Applications of comprehensive clinical genomic analysis in solid tumors: obstacles and opportunities Vincent A. Miller, M.D. Foundation Medicine, Inc. AACR Annual Meeting 2012 Current Concepts session NC005 Comprehensive tumor clinical genomic analysis for treatment selection in clinical oncology
Disclosure information DISCLOSURE INFORMATION AACR 2012 Vincent A. Miller M.D. I have the following financial relationships to disclose: Stockholder in Foundation Medicine Employee of Foundation Medicine I will discuss the following off label use and/or investigational use in my presentation: Potential for investigational targeted therapy selection based on comprehensive clinical genomic profiling 2
Applications of comprehensive clinical genomic analysis in solid tumors: obstacles and opportunities What does a practicing oncologist needs to know about clinical grade NGS? What are the advantages of clinical grade NGS for oncologists, pathologists and pharma? What novel challenges does clinical grade NGS present for physicians and pharma? How can a clinical grade NGS analysis help more cancer patients more quickly everywhere? How do we make this happen routinely? 3
Current challenges of clinical genomic analysis in the clinical setting Sample Limited tissue amounts (e.g., small biopsies) DNA damage by routine fixation (FFPE) Stromal admixture/low tumor purity Assay Heterogeneity of relevant alterations (point mutations, copy changes, fusion genes) Compounding costs of single analyte tests Process Logistics of routing samples to many labs/tests Clinically relevant turn around times Integration and interpretation of results 4
Genomic diversity and complexity of cancer implies relevance of comprehensive view Various genes are mutated in each individual tumor, and cancer cells often contain combinations of mutations 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, 2007 5
Challenges of sequencing clinical cancer samples Low purity cancerous cells may only be a minor fraction of total sample Heterogeneity multiple sub clones of cancer may be present in one tumor sample Mutation of interest (e.g., a resistance mutation) may be present in a low abundance sub clone Aneuploidy chromosomal gains and losses may modify mutation abundance Relevant mutations may be rare in the pool of sequenced DNA 6
Clinical samples commonly contain biologically relevant mutations at low mutant allele frequencies Tumor Purity Clonal Heterozygous Substitution Equal Sub Clones 100% 50% 25% 50% 25% 12.5% 20% 10% 5% 10% 5% 2.5% A Typical Lung Cancer Sample Clinical grade performance: 99%+ sensitivity to detect a mutation with allele frequency of >10%, with no false positive mutation calls. Deep coverage (>500x) is necessary for thorough analysis of clinical grade samples.
Case Report: EGFR mutant lung adenocarcinoma 2 nd gen. EGFR TKI, possibly with cetuximab PARP inhib./plat based chemo Nutlins/MDM2 inhib. Genomic alterations detected in acquired resistance to EGFR-TKIs are diverse and may explain the largely disappointing results seen to date with second generation agents Use of clinical grade NGS may identify one or more tumor specific treatment options 8
Case Report: Adenocarcinoma of the pancreas BRAF inhib. (Vemurafenib) CDK4/6 inhib. BRAF V600E mutations are not routinely tested for in pancreatic adenocarcinoma Use of clinical grade NGS may detect this and other actionable alterations in some cases 9
Case Report: Adenocarcinoma of the pancreas FGFR inhib. KRAS mutations are detected in most pancreatic adenocarcinomas but targeted therapies have been largely ineffective Knowledge of coexistent actionable genomic alterations may expand potential treatment options 10
Case Report: Non mucinous adenocarcinoma of the appendix PKC inhib. Genomic profiling may reveal actionable alterations in rare and neglected tumor types where there is limited genomic knowledge 11
Case Report: Breast cancer Trastuzumab PI3K inhib. Trastuzumab is effective in a subset of ERBB2 amplified breast cancer Coexistent genomic alterations can provide explanations for resistance and rationale for study of select combinations 12
Case Report: Transitional carcinoma of the bladder CDK4/6 inhib. Nutlins / MDM2 inhib. BCL 2 inhib. Genomic analysis of even a chemosensitive tumor type often reveals multiple actionable alterations Findings may suggest targeted therapeutic options if systemic therapy fails 13
Case Report: Cholangiocarcinoma PI3K inhib. NF κb inhib. Genomic profiling may reveal actionable alterations in tumor types in which there is limited genomic knowledge and for which no approved therapy exists 14
Case Report: Salivary gland adenocarcinoma PI3K inhib. Nutlins / MDM2 inhib. CDK 4/6 inhib. Uncommon tumor type with no approved or effective systemic therapies if inoperable; multiple rational targets may be identified
Case Report: Ovarian cancer Aurora kinase inhib. CDK4/6 inhib. IGF1R inhib. Nutlins /MDM2 inhib. Although no genomic testing is routinely undertaken in ovarian cancer, actionable alterations were identified that suggest multiple targeted therapy options either alone, sequentially or in combination 16
Response to crizotinib in patients with ALK Positive NSCLC 2010 New England Journal of Medicine. Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. 17
Case Report: Non small cell lung cancer crizotinib/alk inhib. CDK4/6 inhib. Although crizotinib is efficacious in ALK rearranged NSCLC, little is known to explain variability in response magnitude and duration 18
Long tail of clinical genomic alterations highlights potential benefits of comprehensive profiling (CRC) * 19
The future of oncology. Cancer will no longer be identified primarily by the location in the body where it begins, but also by its panomic characteristics the complex combination of patient specific molecular characteristics that drive the development and behavior of each cancer. Specifically, over the next decade Researchers and clinicians will have the tools to quickly conduct a panomic analysis for every patient with cancer. This analysis will include an examination of the patient s genomic makeup and a complete molecular characterization of their cancer cells. ASCO s Blueprint for Transforming Clinical and Translational Cancer Research ACCELERATING PROGRESS AGAINST CANCER: ASCO s Blueprint for Transforming Clinical and Translational Cancer Research November 2011 20 CONFIDENTIAL
Applications of comprehensive clinical genomic analysis in solid tumors: obstacles and opportunities Cancer genomics are reasonably well annotated in many common tumor types BUT translation of that knowledge to patients is lagging. Many studies across multiple cancer types suggest single marker analysis and single type of analysis are inadequate. Integrated clinical genomic profiling is feasible and necessary in clinical care and research setting. This prospective alliance of clinical genomic profiling and targeted therapies beginning in phase I and with genotypephenotype correlation will accelerate progress, lead to better outcomes and might well save money by generating more powerful unambiguous go no go signals. 21
Acknowledgements Foundation Medicine John Curran Matthew Hawryluk Mary Pat Lancelotta Doron Lipson Jacquelyn Miller Gary Palmer Jeff Ross Phil Stephens Roman Yelensky and many more DFCI Nikhil Wagle Most Importantly Physicians across the US and around the world and all THE PATIENTS 22