Clinical Grade Genomic Profiling: The Time Has Come

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1 Clinical Grade Genomic Profiling: The Time Has Come Gary Palmer, MD, JD, MBA, MPH Senior Vice President, Medical Affairs Foundation Medicine, Inc. Oct. 22,

2 Why We Are Here A Shared Vision At Foundation Medicine, we are leading a transformation in cancer care, whereeach each patient s treatment is informed by a deep understanding of the molecular changes that contribute to their disease. 2

3 The Number of New Targets is Growing Lung Adenocarcinoma Pao and Hutchinson, Nature Medicine : CONFIDENTIAL

4 Targeted Therapies in Cancer Care VEMURAFENIB Selective inhibitor of mutant BRAF Before Courtesy of Dr. Grant McArthur 15 days after 4

5 Cancer Diagnostic Market is Rapidly Evolving Molecular profiling is driving many new targeted cancer therapeutics HGFR RET FBXW7 KRAS VEGF/VEGFR EGFR AURKA CD4 SCR DDR2 CCND ERB4 RAF DNMT3A GNAQ BRCA1 BRAF Target Markers CDK MET PIK3CA FML1 IGF1R TSCI HER2 FGFR1 CDKN2A AKT1 NOTCH1 PTEN FLT3 CD20 RATA RAF1 TEK TNF STK11 MAP2K IGF/IGFR family KDR Coming Today Soon ~500 ~15 compounds approved drugs hitting ~140 hitting targets ~10 in development targets t Years Subset of analyzed targets listed; data from BioCentury Online Intelligence Database 5

6 Genomic is Adding To Histologic Various genes are altered in each individual tumor, and cancer cells often contain combinations of alterations driving uncontrolled growth It is therefore critical to understand entire pathways which incorporate many genes Example pathways Example genes Ding et al. Nature, 2008; Thomas et al. Nature Genetics,

7 Specimens Are FFPE and Small Formalin fixation and subsequent storage can damage nucleic acids Percutaneous needle biopsy of lung nodules under CT fluoroscopic guidance Sample preparation needs be optimized i to maximize i accuracy and isolate sufficient i material for diagnostic testing from tiny specimens

8 Low Tumoral Purity* Requires High Accuracy Mutation allele frequencies of 107 clinically relevant somatic mutations in 40 FFPE non-small cell lung cancer specimens (unpublished data) *Purity = relative proportion of extracted DNA originating from tumor cells Fraction of mutations <5% Fraction of mutations <10% Fraction of mutations <20% Fraction of mutations <25% Fraction of mutations <50% Fraction of mutations <100% 11% 32% 55% 67% 93% 100% Capillary sequencing would have missed over half the mutations in this study as 20% allele frequency is the maximum limit of detection

9 Five Classes of Alterations Are Important Base Substitutions Short Insertions/Deletions e.g. BRAF, EGFR e.g. EGFR, ERBB2 Capillary sequencing, Mass Spectrometry Capillary sequencing, gel size shift assays Focal Amplification & Homozygous Deletion Gene Fusion e.g. HER2, MET e.g. PTEN, TSC1/2 e.g. ALK, RET IHC (overexpression), Fluorescence In Situ Hybridization RT PCR Fluorescence In Situ Hybridization Multiple different diagnostic tests may exhaust precious biopsy material

10 FoundationOne 1) DNA/RNA extraction: ti 2) LC, Hybrid HbidCapture: 3) Analysis pipeline: 4) Clinical i l report: t Extensive optimization Extensive optimization Advanced computational biology Resource intensive Pre Analytic Process (Pre Sequencing) Post Analytic Process (Post Sequencing) Day Turnaround dti Time (From Receipt of Specimen)

11 FoundationOne Report Patient and ordering physician information Summary of results and genomic alterations identified Targeted therapies and clinical trials that may be relevant based on genomic alterations identified Clear results presented on the first page 11

12 FoundationOne Report An interpretive statement for each genomic alteration, including the frequency of alteration (COSMIC), its biological implication and what it may mean for the specific patient The therapies section provides details on approved therapies to which the patient s cancer may be sensitive or resistant based on their genomic profile. The clinical trials section provides detail on currently available clinical trials for which the patient may be eligible. The appendix lists all reference information for studies used in curating the report Additional pages provide background & context 12

13 FoundationOne TM Experience: Diversity, Actionability Lung 17% 82% of cases have actionable findings Others On average (mean), % Breast 14% reportable alterations; 1.6 actionable alterations per sample Ovarian 4% Unknown 8% Head & Neck 4% Colorectal Soft 8% tissue 8% Pancreatic 4% Dataset: First 3,936 qualifying clinical specimens in FMI CLIA lab. Definition of Actionability: 1. FDA approved targeted therapy in tumor type 2. FDA approved targeted therapy in another tumor type 3. Open clinical trial for which alteration confers trial eligibility 13

14 We Find What Other Diagnostic Tests Cannot Rearrangements/ Fusions 3% CNAs 41% Hotspot 31% Hotspot includes alterations detectable by a hypothetical test combining six tests; four commercially available tests that utilize NGS plus two relevant and commonly used hotspot tests Indels 9% Subs 16% FoundationOne TM identifies more than three times the number of actionable alterations compared to a hypothetical panel combining multiple hotspot assays Dataset: First 3,936 qualifying clinical specimens in FMI CLIA lab. 14

15 Most Frequently Altered Genes /155 most commonly altered genes displayed 76.4% ofspecimens harbored 1 actionablealteration alteration The Long Tail Phenomenon Number of altered cases TP53 KRAS PIK3CA CDKN2A APC MYC MCL1 CDKN2B EGFR PTEN ARID1A RB1 CCND1 NF1 ERBB2 MDM2 FGFR1 BRAF CDK4 SMAD4 BRCA2 PTPRD ATM STK11 CCNE1 FBXW7 CTNNB1 BRCA1 NOTCH1 RICTOR LRP1B NRAS DNMT3A KDM6A FGFR3 SMARCA4 SOX2 AKT2 PIK3R1 CDH1 RPTOR IDH1 NF2 AKT1 BAP1 CCND3 CDK6 MET CCND2 TET2 AURKA FGFR2 MAP2K4 NKX2_1 PDGFRA VHL TSC2 RUNX1 ALK KIT MSH6 EWSR1 Oncol 31, 2013 (suppl; abstr 11020) 15 15

16 Distribution of the 116 ERBB2 Alterations Oncol 31, 2013 (suppl; abstr 11020) 16

17 Frequency of the 116 ERBB2 Alterations Esophageal carcinomas 29% (100% amplifications) Endometrial carcinomas 20% (50% amplifications, 50% mutations) Breast carcinomas 14% (75% amplifications, 25% mutations) Likely enriched ihdfor HER2 by previous testing ti Gastric carcinomas 12% (75% amplifications, 25% mutations) Lung cancer (SC & NSCLC combined) 6% (22% amplifications, 78% mutations) Oncol 31, 2013 (suppl; abstr 11020) 17

18 Case Presentation: Novel TRIM33 RET Fusion Middle aged female never smoker StageIV IV B lung adenocarcinoma Sequenom negative ROS1 (FISH) & KIF5B RET (PCR) testing ti negative Pemetrexed (Alimta), cisplatin and bevacizumab (Avastin) started x 6 cycles then pemetrexed and bevacizumab maintenance every 3 weeks 18 months after diagnosis progression of disease with new bony metastasis 18 CONFIDENTIAL

19 Novel TRIM33 RET Fusion: Results Baseline CT scan showing paramediastinal and pleural-based nodularities in left upper lobe. Repeat CT scan after 28 days of anti-ret therapy: disappearance of paramediastinal and near complete resolution of pleural disease. Patient with KIF5B RET fusion also known to have responded to RET inhibitor 19 CONFIDENTIAL

20 From Test To Treatment 20

21 QUESTIONS??