Sorafenib (Nexavar ) Quelle place dans le traitement du carcinome hepatocellulaire?
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1 Sorafenib (Nexavar ) Quelle place dans le traitement du carcinome hepatocellulaire? Pietro Majno Groupe pour le traitement du CHC Services de chirurgie viscérale, transplantation, radiologie, hépato-gastroentérologie Hôpitaux Universitaires de Genève Contributions: J. Bruix et J.-F. Dufour
2 CHC: le contexte 6 ème tumeur au monde ( nouveau cas/an) 3 ème tumeur par mortalité Cause de mortalité la plus fréquente chez les patients cirrhotiques (risque 15-20% à 5 ans) L incidence augmente (Genève: 1 nouveau patient/semaine)
3 Incidence du CHC Incidence (rate/100000) proj age (year) En Suisse ~ 700 ~ 400 ~ 250 El-Serag et. al. Ann Intern Med 2003 Davis et. al. Liver Transplant 2003
4 Stage 0 PST 0, Child-Pugh A Stadiation et traitements HCC Stage A - C PST 0-2, Child-Pugh A-B Stage D PST >2, Child-Pugh C Very early stage (0) Early stage ( A) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Intermediate stage ( B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1,M1, PS 1-2 Terminal stage (D) Single Portal pressure/ bilirubin Increased 3 nodules <3cm Associated diseases Portal invasion, N1,M1 Normal No Yes No Yes Resection Liver Transplantation (CLT / LDLT) PEI/RF Chemoembolization New Agents Research trials Curative Treatments (30%) 50% - 75% at 5 years Non-curative treatments (50%) 3 year survival 10-40% Llovet, Hepatology 2005 Sympt. Treat. (20%)
5 Barcelona-Clínic Liver Cancer (BCLC) Group Liver Unit: J. Bruix MD, JM. Llovet MD AASLD Boston 2007
6 BCLC Staging and Treatment Strategy HCC Stage 0 PST 0, Child-Pugh A Stage A - C PST 0-2, Child-Pugh A-B Stage D PST >2, Child-Pugh C Very early stage (0) Early stage ( A) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Intermediate stage ( B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1,M1, PS 1-2 Terminal stage (D) Single Portal pressure/ bilirubin Increased 3 nodules <3cm Associated diseases Portal invasion, N1,M1 Normal No Yes No Yes Resection Liver Transplantation (CLT / LDLT) PEI/RF Chemoembolization New Agents Research trials Curative Treatments (30%) 50% - 75% at 5 years Non-curative treatments (50%) 3 year survival 10-40% Llovet Hepatology 2005 Sympt. Treat. (20%)
7 BCLC Staging and Treatment Strategy HCC Stage 0 PST 0, Child-Pugh A Stage A - C PST 0-2, Child-Pugh A-B Stage D PST >2, Child-Pugh C Very early stage (0) Early stage ( A) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Intermediate stage ( B) Multinodular, PS 0 Advanced stage (C) Portal invasion, 70% N1,M1, PS 1-2 Terminal stage (D) Single Portal pressure/ bilirubin 3 nodules <3cm des Increased Associated diseases Portal invasion, N1,M1 Normal No Yes No Yes Resection Liver Transplantation (CLT / LDLT) PEI/RF Chemoembolization patients New Agents Research trials Curative Treatments (30%) 50% - 75% at 5 years Non-curative treatments (50%) 3 year survival 10-40% Llovet Hepatology 2005 Sympt. Treat. (20%)
8 Pas de médicament actif! Treatments Studies N Objective response Systemic chemotherapy Doxorubicin as single agent Phase II/III > % Doxorubicin combination (PIAF) Phase II/III % Cisplatin Phase II 48 10% Epirubicin Phase II 62 11% Mitoxantrone Phase II % 5-FU,Paclitaxel, iridotecan, gemcitabine Phase II/III... <10% Anti-androgen Phase III 376 <10% Interferon Phase III 60 <10% Tamoxifen Phase III >1000 < 5% Octreotide Phase III 60 <5% Seocalcitol Phase III 746 <5%
9 Histoire naturelle des stades B et C Invasion vasculaire, ECOG-PS 1-2, Symptômes, Métastases 100 Probability (%) % 29% 65% 16% 50% 8% p< Patients at risk months (BCLC Stage B) (BCLC Stage C) Llovet et al. Hepatology, 1999.
10 Du Nouveau! Stage 0 PST 0, Child-Pugh A HCC Stage A - C PST 0-2, Child-Pugh A-B Stage D PST >2, Child-Pugh C Very early stage (0) Early stage ( A) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Intermediate stage ( B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1,M1, PS 1-2 Terminal stage (D) Single Portal pressure/ bilirubin Increased 3 nodules <3cm Associated diseases Portal invasion, N1,M1 Normal No Yes No Yes Resection Liver Transplantation (CLT / LDLT) PEI/RF Chemoembolization New Agents Research trials Curative Treatments (30%) 50% - 75% at 5 years Non-curative treatments (50%) 3 year survival 10-40% Llovet Hepatology 2005 Sympt. Treat. (20%)
11 Le mérite: mécanismes: traitements pour des molécules cible Wnt pathway EGFR pathway Raf/MAPK pathway Akt pathway Jat/Stat pathway Hanahan. Cell 2000.
12 Treatment of advanced HCC Molecular targeted agents Treatment Action Phase study Tyrosine kinase inhibitors.- Sorafenib RAF inhibitor/vegf inhibitor (TKI) III- stopped.- Erlotinib/Gefitinib EGFR inhibitor (TKI) III- design.- Erlotinib+ bevacizumab EGFR inhibitor (TKI), VEGF inhibitor II- ongoing.- Cetuximab EGFR inhibitor (Ab) II- ongoing.- Lapatinib EGFR/Her2/Un inhibitor (TKI) II- ongoing.- Sunitininb PDGFR/VEGFR/KIT inhibitor (TKI) II- ongoling Anti angiogenic agents.- Bevacizumab VEGF inhibitor (Ab) II - ongoing.- Thalidomide Antiangiogenic III- ongoing Other molecular targeted therapies.- Bortezomib Proteasome inhibitor II-stopped.- Acyclic retinoids Differentiation III- design.- Nolatrexed Thymidylate synthase III- negative.- T Tubulin inhibitor III- negative
13 Sorafenib cible à la fois la prolifération céllulaire et l angiogenèse Cellule Tumorale Cellule endothéliale et pericyte EGF/HGF Autocrine loop Paracrine stimulation PDGF-β VEGF Apoptosis PDGFR-β VEGFR-2 RAS RAS RAF RAF Sorafenib MEK ERK HIF-2 Nucleus Sorafenib EGF/HGF PDGF VEGF Mitochondria Proliferation Survival Mitochondria Apoptosis MEK ERK Nucleus Angiogenesis: Differentiation Proliferation Migration Tubule formation Wilhelm S et al. Cancer Res. 2004;64:
14 Phase 3: Sorafenib vs placebo for patients with advanced hepatocellular carcinoma (SHARP) Design International, multicentre, Phase III study. Inclusion criteria: Histology proven HCC Advanced HCC At least one measurable untreated lesion ECOG 0-2 Child-Pugh A (to reduce confounding liver deaths) No prior systemic treatment Randomization Double-blind placebo-controlled trial; Ratio 1:1 Accrual: March 2005 to April Stade B+ et C!
15 Phase III SHARP Trial Study design Treatment schedule Sorafenib treatment was stopped if: - Both radiologic progression and FHSI8-TSP were achieved - Any adverse event required discontinuation Statistical methods Intention-to-treat analysis Sample size : N= 560 patients (424 OS events) Overall alpha for trial maintained at α=0.025 (one-sided) Overall Survival assessment - α=0.02 (one-sided) - Two interim analyses planned using O Brien-Fleming α spending function - 90% power to detect a 40% improvement : 7 months 9.7 months TTSP assessment (FHSI8-TSP) - α=0.005 (one-sided) - Single analysis performed at time of final survival analysis
16 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 (portal vein) and/or extrahepatic spread * ECOG PS * Geographical region Randomization N=602 Sorafenib (n=299) 400 mg po bid continuous dosing Placebo (n=303) 2 tablets po bid continuous dosing
17 Baseline characteristics of patients Sorafenib Placebo Characteristics (n=299) (n=303) Age (yr, median) Male/Female (%) Region (Europe/N. America/others;%) 65 87/13 88/9/ /13 87/10/3 Etiology (%) Viral Hepatitis (HCV/HBV) Alcohol/other Child-Pugh (A/B;%) Prior therapies: Surgical resection Loco-regional therapies 29/19 26/26 95/5 19% 39% 27/18 26/29 98/2 21% 41%
18 Baseline characteristics of patients Sorafenib Placebo Characteristics (n=299) (n=303) BCLC stage * (%) Stage B (intermediate stage) Stage C (advanced stage) ECOG PS (%) ECOG 0 ECOG 1 ECOG 2 Vascular invasion / extrahepatic spread Present Absent * Llovet JM & Bruix J, BCLC Group. Semin Liver Dis, 1999.
19 Phase III SHARP Trial Overall survival (Intention-to-treat) Survival Probability Sorafenib Median: 46.3 weeks (10.7 mo) (95% CI: 40.9, 57.9) Placebo Median: 34.4 weeks (7.9 mo) (95% CI: 29.4, 39.4) 0 Patients at risk Sorafenib: Placebo: Hazard ratio (S/P): 0.69 (95% CI: 0.55, 0.88). P= * Weeks *O Brien-Fleming threshold for statistical significance was P=
20 Phase III SHARP Trial Time to Progression (Independent central review) 1.00 Probability of progression Sorafenib Median: 24.0 weeks (5.5 mo) (95% CI: 18.0, 30.0) Placebo Median: 12.3 weeks (2.8 mo) (95% CI: 11.7, 17.1) 0 Hazard ratio (S/P): 0.58 (95% CI: 0.44, 0.74) P= Weeks Patients at risk Sorafenib: 299 Placebo:
21 Phase III SHARP Trial Response assessment (RECIST; Independent review) Time to Symptom Progression (FSHI8-TSP)* Overall response Complete response (CR) Partial response (PR) Sorafenib N= (2.3%) Placebo N= (0.7%) Stable disease (SD) 211 (71%) 204 (67%) Progressive disease (PD) 54 (18%) 73 (24%) Progression-free rate at 4 mo Duration of treatment (median; weeks) 62% 23 42% 19 * FSHI8-TSP: No significant differences between treatment groups (P=0.77)
22 Safety events Sorafenib Placebo n=297 n=302 Treatment-emergent serious adverse events (SAE,%) 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 0/- 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 0/- 2 0/- Liver dysfunction <1 <1/- 0 0/- Bleeding 7 <1/- 4 <1/<1
23 Sorafenib AEs: Cutaneous rash (face or body) Patchy and Itchy maculopapular rash, Moisturizing creams, Antidandruff shampoo, non-hot showers Non-tight, cotton clothes. Avoid intense sun exposure Antihystaminics if pruritus Stop treatment for 7 days. Restart at half dose for 1 month. Increase therafter? Severe skin reaction: Stop treatment.
24 Sorafenib AEs: Hand-foot syndrome Grade 1: Numbness, dysestesia Burning/prickling feeling Tingling, Swelling Redness of hands or feet Grade 2: Painful redness/swelling Skin thickening Grade 3: Scalind/shedding of skin Open sores Blistering Severe pain Major discomfort
25 Sorafenib AEs: Hand-foot syndrome Recommendations - Cotton socks - Soft shoes - Pedicure care at baseline - Urea containing cream on feet - Sunburn relief spray/cream Grade 1: support. No dose reduction Grade 2: reduce dose to 50% If solved, maintain for 30 days. If not solved, stop treat. 7 days. If solved. Restart 50% for 30 days Grade 3: stop treatment for 7 days If solved, restart 50% dose for 30d.
26 Phase III SHARP Trial Conclusions (AASLD Boston 2007) Sorafenib prolonged overall survival vs placebo in advanced HCC Median OS 46 weeks vs 34 weeks HR 0.69, P= % increase in overall survival Sorafenib prolonged time to progression vs placebo Median TTP 24 weeks vs 12 weeks HR 0.58, P= % prolongation in time to progression Sorafenib was well-tolerated with manageable side effects
27 Phase III SHARP Trial Conclusions (AASLD Boston 2007) Sorafenib is the first systemic therapy to prolong survival in HCC patients Sorafenib is the new reference standard for systemic therapy of HCC patients
28 BCLC Staging and Treatment Strategy HCC Stage 0 PST 0, Child-Pugh A Stage A - C PST 0-2, Child-Pugh A-B Stage D PST >2, Child-Pugh C Very early stage (0) Early stage ( A) Single< 2cm. Single or 3 nodules < 3cm, PS 0 Intermediate stage ( B) Multinodular, PS 0 Advanced stage (C) Portal invasion, N1,M1, PS 1-2 Terminal stage (D) Single Portal pressure/ bilirubin Increased 3 nodules <3cm Associated diseases Portal invasion, N1,M1 Normal No Yes No Yes Resection Liver Transplantation (CLT / LDLT) PEI/RF Chemoembolization Sorafenib Curative Treatments (30%) 50% - 75% at 5 years Non-curative treatments (50%) 3 year survival 10-40% Sympt. Treat. (20%) Sem Liv Dis 1999 to Hepatology 2005
29 Caveats!
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31
32 Bilan coût/efficacité 23 semaines de traitement = 5.1 mois 3 mois d amélioration de la survie 6000 CHF/mois = CHF = CHF/an de vie gagné (0.5 QALY?) Estimation CHF/QALY Comparatif: TH CHC: CHF/QALY
33 Coûts-per-QALY TH à 3 ans (cholangite sclérosante) 50k/QALY
34 Cost-per-QALY TH à 3 ans (cholangite sclérosante) 50k/QALY Coloscopie femme >50 Vaccination grippe Personnes âgées
35 Cost-per-QALY Palliation CHC Sorafenib TH à 3 ans (cholangite sclérosante) 50k/QALY Coloscopie femme >50 Vaccination grippe Personnes âgées
36 Conclusion Journées HGEC Genève 2007 Médicament efficace: Progrès MAJEUR Rôle encore à définir: Stade avancé Child A Traitement palliatif efficace sur la survie... Attention à la progression des symptômes Donnés supplémentaires requises
37 Comment avancer? 1. Sélection des bons répondeurs 2. Études 3. En clinique
38 Sélection des répondeurs Immunohistochimie pour ERK phosphorylé Abou-Alfa et al. JCO 2006
39 Patients sans progression sous sorafenib Abou-Alfa et al. JCO 2006
40 Etudes SAK/SASL 25 (sunitinib) chez les patients avec CHC avancés (dose-réponse) Ouvert en Suisse (Genève en attente amendements pour CE) Pas de frais de médicament Suivi optimal
41 En Clinique? Consultations structurées Evaluation clinique + AFP tous les mois US tous les 3 mois CT/RMN tous les 6 mois Dépistage et soutien des de non répondeurs pour arrêter (passer à autre chose?) quand il le faut.
42 Phase III SHARP Trial Exploratory subgroup survival analysis Sorafenib benefit Placebo benefit ECOG PS 0 ECOG PS 1 & 2 No extrahepatic spread Extrahepatic spread No macroscopic vascular invasion Macroscopic vascular invasion No macroscopic VI/extrahepatic spread Macroscopic VI and/or extrahepatic spread Hazard Ratio (95%CI)
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