QUANDO LA TERAPIA MEDICA

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1 IL NODULO EATICO dalla diagnosi.. alla terapia Sala Conferenze, Biblioteca "Rosanna Benzi" Genova Voltri 21 Settembre 2013 QUANDO LA TERAIA MEDICA Dott. Gianfranco ercario U.O.S. di Gastroenterologia OEI residio di Genova Voltri

2 Staging Strategy and Treatment for atients With HCC HCC ST 0, Child ugh A ST 0 2, Child ugh A B ST > 2, Child ugh C Very early stage Single < 2 cm Early stage Single or 3 nodules 3 cm, ST 0 Intermediate stage Multinodular, ST 0 Advanced stage ortal invasion, N1, M1, ST 1 2 Terminal stage Single ortal pressure/bilirubin Increased 3 nodules 3 cm Associated diseases ortal invasion, N1, M1 Normal No Yes No Yes Resection Liver transplant EI/RF TACE Sorafenib Curative treatments alliative treatments Symptomatic Llovet JM, et al. J Natl Cancer Inst 2008;100: Brui J, et al. Hepatology 2005; 42:

3 Sorafenib: duplice meccanismo d azione Cellula Tumorale Cellula Endoteliale o pericyta GFR GF Raf-1 MEK ERK roliferazione Sopravvivenza RAS DGF VEGF Nucleus HIF-1 Mitocondrio HIF-2 Apoptosi DGF VEGF X Neavar DGFR- Mitocondrio Apoptosi DGF-BB Raf-1 MEK VEGF-A VEGFR-2 ERK RAS Nucleus VEGF-C VEGFR-3 Angiogenesi: Differenziazione roliferazione Migrazione Formazione dei Tubuli Wilhelm S, et al. Mol Cancer Ther 2008;7:

4 hase III SHAR Trial: SHAR trial design Multicenter, double blind, placebo-controlled trial Eligibility criteria Advanced HCC Child ugh A status ECOG S 0 2 No prior systemic therapy Stratification Region ECOG S (0 vs 1 2) Randomization (1:1) (n=602) Sorafenib 400 mg b.i.d. lacebo rimary endpoints OS TTS Secondary endpoints TT DCR Safety* MVI/EHS (present/absent) ECOG S = Eastern Cooperative Oncology Group erformance Status; MVI = macroscopic vascular invasion; EHS = etrahepatic spread; BID = twice daily; OS = overall survival; TTS = time to symptomatic progression; TT = time to progression; DCR = disease control rate *Assessed using version 3.0 of the USA National Cancer Institute Common Terminology Criteria for Adverse Events Llovet JM, et al. N Engl J Med 2008;359:378-90

5 Summary of Trial Conduct 902 HCC patients screened 602 patients randomised Not randomised n=300 rotocol eclusion criteria n=244 Consent withdrawn n=24 Adverse events n=15 Death n=4 Lost to follow-up/missing n=6 Sorafenib (n=299) Intent-to-treat lacebo (n=303) Intent-to-treat 2 did not receive treatment 1 did not receive treatment Accrual: March 2005 to April interim analysis OS Events: 321 deaths date: Oct 17, 2006 DMC (Data Monitoring Committee) recommended stopping the trial in February 2007 Llovet JM, et al. N Engl J Med 2008;359:378-90

6 Overall Survival (OS) 100 Median OS (intention-to-treat) Sorafenib: 10.7 months lacebo: 7.9 months lacebo (n=303) Sorafenib (n=299) Survival probability HR: 0.69 (95% CI: ) p< Months from randomization CI, confidence interval Llovet JM, et al. N Engl J Med 2008;359:378-90

7 Conclusions Sorafenib prolonged OS versus placebo in advanced HCC median OS 10.7 versus 7.9 months HR: 0.69 (95% CI: ) p<0.001 Sorafenib prolonged TT versus placebo median TT 5.5 vs 2.8 months HR: 0.58 (95% CI: ) p<0.001 Sorafenib improve OS and TT in all subgrup patients Sorafenib was well tolerated with manageable side effects Llovet JM, et al. N Engl J Med 2008;359:378-90

8 Asia-acific Study hase III Asia-acific Study was requested by Asian health authorities Eligibility criteria Advanced HCC n=150 Child ugh A status ECOG S 0 2 No prior systemic therapy Stratification Region ECOG S (0 vs 1 2) Randomization (2:1) (n=226) Sorafenib 400 mg b.i.d. n=76 lacebo End points Overall survival Time to symptom progression Time to progression Response (RECIST) Safety MVI/EHS (present/absent) Cheng AL et al. Lancet Oncol 2009; 10: 25 34

9 Overall Survival (OS) Sorafenib : 6.5 months (95% Cl: ) lacebo: 4.2 months (95% Cl: ) lacebo Sorafenib 1.00 Survival probability atients at risk HR (S/): 0.68 (95% CI: ) p= Months Sorafenib lacebo Cheng AL et al. Lancet Oncol 2009; 10: 25 34

10 Analysis of Sorafenib RCT in HCC Summary of efficacy measures and toicities Variables Asia acific SHAR Overall survival Median OS 6.5 mo vs 4.2 mo 10.7 mo vs 7.9 mo Magnitude benefit (HR) p value Time to progression 0.68 (95%CI, ) (95% CI, ) <0.001 Median TT 2.8 mo vs 1.4 mo 5.5 mo vs 2.8 mo Magnitude benefit (HR) p value 0.57 (95% CI, ) < (95% CI, ) <0.001 Objective response rate <3% <3% Drug-related AEs Overall Hand-foot Sd. (Any: grade 3-4) 81.9 % 45% (11%) 80% 21% (8%) Llovet JM, et al. N Engl J Med 2008;359: Cheng AL et al. Lancet Oncol 2009; 10: 25 34

11 Studio SHAR: eventi avversi Evento avverso Sorafenib (n=297) lacebo (n=302) p Qualsiasi grado Grado 3 Grado 4 Incidenza globale Sintomi costituzionali qualsiasi grado Grado 3 Grado 4 Qualsiasi grado Grado 3 o 4 Fatigue < Calo ponderale < Disturbi dermatologici Alopecia <0.001 NA Secchezza cutanea NA Reazione cutanea mano-piede <1 0 <0.001 <0.001 rurito < Rash o desquamazione Altro < Disturbi gastrointestinali Anoressia 14 < < Diarrea <0.001 <0.001 Nausea 11 < Vomito Alterazioni della voce <0.001 NA Ipertensione Disfunzione epatica <1 < Dolore addominale non altrimenti specificato Sanguinamento < Llovet JM et al. NEJM 2008; 24;359(4):378-90

12 Sorafenib in the treatment of HCC: conclusions Sorafenib is a multikinase inhibitor that target both tumor cell proliferation and tumor angiogenesis Sorafenib is the first systemic therapy to prolong survival in HCC patients Sorafenib has been shown to prolong survival and delay progression across a broad range of patient groups Sorafenib is generically weel tolerated with a predictable side-effect profile Sorafenib is the new reference standard for systemic therapy of HCC patients