Cancer Treatment from the DNA PerspectivePeter J. O’Dwyer, MD
University of PennsylvaniaECOG-ACRIN
Cancer Research Group
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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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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
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