Incorporating biological questions in clinicalIncorporating biological questions in clinical cancer research: biomarkers and translational endpoints in clinical trials.p

Jorge Barriuso MD PhDTranslational Oncology and Oncology Phase I UnitO l D t tOncology DepartmentLa Paz University Hospital, IdiPAZ

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• What is a “biological question”?g q• Do we need to incorporate biological questions?q• What are the key concepts?• What are the needs?• How are we incorporating them?• New paradigm?p g• Conclusions

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What is a “biological question”?What is a biological question ?

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Do we need to incorporate biological questions?Do we need to incorporate biological questions?

Not all the patients are p

the same

Favorable response Increased toxicitypFavorable prognosis

Unfavorable responseUnfavorable prognosis

Increased toxicity

Burke 2004

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Burke 2004

Do we need to incorporate biological questions?Do we need to incorporate biological questions?

• Rising cost to bring new drugs to patients (~1500 million euros)• Long development times averaging 8 10 years• Long development times averaging 8-10 years• Only ~ 5% of agents in the clinical development succeedsucceed• Late stage failures due to lack of efficacy in oncology

• Up to 59% of phase III trials fail• Thousands of patients involved

Kola and Landis 2004

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Do we need to incorporate biological questions?Do we need to incorporate biological questions?

• Identification of the optimal biological dose• Some agents do not have MTD (monoclonal antibodies)antibodies)• Are we hitting the target at the MTD?• Are we looking at the right population?Are we looking at the right population?

• Identification of the right target tumor subpopulation• Optimized and reduced the time for drug p gdevelopment process.

• Early pick the winner strategies.

Baselga 2008

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Do we need to incorporate biological questions?Do we need to incorporate biological questions?

Up to the moment, using the old fashioned way of drug development….

“Are we learning too little too late from theAre we learning too little too late from the clinical trials we are designing?”

De Bono 2008

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What are the key concepts?What are the key concepts?

Biomarker A characteristic that is objectively measuredand evaluated as an indicator of normal biologicprocesses pathogenic processes orprocesses, pathogenic processes, or pharmacologic responses to a therapeuticintervention

Dancey 2010

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What are the key concepts?What are the key concepts?

P ti Any measurement that is associated PerformancePrognostic Any measurement that is associatedwith clinical outcome in the absence of therapy, or with a standard therapy that all patients are likely to receive (a predictor of the natural history of the

Performance status, OncotypeDx test

to receive (a predictor of the natural history of the tumor)

Predictive Any measurement associated withl k f t ti l

HER2 lifi ti dresponse or lack of response to a particular

therapy, where response can be defined using any of the clinical endpoints commonly used in clinical trials

amplification and effectiveness oftrastuzumab; KRAS m tationclinical trials. KRAS mutation and ineffectiveness of cetuximabof cetuximab

Dancey 20109Jorge Barriuso

What are the key concepts?What are the key concepts?

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Clark 2008

What are the key concepts?What are the key concepts?

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Clark 2008

What are the key concepts?What are the key concepts?

Ph d i P id id th t th i D l t dPharmacodynamic Provide evidence that there is a direct pharmacological effect of a drug

Drug-related toxicity, modulation of target proteinphosphorylation, alteration of vascularpermeability, tumor response

Surrogate Subsets of biomarkers that are Progression freeSurrogate Subsets of biomarkers that are intended to serveas a substitute for a clinically

i f l

Progression-free survival

meaningfulendpoint

D 2010Dancey 2010

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What are the needs?What are the needs?

• Biomarker or profile (multiple biomarkers)

Good biomarker

• Analytical validity• Method of measure

G d

Retrospective series

et od o easu evalidation

• Clinical validity

Good assay

Clinical validity•“fit for purpose”

•Clinical utilityGood

ProspectiveSeries

(clinical trials)•Clinical utilitytest

Dancey 201013Jorge Barriuso

What are the needs?What are the needs?

• Retrospective and prospective tissuep p p• Special collections (disease orientated, necropsy…)p y )• Good clinical information

Adapted from Wistuba 2010 14Jorge Barriuso

How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Proof of biology

Pharmacodynamicmarker

Phase 0Phase I

Selection Selection trials

Predictive  and prognostick Phase II

Validation trials

markers Phase IIPhase III

trials

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Doroshow 2011Doroshow 2011

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Yap 2011 17Jorge Barriuso

How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Selection trials

Predictivemarkers

Phase IIPhase III

• Robust preclinical tested biomarker• Validated assay• Prevalence of the biomarker < 20-

• Not sure of biomarker• Assay not validated• Prevalence of the biomarker > 45-

30% 60%

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Sargent 2005Mandrekar 2011

How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Screening for marker

Marker +

Treatment

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Smith 2007

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

New treatment

Marker ‐

Marker +

Randomization

Marker ‐

Standard or BSC

Marker ‐

Marker +

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Amado 2008Amado 2008

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Low risk

No intervention

Biomarker profile Intermediate risk Randomization

High risk

InterventionIntervention

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Cardoso 2008 24Jorge Barriuso

How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Control armStandard treatment

Randomization

Marker ‐Standard 

Biomarker selection

Marker ‐treatment

S ifiMarker +

Specific treatment

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How are we incorporating them? (“the present”)How are we incorporating them? ( the present )

Cobo 2007 26Jorge Barriuso

New paradigm?New paradigm?

Kummar 200727Jorge Barriuso

New paradigm?New paradigm?

Possible outcomes

Drug Drug Control = orBetter Better

Control = orDrug

Better

Control = orControl   orBetter

DrugBetter

Control   orBetter

Active Active drugUseful  marker

drugUseless  marker

Useless  drug

Dancey 2010Moreno García 2011 28Jorge Barriuso

ConclusionsConclusions

• Definitively need to incorporate biological questions• Costs• Thousands of patients not getting our bestp g g

• Select the design taking into account the previous knowledge• Less knowledge in early phases ≈ more technicalLess knowledge in early phases more technical difficulties in late phases = more costs and more chances of failure

• Shifting the paradigm More biological knowledge gain in early phases =• More biological knowledge gain in early phases =

more chances of success with less number of patients involved and lower costs.

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