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    Asco2011 information in hcc Asco2011 information in hcc Presentation Transcript

    • Global Investigation of Therapeutic Decisions in HCC and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1500 Patients: Clinical Findings in Pts with Liver Dysfunction g y Marrero J, et al. J Clin Oncol 29: 2011 (Suppl; Abstr 4001) (1 of 6) bution. Study Design/Methods GIDEON: ongoing global prospective, non interventional study of HCC patients ongoing, global, prospective non-interventional ducational us only. Not for promotio or distrib receiving sorafenib In total, 3,322 patients enrolled from 39 countries on Key Findings Second interim analysis Total† CPA CPB CPC safety population N=1,571 n=1571 (100%) n=957 (61%) n=367 (23%) (n=35) (2%) 800 mg starting dose (% of n) 74 77 71 69 Daily dose (median, mg)* 693 680 721 680 Dose increase (% of n) 16 18 13 3 se Dose increase to 800 mg from 6 6 5 0 lower initial doses (% of n) Dose interruption (% of n) 24 24 22 20Fo internal ed Dose reduction (% of n) 33 37 27 29 Treatment duration (median, wk) 12 14 9 4 DSC due to AE (% of n) 28 24 38 51 or †Dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients; ‡ Assessed in the 79% of patients for whom dosing data were available. Child-Pugh: CP 1 Adapted from Marrero et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Global Investigation of Therapeutic Decisions in HCC and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1500 Patients: Clinical Findings in Pts with Liver Dysfunction g y Marrero J, et al. J Clin Oncol 29: 2011 (Suppl; Abstr 4001) bution. Study Design/Methods GIDEON: ongoing global prospective, non interventional study of HCC patients ongoing, global, prospective non-interventional ducational us only. Not for promotio or distrib receiving sorafenib In total, 3,322 patients enrolled from 39 countries on Key Findings Second interim analysis Total† CPA CPB CPC safety population N=1,571 n=1571 (100%) n=957 (61%) n=367 (23%) (n=35) (2%) 800 mg starting dose (% of n) 74 77 71 69 Daily dose (median, mg)* 693 680 721 680 Dose increase (% of n) 16 18 13 3 se Dose increase to 800 mg from 6 6 5 0 lower initial doses (% of n) Dose interruption (% of n) 24 24 22 20Fo internal ed Dose reduction (% of n) 33 37 27 29 Treatment duration (median, wk) 12 14 9 4 DSC due to any AE (% of n) 28 24 38 51 or †Dosing data missing for 8 patients; Child-Pugh status unknown for 5 patients; ‡ Assessed in the 79% of patients for whom dosing data were available. Child-Pugh: CP 2 Adapted from Marrero et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Global Investigation of Therapeutic Decisions in HCC and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1500 Patients: Clinical Findings in Pts with Liver Dysfunction Marrero J, et al. J Clin Oncol 29: 2011 (Suppl; Abstr 4001) bution. ducational us only. Not for promotio or distrib Total Treatment-Emergent Drug- Any Total CPA CPB CPC Related AEs by Child-Pugh Grade G3/G4 (<7) (7-9) (>9) on Status*,† (% of n) (n=1571) (n=1571) (n=957) (n=367) (n=35) Diarrhea 25 3/0 26 23 9 HFSR 24 5/0 29 15 3 Fatigue 14 3/<1 15 11 17 Rash/desquamation 12 2/<1 13 10 6 se Anorexia A i 9 1/0 10 8 3 Hypertension 7 2/0 9 3 0 Alopecia 6 0/0 8 3 3Fo internal ed Nausea 6 <1/0 5 5 6 Weight loss 5 <1/0 5 4 3 or Pain, abdomen Pain abdomen, NOS 3 <1/0 3 4 6 * Incidence ≥5% in any group and any Grade; † At start of therapy. HFSR=hand-foot skin reaction; NOS=not otherwise specified. 3 Adapted from Marrero JA et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Global Investigation of Therapeutic Decisions in HCC and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1500 Patients: Clinical Findings in Pts with Liver Dysfunction Marrero J, et al. J Clin Oncol 29: 2011 (Suppl; Abstr 4001) bution. ducational us only. Not for promotio or distrib Cause of death*,† within Child-Pugh A║ Child-Pugh B║ Child-Pugh C on 30 days of discontinuing Total§ (<7) (7-9) (>9) therapy‡ n (%) deaths (n=343) (n=154) (n=125) (n=13) HCC-related 138 (40) 61 (40) 50 (40) 4 (31) HCC- and liver-related 38 (11) 15 (10) 15 (12) 3 (23) HCC- and liver-related, 9 (3) 4 (3) 2 (2) 1 (8) se and MOF Liver-related 49 (14) 22 (14) 18 (14) 2 (15) HCC-related and MOF 15 (4) ( ) 8 (5) ( ) 4 (3) ( ) 0Fo internal ed MOF 22 (6) 10 (6) 8 (6) 1 (8) or * Incidence >2% in total group; † Patients may be included in more than one cause of death category; ‡ By Child-Pugh status at study entry; § Child-Pugh status missing for 1 patient; ║ Data missing for 7 Child-Pugh A and 7 Child-Pugh B patients. MOF=multiorgan system failure. 4 Adapted from Marrero JA et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Global Investigation of Therapeutic Decisions in HCC and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1500 Patients: Clinical Findings in Pts with Liver Dysfunction Marrero J, et al. J Clin Oncol 29: 2011 (Suppl; Abstr 4001) (4 of 6) bution. Child-Pugh A (<7) Child-Pugh B (7-9) Child-Pugh C (>9) ducational us only. Not for promotio or distrib (n=984), ( 984) median (95% CI) di (n=376), ( 376) median (95% di (n=36), ( 36) median (95% di 312 (284, 341) days CI) 147 (126, 189) days CI) 62 (46, 94) days 10.3 months 4.8 months 2.0 months 1.0 on 0.9 Survival distributio function Preliminary Overall Survival 0.8 by Child-Pugh Status* at Study Entry 0.7 on 0.6 0.5 0.4 se 0.3 0.2 0.1Fo internal ed 0.0 0 100 200 300 400 500 600 Time since start of treatment (days) or * 207 patients not evaluable. CI=confidence interval. 5 Adapted from Marrero JA et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Global Investigation of Therapeutic Decisions in HCC and of its Treatment with Sorafenib (GIDEON) Second Interim Analysis in More than 1500 Patients: Clinical Findings in Pts with Liver Dysfunction g y Marrero J, et al. J Clin Oncol 29: 2011 (Suppl; Abstr 4001) (6 of 6) bution. Conclusions ducational us only. Not for promotio or distrib Based on the second interim analysis, there is no evidence suggesting that treating physicians use a different dosing strategy for Child-Pugh B patients compared with Child-Pugh A patients on Duration of sorafenib therapy was shorter in Child-Pugh B patients than in Child-Pugh A patients Compared with Child-Pugh A patients, Child-Pugh B patients did not have a higher incidence of drug-related AEs, but had a higher incidence of liver-associated AEs In patients with moderate liver dysfunction, no unexpected AEs were observed The vast majority of deaths were due to HCC or underlying liver disorders se The differences in patient outcomes across Child-Pugh groups likely reflect differences in prognosis Consistent with previously reported studies, these preliminary data indicate that Child- Pugh t t P h status appears to be a useful prognostic factor for overall survival t b f l ti f t f ll i lFo internal ed The GIDEON study is ongoing, and the safety, tolerability, and efficacy of sorafenib in HCC patients will continue to be evaluated or 6
    • Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (1 of 12) bution. Study Design/Methods y g ducational us only. Not for promotio or distrib Open label, Phase III study, comparing efficacy and safety of on sorafenib compared t f ib d to sunitinib The study was stopped after a planned safety review by an independent data se monitoring committee (events: 457 deaths) – Higher incidence of serious adverse events (AEs) with sunitinib resulted in an unfavorable risk-benefit relationship vs sorafenibFo internal ed Enrollment was halted after 1074 patients had been randomized from July 2008 to May 2010 Sunitinib discontinuation recommended and treatment changed to standard of care or CDD=continuous daily dosing; ECOG PS=Eastern Cooperative Oncology Group performance status; PFS=progression-free survival; TACE=transarterial chemoembolization. 7 Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (2 of 12) OS – Primary Endpoint bution. (ITT Population) Sunitinib Median 7 9 months (95% CI: 7 4 9 2) 7.9 7.4-9.2) ducational us only. Not for promotio or distrib 1.00 Sorafenib Median 10.2 months (95% CI: 8.9-11.4) obability (%) on 0.75 HR 1 30 (95% CI 1 13 1 50) 1.30 CI: 1.13-1.50) P=.0010 0.50 OS pro 0.25 se 0.0 0 5 10 15 20 25 30 35 40Fo internal ed Patients at risk Time (months) Sunitinib 530 354 208 112 41 8 0 0 0 Sorafenib 544 388 245 139 61 12 1 0 0 or P-value based on stratified log-rank test. CI=confidence interval; HR=hazard ratio. 8 Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (5 of 12) bution. Sunitinib Sorafenib Hazard ratio (n 530) (n=530) (n 544) (n=544) (95% CI) P value P-value* ducational us only. Not for promotio or distrib Median OS (months), ITT 7.9 10.2 1.30 (1.13-1.50) .0010 Asian regions† 7.7 8.8 1.21 (1.03-1.42) .0171 on Ex-Asian regions‡ 9.3 15.1 1.64 (1.20-2.26) .0036 Median PFS (months), ITT 3.6 3.0 1.13 (0.99-1.30) .1215 Asian regions 2.9 2.8 1.03 (0.88-1.20) .3930 Ex-Asian regions 4.2 5.6 1.46 (1.07-2.00) .0182 se TTP (months), ITT ( th ) 4.1 41 3.8 38 1.13 (0.98-1.31) 1 13 (0 98 1 31) .1688 1688 Asian regions 4.0 2.8 1.03 (0.88-1.21) .3850 Ex Asian Ex-Asian regions 5.0 50 6.1 61 1.41 (1.00 1.99) 1 41 (1 00-1 99) .0495 0495Fo internal ed or Ex-Asian regions=regions excluding Asia; ITT population (sunitinib=529; sorafenib=544). * P-value based on stratified log-rank test; †Asian population: sunitinib=402, sorafenib=410; ‡Ex-Asian population: sunitinib=127, sorafenib=134. 9 Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (6 of 12) bution. ITT Population 1.00 OS in Patients With HBV Infection ducational us only. Not for promotio or distrib (Exploratory Analysis) Sunitinib (n=290) Median 7.6 months 0.75 (95% CI: 6.7-8.6) on %) OS probability (% Sorafenib (n=288) 0.50 Median 8.0 months (95% CI: 6.8-9.1) S HR 1.10 (95% CI: 0.92-1.33) 0.25 P=.1714 se 0.00 0 00 0 5 10 15 20 25 30 35 40 Time (months)Fo internal ed Sunitinib Sorafenib Sunitinib Sorafenib Sunitinib Sorafenib ITT ITT Asia Asia Ex-Asia Ex-Asia Median OS, months 7.6 8.0 7.6 7.9 7.9 15.3 HR (95% CI) 1.10 (0.92 1.33) 1 10 (0 92-1 33) 1.10 (0.91 1.33) 1 10 (0 91-1 33) 1.08 (0.49 2.36) 1 08 (0 49-2 36) or P-value (1-sided) .1714 .1844 .3749 P-values based on stratified log-rank test. 10 Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (8 of 12) bution. OS in Patients With HCV Infection ITT Population 1.00 ( p o ato y (Exploratory Analysis) a ys s) Sunitinib ( 113) S iti ib (n=113) ducational us only. Not for promotio or distrib Median 9.2 months 0.75 (95% CI: 7.0-12.0) Sorafenib (n=119) on %) OS probability (% Median 17.6 months 0.50 (95% CI: 11.4-20.1) HR 1.52 (95% CI: 1.09-2.13) P=.0165 S 0.25 se 0.00 0 00 0 5 10 15 20 25 30 Time (months)Fo internal ed Sunitinib Sorafenib Sunitinib Sorafenib Sunitinib Sorafenib ITT ITT Asia Asia Ex-Asia ex-Asia Median OS, months 9.2 17.6 9.7 12.6 8.6 18.3 HR (95% CI) 1.52 (1.09 2.13) 1 52 (1 09-2 13) 1.40 (0.92 2.14) 1 40 (0 92-2 14) 1.76 (0.99 3.10) 1 76 (0 99-3 10) or P-value (1-sided) .0165 .0721 .0544 P-values based on stratified log-rank test. 11 Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.
    • Most Common Treatment-Emergent AEs Phase III Trial of Sunitinib >5% of Patients; As-Treated Population) (Grade* 3 or 4 in versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (9 of 12) Sunitinib (%; n=526) ( ) Sorafenib (%; n=541) ( )Hematologic AEs Grade 3 Grade 4 Grade 3 Grade 4Thrombocytopenia 24 6 4 1Neutropenia 23 2 2 <1Leukopenia 12 1 <1 0Anemia 6 3 3 1Nonhematologic AEsHand-foot syndrome 13 0 21 <1Increased AST 8 <1 9 <1Diarrhea 7 <1 9 0Fatigue 6 <1 4 <1Asthenia 6 <1 4 0Decreased appetite 6 0 4 0 * National Cancer Institute—Common Terminology Criteria for AEs (NCI-CTCAE) v3.0. AST=aspartate aminotransferase. Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 12
    • Bleeding AEs Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC (All Causes; As-Treated Population) Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (10 of 12) g , ( pp ; )( ) Grade* (%) Sunitinib Sorafenib (n=526) (n=542) All G3/4 G5 All G3/4 G5 Any bleeding 37 10 2 20 4 1 Selected bleeding sites Gastrointestinal G t i t ti l 18 7 1 12 4 <1 1 Hepatic tumor 1 <1 <1 <1 <1 0* NCI-CTCAE v3.0. G=grade. Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 13
    • Deaths on Study* Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC (All Causes; As-Treated Population) Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) (11 of 12) g , ( pp ; )( ) Sunitinib Sorafenib Event (n=526) (n=542) Deaths (all causes; n, %) 92 (17%) 83 (15%) Cause (% of total deaths: SU n=92; SO n 83)† n 92; n=83) Disease progression 76% 86% Toxicity 18% 2% Dehydration D h d ti ± organ f il failure 3% 0 CNS hemorrhage 3% 0 Esophageal varices/GI hemorrhage† 3% 1% Other/unknown cause 7% 13% Pneumonia 2% 1% Septic shock/sepsis 1% 2% Unknown reason 0 2%* Deaths during the study or within 28 days after the last dose of study medication. Participants may have more than one cause of death; †Includes deaths attributed to tumor hemorrhage. CNS=central nervous system; GI=gastrointestinal; SU=sunitinib; SO=sorafenib. Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 14
    • Phase III Trial of Sunitinib versus Sorafenib in Advanced HCC Cheng A, et al J Clin Oncol 29: 2011 (Suppl; Abstr 4000) ( of 12) g , ( pp ; ) (12 ) Conclusions Sunitinib did not demonstrate superiority or noninferiority in OS, compared with sorafenib in patients with advanced HCC p PFS, TTP, and ORR were comparable between treatment arms Frequency and severity of AEs were higher with sunitinib than sorafenib In patients with HBV infection, OS was similar between arms. In patients with HCV infection, OS was significantly longer with sorafenib (17.6 vs 9.2 for sunitinib)ORR=overall response rate.Adapted from Cheng A et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. 15
    • Baseline Patient Characteristics: Phase III Trial of Su vs. So & Phase III SHARP & AP Data vs Phase III Su vs So SHARP AP cational use only. Not for promotion or distribution. Sor (n=299) Sor (n=150) Sun (n=530) Sor (n=544) Median age, years 59 59 64.9 51 HBV/HCV positive (%) 55/21 53/22 19/29a 70/10 Alcoholic liver disease (%) -- -- 26b -- Male (%) 82 84 87 84 Asian (%) ( ) 76 75 -- 100 r ECOG PS 0/1/2 (%) 53/47- - 53/47/- - 54/38/8 25/69/5 Vascular invasion and/or Extrahepatic 79 76 70 36/69 spread* (%) Child Pugh Child-Pugh grade A/B (%) 100/0 100/0 95/5 97/2 o BCLC stage B/C (%) 13/87 16/83 18/82 - -/95c *Indirectly assessed from Independent Response Review Committee assessment; ‡Subjects may have received ≥1 therapy; a: Reported as “Cause of disease: Heptatitis B only or Hepatitis C only”; b: reported as “Cause of disease – Alcohol only”; c: only BCLC C reported, no A/B; d: reported as “Locoregional therapy (TACE, PEI, RFA, RT) w/ RT was applied to t EH metastatic lesions in all pts except 5 sor & 3 pbo”; - -, not reported; BCLC B t t ti l i i ll t t b ” t t d BCLC, Barcelona Cli i Li l Clinic Liver C Cancer; CLIP C CLIP, Cancer of th Liver Italian P f the Li It li Program ; ECOG Eastern ECOG, E t nternal educ Cooperative Oncology Group ; HBV/HCV, hepatitis B/C virus. Patients in this study had better performance status consistent withFor in SHARP but less HBV than AP study 1. Adapted from Chang et al. Presented at: ASCO Annual Meeting; June 3-7, 2011; Chicago, IL.2. Llovet, et al. N Engl J Med 16 2008;359:378-90. 3. Cheng, et al. Lancet Oncol 2009; 10: 25–34.