100% pure beta emitter Decays to zirconium-90 Physical half-life of 64.1 hours (2.67 days) 94% of radiation delivered within 11 days

Transcription

1

2 100% pure beta emitter Decays to zirconium-90 Physical half-life of 64.1 hours (2.67 days) 94% of radiation delivered within 11 days TheraSphere [US package insert]. Surrey, UK: Biocompatibles UK Ltd, a BTG International group company 2. USA TheraSphere Reference Manual. 2010;PCCS 550B 90 Y = yttrium-90

3 Yttrium-90 ( 90 Y) Microspheres Compared Parameter Glass (TheraSphere ) Resin (SIR-Spheres ) Size µm µm Isotope 90 Y in glass matrix 90 Y on resin surface Specific gravity g/dl 1.6 g/dl Activity/sphere (at calibration) 2500 Bq 50 Bq No. of dose sizes 6 (3, 5, 7, 10, 15, 20 GBq) + custom doses 1 (3 GBq) No. spheres/vial million million No. spheres/3-gbq dose 1.2 million million U.S. FDA approval HCC (HDE) CRC metastases with adjuvant intrahepatic artery chemotherapy (IHAC) of FUDR (floxuridine) 1.Salem R, Thurston KG. J Vasc Interv Radiol 2006;17(8): ; 2. Kennedy A et al. Int J Radiat Oncol Biol Phys 2007;68(1):13 23; 3. TheraSphere [US package insert]. Surrey, UK: Biocompatibles UK Ltd, a BTG International group company; 4. SIR-Spheres microspheres [package insert]. Woburn, MA: Sirtex Medical Inc; 2011.

4 1.TheraSphere [US package insert]. Surrey, UK: Biocompatibles UK Ltd, a BTG International group company 2. USA TheraSphere Reference Manual. 2010;PCCS 550B.

5 High level of radioactivity/microsphere reduces embolic load in tumor Importance of minimally embolic effect: - Blood flow stasis reduces radiotherapeutic effect - Deep tumor penetration (small diameter) - Minimizes risk of stasis and reflux - Potential for retreatment and/or alternative liver-directed therapies 1. Hilgard P et al. Hepatology 2010;52(5): ; 2. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:87; 3. Kulik LM et al. Hepatology 2008;47(1):71 81; 4. USA TheraSphere Reference Manual. 2010;PCCS 550B; 5. Salem R, Thurston KG. J Vasc Interv Radiol 2006;17(8): ; 6. Atassi B et al. Radiographics 2008;28(1):81 99.

6 TheraSphere Benefits Overview Role in Management Neoadjuvant to surgery or transplant Downstage to allow for further potentially curative therapies Promising survival data Use in portal vein thrombosis Promising Quality of Life data Post-TheraSphere patients eligible for further therapeutic options due to preserved liver vascularity Safety Low toxicity: well tolerated Minimal postembolization syndrome (PES) vs. ctace 1.TheraSphere [US package insert]. Surrey, UK: Biocompatibles UK Ltd, a BTG International group company; 2. Lewandowski RJ et al. Am J Transplant 2009;9(8): ; 3. Salem R, Thurston KG. J Vasc Interv Radiol 2006;17(8): ; 4. Salem R et al. Gastroenterology 2010;138(1):52 64; 5. Mazzaferro V et al. Hepatology 2013;57(5): ; 6. Salem R et al. Clin Gastroenterol Hepatol 2013;11(10): ; 7. Moreno-Luna LE et al. Cardiovasc Intervent Radiol 2013;36(3): ; 8. Goin JE et al. World J Nucl Med 2004;3(1): ctace = conventional transarterial chemoembolization; QoL = quality of life

7

8

9 Lewandowski RJ et al. Am J Transplant 2009;9(8):

10 TACE Y TACE Y < 5 cm 5-8 cm > 8 cm 0 Solitary Multifocal Lewandowski RJ et al. Am J Transplant 2009;9(8):

11 40 35 WHO EASL 20 UNOS TACE Y90 UNOS New lesion Overall Progression Lewandowski RJ et al. Am J Transplant 2009;9(8):

12 TheraSphere may serve as a bridge to surgery or transplantation WHO ORR, n (%) TTR (months), median (95% CI) EASL ORR, n (%) TTR (months), median (95% CI) ctace n = /122 (36) 10.3 (7.7 16) 84/122 (69) 2.2 ( ) TheraSphere n = /123 (49) 6.6 ( ) 88/123 (72) 1.2 ( ) P value unadjusted/ adjusted 0.052/ / / 0.008/0.016 Overall TTP (months), median (95% CI) 8.4 ( ) 13.3 (9.3 25) 0.023/0.046 Overall survival (months), median (95% CI) 17.4 ( ) 20.5 ( ) 0.232/ TheraSphere patients were significantly older (66 vs 61 years; P<0.001). Both groups were treatment naïve (>90%) and had comparable rates of portal hypertension, ascites, cirrhosis, tumor distribution, bilirubin, and cancer stage. * Significance not maintained in adjusted analyses. Salem R et al. Gastroenterology 2011;140(2):

13 TheraSphere may serve as a bridge to surgery or transplantation Adapted from Salem R et al., * As per univariate analysis. As per multivariate analysis.

14 Tolerability: TACE vs Y90 Clinical toxicity, n (%) Fatigue Abdominal pain Nausea/vomiting Anorexia Fever/chills Diarrhea Grade 3 4 lab toxicity, n (%) Bilirubin Alkaline phosphatase ALT/AST Albumin Creatinine ctace n = (38) 46 (38) 25 (20) 16 (13) 2 (2) 10 (8) 25 (20) 3 (2) 36 (29) 26 (21) 4 (3) TheraSphere n = (55) 18 (15) 18 (15) 13 (11) 10 (8) 2 (2) 20 (16) 3 (2) 14 (11) 15 (12) 4 (3) P value unadjusted/adjusted 0.012/0.074 <0.001/< / 0.675/ 0.034/ / / 1.000/ / / / Gastrointestinal ulcer, n 0 0 Days hospitalized, mean (range) 1.8 (1 11) 0 <0.001 Median (95% CI) administered liver dose of 90 Y was 110 Gy ( ). Salem R et al. Gastroenterology 2011;140(2):

15

16 Portal Vein Thrombosis (PVT) in HCC E and shaded area = tumor embolus extension; M = superior mesenteric vein; P = main portal vein; T = tumor 1. Pirisi M et al. J Cancer Res Clin Oncol 1998;124(7): ; 2. Kuo YH et al. Eur J Cancer 2010;46(4): ; 3. Song DS et al. J Gastroenterol 2014 [Epub ahead of print]; 4. Villa E et al. Hepatology 2000;32(2): ; 5. Llovet JM et al. Hepatology 1999;29(1):62 67; 6. Bruix J, Sherman M. Hepatology 2011;53(3): ; 7. EASL-EORTC. J Hepatol 2012;56(4):

17 Overall survival reported across studies among patients with PVT 1. Mazzaferro V et al. Hepatology 2013;57(5): ; 2. Hilgard P et al. Hepatology 2010;52(5): ; 3. Salem R et al. Gastroenterology 2010;138(1):52 64; 4. Bruix J et al. J Hepatol 2012;57(4):

18 TTP reported across studies among patients with PVT 1. Mazzaferro V et al. Hepatology 2013;57(5): ; 2. Hilgard P et al. Hepatology 2010;52(5): ; 3. Salem R et al. Gastroenterology 2010;138(1):52 64; 4. Bruix J et al. J Hepatol 2012;57(4):

19 TheraSphere in the Setting of PVT A single-center, prospective, phase 2 study of patients originally referred for liver transplantation who exhibited tumor extension that precluded transplant, and had intermediate to advanced stage HCC (BCLC B or C). Mazzaferro V et al. Hepatology 2013;57(5):

20

21 RADIATION SEGMENTECTOMY AND LOBECTOMY

22 Riaz A et al. Int J Radiat Oncol Biol Phys 2011;79:

23 Prospective Study Radiation Segmentectomy Objective Define radiation segmentectomy Assess safety and efficacy Methods 84 patients treated in a segmental fashion over 5 years BCLC: 32% A, 30% B, 37% C, and 1% D Child-Pugh class: 49% A, 50% B, and 1% C Response based on WHO and EASL Guidelines Riaz A et al. Int J Radiat Oncol Biol Phys 2011;79:

24 Radiation Segmentectomy Prospective Study Results Efficacy Parameter Time (months) One-Year Rates Two-Year Rates Three-Year Rates Overall Survival (median) Time to Progression (median) Lobar dose = 97 Gy Median segmental dose = 521 Gy Estimated dose to the tumor = 1657 Gy Dose to the liver does not exceed 150 Gy Riaz A et al. Int J Radiat Oncol Biol Phys 2011;79:

25 Multicenter Study Radiation Segmentectomy Objective Assess efficacy including response rates, overall survival and pathologic analysis of radiation segmentectomy in solitary HCC 5 cm not amendable to ablation Methods 102 patients treated in a segmental fashion from 2005 to 2013 Child-Pugh class: 48% A, 50% B, and 2% C ECOG PS: 60% 0, 39% 1, 1% 2 Response mrecist Vouche M et al. Hepatology 2014;60:

26 Radiation Segmentectomy Multicenter Study Outcomes Efficacy Outcomes Complete Response 47/99 Partial Response 39/99 Stable Disease 12/99 Pathologic Analysis and Dose Correlation Radiation Dosage Complete Necrosis Partial Necrosis Total <190 Gy >190 Gy Total Median OS = 53.4 months with median follow-up of 27.1 months For 33 transplanted, median survival was 56.5 months Median OS = 34.5 months when censored for transplant Vouche M et al. Hepatology 2014;60:

27

28 Radiation Lobectomy Treats liver tumor Biologic test of time Volumetric changes occur 1 month after TheraSphere ; median % FLR reached 45% after 9 months PVE Does not treat liver tumor or reveal tumor biology Hypertrophy rates of 8% 16% after 3 8 weeks in cirrhotic patients 1. Vouche M et al. Hepatology 2014;60: Anaya DA et al. Semin Intervent Radiol 2008;25(2): FLR = future liver remnant

29 Radiation segmentectomy is treatment of tumor(s) confined to 2 segments along an arterial plane -Bridging option for curative intent (OLT/resection) Radiation lobectomy is ipsilateral (e.g., treated lobe) hepatic lobar atrophy coinciding with contralateral (e.g., untreated lobe) lobar hypertrophy -Surgical eligibility is re-assessed following tumor treatment, biologic test of time and volumetric changes

30 Patient Selection The ideal patient for TheraSphere presents with: Minimal comorbidities Liver-only or liver-dominant disease Normal liver function Absence of pretreatment high-risk factors - Non-infiltrative tumor type - <70% bulk disease or tumor nodules that are not too numerous to count - AST/ALT <5 x ULN - Bilirubin <2 mg/dl - Tumor volume <50% and albumin >3 g/dl 1.TheraSphere [US package insert]. Surrey, UK: Biocompatibles UK Ltd, a BTG International group company. 2. USA TheraSphere Reference Manual. 2010;PCCS 550B.

31 TheraSphere has been associated with improvements in patient QoL In a prospective observational study, 56 consecutive HCC patients had HRQoL assessed using Functional Assessment of Cancer Therapy Hepatobiliary (FACT-Hep) Salem R et al. Clin Gastroenterol Hepatol 2013;11(10):

32