SIRveNIB: Randomized Phase III Trial of Selective Internal Radiation Therapy vs Sorafenib in Locally Advanced HCC CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals HCC, hepatocellular carcinoma. This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Management of Locally Advanced HCC Most pts with HCC have locally advanced disease at diagnosis (± PVT) Both SIRT and sorafenib have efficacy in this setting but through different mechanisms of action SIRT: brachytherapy that delivers radiation to tumor bed via Y90 resin microspheres Sorafenib: multikinase and angiogenesis inhibitor Definitive trial comparing these 2 modalities needed to inform decision making SIRveNIB: randomized, controlled, open-label phase III trial of SIRT vs sorafenib in locally advanced HCC not amenable to curative therapy Current report detailed SIRveNIB findings HCC, hepatocellular carcinoma; PVT, portal vein thrombosis; SIRT, selective internal radiation therapy. Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

SIRveNIB: Study Design Randomized, controlled, open-label phase III trial conducted at 27 centers in 11 countries in Asia-Pacific region Stratified by site, portal vein thrombosis Pts with locally advanced HCC* not amenable to curative therapy and without extrahepatic metastases (N = 360) SIRT with Y90 resin microspheres  (n = 182) Followed Q3 mos until PD by central CT review and for survival Sorafenib 400 mg BID  (n = 178) BCLC, Barcelona Clinic Liver Cancer; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PD, progressive disease; PS, performance status; PVT, portal vein thrombosis; RECIST, Response Evaluation Criteria in Solid Tumors; SIRT, selective internal radiation therapy; TTP, time to tumor progression; CT, computed tomography. *Locally advanced HCC without extrahepatic metastases; PVT permitted; BCLC B and BCLC C without distant metastases; ECOG PS 0-1; Child–Pugh A-B (up to 7 points); life expectancy ≥ 3 mos; ≤ 2 prior administrations of hepatic artery-directed therapy Primary endpoint: OS; secondary endpoints: ORR (RECIST 1.1), DCR, TTP, PFS, safety Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

SIRveNIB: Baseline Characteristics ITT Population Treated Population Characteristic SIRT (n = 182) Sorafenib (n = 178) SIRT (n = 130) Sorafenib (n = 162) Mean age, yrs (SD) 59.5 (12.9) 57.7 (10.6) 60.9 (11.5) 57.5 (10.6) Male, % 81 85 82 Mean BMI (SD) 23.2 (4.2) 24.0 (4.6) 23.2 (4.3) 24.1 (4.7) Portal vein thrombosis, % 31 30 23 ECOG PS 0, % 74 79 78 Child–Pugh stage A, % 90 88 BCLC stage B, % 55 61 64 59 Tumor size > 50% of liver, % 24 18 22 Hepatitis, % B C B and C 51 14 2 58 11 3 52 15 12 1 BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; ITT, intent to treat; SD, standard deviation; SIRT, selective internal radiation therapy. Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

SIRveNIB: Treatment Exposure SIRT (n = 130 treated) 52 pts (28.6%) did not receive allocated treatment Median time from randomization to treatment: 21 days Mean activity administered (single dose): 1.8 GBq Sorafenib (n = 162 treated) 9% did not receive allocated treatment Median time from randomization to start of treatment: 3 days Mean daily dose: 644.5 mg Median treatment duration: 13.8 wks Proportion with ≥ 80% adherence to planned doses: 89% SIRT, selective internal radiation therapy. Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

SIRveNIB: OS in ITT and Treated Populations OS results generally consistent across subgroups OS ITT OS Treated 1.0 SIRT (n = 182) Sorafenib (n = 178) Median OS, mos 8.84 10.02 HR: 1.12 (95% CI: 0.88-10.02; P = .360) 1.0 SIRT (n = 130) Sorafenib (n = 162) Median OS, mos 11.27 10.41 HR: 0.86 (95% CI: 0.66-1.13; P = .273) 0.8 0.8 0.6 0.6 SIRT Sorafenib SIRT Sorafenib Proportion of Pts Achieving OS Proportion of Pts Achieving OS 0.4 0.4 0.2 DCR, disease control rate; ITT, intent to treat; SIRT, selective internal radiation therapy; TTP, time to tumor progression 0.2 0.0 0.0 6 12 18 24 30 36 6 12 18 24 30 36 Mos Since Randomization Mos Since Randomization Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002. Reproduced with permission.

SIRveNIB: Secondary Efficacy Outcomes ITT Population Treated Population Efficacy Outcome SIRT (n = 182) Sorafenib (n = 178) HR P Value SIRT (n = 130) Sorafenib (n = 162) Median TTP, mos Overall In liver 6.08 6.11 5.36 5.39 0.88 -- .287 .241 6.41 6.77 5.45 0.73 -- .019 .013 Median PFS, mos 5.85 6.01 5.06 0.89 .306 .259 6.28 6.67 5.22 .009 ORR, % 16.5 1.7 < .001 23.1 1.9 DCR, % 41.8 42.7 .915 58.5 46.9 .059 DCR, disease control rate; ITT, intent to treat; SIRT, selective internal radiation therapy; TTP, time to tumor progression Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

SIRveNIB: Safety Outcomes 60.0% (P < .001) Pts who experienced at least 1 AE 84.6% 31.5% (P < .0001) Pts who experienced at least 1 TRAE 74.7% 27.7% (P < .0001) Pts who experienced at least 1 ≥ grade 3 AE 50.6% 13.1% (P < .0001) Pts who experienced at least 1 ≥ grade 3 TRAE 37.7% 20.8% (P = .0091) Pts who experienced at least 1 serious AE 35.2% AE, adverse event; SIRT, selective internal radiation therapy; TRAE, treatment-related adverse event. 4.6% (P = .1715) Pts who experienced at least 1 serious TRAE 9.3% 20 40 60 80 100 SIRT (N = 130) Sorafenib (N = 162) Pts (%) Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002. Reproduced with permission.

SIRveNIB: Select Adverse Events Grade 1/2 Grade 3-5 SIRT (n = 130) Sorafenib (n = 162) P Value Constipation 5.6 .0051 -- Diarrhea 1.5 25.9 < .001 3.7 .0353 Fatigue 3.8 11.7 .0175 Alopecia 9.9 < .0001 PPE syndrome 0.8 38.3 16.7 Rash 11.1 Hypertension 13.6 1.2 .5043 PPE, palmar-plantar erythrodysesthesia. All other events not significantly different between groups Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

SIRveNIB: Investigator Conclusions Study failed to meet primary endpoint SIRT and sorafenib yielded similar OS in patients with locally advanced HCC not amenable to curative therapy However, pts treated with SIRT vs sorafenib demonstrated Significantly higher ORR Fewer AEs and serious AEs AE, adverse event; HCC, hepatocellular carcinoma; SIRT, selective internal radiation therapy. Slide credit: clinicaloptions.com Chow M, et al. ASCO 2017. Abstract 4002.

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