Cancer Treatment from the DNA PerspectivePeter J. O’Dwyer, MD

University of PennsylvaniaECOG-ACRIN

Cancer Research Group

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R

DNA Mutation

Additions

Deletions

Normal gene

Single base change

DNA

CT

A G C G A A C TAC

A G G C G C T AAC A C T

A G C T A A C TAC

A G A A C TAC

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R

Oncogenes

Mutated/damaged oncogene

Oncogenes accelerate cell growth and division

Cancer cell

Normal cell Normal genes regulate cell growth

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Tumor Suppressor GenesAct Like a Brake Pedal

Tumor Suppressor Gene Proteins

DNACell nucleus

Signalingenzymes

Growth factor

Receptor

Transcriptionfactors

Cell proliferation

Genomics-Driven Trials

• Assumption: Given a specific mutation, a particular growth or survival pathway will be activated, so therapy can be directed specifically to it

• Disease-Specific– Breast Cancer – I-SPY– Lung Cancer – LUNG-MAP, ALCHEMIST– Colorectal Cancer – ASSIGN (in development)

• “Disease-Agnostic”– MATCH

MATCH – Preliminary Hypothesis

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Primary:

That tumors that share common somatic genetic alterations in oncogenes will be variably responsive to therapies targeting the oncogenic pathway based on lineage specific factors. 

Secondary:

That concomitant somatic genetic alterations will predict responsiveness or resistance.

MATCH TRIAL OVERVIEW

• Identify mutations/amplifications/translocations in patient tumor sample - eligibility determination

• Assign patient to relevant agent/regimen – single-arm Phase II design

• Need to sequence large numbers of tumors (3000pts) and need to have large numbers of targeted treatments

• Tumor biopsies & sequencing at progression to investigate resistance mechanisms– De-identified samples submitted to central labs – Whole-exome sequencing (research purposes) to detect

non-ambiguous germline variants

Alliance Spring Group Meeting / May 9, 2014 7

MATCH: SCHEMA

Tumor Biopsy

Statistical Considerations

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Within each drug-by-mutation category:

Dual Primary Endpoints: Overall Response Rate 5% vs. 25% or Progression Free Survival 6 months 15%

(median PFS 2.2 m) vs 35% (median PFS 4 m) One stage design 31 evaluable patients per arm

ORR = proportion of patients with objective response (PR+CR) on initial course of study agent

PFS6 = proportion of patients alive and progression free at 6 months from initiation of study agent

CLIA LAB NETWORK• Genetic platform: Ion Torrent PGM AmpliSeq custom

panel; Oncomine under evaluation– About 200 genes– SNV, indel, CNV, targeted translocations

• Immunohistochemical expression of PTEN• Validation within and across sites: same SOP• Possibly additional IHC and FISH, if needed• Lead laboratory: Frederick National Laboratory for

Cancer Research (Williams)– Competitively chosen lab sites:

• MD Anderson (Hamilton)• MGH (Iafrate)• Yale (Sklar)

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SUMMARY

• In planning for a year, MATCH slated to open by end 2014.

• Robust state-of-the-art platform finalized September 2014

• Agreements close to final with four companies for genotype-specific drugs

• Strong CTEP-Intergroup collaboration in developing the trial

• Broad community oncologist and advocate input refined design

NCI MATCHPARTICIPATION