Cancer Treatment from the DNA Perspective

1. Cancer Treatment from the DNA Perspective Peter J. O’Dwyer, MD University of Pennsylvania ECOG-ACRIN Cancer Research Group

2. DNA Mutation C A A G C T A A C T DNA Normal gene C A A G C G A A C T Single base change C A A G G C G C T A A C T Additions C T C A A G A A C T Deletions

3. Oncogenes Normal cell Normal genes regulate cell growth Oncogenes accelerate cell growth and division Cancer cell Mutated/damaged oncogene

4. Tumor Suppressor Genes Act Like a Brake Pedal Tumor Suppressor Gene Proteins Growth factor Receptor Signaling enzymes Transcriptionfactors DNA Cell nucleus Cell proliferation

5. 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

6. MATCH – Preliminary Hypothesis 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.

7. 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

8. MATCH: SCHEMA Tumor Biopsy

9. Statistical Considerations 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

10. 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)

11. 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

12. NCI MATCH PARTICIPATION