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

DNA Mutation DNA Normal gene Single base change Additions Deletions C National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer 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 Genes can be mutated in several different ways. The simplest type of mutation involves a change in a single base along the base sequence of a particular gene--much like a typographical error in a word that has been misspelled. In other cases, one or more bases may be added or deleted. And sometimes, large segments of a DNA molecule are accidentally repeated, deleted, or moved. Additions C T C A A G A A C T Deletions NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Oncogenes Normal cell Cancer cell Mutated/damaged oncogene Normal National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Oncogenes Normal cell Normal genes regulate cell growth One group of genes implicated in the development of cancer are damaged genes, called “oncogenes.” Oncogenes are genes whose PRESENCE in certain forms and/or overactivity can stimulate the development of cancer. When oncogenes arise in normal cells, they can contribute to the development of cancer by instructing cells to make proteins that stimulate excessive cell growth and division. Oncogenes accelerate cell growth and division Cancer cell Mutated/damaged oncogene NCI Web site: http://cancer.gov/cancertopics/understandingcancer

Tumor Suppressor Genes Tumor Suppressor Gene Proteins Act Like a Brake Pedal National Cancer Institute Understanding Cancer and Related Topics Understanding Cancer Tumor Suppressor Gene Proteins Growth factor Receptor Signaling enzymes Transcription factors DNA Cell nucleus Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is like having a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually. Cell proliferation NCI Web site: http://cancer.gov/cancertopics/understandingcancer

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 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.

Alliance Spring Group Meeting / May 9, 2014 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

MATCH: SCHEMA Tumor Biopsy

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

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)

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 MATCH PARTICIPATION