azienda ulss 13 – mirano ve dipartimento di scienze mediche u.o.c. di oncologia & ematologia...

Azienda ULSS 13 – Mirano VEAzienda ULSS 13 – Mirano VE

Dipartimento di Scienze MedicheDipartimento di Scienze MedicheU.O.C. di Oncologia & Ematologia OncologicaU.O.C. di Oncologia & Ematologia Oncologica

Ufficio di Epidemiologia & Sperimentazioni ClinicheUfficio di Epidemiologia & Sperimentazioni Cliniche

Giovanni L. PappagalloGiovanni L. Pappagallo(giovanni.pappagallo@tin.it)(giovanni.pappagallo@tin.it)

MULTIPLE TREATMENT CHOICES:MULTIPLE TREATMENT CHOICES:ARE THEY EQUALLYARE THEY EQUALLY(cost) EFFECTIVE?(cost) EFFECTIVE?

YOUR TREATMENT CHOICE…YOUR TREATMENT CHOICE…

Statistical Significancevs

Clinical Significance

Registrative Studiesvs

Therapeutic Strategies

Controllingthe Cost of InnovativeCancer Therapeutics

YOUR TREATMENT CHOICE…YOUR TREATMENT CHOICE…

Statistical Significancevs

Clinical Significance

Registrative Studiesvs

Therapeutic Strategies

Controllingthe Cost of InnovativeCancer Therapeutics

A. Stone & K. Carroll, ASCO 2008

A. Stone & K. Carroll, ASCO 2008

P<0.05P<0.05

• Early terminationEarly termination

• OverpoweringOverpowering

• Inadequate Inadequate control groupcontrol group

• Inadequate (?) Inadequate (?) primary endpointprimary endpoint

• Subgroup analysisSubgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

RL Schilsky, ASCO 2005

RL Schilsky, ASCO 2005

J Slutsman, ASCO 2005

J Slutsman, ASCO 2005

HR 0.54(95%CL 0.43-0.67)

target Δ ofHERA trial:RRR 23%

Trastuzumabbetter

Controlbetter

J Slutsman, ASCO 2005

HR 0.62(95%CL

0.41-0.95)

target Δ ofCALGB 9633:RRR 33%

CarboTaxolbetter

Controlbetter

J Slutsman, ASCO 2005

P<0.05P<0.05

• Early terminationEarly termination

• OverpoweringOverpowering

• Inadequate Inadequate control groupcontrol group

• Inadequate (?) Inadequate (?) primary endpointprimary endpoint

• Subgroup analysisSubgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

Target Δ: HR erlotinib:placebo = 0.75 (2 months OS improvement)Analysis after 381 events (450 patients; α 5%, power 80%)

Analysis after 486 events (569 patients)

Actual difference:0.33 months (10 days)

Analysis after ??? events (1125 patients)

Actual difference: 1.2 months

Target Δ: HR cetuximab:placebo = 0.80 (2.5 months OS improvement)Analysis after 845 events (1100 patients; α 5%, power 90%)

P<0.05P<0.05

• Early terminationEarly termination

• OverpoweringOverpowering

• Inadequate Inadequate control groupcontrol group

• Inadequate (?) Inadequate (?) primary endpointprimary endpoint

• Subgroup analysisSubgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

“Standard” therapy?

Equipoise?

“Standard” therapy?

Equipoise?

“Standard” therapy?

New “standard”?

Equipoise?

S.D. Averbuch, ASCO 2008

P<0.05P<0.05

• Early terminationEarly termination

• OverpoweringOverpowering

• Inadequate Inadequate control groupcontrol group

• Inadequate (?) Inadequate (?) primary endpointprimary endpoint

• Subgroup analysisSubgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

F. Pignatti, ESMO 2008

S T

Prentice, Statist Med 1989;8:431.

Effect of Effect of

treatment on treatment on

surrogatesurrogate

Effect of Effect of

surrogate on true surrogate on true

endpointendpoint

VALIDATION OF SURROGATE ENDPOINTS:VALIDATION OF SURROGATE ENDPOINTS:

“FULL CAPTURE OF EFFECT”“FULL CAPTURE OF EFFECT”

Effect of treatment on true endpointEffect of treatment on true endpoint

must be fully captured by surrogatemust be fully captured by surrogate

Trt

S T

Prentice, Statist Med 1989;8:431.

Effect of Effect of

treatment on treatment on

surrogatesurrogate

Effect of Effect of

surrogate on true surrogate on true

endpointendpoint

VALIDATION OF SURROGATE ENDPOINTS:VALIDATION OF SURROGATE ENDPOINTS:

“FULL CAPTURE OF EFFECT”“FULL CAPTURE OF EFFECT”

Effect of treatment on true endpointEffect of treatment on true endpoint

must be fully captured by surrogatemust be fully captured by surrogate

Trt

P<0.05

• Early termination

• Overpowering

• Inadequate control group

• Inadequate (?) primary endpoint

• Subgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

AO Sartor

A. Gennari, 2008

S.L. George

F. Cappuzzo, WCLC 2009

P<0.05P<0.05

• Early terminationEarly termination

• OverpoweringOverpowering

• Inadequate Inadequate control groupcontrol group

• Inadequate (?) Inadequate (?) primary endpointprimary endpoint

• Subgroup analysisSubgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

P<0.05P<0.05

• Early terminationEarly termination

• OverpoweringOverpowering

• Inadequate Inadequate control groupcontrol group

• Inadequate (?) Inadequate (?) primary endpointprimary endpoint

• Subgroup analysisSubgroup analysis

P≥0.05P≥0.05

• UnderpoweringUnderpowering

• Inadequate (?) Inadequate (?) patient selectionpatient selection

Poor ClinicalPoor ClinicalSignificanceSignificance

whenwhen

Possible ClinicalPossible ClinicalSignificanceSignificancealso whenalso when

E. Winer, St. Gallen 2009

Competing causes of mortality

Hanrahan et al. J Clin Oncol 2007; 25: 4952-60

Probability

10 1500.0

0.1

0.2

0.3

0.4

5Time from diagnosis (years)

Breast-cancer deathsOther deaths

Age ≥50 years and ER+

ER+, oestrogen receptor-positive

E. Winer, St. Gallen 2009

YOUR TREATMENT CHOICE…YOUR TREATMENT CHOICE…

Statistical Significancevs

Clinical Significance

Registrative Studiesvs

Therapeutic Strategies

Controllingthe Cost of InnovativeCancer Therapeutics

C. Belani, ASCO 2009 F. Cappuzzo, WCLC 2009Only 19% of placebo pts received Pemetrexed at any time

Only 16% of placebo pts received Erlotinib at any time

MAINTENANCE THERAPY IN ADVANCED NSCLC: MAINTENANCE THERAPY IN ADVANCED NSCLC: PROOF OF PRINCIPLEPROOF OF PRINCIPLE

OR READY-TO-USE STRATEGY?OR READY-TO-USE STRATEGY?

(one of)The Best 1st Line The Best 2nd Line

YOUR TREATMENT CHOICE…YOUR TREATMENT CHOICE…

Statistical Significancevs

Clinical Significance

Registrative Studiesvs

Therapeutic Strategies

Controllingthe Cost of InnovativeCancer Therapeutics

YOUR TREATMENT CHOICE…YOUR TREATMENT CHOICE…

Statistical Significancevs

Clinical Significance

Registrative Studiesvs

Therapeutic Strategies

Controllingthe Cost of InnovativeCancer Therapeutics

YOUR TREATMENT CHOICE…YOUR TREATMENT CHOICE…

Statistical Significancevs

Clinical Significance

Registrative Studiesvs

Therapeutic Strategies

Controllingthe Cost of InnovativeCancer Therapeutics

Thank You for Your Attention!Thank You for Your Attention!