#hcaqofq tariq mughal

Tariq Mughal Vice-President Medical affairs, Foundation Medicine

Professor of Hematology-Oncology

Personalized Cancer Medicine

HCA-SCRI Healthcare Meeting London; 25 Feb 2016

‘Moon-shot’ Cancer Medicine - Obama State of the Union Address, Jan 2016

Cancer Core Europe: Sep 2015 Cambridge

Cambridge Cancer Centre, Cambridge Institute Gustave Roussy, Paris Karolinska Institute, Stockholm

Netherlands Cancer Institute, Amsterdam Vall d’Hebron Institute of Oncology, Barcelona German Cancer Research Center, Heidelberg

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Largest

Aggregation

of Validated

Oncology

Genomic

Information

68,000

+ Tests

FoundationCORE™ Knowledgebase

Significant Value Creation from Molecular Information

Personalized Cancer Medicine: Some

Conceptual thoughts

1. A brief history of precision medicine

2. What really is a driver mutation?

3. How can be best identify driver mutations?

4. Some case histories

5. Concluding thoughts

Philadelphia Chromosome: t(9;22)(q34;q11)

1960 Peter Nowell David Hungerford 1973 Janet Rowley

http://news.uchicago.edu/sites/all/files/imagecache/image_landingpage_zoom/images/image/20131217/zditqpecum.7815.20131217.jpg

28 May 2001

N

N

N

H

N

H

N N

N

O

N

(C30H35N7SO4)

Imatinib mesylate

(STI571; Glivec®)

Survival for Patients with CML by Treatment Era

Courtesy of Prof H Kantarjian; adapted, with permission, from Harrison’s Principles of Internal Medicine, 2014.

EVOLUTION OF GENOME DRIVEN THERAPIES FOR CANCER

• 1970’s ER Testing and Hormonal Therapy for Breast Cancer

• 1990’s Cytogenetics/FISH Testing and Therapy for Heme Malignancies

• 1998 HER2 Testing and Trastuzumab for Breast Cancer

• 2001 BCR-ABL Testing and Imatinib for CML

• 2003 EGFR Mutation Testing and Erlotinib for NSCLC

• 2007 KRAS Mutation Testing and Cetuximab/Panitumumab for CRC

• 2010 EML4-ALK Testing and Crizotinib in NSCLC

• 2011 BRAF Mutation Testing and Vemurafenib in Melanoma

• 2012 ROS1 and RET Fusion Testing for Crizotinib and RET inhibitors in NSLC

• 2013 HER2 mutations in and targeted therapy for NSCLC, Breast Cancer, and MPUC

NTRK1 Fusion Testing and Crizotinib in NSCLC

• 2014 Pembrolizumab, Nivolumab for Melanoma and NSCLC

Olaparib for BRCA-mutated Ovarian Cancer

• 2015 Alectinib for Crizotinib-resistant ALK-mutated tumors

Osimertinib for T790M EGFR

Microsatellite instability indicates immunotherapy responses

• 2016 Tumor mutation burden indicates immunotherapy responses

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Targeted Therapies: Evolution into a Revolution

1998 to 2000 2000 to 2005 2000 to 2010 2010 to 2015 2015 to 2020

~150 targets in development

~700 compounds evaluated

Coming Soon

Extrapolated from BioCentury Online Intelligence Database


conceptual thoughts






What is a driver mutation?

Biological definition: a mutation that directly or indirectly confers a selective growth advantage to the cell in which it occurs Clinical definition: a mutation that has significant diagnostic, prognostic, or therapeutic implications in subsets of cancer patients and for specific therapies

©2015 Foundation Medicine, Inc. | Confidential 16

Personalized approach improves

cancer treatment outcomes

Genomics-matched targeted therapy = Best Outcome

Targeted therapy w/o mutation matching = Worst outcome

(Ref: Schwaederle et al., JCO 2015)

Response Rate to Therapy Progression Free Survival Overall Survival

P <0.001 P <0.001 P <0.001


conceptual thoughts






©2015 Foundation Medicine, Inc. 18

Test Detects Can Miss

IHC Protein expression Any alteration not known of ahead of time

FISH Copy number alterations, Rearrangements Indels, Substitutions

Hot Spot Panels Substitutions Indels, Copy number alterations, Rearrangements

Copy Number

Alterations

HER2 amplification

Trastuzumab

Insertions and

Deletions

EGFR Exon 19

Deletion- Erlotinib

Base

Substitutions

BRAF V600E

Vemurafenib

Rearrangements

ALK Fusion

Crizotinib

FOUR TYPES OF GENOMIC ALTERATIONS DRIVE TUMOR GROWTH

Limitations of traditional testing

NGS: Various Approaches • Whole Genome Sequencing (WGS)

– Determines the complete DNA sequence of an organism's genome at a single time

• Whole Exome Sequencing (WES)

– Selectively sequences only the coding areas of the genome

• Comprehensive Genomic Profiling

– Massively parallel sequencing of the entire coding region in a defined subset of genes of interest and detects all four classes of alterations

• Targeted Sequencing (Hot spot)

– Sequences only the hot spots of a subset of genes of interest

Founding Team Of Foundation Medicine Eric Lander, PhD

• Cancer genomics innovator and creator of OncoMap project

• Medical Oncology, Dana Farber Cancer Institute, Broad Institute

• NIH “New Innovator”

Levi Garraway, MD, PhD

• Recognized leader in cancer genomics, targeted therapeutics

• Founding director of Broad Institute Cancer Program

• Dana Farber, HHMI, NCI advisor

Todd Golub, MD

• Principal Investigator of The Cancer Genome Atlas program

• Clinical Pathology, Dana Farber Cancer Institute, Broad Institute

• Co-discoverer of EGFR mutations in lung cancer

Matthew Meyerson, MD, PhD

• Recognized driving force in genomics

• Founding Director of the Broad Institute

• MIT, Harvard Medical School

• Founder Millennium Pharmaceuticals

• Successful biotechnology entrepreneur

• Founder, CEO of CombinatoRx, $750M, public listing

• TR Innovator of the Year

• Boards of BIO, Forma Therapeutics, Science Museum

Alexis Borisy

2010


Analytic Validation Demonstration of high accuracy and reproducibility required for clinical use

Controlled validation studies: Cell-line pools with known alterations:

- 2056 subs 227 indels

- 210 CNAs 32 fusions

Base Substitutions (MAF 5-100%)

Sensitivity: >99.9% PPV: >99.9%

Insertions/Deletions (1-40bp, MAF 10-100%)

Sensitivity: 98% PPV: >99%

Copy Number Alterations (>20% tumor content, zero or ≥8 copies)

Sensitivity: >95% PPV: >99%

Gene Fusions (>20% tumor content, select introns)

Sensitivity: >99% PPV: >99%

Concordance studies with existing platforms on clinical samples:

- 118 subs/indels: Sequenom, PCR

- 185 CNAs: FISH, IHC

- 43 fusions: break-apart FISH

Frampton et al, Nature Biotechnology 2013

CASE PRESENTATION

22 ©2015 Foundation Medicine, Inc. | Confidential

Drilon A, Clin Cancer Res, 2015

MSKCC vs FoundationOne Comparison: In 65% of patients, a targeted therapy was identified

Targeted agent on or off

clinical trial

Targeted therapy in NCCN guidelines

No genomic alteration identified

Genomic alterations

identified, but no targeted

therapy options available

Why FoundationONEHemeTM Test was

Developed

• Detects all clinically relevant classes of genomic alterations in hematologic and soft tissue tumors

• DNAseq of the entire coding region of 405 genes and select intronic regions in 31 genes known to be clinically & biologically relevant in cancer

• RNAseq of 265 genes recurrently rearranged in cancer

• Validated high accuracy achieved by high, uniform coverage: at median exon depth of 250x, >99.5% of exons covered >100X

• Requires only small amounts of fresh (peripheral blood/bone marrow aspirate) or FFPE clinical specimens (≥50ng of DNA, lesional tissue >20% of nucleated elements)

• Customized computational biology algorithms validated for high accuracy in clinical samples with high stromal contamination

He, et al, in press, Blood, 2016


Combined DNA/RNA Sequencing Markedly Increases The Ability To Detect Fusion Genes

416 samples: Detected 56 distinct fusion/rearrangement events:

DNA- seq

Common isoforms: BCR-ABL1; PML-RARA;

MLL-PTD

RNA-seq 285 genes: Uncommon fusions/isoforms: BCR-ABL1; ETV6-ABL1

MYST3-CREBBP; P2RY8-CRLF2

PAX5-FLI1; ETV6-EVI1; CBFB-MYH11

NUP214-DEK; TCF3-PBX1

BOTH

405 genes: Extra-gene rearrangements: IGH-MYC; IGH-BCL2

IGH-BCL6

Lipson et al, Presented at American Society of Hematology Annual Meeting, December 2013.

He, et al, in press, Blood, 2016

Mutations detectable by first-generation vs NGS

Y253H

M343V

T315I

L248Q

M351V

Lower detection limit of Sanger Sequencing


conceptual thoughts






• 57 year old patient with triple negative inflammatory breast cancer

• ER/PR/HER2 negative

• Extensive prior chemotherapy with multiple regimens

• Widespread metastatic disease with extensive skin involvement

• Patient was started on HER-2 targeted therapies with chemotherapy:

• Lapatinib/Oral capecitabine 4/12-5/12->SD (difficulty swallowing)

• Lapatinib/Trastuzumab-Albumin bound paclitaxel 5/12-6/12 *

• Lapatinib/Trastuzumab-Vinorelbine 6/12-7/12- PR; she continues treatment off steroids

ERBB2 Mutated Inflammatory Breast Cancer

Cristofanilli M et al., SABCS, 2012/Ali SM et al., J

Clin Oncol. In press May 2012

Inflammatory Breast Cancer (ILC) With ERBB2 Mutation Response to anti-HER Targeted Therapy

5/15/12

8/14/12

Images provided by Dr. M Cristofanilli, Jefferson U, Philadelphia, PA

Response to Anti-HER2 Targeted Therapy

Pre-therapy: extensive active disease

Post-therapy: good response with lower/less activity

Cristofanilli M et al., SABCS, 2012/Ali SM et al., J Clin Oncol. In press May 2012

Cervix Squamous Cell Carcinoma with FBXW7 Mutation Responds to Everolimus

Before targeted therapy On Everolimus x 2 mo

Recurrent/Metastatic Uterine Carcinoma Found to Have an ALK Fusion and Responds to Crizotinib

A

Baseline

B

Follow-up


conceptual thoughts






Complexity of Cancer Genome

• Cancer evolves & adapts (in a Darwinian fashion) to both host defenses and to therapy - driven by clonal heterogeneity

• Clonal evolution contributes to resistance to therapy; treatment may hasten the evolutionary process

• Functionality: Lineage specificity of genomic abn: BRAF V600E no response to vemurafenib in colorectal cancer; HER2 amplification no benefit to trastuzumab in endometrial cancer

• Different areas of the genome may have different rates of mutation acquistion and indeed the order

Hyman et al, NEJM 2015

Concluding thoughts

• Hybrid-capture NGS technology is enabling us

to deliver evidence-based precision cancer medicine

• In the near future, comprehensive genomic profiling will incorporate predictive biomarkers for immunotherapy enabling even greater clinical application

Acknowledgements