Cuando el tiempo libre a la progresión es el objetivo

Agustí Barnadas

Servicio de Oncología Médica

Hospital de Sant Pau

Barcelona

Fiabilidad de la estimación de variables temporales

Inicio Final

Fiabilidad de la estimación de variables temporales

Inicio Final

Caso censurado

Fiabilidad de la estimación de variables temporales

Inicio Final

Caso censurado

Fiabilidad de la estimación de variables temporales

Inicio Final

Caso censurado

Evento

Objetivos en los ensayos clínicos

• Objetivos centrados en el paciente – Calidad de vida – Supervivencia – Tolerancia/Seguridad

• Objetivos centrados en la enfermedad – Respuesta objetiva – Intervalo libre de enfermedad – Tiempo a la progresión – Valor del cambio de:

• CTCs • Marcadores tumorales: PSA, B-HCG

Objetivo centrado en el paciente: Supervivencia

• Reconocido como objetivo primario en una proporción importante de estudios de registro (“gold standard”)

• Definición: – Tiempo desde la aleatorización hasta la muerte

independientemente de su causa

• Corrección: Supervivencia específica de cáncer – Secundaria al tumor índice del estudio

– Secundaria a un segundo tumor de la misma estirpe

– Exclusión de muertes por otros tumores u otras causas

Supervivencia: limitaciones

• Efecto de los tratamientos administrados en una/varias líneas posteriores

• Necesita un mayor tiempo de observación

• Necesita de un gran número de pacientes para poder detectar diferencias

• Efecto de la historia natural de la enfermedad:

– Tumores con una progresión lenta

– Tumores con mayor agresividad

Letrozol vs TMX: Supervivencia

efecto del “crossover”

(19%) in the randomized letrozole arm compared with 132

deaths (29%) in the randomized tamoxifen arm (data not shown).

The repeated log-rank tests indicated that all tests between 6 and

24 months were nominally statistically significant (ie, not ad-

justed for multiple tests), whereas the test at 30 months showed

a (nominal) strong trend in favor of the randomized letrozole arm

(Table 3).The two survival curves crossed at around 3 years

(clearly indicating nonproportional hazards; Fig 4), by which

time cross-overs were virtually complete.

Additional analyses were performed to explore whether the

evaluation of OS attributable to the first-line endocrine therapy

might be impaired by the cross-over to the other endocrine agent.

Median OS from initial randomization, censoring time to death at

cross-over, was 42 months (95% confidence interval [CI], 36

months to not estimable) for letrozole and 30 months (95% CI, 27

to 36 months) for tamoxifen. For the cross-over data, the numbers

of patients who progressed on first-line treatment and who crossed

over in each sequence are listed in Table 1. Of the patients who

crossed over, 63% crossing from letrozole first-line to tamoxifen

second-line died either during second-line therapy or, more usually,

during the follow-up period after their second progression. This

mortality rate was substantially higher than for patients crossing

from tamoxifen first-line to letrozole second-line (47%). Median OS

from the date of cross-over was 19 months (95% CI, 17 to 24

Fig 3. Forest plot of treatment compari-

sons for objective response rate by key

baseline covariates. Squares denote odds

ratios, drawn proportional to the number of

events, and lines represent 95% confidence

intervals. Odds ratios > 1 favor letrozole.

Fig 4. Overall survival (OS) at median

follow-up of 32 months, by randomized

treatment arm. Median OS was not signifi-

cantly different (overall log-rank, P .53).

There was a significant difference in favor of

the randomized letrozole arm between 6

and 20 months (Kolmogorov-Smirnov-type

test, P .003).

2105LETROZOLE VERSUS TAMOXIFEN IN BREAST CANCER

Letrozol Tamoxifeno

Mouridssen H, et al. J Clin Oncol 2001

TMX L

TMX

L

L

TMX

100

50

0 0 6 12 18 24 30 36 42 48 54 60

Mediana tiempo “crossover”

Letrozol a TMX: 17 m

TMX a letrozol: 13 m

Cleopatra: SV global

HR: 0.63

Swain S, et al. N Engl J Med 2015

Estudio Cleopatra: SV global excluyendo pacientes “crossover”

Swain S, et al. N Engl J Med 2015

HR: 0.55

Objetivos en los ensayos clínicos

• Objetivos centrados en el paciente – Calidad de vida – Supervivencia – Tolerancia/Seguridad

• Objetivos centrados en la enfermedad – Respuesta objetiva – Intervalo libre de enfermedad – Tiempo a la progresión – Valor del cambio de:

• CTCs • ctDNA • Marcadores tumorales: PSA

• Variable que define el efecto de una única intervención

• Su resultado no depende de la actividad de un tratamiento posterior

• Retos: – Definición – Frecuencia en la medición de las lesiones diana/no

diana – Estimación subjetiva/objetiva – Comité independiente de valoración – ¿Son variables subrogadas?

Objetivos centrados en el tumor

Retos: definición DFS

• Tiempo entre la aleatorización hasta:

– la recaída del tumor local/distancia

– segundo tumor de la misma localización/otra

– o muerte por cualquier causa

• ¿Todos los estudios lo definen igual?

Estudios de adyuvancia HER2+: Definición DFS Evento HERA NSABP

B31/NCCTG/N9831

BCIRG-006 FinHER

Recidiva loco/regional

X X X

Metástasis X X X X

Segundo tumor X

Tumor contralateral invasivo

X

X

X

X

Muerte por cualquier causa

X

Muerte antes de recaÍda o segundo tumor primario

X

X

DCIS ipsilateral

DCIS contralateral

X

PFS/TTP

• Tiempo desde la aleatorización hasta la progresión o muerte – TTP: progresión pero excluye las muertes

• Retos: – Medición con la misma metodología: RECIST

• Incremento de al menos 20% suma de los diámetros de las lesiones diana

• Enfermedad voluminosa/indolente

– Frecuencia de las mediciones: 6/8/12 semanas – Papel de los comités centralizados de evaluación de

respuesta – Variables de confusión

Bolero-2: PFS evaluación investigador

Yardley, et al. Adv Ther. 2013;30(10):870-884.

Dif: 4,6 meses

Bolero-2: PFS evaluación comité independiente

Yardley, et al. Adv Ther. 2013;30(10):870-884.

Dif: 6,9 meses

Objetivos centrados en el tumor

• ¿Pueden ser subrogados de los objetivos centrados en el paciente? – De la Supervivencia??

• La respuesta objetiva impacta en SV?

• DFS impacta en la SV??

• PFS impacta en la SV?

• TTP impacta en SV??

• ¿Cómo ponerlo en evidencia? – En un ensayo clínico específico Obj. 1º/obj 2º

– Metaanálisis

• PFS ¿tiene influencia en al calidad de vida?

Efecto potencial de PFS en SV Ausencia de efecto

A

B

El tratamiento experimental A tiene un mayor efecto en PFS sin impacto en SV

El cruzamiento esta permitido con un mayor efecto del tratamiento experimental

Efecto potencial de PFS en SV Ausencia de efecto

A

B

El tratamiento experimental A tiene un MODESTO PFS sin impacto en SV

El cruzamiento esta permitido

El impacto de PFS es similar tras cruzamiento

Falso positivo, o bien la enfermedad es agresiva tras la primera terapia

Efecto potencial de PFS en SV Ausencia de efecto

A

B

El tratamiento experimental A tiene un MODESTO PFS sin impacto en SV

No se permite el cruzamiento

El impacto de un segundo tratamiento convencional es mayor

Falso positivo, o bien la enfermedad es agresiva tras la primera terapia

Efecto potencial de PFS en SV Visualización del efecto

A

B

El tratamiento experimental A tiene un MODESTO PFS pero la SV es superior

El impacto de un segundo tratamiento convencional es mayor

El incremento en PFS asociado a un tratamiento de segunda línea es superior

y conlleva una mejora en la SV

Shi Loo J, et al J Clin Oncol 2015

314 | JUNE 2010 | VOLUME 7 www.nature.com/ nrclinonc

being correlated (‘tr ial-level’ surrogacy) (Figures 2

and 3).66 On the basis of a historical series of 10 random-

ized trials evaluating fluoropyrimidine-based treatment,

the surrogate threshold effect was equal to 0.86, or 0.77

after elimination of a highly influential trial, indicating

that if a new treatment reduced the hazard of tumor

progression by at least 23%, it would be very likely to

produce a benefit on survival (Figure 3).65

A major difficulty for the validation of surrogate end

points, however, arises from the fact that they are vali-

dated with respect to a specific treatment or set of treat-

ments. For a new treatment with a novel mechanism of

action, it is uncertain if the same surrogacy relationship is

applicable to that demonstrated for previous treatments.

For instance, in first-line trials in advanced colo rectal

cancer, PFS has not yet been demonstrated to be a surro-

gate for overall survival with respect to novel targeted

therapies such as bevacizumab (Avastin®, Genentech, San

Francisco, CA), panitumumab and cetuximab. The ques-

tion arises as to whether it is reasonable to assume that a

surrogacy that was demonstrated for prior therapeutics

can legitimately be treated as a surrogate in clinical assess-

ment of every new treatment that emerges. A further dif-

ficulty arises from the fact that treatment options evolve

with time. For instance, PFS was validated as a surrogate

for classical 5-fluorouracil-based chemotherapy in colo-

rectal cancer before the introduction of novel cyto toxics

and targeted therapies, which now provide a greater

range of salvage therapies. Had such therapies been

available at an earlier stage in the evo lu tion of colorectal

cancer treatment, it is unlikely that the surrogacy of PFS

for overall survival would have been demonstrated for

5- fluorouracil-based chemotherapy.66

Indeed, as standards of care in clinical oncology evolve,

the difficulties of demonstrating surrogacy between

proximal end points and overall survival will inevit-

ably mount as the number of active treatment options

increase and survival is extended. A recent study in the

area of advanced breast cancer found that although tumor

response, PFS, disease control and time-to-disease pro-

gression were all associated with overall survival at an

individual-level, none had a sufficiently strong associ ation

at trial-level to qualify as a validated surrogate end point.67

An example of this situation was demon strated in a large

trial of bevacizumab in advanced breast cancer whereby

bevacizumab treatment was associated with a highly

signifi cant PFS benefit, but no overall survival benefit.68

These observations suggest that it might be difficult to

formally establish PFS as a surrogate for overall survival

in solid tumors for which several lines of treatment are

currently available, but this does not imply that PFS does

not have utility as an end point in its own right. Indeed,

PFS might be the only sensitive (and realistic) end point

for drug evaluation, given the availability of multiple

active therapeutic lines (all of which have the potential to

improve overall survival).69

Strict or pragmatic validat ion?The current shortage of validated predictive and surro-

gate biomarkers in oncology reflects not only the statisti-

cal challenges discussed in this article, but difficulties at

every stage of the discovery and evaluation process.70 The

US National Cancer Institute’s Early Detection Research

Network has proposed five distinct phases for the devel-

opment of biomarkers for early cancer detection.70,71 In

Table 3, we adapt these five phases to the development

of any biomarker, and outline the current status of

MammaPrint® with respect to these phases as an example.

One of the greatest challenges of validation is the lack of

availability of both high-quality biological samples and

standardized measures of response from all major trials,

whether the trials are run by government-funded agen-

cies or by industry. Regulatory authorities, such as the

European Medicines Agency (EMEA) and the FDA should

consider making stipulations to alleviate this problem

to their industry and academic partners. For example,

the generation of multi-trial tissue banks and databases

would accelerate the search for bio markers and provide

a resource for retrospective analysis. The Foundation for

the NIH Biomarkers Consortium in the USA represents a

welcome but modest step in this direction.72

Despite the difficulties involved, the next few years are

likely to see the accumulation of an increasing number of

biomarker candidates with varying degrees of statistical

Figure 2 | Progression-free survival (PFS) and overall survival (OS) in advanced

colorectal cancer.

Figure 3 | Surrogate end point in advanced colorectal cancer: ‘trial level’ (effect)

surrogacy and surrogate threshold effect.

543210

0.0

0.25

Time (years)

5-FU + LV, PFS

5-FU/ raltitrexed, PFS

Irinotecan/ oxaliplatin, PFS

5-FU + LV, OS

5-FU/ raltitrexed, OS

Irinotecan/ oxaliplatin, OS

0.5

0.75

1.0

Ove

rall/pro

gre

ssio

n-fre

e s

urv

ival

1.751.51.251.00.5 0.750.25

0.25

0.75

0.5

Treatment effect (HR) on progression-free sur vival

Surrogatethreshold effect

Historical trials

Irinotecan-US

Prediction line

Irinotecan-EU

Oxaliplatin-EU

95% prediction limits

1.16

0.86

Treatm

ent

eff

ect

(HR

) on o

vera

ll s

urv

ival

1.0

1.25

1.75

2.0

1.5

2.0

REVIEWS

nrclinonc_43_JUN10.indd 314 12/5/10 14:51:56

© 20 Macmillan Publishers Limited. All rights reserved10

Buyse M. Nat Rev Clin Oncol 2010; 7: 309-17

Surrogate end-point: surrogacy and surrogate threshold effect

Surrogate end-point: surrogacy and surrogate threshold effect

314 | JUNE 2010 | VOLUME 7 www.nature.com/ nrclinonc

being correlated (‘tr ial-level’ surrogacy) (Figures 2

and 3).66 On the basis of a historical series of 10 random-

ized trials evaluating fluoropyrimidine-based treatment,

the surrogate threshold effect was equal to 0.86, or 0.77

after elimination of a highly influential trial, indicating

that if a new treatment reduced the hazard of tumor

progression by at least 23%, it would be very likely to

produce a benefit on survival (Figure 3).65

A major difficulty for the validation of surrogate end

points, however, arises from the fact that they are vali-

dated with respect to a specific treatment or set of treat-

ments. For a new treatment with a novel mechanism of

action, it is uncertain if the same surrogacy relationship is

applicable to that demonstrated for previous treatments.

For instance, in first-line trials in advanced colo rectal

cancer, PFS has not yet been demonstrated to be a surro-

gate for overall survival with respect to novel targeted

therapies such as bevacizumab (Avastin®, Genentech, San

Francisco, CA), panitumumab and cetuximab. The ques-

tion arises as to whether it is reasonable to assume that a

surrogacy that was demonstrated for prior therapeutics

can legitimately be treated as a surrogate in clinical assess-

ment of every new treatment that emerges. A further dif-

ficulty arises from the fact that treatment options evolve

with time. For instance, PFS was validated as a surrogate

for classical 5-fluorouracil-based chemotherapy in colo-

rectal cancer before the introduction of novel cyto toxics

and targeted therapies, which now provide a greater

range of salvage therapies. Had such therapies been

available at an earlier stage in the evo lu tion of colorectal

cancer treatment, it is unlikely that the surrogacy of PFS

for overall survival would have been demonstrated for

5- fluorouracil-based chemotherapy.66

Indeed, as standards of care in clinical oncology evolve,

the difficulties of demonstrating surrogacy between

proximal end points and overall survival will inevit-

ably mount as the number of active treatment options

increase and survival is extended. A recent study in the

area of advanced breast cancer found that although tumor

response, PFS, disease control and time-to-disease pro-

gression were all associated with overall survival at an

individual-level, none had a sufficiently strong associ ation

at trial-level to qualify as a validated surrogate end point.67

An example of this situation was demon strated in a large

trial of bevacizumab in advanced breast cancer whereby

bevacizumab treatment was associated with a highly

signifi cant PFS benefit, but no overall survival benefit.68

These observations suggest that it might be difficult to

formally establish PFS as a surrogate for overall survival

in solid tumors for which several lines of treatment are

currently available, but this does not imply that PFS does

not have utility as an end point in its own right. Indeed,

PFS might be the only sensitive (and realistic) end point

for drug evaluation, given the availability of multiple

active therapeutic lines (all of which have the potential to

improve overall survival).69

Strict or pragmatic validat ion?The current shortage of validated predictive and surro-

gate biomarkers in oncology reflects not only the statisti-

cal challenges discussed in this article, but difficulties at

every stage of the discovery and evaluation process.70 The

US National Cancer Institute’s Early Detection Research

Network has proposed five distinct phases for the devel-

opment of biomarkers for early cancer detection.70,71 In

Table 3, we adapt these five phases to the development

of any biomarker, and outline the current status of

MammaPrint® with respect to these phases as an example.

One of the greatest challenges of validation is the lack of

availability of both high-quality biological samples and

standardized measures of response from all major trials,

whether the trials are run by government-funded agen-

cies or by industry. Regulatory authorities, such as the

European Medicines Agency (EMEA) and the FDA should

consider making stipulations to alleviate this problem

to their industry and academic partners. For example,

the generation of multi-trial tissue banks and databases

would accelerate the search for bio markers and provide

a resource for retrospective analysis. The Foundation for

the NIH Biomarkers Consortium in the USA represents a

welcome but modest step in this direction.72

Despite the difficulties involved, the next few years are

likely to see the accumulation of an increasing number of

biomarker candidates with varying degrees of statistical

Figure 2 | Progression-free survival (PFS) and overall survival (OS) in advanced

colorectal cancer.

Figure 3 | Surrogate end point in advanced colorectal cancer: ‘trial level’ (effect)

surrogacy and surrogate threshold effect.

543210

0.0

0.25

Time (years)

5-FU + LV, PFS

5-FU/ raltitrexed, PFS

Irinotecan/ oxaliplatin, PFS

5-FU + LV, OS

5-FU/ raltitrexed, OS

Irinotecan/ oxaliplatin, OS

0.5

0.75

1.0

Ove

rall/

pro

gre

ssio

n-fre

e s

urv

ival

1.751.51.251.00.5 0.750.25

0.25

0.75

0.5

Treatment effect (HR) on progression-free sur vival

Surrogatethreshold effect

Historical trials

Irinotecan-US

Prediction line

Irinotecan-EU

Oxaliplatin-EU

95% prediction limits

1.16

0.86

Treatm

ent

eff

ect

(H

R)

on o

vera

ll surv

ival

1.0

1.25

1.75

2.0

1.5

2.0

REVIEWS

nrclinonc_43_JUN10.indd 314 12/5/10 14:51:56

© 20 Macmillan Publishers Limited. All rights reserved10

Buyse M. Nat Rev Clin Oncol 2010; 7: 309-17

Therapy effect

TTG: time to tumor growth

Venook AP, Tabernero JM. J Clin Oncol 2015; 33: 4-7

Relation TTG – PFS and SV

Relation TTG – PFS and SV

Smerage JB, et al J Clin Oncol 2014; 32: 3483

Smerage JB, et al J Clin Oncol 2014; 32: 3483

Hormone receptor positive Triple negative

Smerage JB, et al J Clin Oncol 2014; 32: 3483

Terapia antiangiogénica: bevacizumab

O’Shaugnessy R, et al. ASCO 2010 Rossari J, et al . J Oncol 2012

Metaanálisis en el tratamiento de primera línea Tiempo libre de progresión

Non-BV

(n=1008)

BV

(n=1439)

Median, mo 26.4 26.7

HR (95% CI) 0.97 (0.86–1.08)

1-yr survival

rate (%) 77 82

Terapia antiangiogénica: bevacizumab

O’Shaugnessy R, et al. ASCO 2010 Rossari J, et al . J Oncol 2012

SUPERVIVENCIA

“Despite the reduced ability to predict overall survival in modern trials, we feel that PFS

remains an appropriate end point for first-line superiority trials in advanced disease”

Quian S, De Gramont A, et al. J Clin Oncol 2015; 33: 22-28

Definición y objetivos

PFS online: herramienta de ayuda al clínico para visualizar el beneficio que aportan diferentes estrategias de tratamiento para la enfermedad avanzada

Se fundamenta en la evidencia disponible a partir de los resultados de los estudios fase III y metaanálisis

Incorpora información adicional con: Descripción de la población de los estudios seleccionados

Enlace con las referencias bibliográficas

Las fichas técnicas de los fármacos: EMA/AEMPs

Selección bibliográfica

Bases de datos: PubMed y Google Scholar.

Palabras clave: • Por ejemplo, para inhibidores de aromatasa: ("advanced breast cancer"

OR "advanced breast carcinoma") AND ("endocrine therapy" OR "tamoxifen") AND ("aromatase inhibitor" OR "anastrozole" OR "letrozole" OR "exemestane").

Filtros: • Tipo de artículo: “clinical trial” y “meta-analysis”.

• From 1999 (dado el tiempo transcurrido desde la introducción de los inhibidores de aromatasa).

Búsqueda manual de artículos clave.

Selección de los artículos de referencia

Extracción y validación de la información de cada artículo

• Cálculo de las medianas PFS: se utiliza el modelo paramétrico de Weibull

S(t)=exp(-α.tγ ) • La mediana de PFS se calcula a partir de los parámetros del

modelo

Med=(log(2) /α)1/γ

• El modelo permite incorporar las HR entre tratamientos asumiendo el principio de riesgos proporcionales

S2(t)=S1(t)HR = exp(-α.tγ )HR

Fundamentos estadísticos

Variables consideradas

Edad.

Estado menopáusico.

HER2 y receptores hormonales.

Afectación visceral.

Tratamientos previos administrados.

Intervalo hasta metástasis.

Indicaciones de ficha técnica.

Opción de tratamiento preferida por el clínico para cada paciente.

Trabajo desarrollado (siguiendo las indicaciones aprobadas por AEMPs)

Terapia endocrina 1ª , 2ª línea

Quimioterapia 1ª, 2ª línea

Terapia antiangiogénica

“En construcción”: • Primera línea terapia anti-HER2

• Segunda línea terapia anti-HER2

Próximos objetivos

• Acceso en: http://www.pfsonline.es

• Estudio de validación prospectivo: REGISTREM

Comité científico Agustí Barnadas Molins Teresa Ramón y Cajal César A. Rodríguez Sánchez

Comité Asesor Isabel Álvarez López Lourdes Calvo Martínez Eva Carrasco Ana Lluch Hernández Miguel Martín Jiménez Miguel Ángel Seguí Palmer

GEICAM Roser Trilla

Agradecimientos

NPGI María José Jerez Paula Peral

Metodología Jesús Herranz Xavier Mas

Novartis Marion Chalumeau Ariela Beliera Cristina Puig