Costo-efficacia della terapia con Costo-efficacia della terapia con Sorafenib nel trattamento dell’HCCSorafenib nel trattamento dell’HCC

Prof. C. CammàProf. C. CammàUniversità degli studi di PalermoUniversità degli studi di Palermo

Mega-RCTMA Clinical

practice

Affordability

BCLC Staging and Treatment ScheduleBCLC Staging and Treatment Schedule

HCC

Stage 0 PST 0, Child-Pugh A

Stage A-C Okuda 1-2, PST 0-2, Child-Pugh A-

B

Stage D Okuda 3, PST>2, Child-Pugh

C

Early stage (A) Single or 3 nodules

< 3 cm, PS 0

Intermediate stage (B) Multinodular, Ps 0

Advanced stage (C)Portal invasion,N1, M1, PS 1-2

Terminalstage (D)

Very early stage (O) Single < 2 cm

Carcinoma in situ

Single 3 modules 3 cm

Portalpressure/bilirubin

Normal No Yes

AssociateddiseasesIncreased

Resection Liver Transplantation(CLT/LDLT) PEI/RF Chemoembolization Sorafenib

Curative Treatments (30%)5-yr survival: 50-70%

Randomized controlled trials (50%)3 yr survival: 20-40%

Symptomatic ttc (20%)1 yr survival: 10-20%

Portalinvasion, N1, M1

ttc: treatmentLlovet JM et al. J Natl Cancer Inst 2008

Multicenter, double blind, placebo-controlled trial

conducted at 121 centers in 21 countries in

Europe, North America, South America, and

Australasia

Phase III SHARP Trial: Phase III SHARP Trial: SHARP trial designSHARP trial design

•Multicenter, double blind, placebo-controlled trial conducted at•121 centers in 21 countries in Europe, North America, South America, and Australasia

Primary endpoints

OS

TTSP

Secondary endpoints

TTP

DCR

Safety*

• Nexavar®

400 mg b.i.d.

•Placebo

Eligibility criteria Advanced HCC

Child–Pugh A status

ECOG PS 0–2

No prior systemictherapy

Stratification Region

ECOG PS(0 vs 1–2)

MVI/EHS(present/absent)

• Ran

dom

izat

ion

(1:1

)(n

=60

2)

•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

N=299N=299

N=303N=303

Llovet JM, et al. N Engl J Med. 2008;359:378-390.

The SHARP Trial: Overall SurvivalThe SHARP Trial: Overall Survival

Months Since Randomization

Pro

bab

ility

of

Su

rviv

al

0

0.25

0.50

0.75

1.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

SorafenibMedian: 10.7 months (95% CI: 9.4-13.3)

SorafenibMedian: 10.7 months (95% CI: 9.4-13.3)

PlaceboMedian: 7.9 months (95% CI: 6.8-9.1)

PlaceboMedian: 7.9 months (95% CI: 6.8-9.1)

HR (S/P): 0.69 (95% CI: 0.55-0.87)P < .001

HR (S/P): 0.69 (95% CI: 0.55-0.87)P < .001

THE CASE OF HEPATOCELLULAR CARCINOMATHE CASE OF HEPATOCELLULAR CARCINOMA

Marcata eterogeneità

1) Biologica

2) Epidemiologica

3) Diagnostica

4) Clinica

Cabibbo et al. Hepatology 2010

Range 0 – 75% Range 0 – 50%Range 0 – 75% Range 0 – 50%

p for heterogeneity < 0.0001

Untreated control groups of 30 RCTs Untreated control groups of 30 RCTs Untreated control groups of 30 RCTs Untreated control groups of 30 RCTs

17.5%17.5% 7.3%7.3%

• 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).

Safety

1. Ioannidis JPA, Lau J. JAMA 2001

2. Moore TJ & al. JAMA 1998

RCTs 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 view results of RCTs stopped early for benefit with skepticism.

143 RCTs stopped early for benefit

Field-practice study of sorafenib therapy for

hepatocellular carcinoma:

a prospective multicenter study in Italy.

Hepatology 2011.

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.

PATIENTS AND METHODS

Study Multicenter, prospective, observational study

Centers Milan Policlinico, Palermo, Bologna, Milan

Niguarda, Rome, Modena

Patients Consecutive patients with BCLC-C or BCLC-

B with PD/unsuitable to locoregional therapy

Enrollment July 2008 – July 2010

Treatment Sorafenib 400 mg twice daily

Inclusion - compensated cirrhosis

- ECOG 0-2

PATIENTS AND METHODS

Management of HCC AASLD guidelines, 2005

Dose reduction 400 mg once daily

AE (grade 3/clinical

judgement)

Discontinuation Radiological or clinical

progression

SAE

DEMOGRAPHY

BCLC-C BCLC-B Overall

Patients 226 (76%) 70 (24%) 296

Age, yr* 6610 6910 6710

Male 185 (82%) 57 (81%) 242 (82%)

HCV/HBV/alcohol abuse/other 118/45/21/42 34/13/10/13 152/58/31/55

ECOG 0/1/2 89/126/11 70/0/0 159/126/11

Child-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

EFFECTIVENESS

1-yr survival rate 49%

Early radiological response (month 2)*

Complete

Partial

Stable

Progressive disease

2 (1%)

22 (7%)

217 (73%)

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)

Overall survival of patients treated with Overall survival of patients treated with sorafenibsorafenib

(from RCTs to clinical practice)(from RCTs to clinical practice)

Median Survival (n= 296): 10.5 mo

°Llovet JM, et al. N Engl J Med. 2008. § Iavarone, Cabibbo et al. Hepatology 2011.

Sorafenib Arm

Median Survival (n= 299): 10.7 mo

SHARP trial ° SOFIA study §

1-year survival: 44% 1-year survival: 49%

Months

0 4 8 12 160

0.25

0.50

0.75

1.00

Pro

bab

ility

of

Sur

viva

l

BCLC B (n= 54; 18%) Median: 14.5 mo

BCLC C (n= 245; 82%) Median: 9.7 mo

SHARP trial °* SOFIA study §

P =ns

BCLC B (n= 74; 25%) Median: 20.6 mo

BCLC C (n= 222; 75%) Median: 8.4 mo

Overall survival of patients treated with Overall survival of patients treated with sorafenibsorafenib

according to BCLCaccording to BCLC

°Llovet JM, et al. N Engl J Med. 2008;

° Bruix J, et al. J Hep 2009; S28. § Iavarone, Cabibbo et al. Hepatology 2011.

B

C

SHARP

SHARP

SOFIA

Liver dysfunction < 1% Liver function deteriorated 15%(≥ 2 points of Child-Pugh score)

Treatment compliance of patients Treatment compliance of patients treated with sorafenibtreated with sorafenib

(from RCTs to clinical practice)(from RCTs to clinical practice)

SHARP trial ° SOFIA study §

°Llovet JM, et al. N Engl J Med. 2008. § Iavarone, Cabibbo et al. Hepatology 2011.

Discontinuation due to AEs

38%

Dose reductions due to AEs

26%

Dose interruptions due to AEs

44%

vs.

Discontinuation due to AEs

45%

Dose reductions due to AEs

54%

Dose interruptions due to AEs56%

Ma la riduzione di dose nel corso del trattamento, Ma la riduzione di dose nel corso del trattamento,

inficia l’efficacia della terapia?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 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.

§ Iavarone, Cabibbo et al. Hepatology 2011.

Survival according to sorafenib dose reductionSurvival according to sorafenib dose reduction((Post-hoc analysisPost-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)

Predictors of mortality in 296 HCC patients Predictors of mortality in 296 HCC patients treated with sorafenibtreated with sorafenib

Multivariate analysis

Predictor HR (95% CI) P-value

ECOG 1.9 (1.5 – 2.5) <.0001

Vascular invasion 1.9 (1.4 – 2.6) 0.0009

Full dose 1.8 (1.4 – 2.4 ) 0.001

Extrahepatic spread 1.4 (1.1 – 1.9) 0.01

Early radiological progression 1.4 (1.1 – 2.1) 0.02

Total bilirubin – mg/dl - -

Platelet x 103/mmc - -

Age - -

Albumin – g/dl - -

§ Iavarone, Cabibbo et al. Hepatology 2011.

“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

OS

pro

bab

ility

(%

)

0 5 10 150.0

20 25 30 35 40

SunitinibMedian 7.9 months (95% CI: 7.4-9.2)

SunitinibMedian 7.9 months (95% CI: 7.4-9.2)

SorafenibMedian 10.2 months (95% CI: 8.9-11.4)

SorafenibMedian 10.2 months (95% CI: 8.9-11.4)

1.00

0.75

0.50

0.25

HR 1.30 (95% CI: 1.13-1.50)P=.0010

HR 1.30 (95% CI: 1.13-1.50)P=.0010

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, senza

nessun interesse per alcun valore aggiunto, non pone

alcuna domanda clinicamente rilevante.

Inoltre, a meno che non sia già nota una maggiore

tollerabilità del nuovo farmaco, comporta

inevitabilmente un inaccettabile eccesso di eventi

avversi nella popolazione dei pazienti.

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

Kaplan-Meier curves: stair-step line

Estimated curves: smooth line

Survival curves of BCLC B patients treated with full dose or dose-adjusted sorafenib

Kaplan-Meier curves: stair-step line

Estimated curves: smooth line

Survival curves of BCLC C patients treated with full dose or dose-adjusted sorafenib

General structure of the Markov model

Treatment Strategies according BCLC and dose

Costs in 2012euros

QALY ICER/QALYbase-case analysis

(2012 euros)Full dose for BCLC B and C 16,081 0.16 69,344

Dose-adjusted for BCLC B and C 19,944 0.44 34,534

Full dose for BCLC B 24,224 0.32 57,385

Dose-adjusted for BCLC B 26,914 0.38 54,881

Full dose for BCLC C 14,841 0.16 65,551

Dose-adjusted for BCLC C 16,625 0.44 27,916

Results of cost-effectiveness analyses

Results of cost-effectiveness analyses

BCLC B

One-Way Sensitivity Analysis for dose-adjusted sorafenib in BCLC C

HCC patients

One-Way Sensitivity Analysis for dose-adjusted sorafenib in BCLC B

HCC patients

Probabilistic Sensitivity Analysis by Montecarlo Simulation for dose-adjusted

sorafenib strategies

CONFRONTO CON ALTRI INTERVENTI

ICER = 10.000 € triplice terapia HCV

ICER = 60.000 € erlotinib Ca pancreas

ICER = 100.000 € epo nei dializzati

ICER = 15.000 € trapianto di cuore

ICER = 74.000 € sorafenib HCC

ICER/LYG

Cost/Risk/Benefit

400 mg/die

800 mg/die

ICER < 30.000 euro/LYG

Cammà, Hepatology, accepted

EBM ha implementato l’uso delle “evidenze” dalla ricerca clinica come 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.

CONCLUSIONI

Farmaci innovativi:previsioni di spesa

10.000 pts200 mln

100-150 mln

120-150 mln

125 milioni euro

Farmaci innovativi:previsioni di spesa

Ciascun individuo è un esperimento biologico inripetibile, ……………..

nella storia dell’umanità.

Giovanni Paolo II