azienda ulss 13 – mirano ve dipartimento di scienze mediche u.o.c. di oncologia & ematologia...
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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([email protected])([email protected])
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!