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Costo-efficacia della terapia conSorafenib nel trattamento dell’HCC                Prof. C. Cammà        Università degli ...
Mega-RCT           ClinicalMA           practice                      Affordability
BCLC Staging and Treatment Schedule                                                                HCC                    ...
Multicenter, double blind, placebo-controlled trial   conducted at 121 centers in 21 countries in  Europe, North America, ...
Phase III SHARP Trial:                                      SHARP trial design •Multicenter, double blind, placebo-control...
The SHARP Trial: Overall Survival                                1.00                                                     ...
THE CASE OF HEPATOCELLULAR CARCINOMA                 1) Biologica  Marcata        2) Epidemiologicaeterogeneità           ...
Untreated control groups of 30 RCTs                 p for heterogeneity < 0.0001       7.3%    17.5%Range 0 – 75%         ...
Safety•   The quality and quantity of safety reporting in    randomized trials are largely inadequate (1);•   RCTs often f...
143 RCTs stopped early for benefitRCTs can overestimate the magnitude of the treatment effect depending on the timing (ie,...
Field-practice study of sorafenib therapy for           hepatocellular carcinoma:  a prospective multicenter study in Ital...
PATIENTS AND METHODSStudy        Multicenter, prospective, observational studyCenters      Milan Policlinico, Palermo, Bol...
PATIENTS AND METHODSManagement of HCC   AASLD guidelines, 2005Dose reduction      400 mg once daily                    AE ...
DEMOGRAPHY                                       BCLC-C             BCLC-B              OverallPatients                   ...
EFFECTIVENESS 1-yr survival rate                                                           49% Early radiological response...
Overall survival of patients treated with                          sorafenib              (from RCTs to clinical practice)...
Overall survival of patients treated with                                                  sorafenib                      ...
SHARP
SOFIA       SHARPLiver dysfunction   < 1%   Liver function deteriorated 15%                           (≥ 2 points of Child...
Treatment compliance of patients                       treated with sorafenib                  (from RCTs to clinical prac...
Ma la riduzione di dose nel corso del trattamento,         inficia l’efficacia della terapia?
-   77 (26%) patients received a half-dose of sorafenib for ≥ 70% of    the treatment period, which lasted a median of 6.8...
Survival according to sorafenib dose reduction             (Post-hoc analysis)                                            ...
Predictors of mortality in 296 HCC patients            treated with sorafenib                                        Multi...
The open-label, Phase III SUN1170 trial compared the efficacy and safety of sunitinib   with that of sorafenib            ...
Ma uno studio pianificato per verificare se un farmaco è«non peggiore» rispetto ai trattamenti standard, senzanessun inter...
Survival curves of BCLC B+C patients treated  with full dose or dose-adjusted sorafenib                   Kaplan-Meier cur...
Survival curves of BCLC B patients treated with full dose or dose-adjusted sorafenib                  Kaplan-Meier curves:...
Survival curves of BCLC C patients treated with full dose or dose-adjusted sorafenib                  Kaplan-Meier curves:...
General structure of the Markov model
Results of cost-effectiveness analysesTreatment Strategies according   Costs in 2012   QALY       ICER/QALYBCLC and dose  ...
Results of cost-effectiveness analyses
One-Way Sensitivity Analysis for  dose-adjusted sorafenib in BCLC C            HCC patientsBCLC B
One-Way Sensitivity Analysis fordose-adjusted sorafenib in BCLC B          HCC patients
Probabilistic Sensitivity Analysis byMontecarlo Simulation for dose-adjusted         sorafenib strategies
CONFRONTO CON ALTRI INTERVENTI              ICER/LYG  ICER = 10.000 € triplice terapia HCV  ICER = 15.000 € trapianto di c...
Cost/Risk/Benefit      400 mg/die                    ICER < 30.000 euro/LYG800 mg/die             Cammà, Hepatology, accep...
CONCLUSIONIEBM ha implementato l’uso delle “evidenze” dalla ricerca clinicacome strumento principale di decision making. T...
Farmaci innovativi:previsioni di spesa          10.000 pts          200 mln       100-150 mln        120-150 mln
Farmaci innovativi:previsioni di spesa           125 milioni euro
Ciascun individuo è un esperimentobiologico inripetibile, ……………..nella storia dell’umanità.                   Giovanni Pao...
Costo efficacia della terapia con sorafenib nel trattamento dell’HCC - Gastrolearning®
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Costo efficacia della terapia con sorafenib nel trattamento dell’HCC - Gastrolearning®

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Costo efficacia della terapia con sorafenib nel trattamento dell’HCC - Prof. C. Cammà (Università di Palermo)
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Costo efficacia della terapia con sorafenib nel trattamento dell’HCC - Gastrolearning®

  1. 1. Costo-efficacia della terapia conSorafenib nel trattamento dell’HCC Prof. C. Cammà Università degli studi di Palermo
  2. 2. Mega-RCT ClinicalMA practice Affordability
  3. 3. BCLC Staging and Treatment Schedule HCC Stage A-C Stage D Stage 0 Okuda 1-2, PST 0-2, Child-Pugh A- Okuda 3, PST>2, Child-Pugh PST 0, Child-Pugh A B C Very early stage (O) Early stage (A) Intermediate stage (B) Advanced stage (C) Terminal Single < 2 cm Single or 3 nodules Multinodular, Ps 0 Portal invasion, stage (D) Carcinoma in situ < 3 cm, PS 0 N1, M1, PS 1-2 Single 3 modules ≤ 3 cm Portal Associated Portal Increasedpressure/bilirubin diseases invasion, N1, M1 Normal No Yes Liver Transplantation Resection PEI/RF Chemoembolization Sorafenib (CLT/LDLT) Curative Treatments (30%) Randomized controlled trials (50%) Symptomatic ttc (20%) 5-yr survival: 50-70% 3 yr survival: 20-40% 1 yr survival: 10-20% ttc: treatmentLlovet JM et al. J Natl Cancer Inst 2008
  4. 4. Multicenter, double blind, placebo-controlled trial conducted at 121 centers in 21 countries in Europe, North America, South America, and Australasia
  5. 5. Phase III SHARP Trial: SHARP trial design •Multicenter, double blind, placebo-controlled trial conducted at •121 centers in 21 countries in Europe, North America, South America, and Australasia Eligibility criteria  Advanced HCC Primary endpoints •Randomization (1:1)  Child–Pugh A status • Nexavar®  ECOG PS 0–2 400 mg b.i.d.  OS  No prior systemic N=299  TTSP (n=602) therapy Secondary endpoints Stratification  TTP  Region •Placebo  DCR  ECOG PS (0 vs 1–2)  Safety* N=303  MVI/EHS (present/absent)•ECOG PS = Eastern Cooperative Oncology Group Performance Status; MVI = macroscopic vascular invasion;EHS = extrahepatic spread; BID = twice daily; OS = overall survival; TTSP = time to symptomatic progression;TTP = time to progression; DCR = disease control rate*Assessed using version 3.0 of the USA National Cancer InstituteCommon Terminology Criteria for Adverse Events•Llovet JM et al. ASCO Annual Meeting 2007; Abstr LBA1/oral presentation available at www.asco.org
  6. 6. The SHARP Trial: Overall Survival 1.00 Sorafenib Median: 10.7 months Probability of Survival (95% CI: 9.4-13.3) 0.75 Placebo Median: 7.9 months (95% CI: 6.8-9.1) 0.50 0.25 HR (S/P): 0.69 (95% CI: 0.55-0.87) P < .001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months Since RandomizationLlovet JM, et al. N Engl J Med. 2008;359:378-390.
  7. 7. THE CASE OF HEPATOCELLULAR CARCINOMA 1) Biologica Marcata 2) Epidemiologicaeterogeneità 3) Diagnostica 4) Clinica
  8. 8. Untreated control groups of 30 RCTs p for heterogeneity < 0.0001 7.3% 17.5%Range 0 – 75% Range 0 – 50% Cabibbo et al. Hepatology 2010
  9. 9. Safety• The quality and quantity of safety reporting in randomized trials are largely inadequate (1);• RCTs often fail to detect infrequent but serious adverse drug reactions (1);• Overall, 50% of approved drugs have serious adverse effects not detected prior to approval (2). 1. Ioannidis JPA, Lau J. JAMA 2001 2. Moore TJ & al. JAMA 1998
  10. 10. 143 RCTs stopped early for benefitRCTs can overestimate the magnitude of the treatment effect depending on the timing (ie, expected number of events) of the decision to stop.Lack of adequate safety data may in turn affect the perceived and actual risk-benefit ratios (overestimating the benefit,underestimating the risk) of implementing the intervention in clinical practice.These considerations suggest that clinicians should viewresults of RCTs stopped early for benefit with skepticism.
  11. 11. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Iavarone M, Cabibbo G, Piscaglia F, Zavaglia C, Grieco A, Villa E, Cammà C, Colombo M; on behalf of the SOFIA (SOraFenib Italian Assessment) study group. Hepatology 2011.
  12. 12. PATIENTS AND METHODSStudy Multicenter, prospective, observational studyCenters Milan Policlinico, Palermo, Bologna, Milan Niguarda, Rome, ModenaPatients Consecutive patients with BCLC-C or BCLC- B with PD/unsuitable to locoregional therapyEnrollment July 2008 – July 2010Treatment Sorafenib 400 mg twice dailyInclusion - compensated cirrhosis - ECOG 0-2
  13. 13. PATIENTS AND METHODSManagement of HCC AASLD guidelines, 2005Dose reduction 400 mg once daily AE (grade 3/clinical judgement)Discontinuation Radiological or clinical progression SAE
  14. 14. DEMOGRAPHY BCLC-C BCLC-B OverallPatients 226 (76%) 70 (24%) 296Age, yr* 66±10 69±10 67±10Male 185 (82%) 57 (81%) 242 (82%)HCV/HBV/alcohol abuse/other 118/45/21/42 34/13/10/13 152/58/31/55ECOG 0/1/2 89/126/11 70/0/0 159/126/11Child-Pugh A 196 (87%) 63 (90%) 259 (88%)Macroscopic vascular invasion 115 (51%) NA 115 (39%)Extrahepatic spread 104 (46%) NA 104 (35%)*mean±SD, §upper gastrointestinal endoscopy was performed in 256 patients
  15. 15. EFFECTIVENESS 1-yr survival rate 49% Early radiological response (month 2)* Complete 2 (1%) Partial 22 (7%) Stable 217 (73%) Progressive disease 55 (19%) Time to radiological progression, months 9.2 (5.5-12.9)*according to modified RECIST criteria (Llovet JM et al. J Natl Cancer Inst 2008;100:698-711)
  16. 16. Overall survival of patients treated with sorafenib (from RCTs to clinical practice) SHARP trial ° SOFIA study § 1-year survival: 44% 1-year survival: 49% Sorafenib Arm Median Survival (n= 299): 10.7 mo Median Survival (n= 296): 10.5 mo°Llovet JM, et al. N Engl J Med. 2008. § Iavarone, Cabibbo et al. Hepatology 2011.
  17. 17. Overall survival of patients treated with sorafenib according to BCLC SHARP trial °* SOFIA study § 1.00 Probability of Survival P =ns 0.75 B 0.50 0.25 C 0 0 4 8 12 16 MonthsBCLC B (n= 54; 18%) Median: 14.5 mo BCLC B (n= 74; 25%) Median: 20.6 moBCLC C (n= 245; 82%) Median: 9.7 mo BCLC C (n= 222; 75%) Median: 8.4 mo °Llovet JM, et al. N Engl J Med. 2008; § Iavarone, Cabibbo et al. Hepatology 2011. ° Bruix J, et al. J Hep 2009; S28.
  18. 18. SHARP
  19. 19. SOFIA SHARPLiver dysfunction < 1% Liver function deteriorated 15% (≥ 2 points of Child-Pugh score)
  20. 20. Treatment compliance of patients treated with sorafenib (from RCTs to clinical practice) SHARP trial ° SOFIA study § Discontinuation due to AEs Discontinuation due to AEs 38% 45% vs. Dose reductions due to AEs Dose reductions due to AEs 26% 54%Dose interruptions due to AEs Dose interruptions due to AEs 44% 56%°Llovet JM, et al. N Engl J Med. 2008. § Iavarone, Cabibbo et al. Hepatology 2011.
  21. 21. Ma la riduzione di dose nel corso del trattamento, inficia l’efficacia della terapia?
  22. 22. - 77 (26%) patients received a half-dose of sorafenib for ≥ 70% of the treatment period, which lasted a median of 6.8 months (95% CI 4.2-9.4).- Among the remaining 219 patients (74%),136 maintained a full dose of sorafenib for a median of 3 months (95% CI 2.2-3.8), whereas 83 received a half-dose for <70% of the whole treatment period of 3 months.
  23. 23. Survival according to sorafenib dose reduction (Post-hoc analysis) --- Full dose No. = 219 --- Half-dose No. = 77 P = 0.0006 Median 21.6 months (95% CI 13.6-29.6) vs 9.6 months (95% CI 6.9-12.3) § Iavarone, Cabibbo et al. Hepatology 2011.
  24. 24. Predictors of mortality in 296 HCC patients treated with sorafenib Multivariate analysisPredictor HR (95% CI) P-valueECOG 1.9 (1.5 – 2.5) <.0001Vascular invasion 1.9 (1.4 – 2.6) 0.0009Full dose 1.8 (1.4 – 2.4 ) 0.001Extrahepatic spread 1.4 (1.1 – 1.9) 0.01Early radiological progression 1.4 (1.1 – 2.1) 0.02Total bilirubin – mg/dl - -Platelet x 103/mmc - -Age - -Albumin – g/dl - - § Iavarone, Cabibbo et al. Hepatology 2011.
  25. 25. The open-label, Phase III SUN1170 trial compared the efficacy and safety of sunitinib with that of sorafenib Sunitinib 1.00 Median 7.9 months (95% CI: 7.4-9.2) Sorafenib Median 10.2 months (95% CI: 8.9-11.4) OS probability (%) 0.75 HR 1.30 (95% CI: 1.13-1.50) P=.0010 0.50 0.25 0.0 0 5 10 15 20 25 30 35 40 “The SUN 1170 trial was stopped early because of a higher incidence of serious adverse events in the sunitinib arm, and because sunitinib did not demonstrate superiority or non- inferiority to sorafenib.” Zhu A, et al. NATURE REVIEWS | CLINICAL ONCOLOGY 2011
  26. 26. Ma uno studio pianificato per verificare se un farmaco è«non peggiore» rispetto ai trattamenti standard, senzanessun interesse per alcun valore aggiunto, non ponealcuna domanda clinicamente rilevante.Inoltre, a meno che non sia già nota una maggioretollerabilità del nuovo farmaco, comportainevitabilmente un inaccettabile eccesso di eventiavversi nella popolazione dei pazienti.
  27. 27. Survival curves of BCLC B+C patients treated with full dose or dose-adjusted sorafenib Kaplan-Meier curves: stair-step line Estimated curves: smooth line
  28. 28. Survival curves of BCLC B patients treated with full dose or dose-adjusted sorafenib Kaplan-Meier curves: stair-step line Estimated curves: smooth line
  29. 29. Survival curves of BCLC C patients treated with full dose or dose-adjusted sorafenib Kaplan-Meier curves: stair-step line Estimated curves: smooth line
  30. 30. General structure of the Markov model
  31. 31. Results of cost-effectiveness analysesTreatment Strategies according Costs in 2012 QALY ICER/QALYBCLC and dose euros base-case analysis (2012 euros)Full dose for BCLC B and C 16,081 0.16 69,344Dose-adjusted for BCLC B and C 19,944 0.44 34,534Full dose for BCLC B 24,224 0.32 57,385Dose-adjusted for BCLC B 26,914 0.38 54,881Full dose for BCLC C 14,841 0.16 65,551Dose-adjusted for BCLC C 16,625 0.44 27,916
  32. 32. Results of cost-effectiveness analyses
  33. 33. One-Way Sensitivity Analysis for dose-adjusted sorafenib in BCLC C HCC patientsBCLC B
  34. 34. One-Way Sensitivity Analysis fordose-adjusted sorafenib in BCLC B HCC patients
  35. 35. Probabilistic Sensitivity Analysis byMontecarlo Simulation for dose-adjusted sorafenib strategies
  36. 36. CONFRONTO CON ALTRI INTERVENTI ICER/LYG ICER = 10.000 € triplice terapia HCV ICER = 15.000 € trapianto di cuore ICER = 60.000 € erlotinib Ca pancreas ICER = 74.000 € sorafenib HCC ICER = 100.000 € epo nei dializzati
  37. 37. Cost/Risk/Benefit 400 mg/die ICER < 30.000 euro/LYG800 mg/die Cammà, Hepatology, accepted
  38. 38. CONCLUSIONIEBM ha implementato l’uso delle “evidenze” dalla ricerca clinicacome strumento principale di decision making. Tuttavia, i problemi maggiori degli RCTs sono: • i risultati favorevoli ottenuti attraverso disegno, conduzione ed analisi inadeguati; • l’eccessiva fiducia nel risultato “medio” nonostante la verosimile eterogeneità tra pazienti; • la sottovalutazione di sicurezza e tollerabilità; • la validità esterna insufficiente; • l’influenza pervasiva dell’industria.
  39. 39. Farmaci innovativi:previsioni di spesa 10.000 pts 200 mln 100-150 mln 120-150 mln
  40. 40. Farmaci innovativi:previsioni di spesa 125 milioni euro
  41. 41. Ciascun individuo è un esperimentobiologico inripetibile, ……………..nella storia dell’umanità. Giovanni Paolo II

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