New Drug development and Personalized Therapy in The Era of Molecular Medicine

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1 New Drug development and Personalized Therapy in The Era of Molecular Medicine Ramesh K. Ramanathan MD Virginia G. Piper Cancer Center Translational Genomics Research Institute Scottsdale, AZ Clinical Professor of Medicine College of Medicine, Phoenix Campus University of Arizona, AZ

2 One Size Does Not Fit All: Cancer Agents work in a Minority Agent Effective in ANTI-DEPRESSANTS 60-65% (SSRI s) ASTHMA DRUGS 60-65% DIABETES DRUGS 40-50% ARTHRITIS DRUGS 50% ALZHEIMER S DRUGS 30-35% CANCER DRUGS 20-25% Spear BB et al. Clinical trends mol med. 5: : 2001

3 Targeted Therapies Benefit a Minority of patients Steroid receptors: ER+ breast cancer, HER2: for breast and gastric ca KRAS-Colon cancer EGFR & ALK: for NSCLC CD20: for lymphoma BCR/Abl: for CML c-kit: for GIST Hedgehog: for basal cell and medulloblastoma RET: for medullary thyroid ca b-raf: for melanoma

4 Phase II Study of Molecular Profiling for Refractory Solid Tumors The Bisgrove Study Group The Stardust and Scottsdale Healthcare Foundations Von Hoff D D et al. JCO 2010;28:

5 Some Examples of Treatment that 18 patients with PFS > 1.3 Received (based on molecular profiling) Tumor Type Therapy patient received Breast Breast Breast Colorectal Ovarian Cholangiocarcinoma GIST Eccrine sweat gland exemestane nab-paclitaxel + trastuzumab doxorubicin temozolomide +sorafenib lapatinib + tamoxifen cetuximab + irinotecan cetuximab + gemcitabine sunitinib

6 Study Schema- Profiling Study for Pancreatic Cancer Diagnosed with APC. N=35 Progression after 1 st line therapy Verify Eligibility Schedule biopsy Treat with drug or drugs from profiling Measure 1 year survival Biopsy of metastatic lesion Send material in 3 parts to IGC-stored under CLIA (1)IHC (Caris)- first priority for tissue (2) CGH (TGen) (3) Microarray (Hopkins)

7 Breast Cancer Study- G Jameson, ASCO 2013 Refractory Breast Cancer Progression after 3 regimens N=25 Tumor biopsy performed IHC/FISH by Target Now, Microarray & Reverse Phase Protein Microarray (RPMA) Yes Treat patients according to MP Findings. Target Found? No Treat patient with clinician's choice

8 Visualization Of Complete Genome By Circos Map Circos map legend: Coverage - Germline and Tumor All De Novo changes Cyan tics Somatic synonymous Orange tics Somatic nonsynonymous Red tics Somatic copy number Deletion

9 Genome and Transcriptome Sequencing in Triple-Negative Breast Cancer Prospective clinical trial (n=14) Genes mutated included TP53, LRP1B, HERC1, CDH5, RB1, and NF1. Genes involved in focal structural events: CTNNA1, PTEN, FBXW7, BRCA2, WT1, FGFR1, KRAS, HRAS, ARAF, BRAF, and PGCP. Homozygous deletion of CTNNA1 in 2 of 6 African Americans. Craig D et al. Mol Cancer Ther. 12:104-16: 2013

10 SU2C-Phase II Randomized Study of Molecularly-Guided Therapy for Patients with BRAFwt Metastatic Melanoma: PIs-Pat Lo Russo/Jeff Trent N=96 Endpoint is response Randomize 2:1 to either molecularly guided therapy based on sequencing or physician choice Therapy: Commercial agents or investigational agents

11 Molecular Profiling Services Caris Diagnostics (Target Now) IHC, FISH/CISH, PCR and targeted Next-Generation Sequencing (NGS) Response Genetics Targeted genes for lung, colon, gastric and melanoma Foundation Medicine Exome sequencing of 236 cancer-related genes (3,769 exons) plus 47 introns, average depth of coverage >250X. Whole Genome Sequencing Gene Key Mayo Clinic Scottsdale/TGen

12 The Caris Target Now Database 1. 42,000 cases in database of a referral CLIA certified oncology reference laboratory Caris Life Sciences 2. Gender 27,900 females (66%) High volume of ovarian and breast cases 14,100 males (34%) 3. Age range from 1 to Prior Treatment regimens largely unknown Majority had prior therapies Gatalica et al. ASCO 2013

13 Comprehensive Genetic Characterization of Tumors for Personalized Cancer Care DNA epigenetics DNA mutations Proteomics DNA chromosomal alterations mrna and mirna profiling

14 A Lot More Work to be done Tissue is the issue- small amounts, low cellularity, multiple clones, DNA damage by fixation What are the druggable genes? Most are passenger mutations Targeted therapy often leads to short-lived responses, impact on survival? Redundant Pathways: Targeting one pathway is not enough Accuracy of genome sequencing: 70% are true positive & true negative?. Reimbursement, Ethics, & drug approval process. Costs associated with gene sequencing: The $1000 genome 24 hours? But storage and interpretation >$ 30,000

15 French Genomic Centers 28 genomic centers Deliver results for clinical decision Yearly funding from French NCI and Ministry of Health (12 M Euros in 2010) Coordination of the 28 centers for quality Control, SOP Molecular epidemiology through single database Andre F, Clin Cancer Res, 2012

16 Molecular screening: Which candidate target? MOSCATO trial Prospective evaluation of integrated biology for treatment decision Institut Gustave Roussy Biopsy of metastatic sites Frozen sample CGH/hot spot mutations (96 amplicons by NGS) N=600 Target discovery Targeted agents Hypothesis: PFS post genomic > PFS pre genomic (similar as Von Hoff, J Clin Oncol, 2010)

17 WINTHER trial

18 The Clinical Trials Team at Virginia G. Piper Cancer Center Dan Von Hoff, MD Ramesh Ramanathan MD Gayle Jameson, NP Cathy Mast, NP Sam Ejadi MD Jasgit Sachdev MD Mike Demeure, MD