recognize) By controlling MDSCs, suppressor T-cells, and TAM, VEGF inhibitors change the immunosuppressive environment to an immunoresponsive environment (Reprogram) Immunotherapy Releases the immunosuppression mechanism on CTL and restores antitumor effect VEGF inhibitors normalize tumor vessels, allowing T-cells to move Molecular efficiently targeted to the tumor (Recruit) therapy Inhibits angiogenesis Improves immunosuppressive microenvironment Immune checkpoint inhibitors activate T-cells, but VEGF inhibitors change the immunological microenvironment, suppressing IL-10 and TGF-β for further synergistic effect (Restore) 52 CTL: cytotoxic T lymphocyte, MDSC: myeloid-derived suppressor cells, TAM: tumor-associated macrophage

Scientific Rationale for Combining Molecular Targeted Therapy and Immunotherapy (4Rs) Create the optimal environment for removing tumors Recognize, Recruit, Reprogram, and Restore VEGF impedes the

54 Scientific Rationale for Combining Molecular Targeted Therapy and Immunotherapy (4Rs) Create the optimal environment for removing tumors Recognize, Recruit, Reprogram, and Restore VEGF impedes the maturation of dendritic cells, but VEGF inhibitors have an important function in the priming and activation of T-cells (Recognize) VEGF inhibitors normalize tumor vessels, allowing T-cells to move efficiently to the tumor (Recruit) By controlling MDSCs, suppressor T-cells, and TAM, VEGF inhibitors change the immunosuppressive environment to an immunoresponsive environment (Reprogram) Immune checkpoint inhibitors activate T-cells, but VEGF inhibitors change the immunological microenvironment, suppressing IL-10 and TGF-β for further synergistic effect (Restore) 52 CTL: cytotoxic T lymphocyte, MDSC: myeloid-derived suppressor cells, TAM: tumor-associated macrophage

Improving the Immunosuppressive Tumor Microenvironment with Combination of Lenvatinib and PD-1/PD-L1 Antibodies Before administering lenvatinib

Lenvatinib strengthens action of PD-1 signal inhibitor Monocyte TAM VEGF MHC antigen TCR Cancer cells PD-L1 PD-1 Immune inhibitory cytokine (TGF-β)

IFN-γ) Down Up IFN-γ CTL Anti PD-1 antibody 53 Lenvatinib potentially suppresses immune suppressive TAM, and by activating cytotoxic T-cells,

55 Improving the Immunosuppressive Tumor Microenvironment with Combination of Lenvatinib and PD-1/PD-L1 Antibodies Before administering lenvatinib Immune suppressive tumor microenvironment Monocyte Changed to immune stimulating environment due to lenvatinib TAM After administering lenvatinib Lenvatinib strengthens action of PD-1 signal inhibitor Monocyte TAM VEGF MHC antigen TCR Cancer cells PD-L1 PD-1 Immune inhibitory cytokine (TGF-β) Immune inhibitory receptor (PD-1, Lag3) Decrease Down TAM MHC antigen TCR Cancer cells Attack TGF-β CTL Treg Immune stimulatory cytokines (IL-12, IFN-γ) Down Up IFN-γ CTL Anti PD-1 antibody 53 Lenvatinib potentially suppresses immune suppressive TAM, and by activating cytotoxic T-cells, strengthens the activity of immune checkpoint inhibitors MHC antigen: major histocompatibility complex antigen, TCR: T-cell receptor Kato et al., EORTC-NCI-AACR 2015

56 55 Hepatocellular Carcinoma Treatment Algorithm From Now On : My Thoughts

57 Revolutionizing Hepatocellular Carcinoma Treatment at the Cutting-Edge of Medicine Key Message 7 Due to treatments for hepatitis B and C, the number of deaths have been decreasing, however there is still the possibility of liver cancer onset even after hepatitis C virus has been controlled, and careful follow-up is required Although cases of liver cancer due to hepatitis C virus are decreasing, there is a rising trend in cases with diabetes, NASH or other conditions in the background The treatment algorithm for hepatocellular carcinoma has changed due to the debut of lenvatinib, and response rates of 40% or greater have been reproduced in clinical practice Lenvatinib is associated with lower incidence of palmar-plantar erythrodysesthesia, good QoL and significant clinically meaningful antitumor effect, increasing motivation of healthcare professionals and patients toward treatment Development is progressing on combinations of molecular targeted therapies such as lenvatinib with immune checkpoint inhibitors* 57 * No combination therapy consisting of lenvatinib and an immune-checkpoint inhibitor is approved at present

Il treatment plan nella terapia sistemica dell epatocarcinoma

Il treatment plan nella terapia sistemica dell epatocarcinoma M. Iavarone, MD PhD CRC A.M. e A. Migliavacca Center for the Study of Liver Disease Division of Gastroenterology and Hepatology Fondazione