蕾莎瓦 Nexavar 臨床試驗資料 (HCC 肝細胞癌 )

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1 蕾莎瓦 Nexavar 臨床試驗資料 (HCC 肝細胞癌 ) 1

2 Sorafenib Improves Survival in Hepatocellular Carcinoma: Results of a Phase III Randomized, -Controlled Trial Josep M. Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Jean-Luc Raoul, Stefan Zeuzem, Armando Santoro, Minghua Shan, Marius Moscovici, Dimitris Voliotis, and Jordi Bruix, for the SHARP Investigators Study Group Supported by Bayer HealthCare and Onyx Pharmaceuticals SHARP: Sorafenib HCC Assessment Randomized Protocol Trial

3 Randomization N=62 Phase III SHARP Trial Study design Primary end-points: Overall survival Time to symptomatic progression (FHSI8-TSP) Secondary end-points: Time to progression (independent review) Stratification: Macroscopic vascular invasion and/or extrahepatic spread Nexavar (n=299) 4 mg po bid continuous dosing ECOG PS Geographical region (n=33) 2 tablets po bid continuous dosing Llovet JM et al., et al. ASCO 27, Chicago, US

4 Baseline Characteristics of Patients Characteristics Nexavar (n=299) Age (yr, median) (n=33) Male/Female (%) 87/13 87/13 Region (Europe/N. America/other; %) 88/9/3 87/1/3 Etiology (%) Viral hepatitis (HCV/HBV) Alcohol/other 29/19 26/26 27/18 26/29 Child-Pugh (A/B; %) 95/5 98/2 Prior therapies: Surgical resection Loco-regional therapies 19% 39% 21% 41% Llovet JM et al., et al. ASCO 27, Chicago, US

5 Baseline Characteristics of Patients Characteristics BCLC stage (%) Stage B Stage C ECOG PS (%) ECOG ECOG 1 ECOG 2 Vascular invasion / extrahepatic spread Present Absent Nexavar (n=299) (n=33) Llovet JM et al., et al. ASCO 27, Chicago, US

6 Phase III SHARP Trial 44% increase in overall survival Survival Probability Nexavar Median: 46.3 weeks (1.7 mo) (95% CI: 4.9, 57.9) Median: 34.4 weeks (7.9 mo) (95% CI: 29.4, 39.4).25 Patients at risk Sorafenib: : Hazard ratio (S/P):.69 (95% CI:.55,.88) P=.58* Weeks *O Brien-Fleming threshold for statistical significance was P=.77. Llovet JM et al., et al. ASCO 27, Chicago, US

7 Probability of Progression Phase III SHARP Trial 73% prolongation in time to progression Hazard ratio (S/P):.58 (95% CI:.44,.74) P=.7 Nexavar Median: 24. weeks (5.5 mo) (95% CI: 18., 3.) Median: 12.3 weeks (2.8 mo) (95% CI: 11.7, 17.1) Weeks Patients at risk Sorafenib: 299 : Llovet JM et al., et al. ASCO 27, Chicago, US

8 Phase III SHARP Trial Response assessment (RECIST; Independent review) Time to symptom progression (FSHI8-TSP)* Nexavar (n=299) (n=33) Overall response Complete response (CR) Partial response (PR) 7 (2.3%) 2 (.7%) Stable disease (SD) 211 (71%) 24 (67%) Progressive disease 54 (18%) 73 (24%) Progression-free rate at 4 mo 62 % 42 % Duration of treatment (median, weeks) *FSHI8-TSP: No significant differences between treatment groups (P=.77) Llovet JM et al., et al. ASCO 27, Chicago, US

9 Phase III SHARP Trial Exploratory subgroup analysis Nexavar benefit benefit ECOG PS ECOG PS 1 & 2 No extrahepatic spread Extrahepatic spread No macroscopic vascular invasion Macroscopic vascular invasion No macroscopic VI/extrahepatic spread Macroscopic VI/extrahepatic spread Hazard Ratio Llovet JM et al., et al. ASCO 27, Chicago, US

10 Safety Events Treatment-emergent serious adverse events (SAE, %) Nexavar (n=297) (n=32) Drug related treatment-emergent SAE (%) 13 9 Drug-related adverse events (%) All Grade 3/4 All Grade 3/4 Diarrhea 39 8/- 11 2/- Pain (abdomen) 8 2/- 3 <1/- Weight loss 9 2/- <1 /- Anorexia 14 <1/- 3 <1/- Nausea 11 <1/- 8 1/- Hand-foot skin reaction 21 8/- 3 <1/- Vomiting 5 1/- 3 <1/- Alopecia 14 /- 2 /- Liver dysfunction <1 <1/- /- Bleeding 7 <1/- 4 <1/<1 Llovet JM et al., et al. ASCO 27, Chicago, US

11 Phase III SHARP Trial Conclusions Nexavar prolonged overall survival vs placebo in advanced HCC Median OS, 46 weeks vs 34 weeks HR=.69, P=.58 44% increase in overall survival Nexavar prolonged time to progression vs placebo Median TTP, 24 weeks vs 12 weeks HR=.58, P=.7 73% prolongation in time to progression Nexavar was well-tolerated with manageable side effects Llovet JM et al., et al. ASCO 27, Chicago, US

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14 Median overall survival (months) Nexavar prolongs survival in advanced HCC regardless of patient characteristics or extent of disease 16 SHARP exploratory subgroup analyses Nexavar HR =.69 (95% CI:.55.87) p<.1 Overall population 1 n=62 HR=.79 Prior curative therapy 2 n=158 HR=.75 HR=.58 HR=.76 HR=.68 HR=.71 Prior TACE 2 n=176 HCV 3 n=178 Alcoholic cirrhosis 4 n=159 ECOG PS 5 n=325 ECOG PS n=277 HR=.77 MVI and/or EHS 6 n=421 HR=.52 No MVI and/or EHS 6 n= Llovet JM, et al. N Engl J Med 28;359:378 9; 2. Galle P et al. EASL 28, Milan, Italy MVI = macroscopic vascular invasion 3. Bolondi L, et al. ASCO-GI 28, Orlando, FL, USA; 4. Craxi A, et al. ASCO 28, Chicago, IL, USA EHS = extrahepatic spread 5. Raoul J, et al. ASCO 28, Chicago, IL, USA; 6. Sherman M, et al. ASCO 28, Chicago, IL, USA

15 Randomized Phase III Trial of Sorafenib vs in Asian Patients With Advanced Hepatocellular Carcinoma A. Cheng, Y. Kang, Z. Chen, C. Tsao, S. Qin, J. Kim, K. Burock, J. Zou, D. Voliotis, Z. Guan 15

16 Study Schema Eligibility Advanced HCC ECOG -2 Child-Pugh A No prior systemic therapy Stratification Macroscopic vascular invasion (portal vein) and/or extrahepatic spread ECOG PS Geographic region R A N D O M I Z E 2:1 n=15 n=76 Sorafenib 4 mg bid End points: Overall survival, time to symptomatic progression (FSHI8-TSP), time to progression, response (RECIST), and safety No primary end point defined Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 16

17 Baseline Patient Characteristics Sorafenib (n=15) (n=76) Median age (range), y 51 (23-86) 52 (25-79) Male, % ECOG PS, % Macroscopic vascular invasion, % No Yes Extrahepatic spread, % No Yes BCLC Stage C, % Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 17

18 Baseline Patient Characteristics (cont d) Sorafenib (n=15) (n=76) No. of tumor sites, % Sites of disease, % Lung Lymph node Hepatitis virus status, % HBV HCV 11 4 Child-Pugh Class A, % Liver cirrhosis (clinical), % 4 5 AFP > ULN (laboratory), % Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 18

19 Survival Probability Overall Survival 47% increase in overall survival Sorafenib Median: 6.5 months (95% CI: ) Median: 4.2 months (95% CI: ).25 HR (S/P):.68 95% CI: P= Months Patients at Risk Sorafenib Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 19

20 Progression-free Probability Time to Progression 74% increase in TTP Sorafenib Median: 2.8 months (95% CI: ) Median: 1.4 months (95% CI: ) HR (S/P):.57 95% CI: P< Months Patients at Risk Sorafenib Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 2

21 Response by RECIST Sorafenib (n=15) (n=76) ORR (CR+PR), % 3 1 CR PR 3 1 SD, % PD, % DCR*, % *DCR = complete response (CR) + partial response (PR) maintained for > 4 weeks + stable disease (SD) documented at least 12 weeks from baseline Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 21

22 Adverse Events Occurring in 1% of Patients in Either Arm Sorafenib (n=149) (n=75) Treatment-emergent SAEs, % Drug-related SAEs, % 9 1 Drug-Related AEs, % Grade Any 3/4 Any 3/4 Hand-foot skin reaction Diarrhea Alopecia Fatigue Rash/desquamation Hypertension Anorexia 13 3 Nausea Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 22

23 Subset Analyses Favors sorafenib Favors placebo Age 65 Macroscopic vascular invasion (MVI) Extrahepatic spread (EHS) MVI and/or EHS Yes No Yes No Yes No Yes No ECOG PS 1/ Hazard Ratio for OS Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 23

24 Median overall survival (months) Nexavar prolongs survival in advanced HCC regardless of patient characteristics or extent of disease 15 AP Study exploratory subgroup analyses Nexavar HR =.68 (95% CI:.5.93) p=.14 Overall population 1 n=226 HR=.74 HBV 2 n=16 HR=.75 MVI and/or EHS 3 n=179 HR=.45 No MVI and/or EHS 3 n=47 HR=.87 HR=.53 HR=.64 Lung No lung LN metastasis 4 metastasis 4 metastasis 4 n=112 n=167 n=72 HR=.7 No LN metastasis 4 n=154 MVI = macroscopic vascular 1. invasion Cheng AL, et al. Lancet Oncol. 29;1:25-34; 2. Guan Z, et al. ESMO 28 Stockholm, Sweden EHS = extrahepatic spread 3. Kang YK, et al. ESMO 28 Stockholm, Sweden; 4. Guan Z. et al. ASCO GI 29, San Francisco, USA 24

25 Comparison of Efficacy Between the Asia-Pacific and SHARP Trials Asia-Pacific (ORIENTAL) SHARP 1 Hazard Ratio Hazard Ratio End point (95% CI) P-value (95% CI) P-value OS (.5-.93) ( ) <.1 TTSP TTP PFS ( ) ( ) <.1 ( ) ( ) <.1 ( ) ( ).768 <.1 <.1 1. Llovet JM et al. 28:In Press. Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 25

26 Conclusions Sorafenib significantly prolonged OS and TTP compared with placebo in patients from the Asia-Pacific region with advanced HCC Sorafenib improved survival across multiple patients subsets Adverse events were mild to moderate in severity, and treatment was generally well tolerated These findings confirm the clinical benefit of sorafenib in Asian patients with HCC Adapted from Cheng A et al. Presented at ASCO Annual Meeting; May 3-June 3, 28; Chicago, IL. 26