Evaluación de fármacos en oncología De oncólogos para ... · cancer de mama Zoledronic acid 4...

Evaluación de fármacos en oncología

De oncólogos para farmacéuticos

Miguel Martin

Instituto de Investigación Sanitaria Gregorio Marañón

Universidad Complutense

Madrid

•Criterios de eficacia

•Generalización de resultados

•Valor de las Guias Clínicas

•El problema del coste de los fármacos

•Papel de la Academia en la generación de evidencia

práctica

Del ensayo clínico a la práctica real:

problemas de interpretación

práctica

Trasladando los avances científicos a la

práctica diaria

Práctica clínica

Avances en

investigación

básica

Ensayos

clínicos Diseño de

nuevos

fármacos

Criterios de eficacia de los

medicamentos oncológicos

TRATAMIENTO

Prevención

de complicaciones Alivio de

síntomas

Aumento de

Supervivencia

Mejoría de la

Calidad de vida

Aumento del tiempo

de control de la

enfermedad (THP)

Objetivos del tratamiento del cáncer

Jerarquía de objetivos terapéuticos en

cáncer

AUMENTO DE SUPERVIVENCIA

AUMENTO DE THP

TASA DE RESPUESTA TUMORAL

AUMENTO DE CALIDAD DE VIDA

REDUCCION DE COMPLICACIONES

MEJORIA DE LOS SINTOMAS

Gianni L et al Lancet Oncol 12:236, 2011

Sorensen S et al, Intl. J. Techn. Assess. Health Care 28:12, 2012

cáncer

AUMENTO DE THP

Fizari K et al, Lancet Oncol, online 2012 http://dx.doi.org/10.1016/S1470-2045(12)70379-0

Ipilimumab Conveys Long-Term Survival in Pooled

Analysis of Metastatic Melanoma Patients

http://www.ascopost.com/issues/november-15,-2013/ipilimumab-conveys-long-term-survival-in-pooled-analysis-of-metastatic-melanoma-

patients.aspx

cáncer

AUMENTO DE THP

Optional

second-line chemotherapy +

bevacizumab (AVADO and

RIBBON-1 only)

Chemotherapy +

bevacizumab

Treat until PD

Previously untreated

RIBBON-1 Capecitabine,

taxane, or

anthracycline

AVADO Docetaxel

E2100 Paclitaxel

Chemotherapy + no

bevacizumab

O’Shaughnessy J et al, SABCS 2010

Meta-Analysis of Bevacizumab trials in MBC

Meta-Analysis of Bevacizumab trials in MBC: PFS

Non-BV

(n=1008)

(n=1439)

Median, mo 6.7 9.2

HR (95% CI) 0.64 (0.57–0.71)

Standard first-line

treatment

Second, third and successive

lines of chemotherapy

Months from the start of first-line therapy

1/3 2/3

Disease progression Death

Chronology of MBC

Chronology of MBC:

randomized trials without cross-over

Standard first-line

treatment

Disease progression

Experimental first-line

treatment

Chronology of MBC:

Standard first-line

treatment

Disease progression

treatment

SAMPLE SIZE FOR PFS

n=300–1,000 patients

Chronology of MBC:

Standard first-line

treatment

Disease progression

treatment

SAMPLE SIZE FOR PFS

n=300–1,000 patients

SAMPLE SIZE FOR OS

n=3,000–5,000 patients

Broglio, Berry. JNCI 2009 PPS = post-progression survival

The chance of obtaining a significant OS improvement depends on

the length of time that patients live after progression (PPS)

If PPS is longer than 12 months, there is a less than 30% chance

that a trial will report a significant OS, even after reporting 9 months

PFS improvement at a high level of significance (p<0.001)

The influence of PPS means that a lack of statistical significance in

OS does not imply lack of improvement in OS

“OS is a reasonable primary endpoint when median PPS is short,

but is too high a bar when median PPS is longer than 12 months”

Significant OS improvements are more difficult

to measure as patients survive longer after

progression

Patients with heavily

pretreated advanced

breast cancer (N = 762)

Eribulin Mesylate

1.4 mg/m2 2-5 min IV on Days 1, 8

(n = 508)

Treatment of Physician’s Choice (TPC)

Any monotherapy approved for cancer treatment

(chemotherapeutic, hormonal, or biological),*

or supportive care only†

(n = 254)

•Stratified by geographic region,

previous capecitabine treatment,

HER2/neu status

•Randomized 2:1

*FDA approved for the treatment of cancer. †Palliative treatment or radiotherapy according to local practice.

96% of patients in TPC arm received chemotherapy

Cortes J et al. Lancet Oncol 377:914, 2011

Overall survival (months)

0 28 26 24 22 20 18 16 14 12 10 8 6 4 2

EMBRACE: Overall survival

Eribulin

Median 13.12 months

Median 10.65 months

HR* 0.81 (95% CI 0.66, 0.99)

p value†=0.041

2.47 months

Cortes J et al, Lancet Oncol 377: 914, 2011

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.

Unstratified HR=0.521 (P<0.0001).

198 120 62 28 13 6 1 0

404 334 241 114 66 27 12 0

No. at risk: Time (months)

14 12 10 8 6 4 2

(n=198)

(n=404)

Median (months) 3.3 6.2

No. of events 129 219

Stratified HR=0.528 (95% CI, 0.422, 0.661)

P<0.0001

TH3RESA: PFS

TH3RESA: OS

No. at risk:

Time (months)

44 patients in the TPC arm received crossover T-DM1 treatment after documented progression.

Unstratified HR=0.57 (P=0.004).

16 12 10 8 6 4 2

Observed 21% of targeted events

(n=198)

(n=404)

Median (months) 14.9 NE

No. of events 44 61

Stratified HR=0.552 (95% CI, 0.369, 0.826); P=0.0034

Efficacy stopping boundary HR<0.363 or P<0.0000013

Meta-Analysis of Bevacizumab trials in MBC: OS

Non-BV

(n=1008)

(n=1439)

Median, mo 26.4 26.7

HR (95% CI) 0.97 (0.86–1.08)

PFS as main endpoint

•The value of PFS as main endpoint for drug approval in

MBC is under debate

•Prolonging disease control could be good enough by itself

•An increase in PFS is usually translated into an increase on

OS, although of inferior magnitude

•Demonstrating an OS advantage in first-line is difficult,

except for very effective drugs

•If we require an OS benefit for approval, we can miss drugs

of moderate efficacy in MBC

Beluga S et al, Annals of Oncology 23: 2977–2982, 2012

cáncer

AUMENTO DE THP

Progression-based endpoints are dominant

in randomized MBC trials

Progression-based primary endpoints are now used much more

frequently in mBC randomized trials (62%) than OS (2%)

The use of OS as a primary endpoint in breast cancer clinical trials

is uncommon

Saad, et al. Ann Oncol 2009

36 of 58 randomized trials in leading journals used progression-based

primary endpoints

PFS/TTP/TTF

Palliative effect of chemotherapy: objective

tumor response is associated with symptom

improvement

Geels et al, JCO 18:2395, 2000

Pain Mood

CR/PR SD PD

Proportion of patients with symptom response

according to response to chemotherapy

SOB Depression

Fármacos antitumorales aprobados en

base a estudios fase II

Paclitaxel (década de los 90):

• cáncer de ovario (refractario a

cisplatino)

• cáncer de mama refractario a

antraciclinas

Capecitabina (2000):

• cáncer colorectal

• cáncer de mama refractario a

taxanos y antraciclinas

cáncer

AUMENTO DE THP

Círculo vicioso de la destrucción ósea

resorption

Osteoclast

Cancer cells in bone

Growth factors

(TGF-β, IGFs, FGFs,

PDGFs, BMPs)

Cytokines and growth factors (IL-

6, IL-8, IL-1β, PGE-2,

TNFα, CSF-1, PTHrP) R

Direct effects

on tumor?

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

1.McClung MR et al. New Engl J Med 2006;354:821–31;

2. Prolia® (Denosumab) Summary of product characteristics, Amgen.

Anticuerpo monoclonal humanizado dirigido contra el ligando

de RANK, de gran afinidad y especificidad specificity1

Denosumab

Consecuencias de las metástasis óseas

METASTASIS

HIPERCALCEMIA

COMPRESION

MEDULAR

FRACTURAS

PERDIDA DE

ATONOMIA

INCREMENTO DE

SANITARIO

REDUCCION DE

SUPERVIVENCIA

CIRUGIA

RADIOTERAPIA

Denosumab frente a acido zoledronico en

cancer de mama

Zoledronic acid 4 mg IV

(N = 1020)

Denosumab 120 mg SC

(N = 1026)

Supplemento de calcio y vitamina D

Criterios de inclusión

Adultos con cáncer de

mama y metástasis óseas

Criteripos de exclusión

Previos bifosfonatos

Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation.

Denosumab frente a ácido zoledrónico

en cáncer de mama

Martin M et al, Clinical Cancer Research, 18:4841-4849, 2012.

Denosumab frente a ácido zoledrónico en

cáncer de mama

Martin M et al, Clinical Cancer Research, 18:4841-4849, 2012.

práctica

Eficacia frente a eficiencia

•relative efficacy can be defined as the extent to which an

intervention does more good than harm, under ideal

circumstances, compared to one or more alternative

interventions

•relative effectiveness can be defined as the extent to

which an intervention does more good than harm

compared to one or more alternatives for achieving the

desired results when provided under the usual

circumstances of health care practice

Efficacy vs effectiveness: definitions of

the EFPIA

EUROPEAN FEDERATION OF PHARMACEUTICAL INDUSTRIES AND ASSOCIATIONS, 2010

From clinical trials to clinical practice:

Generalization

Clinical

trials

practice

From clinical trials to clinical practice:

Generalization

Clinical trials Daily practice

Incertidumbres en la aplicación práctica de

los resultados de los EECC

La mayoría de los EECC actuales son promovidos por la industria, con

registro de fármaco como objetivo final

El diseño de los estudios se adapta esencialmente a este objetivo

En publicaciones, la eficacia es a menudo sobre-enfatizada y la toxicidad

minimizada

Los pacientes son seleccionados en base a criterios de buen pronóstico y

no representan necesariamente a la población general

Los estudios se centran en un nicho terapéutico (por ejemplo, enfermos

refractarios a una terapia estándar) en lugar de analizar el manejo global

de la enfermedad

Clin Pharmacol & Ther 87: 398, 2010

Niraula S et al, J Clin Oncol 30:3012,2012

Uncertainty in medical

treatment of cancer

Mullins CD, et al, The Oncologist 15(suppl 1):58, 2010

Significant evidentiary uncertainty to establish the

greatest level of benefit possible at a given level of cost

Significant gaps in real-world evidence exist

“Pragmatic” trials should be encouraged

•Valor de las Guías Clínicas

práctica

Value of clinical guidelines

NCCN Guidelines are widely recognized and used

as a standard reference for clinical policy in

oncology by clinicans and payors

Categories of evidence and consensus:

Category 1: Based upon high-level evidence, there is uniform NCCN

consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform

NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN

consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN

disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

NCCN GUIDELINES

Poonacha T K , Go R S JCO 2011;29:186-191

•In 2005 the NCCN estimated that 50% to 75% of drugs

used to treat cancer in the United States was off label

•The supporting evidence base for efficacy or superiority to

other drugs may be limited or nonexistent, and patients are

exposed to potential risks without the associated safeguards

•The accrual to legitimate clinical trials may be undermined

•The cost of unproven use of off label drugs is of concern

Off-label use of oncology drugs: the need

for more data and then some

Pfister DG, JCO 30:584-596, 2012

The problem of off-label uses of drugs should be urgently

addressed and solved positively

Regulatory bodies (EMA) should take some responsibility on the

off-label issue

Pragmatically, lists of drugs with acceptable indications should be

worked out and in the European Union (EU) this might follow the

principle underlying the centralized procedure for approval of new

New regulatory mechanisms should be searched, by which uses of

drugs could be expanded even beyond the initiative of

pharmaceutical companies

The off-label use of drugs in oncology: a position

paper by the european society for medical oncology

(ESMO)

Casali PG, Ann Oncol 18:1923-1925, 2007

práctica

The cost issue

efficacy toxicity

Treatment of metastatic cancer:

efficacy vs toxicity

efficacy toxicity

Treatment of metastatic cancer:

efficacy vs toxicity

Factors influencing selection of anticancer

treatments

Magnitude of

benefit

Scientific

evidence Cost

Guirgis HM, J Oncol Pract 8:224,2012

Conclusiones (1)

Translating results from clinical trials to everyday practice in

cancer is not always easy

The role of very effective therapies (based on a strong

molecular rationale) is usually easy to establish

The evidence for less effective therapies is often in the grey

This is particularly relevant due to the high cost of the new

Conclusiones (2)

Significant gaps in real-world evidence

Most trials are aimed at drug approval

Few trials addressing practical issues

Urgent need for academic (“pragmatic”) studies to

bridge the gaps

Evaluación de fármacos en oncología De oncólogos para ... · cancer de mama Zoledronic acid 4...

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