2014 northwest melanoma symposium slide deck

Welcome to the 2014 Melanoma Symposium* 8:30 am – 8:40 am Introduction Dr. David Byrd 8:40 am – 9:40 am Familial Melanoma & Genetic Predisposition Dr. Sancy Leachman Predisposition 9:40 am – 10:10 am Intra-tumoral Immunotherapy of Dr. Shailender Bhatia Melanoma: What happens in there, does not always stay there! 10:10 am – 10:25 am Morning Break 10:25 am – 10:55 am Radiotherapy and Immune Therapy: Dr. Upendra Parvathaneni An alliance for the future 10:55 am – 11:30 am Questions & Answers with Morning Presenters 11:30 am – 12:30 pm Lunch and Networking 12:30 pm – 1:00 pm Precision Medicine Dr. David Byrd 1:00 pm – 2:45 pm Patient Panel 2:45 pm – 3:15 pm Afternoon Break – Enjoy smoothie samples from SCCA Nutrition 3:15 pm – 3:45 pm Getting Involved Dr. Tim Turnham 3:45 pm – 4:00 pm Closing Remarks Dr. David Byrd Dr. Kim Margolin

*Speakers/presentations are being filmed. Video will be available online at www.SCCAblog.org.

Welcome & Introduction

Thank You to Fred Hutchinson Cancer Research Center

Familial Melanoma & Genetic Predisposition

Sancy Leachman, MD, PhD – Keynote Speaker Chair of the Department of Dermatology

Director of the Knight Cancer Institute Melanoma Program Oregon Health and Science University

Familial Melanoma & Genetic Predisposition

Sancy Leachman, MD PhD Oregon Health & Science University

Disclosures

• Myriad Genetics

Overview

• When is genetic testing helpful?

• Available genetic tests for melanoma

• Current state of DTC genetic testing

What Is Familial Melanoma?

Hansen et al, Lancet Oncol., 2004

Hereditary Melanoma: An autosomal dominant cutaneous cancer syndrome

Pancreatic

Melanoma

Pancreatic & Melanoma

Background: Inheritance of Melanoma Risk Is Complex

Population Risk

“Low” Elevation of Risk

Moderately Elevated Risk

High-Risk

Genetics of Pigmentation & Melanoma: Low Penetrance

• Genome-wide association studies (common, low-penetrance, SNP) – Agouti signaling protein (ASIP, an MSH antagonist) – Tyrosinase (Tyr, key enzyme in melanin synthesis) – Oculocutaneous albinism 2 (OCA2, regulates melanin

synthesis) – Tyrosinase related protein (TYRP1, regulates melanin

synthesis) – SLC45A2 (melanocyte differentiation & pigmentation)

Brown et al., Nat Genet 2008; Bishop et al., Nat Genet 2009

DNA Repair Genes Associated with Melanoma: Low Penetrance

• TERT - Telomerase Reverse Transcriptase

• PARP1 • ATM • CASP8

Barrett JH, Nat Genet, 2011; 43:1108-1113 Bishop DT, Nat Genet, 2009; 41:920-925 MacGregor S, Nat Genet, 2011; 43:1114-1118

≥3 melanomas in a family (any degree of relationship) 12%-41%

≥3 melanomas in an individual 5%-23%

≥3 “cancer events” in a family (any combination of melanoma and pancreatic cancer) ~68%

Which Patients Are Candidates for Genetic Testing: “Rule of Threes”

*Only 1 criteria needs to be met. Consideration should be given to age at diagnosis, UV exposure, skin type, and ethnicity, as there may be exceptions to the “Rule of Threes.”

Leachman et al, JAAD 2009

MC1R: A Gene That Causes Red Hair

Photo courtesy of Rick Sturm, Australia

Effects of MC1R Mutation

• Melanoma risk in the general population • 2-fold increased risk per R allele

• MC1R mutations make CDKN2A mutations worse

• Penetrance in 15 kindreds with CDKN2A mutation was 50% with mean age of onset 58 years • Penetrance was increased to 84% by presence of R allele with a mean age of onset 38 years.

Palmer et al., Am J. Hum. Genet. 2000; Fargnoli et al., JID, 2009; Box et al., Am. J. Hum. Genet. 2001; Hacker et al., JID 2009

Why Test? Exceptional Lifetime Risk!

*Bishop DT, et al. J Natl Cancer Inst 2002;94:894-903. **Rulyak SJ, et al. Cancer 2003;98(4):798-804.

**Parker JF, et al. Arch Dermatol 2003;139:1019-25.

010

20

3040

50

6070

80

Melanoma Pancreatic

MelanomaPancreatic

76%

17%

Can Genetic Testing Improve Compliance with Prevention Behaviors?

Study Design • 2 large p16

mutation families • 3 study groups • Good, balanced

retention • 5 time points • Endpoints:

– Photoprotection – Skin self-exam – Total body

provider exam

Aspinwall et. Al, CEBP, 2013

Photoprotection in Unaffected Carriers (% Time Utilized)

p < 0.024

Genetic testing improved photoprotective behavior in unaffected carriers

TBSEs in the past year at 2 yrs P = 0.0002

P = 0.635

P = 0.032 P = 0.033

% re

porti

ng T

BS

E in

pas

t yea

r

Genetic testing alters compliance with TBSEs

SSE adherence from baseline to 2 yrs

Genetic testing alters compliance with SSEs

What tests are available?

Single Gene Testing for Hereditary Melanoma CDKN2A

Company Price

PreventionGenetics $540

University of Oklahoma $548

GeneDX $660

Center for Human Genetics $675

Emory Genetics $700

Ambry $900

Myriad $900

InVitae $1500

Single Gene Testing for Hereditary Melanoma CDK4

Company Price

PreventionGenetics $680

InVitae $1500 (same price if bundled with CDKN2A, so $750/gene if ordering both)

Panel Testing for Hereditary Melanoma

Company Price Genes

Yale DNA Lab $561 CDKN2A, CDK4

GeneDX $825 CDKN2A, CDK4

Fulgent $1,450 CDKN2A, CDK4, MC1R, BRCA1&2 + 8 others

Myriad $4,040 CDKN2A, CDK4, BRCA1&2 + 21 others

Ambry 4,250 CDKN2A, CDK4, BRCA1&2 +24 others

Example Panel Report - Positive

Example Panel Report - Negative

Current Status of Direct to Consumer Genetic Testing

Increasing Public Awareness: Google Trends

“23andMe”

“BRCA”

Angeline Jolie double mastectomy

FDA instructs 23andMe to stop selling tests

Reactions to New Technology: Utopian

Reactions to New Technology: Terror

Rapidly Evolving Landscape

2011 2013

Current Landscape Company Price What Tested? Results to? Counseling?

23andMe* $99 SNPs Consumer Yes/No (Informed DNA)

DNA DTC $900 $7,000

Exome @ 80x Genome @ 30x

Consumer, raw data

No

Genetic Testing Laboratories

$315 SNPs MD Yes

Pathway Genomics

$399 SNPs MD Yes

Counsyl

$600 $1,000

SNPs via PCR SNPs via exon seq

MD Yes

*Not currently offering tests

Timeline of a Landmark Year: 2010

• Beginning of Myriad litigation culminating in Supreme Court decision in 2013 against Myriad stating that a “DNA segment is a product of nature and not patent-eligible merely because it has been isolated”

• FDA warns genetic companies doing DTC testing that tests will be considered medical devices

• Two companies, deCODEme and Navigenics, stop sales and are acquired by other companies in 2012

• Other companies (Counsyl, Pathways) quickly end DTC sales

23andMe and the FDA • Saliva sample ‘spit kits’ submitted for SNP

genotyping • Time magazine ‘Invention of the Year’ 2008 • 650,000 tests to date • Affiliation with Google and access to ‘big data’ • FDA’s 2010 take: medical devices, have not

been analytically or clinically validated • November 2013: FDA stops sales of 23andMe

kits • Two class-action lawsuits pending for

“misleading advertising”

Summary

• When to test: Rule of threes

• Available genetic tests for melanoma: Single gene and panel tests available

• Current status of DTC genetic testing: Controlled

Future Questions

• What is the future for direct-to-consumer genetic testing? Is there one? Should there be one?

• Should DTC testing be considered a medical device, or something else?

• What will the real legacy of this new, powerful technology become?

Acknowledgements

• Matthew Majerus, M.D. – OHSU Dermatology Resident, PGY-2

Intra-tumoral Immunotherapy of Melanoma: What happens in there, does not always stay there!

Shailender Bhatia, MD

Assistant Professor, Medical Oncology Department of Medicine UW / SCCA / FHCRC

Intra-tumoral Immunotherapy: What happens in there,

does not always stay there

Shailender Bhatia, MD University Of Washington

1. Establish goals of care • Durable disease-control (CURE) • Prolong lifespan • Preserve/improve Quality-of-life

2. Match desired goals to the safety/efficacy characteristics of the therapy

• Rate of tumor shrinkage or clinical benefit • Kinetics of response (rapid vs delayed) • Duration of response • Side-effects • ?Cost

Systemic therapy is the mainstay of therapy for metastatic disease

Until 2011, few standard therapy options existed.

Treatment of Metastatic Melanoma: An Overview Bhatia S et al. ONCOLOGY. 2009; 23:6; 488-500

US-FDA approved therapies for metastatic melanoma. Dacarbazine (1975) No proven OS benefit High-dose IL-2 (1998)

Cancer Immunotherapy Works (Albeit only in a small subset of melanoma patients)

Response

ORR ~16%

CR 6%

Majority of CR’s are durable.

Likely CURED

Toxicity is substantial

Retrospective Analysis of 270 patients treated at the NCI by High-Dose IL-2

[Atkins, MB et al. JCO (1999)]

Hodi FS et al. NEJM. 2010

2010: The ceiling was finally broken

Ipilimumab: An Example of Response

Maggon et al, 2011

However, responses are infrequent, and complete remissions (CR) rare.

Adverse Events from Ipilimumab

[Hodi FS et al. NEJM. 2010]

Immune-related AE Any grade (%)

Grade 3 or higher (%)

Any IrAE 60 15 Dermatologic (pruritus, rash, vitiligo)

43 2

GI (Diarrhea, colitis) 29 8 Endocrine (Hypophysitis, hypothyroidism, adrenal insufficiency)

8 2

Hepatic 4 0 Others 5 2

True impact of Ipilimumab’s success story goes far beyond Melanoma

[Topalian S et al. NEJM. 2012; Brahmer J et al. NEJM. 2012]

[Wolchok J et al. NEJM. 2013]

Near-CRs seen in a large proportion of pts

ORR 40% N=47; All dose levels included


Toxicities can be a problem though

• Grade 3/4 treatment-related AEs: 53% – Elevations in Lipase (13%), AST (13%, ALT (11%)

• Cohort 3 (Nivo 3 + Ipi 3) deemed to have unacceptable

level of toxicity – 3/6 patients had Gr 3 or 4 lipase elevations lasting

more than 3 weeks.


Why does immunotherapy not work all the time?

[Weiner L NEJM 2008 ]

http://content.nejm.org.offcampus.lib.washington.edu/content/vol358/issue25/images/large/02f1.jpeg

Intra-tumoral Immunotherapy

53

• Takes the action into the heart of the tumor, where it is needed

• May have a better chance of overcoming local immune evasion mechanisms.

• Avoid systemic toxicity

Systemic versus Local Immunotherapy

SYSTEMIC

Potential for ‘Global’ responses in what is essentially a ‘systemic’ disease. Systemic toxicities - Overkill for solitary or oligo-metastatic disease.

? Adequate intratumoral drug levels – limited dose-escalation due to systemic side-effects. – penetration into the tumor microenvironment.

LOCAL

Mostly local toxicities

? Feasibility – dependent upon location of the lesions (superficial versus deep; critical organs)

? Decreased potential for ‘global’ responses

Several potential advantages to intratumoral immunotherapy

• Improve the risk:benefit ratio of otherwise-toxic drugs.

• Stimulate immune responses against diverse (including unknown) tumor antigens.

• May overcome the hostile immune-suppressive tumor microenvironment (TME)

But, can the local benefits spill over into the

systemic circulation?

Scientific hypothesis: What happens there, does not always stay there.

How to assess systemic immune responses from local immunotherapy?

• Regression of distant non-injected lesions. - Preferably in a different organ type (e.g. visceral tumor regression from injection of cutaneous tumors)

• Prolonged stable disease or progression-free

interval.

• Anti-tumor immune responses in peripheral blood.

Intratumoral Injection of IL-12 plasmid followed by in vivo Electroporation

Interleukin-12 (IL-12)

• Powerful immune stimulant

• Anti-cancer efficacy seen in early clinical trials

• However, systemic administration of IL-12 was

associated with severe toxicities. - GI, Liver toxicity - Death.

Adil Daud, MD UCSF

[Daud A et al. J Clin Oncol 2008]

Treatment led to Increased Intratumoral Expression of IL-12 protein

(for up to 5 weeks after only 3 injections on days 1,5, 8)


Clinical Efficacy

Distant responses in 4/19 patients – 3 CRs Disease Control Rate = 10/19 or 53%



Development of Vitiligo

Phase 2 Study of IL-12 EP in patients with

Merkel Cell Cancer And

Melanoma

• IL-12 EP is delivered on days 1, 5 and 8 of each cycle.

• Maximum of 4 tumors (or treatment zones) are treated in each cycle; different set of tumors can be picked for a new cycle.

• The total daily dose of IL-12 plasmid is 1 mg in 2 mL (0.5

mg/mL); 0.25 mg per each treatment zone.

Study Methods (Contd)

The EP applicator (OncoSec Medical Inc) delivers six pulses at a field strength (E+) of 1300 V/cm and pulse width of 100 µs.

Study Methods (Contd)

Then the show begins.

Increased Intra-tumoral IL-12 protein expression

• 3 patients have paired baseline and post-treatment (week 3) tumor IL-12 protein levels available (as measured by a validated ELISA). – The IL-12 protein level is

increased [25-1000 fold] post-treatment in 3/3 (100%) patients’ biopsy samples [Figure].

Figure: Increased IL-12 protein expression in post-treatment versus baseline tumor biopsy in 3/3 patients.

[Bhatia S et al. SITC poster. 2012]

Impressive response in some patients

Pre-treatment Post-treatment (Day 270)

Intriguing evidence of systemic immune response in another patient

Post-treatment (Day 25)

Therapy has been tolerated well with mostly mild local side effects.

Most common treatment-related AE is transient (lasting ~ 3 seconds) pain associated with electroporation.

– No systemic side-effects (such as flu-like symptoms) have been noted in any patients so far.


002: C2 Wk2 002: C2 Wk6

Mild injection-site discoloration has been noted in some patients.


W420 TIL samples

IFNg response by W420 TIL in presence MCPyV CT44-52 peptide

Oct’11 Jan’12 Feb’12 Sep’12 Oct-Nov’12

No IFNg response by W420 TIL in presence of ST83-91 peptide IFNg response by W420 TIL in presence of ST83-91 peptide

Patient 002: Suggestion of epitope

spreading

IT CD8+ Infiltration (prelim)

Figure: There appears to be increased CD8+ infiltration into the tumors after therapy (patient 005).

In 1/2 patients, there appears to be increased CD8+ infiltration into the tumors; rest had insufficient tumor tissue for comparison.

Summary

• Local delivery of IL-12 is feasible via intratumoral injection of IL-12 plasmid DNA followed by in vivo EP.

• Treatment is tolerated well overall, with transient

grade 1 pain associated with EP.

• No systemic treatment-related AEs occurred so far.

• Preliminary evidence of efficacy has been noted with regression of injected as well as non-injected tumors in some (but not all) patients.

Intratumoral Immunotherapy of skin cancers at SCCA.

A phase 2 study of pIL-12 EP in patients with MCC. {PI: Bhatia} A phase 2 study of pIL-12 EP in patients with Melanoma. {PI: Adil Daud, UCSF} A proof-of-concept trial of intratumoral GLA (synthetic TLR-4 agonist) in MCC. {PI: Bhatia} Single 8-Gy Radiation therapy of MCC tumors. {Led by: Parvathaneni}

OncoVEXGMCSF in melanoma (Oncoloytic HSV-1 expressing GM-CSF)

Talimogene laherparepvec (T-VEC)

Phase 2 results with OncoVEXGMCSF

[Senzer NN. JCO 2009]

Disease may be too aggressive for immunotherapy in some patients

003 C1 D1

Pt 003 (SM) - Recurrent MCC – 4 zones treated – PD after 1 cycle – responded nicely to salvage RT

003 C1 D29

0 50 100 150 200 250 300 350 400

Days from diagnosis

Response to therapy or stable disease on the CT scan

Progressive disease on the CT scan

41BB (164 dys without PD)

W787, 56 yo woman (nurse), 7 cycles of 41BB at 0.12 mg/kg

XRT XRT

Combining local with systemic immunotherapy

Combining local with systemic immunotherapy

Conclusions

• Local intratumoral immunotherapy can result in clinically meaningful systemic immune responses.

• Toxicity is generally favorable with mostly local AEs.

• Combination of local and systemic immunotherapy

approaches may overcome some limitations of either approach and deserve further investigation.

What happens in Vegas, does not always stay in Vegas!

Acknowledgments

Patients/Families

Kim Margolin John Thompson Paul Nghiem

Clinicians Scott Tykodi Upendra Parvathaneni David Byrd Sylvia Lee Aude Chapuis

Clinical Support Staff Jeanette Hammond, PA RNs (Jon, Debbie, Christine, Sharon) Marla Teeny (TC)

Research Support Staff Nichole Real (RC) RCs (Cassie Oh, Mike Donahue) Phase 1 team Sandy Bergevin, Sarah P

Nghiem Lab

Adil Daud, Rich Heller, OncoSec

Kauai, here I come!!

Morning Break

10:10 – 10:25 am

Radiotherapy and Immune Therapy: An alliance for the future

Upendra Parvathaneni, MD

Assistant Professor, Radiation Oncology University of Washington School of Medicine

Radiation Oncologist, Seattle Cancer Care Alliance

Radiotherapy and Immunotherapy : an alliance for the future

Upendra Parvathaneni Radiation Oncologist, University of Washington

April 2014

disclosures

• none

Objectives

• Brief introduction to radiotherapy (RT) in melanoma

• Observations of systemic/immunologic effects of RT

• RT interaction with immunotherapy – the new frontier

• Modern RT tools to target tumors

RT effects on melanoma

Traditional role of RT in melanoma

• Post operative treatment of “high risk” node positive patients

• To prevent local cancer relapse within the treated field

• RT was fractionated over 3-6 weeks to allow normal structures to repair between treatments

• RT for palliation of metastases

Palliative RT for melanoma

Dose = energy absorbed in tissues at a specified depth Units : Gray (100 cGy)

Megavoltage linear accelerator

Major types of RT & physical properties

• Photons/Xrays

• Electrons

Depth in tissue

absorbed dose

Depth in tissue

absorbed

dose

RT target = DNA

• maximum effect on dividing cells that rely on intact DNA during cell division

• Hence, tumors with dividing cells responded to RT

• Normal cells are relatively spared, if allowed to repair

Immune system is needed to fight cancer

Immunotherapy in Melanoma

• Interferon 2a • Interleukin -2 • CTLA 4 blockade (ipilumimab) • Anti PD -1 therapy • Therapeutic vaccines

Systemic/Immunological effects of RT – the new biology

Demaria et al. IJROBP. 2005;63(3):655-66.

Immunological effects of RT in melanoma

• Animal modals – eg fewer lung mets in mice that had RT (25 Gy) to melanoma vs no RT b4 surgery. Perez et al Int J Radiat Biol 2009;85:1126-36

• Clinical data :

- abscopal effects - vitiligo effects

Abscopal effects of RT

• ab = away from (latin) scopus = target, aim (greek)

• Abscopal effect is a phenomenon where localized irradiation of a tumor causes not only a shrinking of the irradiated tumor but also a shrinking of tumors far from the irradiated area.


• Described in melanoma, renal cell ca, lymphomas, merkel cell ca, etc…

• First reported in a case of melanoma in 1975 - treatment with neutrons (14.4 Gy) to groin nodes regressed pelvic and para aortic lymph nodes. Kingsley DP Br J Radiology 1975;48:863-66

Abscopal effects of RT +

ipilumimab

N Engl J Med 2012;366:925-31.

RT: 28.5 Gy in 3 fx

Regression of untreated mass in hilum of lung Regression of Untreated masses in liver and spleen

RT = 27 Gy in 3 # 3 and 6 months post RT

Abscopal effects RT + ipilumimab

Immunological effects of RT in melanoma

Note - depigmentation “vitiligo” effect : sign of effective immunotherapy Vitiligo in non irradiated sites noted in some cases

Halo depigmentation – an immunologic effect of RT note : around treated lesions

compared with RT skin reaction in the rest of the field

RT + high dose IL2 immunotherapy

• Pilot study of 7 pts with metastatic melanoma • 1-3 doses of RT (20-60Gy) + high dose IL-2 • 71% achieved a response - 1 CR and 4 PR • Median duration of response = 553 days • Much higher than historically expected

response rates (10-15%)

www.ScienceTranslationalMedicine.org 6 June 2012 Vol 4 Issue 137

Discordant effects of RT

• Systemic RT – total body irradiation = immune suppressive - used to suppress host immunity against foreign graft during allogeneic bone marrow transplantation

• Local RT = immune stimulatory

• High dose per fraction reqd for immune

stimulatory effects - possible only with newer techniques

Developments in RT technology allow for the use of

high-dose ablative RT (8-20 Gy) to target tumors

with limited damage to the surrounding normal tissue

Historical RT = crude techniques accurate BUT morbid

Technological advances : IMRT

multiple beam angles

parts of target are treated by “segments” of a beam

intensity map of each field conforms with target in 3 dimensions

IMRT = highly conformal steep dose gradients

Proton RT at UW Feb 2013

protons vs photons

Our 1st H&N proton patient

Optic chiasm sparing treatment

RT available at UW

• Conventional RT with conformal techniques: IMRT, SBRT

• Gamma knife • Protons

• Neutrons

Thank you

Questions & Answers with Morning Presenters

Dr. Sancy Leachman

Dr. Shailender Bhatia

Dr. Upendra Parvathaneni

Lunch & Networking

11:30 am – 12:30 pm

Personalized and Precision Medicine in Cancer Care

David Byrd, MD Director of Surgery, Seattle Cancer Care Alliance

Co-Chair, Northwest Melanoma Symposium

Personalized and Precision Medicine in

Cancer Care David R Byrd, MD

Director of Surgical Oncology SCCA

Professor, Department of Surgery University of Washington

IOM Report Sept 10, 2013 Delivering High-Quality Cancer Care:

Charting a New Course for a System in Crisis

• Crisis is due to: – Growing demand for cancer care:

• In U.S. 14M have had cancer • 1.6M new diagnoses/year

– By 2030, expect 2.3M new diagnoses/year

• By 2022, expect 18M cancer survivors – Increasing complexity of treatment – Shrinking workforce – Rising costs

www.iom.edu/qualitycancercare

Personalized Medicine - covers the entire continuum of

quality cancer care Tesla

Diagnosis and Staging of Cancer

• Histology • Immunohistochemistry • Molecular diagnostics:

– Genomics of tumor – Pharmacogenomics – Other omics

Histologic Diagnosis and Cancer Staging (TNM)

• Primary tumor organ of origin – Breast, colon, etc. = T

• Spread to regional lymph nodes = N • Spread to distant sites/organs = M

Melanoma (Tissue level)

Normal skin melanoma

Primary tumor thickness– 1.2 mm, ulcerated: (T2b)

Lymph node metastasis – N1

Lymphocytes

melanoma cells

Metastasis to bone - M1

Pathologic Staging T2b N1 M1 – Stage IV Provides clinicians and patients with: - size/local invasion of primary - extent of spread of disease - prognostic information

Melanoma Survival Curves by Stage

Sur

viva

l Rat

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival Time in Years

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Stage I (n=18,370)

Stage II (n=9,269)

Stage III (n=3,307)

Stage IV (n=7,972)

AJCC Cancer Staging Manual, 7th ed, 2009

Dr. Michael Kattan

Chairman of Quantitative Health Sciences, Cleveland Clinic

-Apply molecular diagnostics -Deliver targeted therapy to actionable mutations in tumor

Precision Medicine

The Promise of Precision Medicine in Cancer Care

Morphologic diagnosis and phenotypic tumor classification Generic therapeutic regimens with unpredictable effectiveness Treatments with unpredictable adverse effects on patients

Molecular characterization of tumors and pathways Targeted therapies tailored to the molecular profile of the disease Drug regimens planned around host genetics that portend toxicity

Advances in Molecular Technologies and Research

Understanding Molecular Biology of Host and Disease

Empiric – population-based Precision Medicine

Courtesy of Dr. Carolyn Compton

Precision Medicine Issues

• Technology – evolving rapidly • Genetic and molecular diagnostics • Effectiveness of targeted treatment • Affordability/Costs • Ethics • Prevention

Personalized Medicine: Replacing Trial and Error Medicine

Reproduced with Permission from the Personalized Medicine Coalition.

Immunohistochemistry IHC – Melanoma (Cell level)

Precision Medicine What’s Under the Hood?

Genetic Mutations in Cancer

• Germline mutations: – Present at birth – Present in all cells – Can identify predisposition to cancer(s)

• Somatic mutations: – Acquired during life – Found in tumors in abundance – Can be exploited as specific targets for

treatment of cancers

BROCA Comprehensive Cancer Panel (Germline Genetic Testing)

Disclosure of Genetic Testing Results

• Genetic Counseling up front • Panels of genes may identify other

consequential mutations – Should the patient be informed of all the

information that will be obtained? – Who “owns” the management of unintended

genetic results? • The ethics have not been worked out!

Lolkema et al JCO, 2013

Somatic Mutations Schema of Precision Medicine

MacConaill L E , Garraway L A JCO 2010;28:5219-5228

©2010 by American Society of Clinical Oncology

Genetic and Molecular Diagnostics (Intracellular)

• Sequencing of segments of DNA coding for mutated proteins – e.g. EGFR, KRAS, BRAF, ALK

• Gene Panel testing of known or suspected mutations – UW: OncoplexTM

• Whole exom DNA sequencing

Exemplary Oncoproteins and Targeted Cancer Pathways

Cell surface membrane

DNA

Garraway, et al. JCO 31:1806-1814, 2013

Cell signaling



DNA


Cell signaling

Therapeutic targets In lung carcinoma



DNA


Cell signaling

Therapeutic target in melanoma



DNA


Cell signaling

Therapeutic target in hereditary breast CA

Colin Pritchard, UW Lab Medicine

Tier 1: Currently Actionable

ABL1 ALK BCR BCL2L11 BRAF RET CDK4 CEBPA KIF5B DDR2 EML4 EGFR ERBB2 FLT3 IDH1 IDH2 JAK2 RARA

KIT KRAS MPL NPM1 NF2 NRAS PDGFRA PML RICTOR ROS1 TSC1 TSC2

Tier 2: Actionable in the Near Future

ABL2 AKT1 AKT2 AKT3 ASXL1 ATM AURKA AURKB BAP1 BCOR CBL CBLB CDK6 CDK8 CHEK1 CHEK2 DNMT3A EPHB2 ERBB3 ERBB4 FGFR1 FGFR2 FGFR4 FLT1 FLT4 GATA2 GNA11 GNAQ GRM3 HDAC4 HIF1A HRAS IGF1R JAK3 KDM6A KDR

MAP2K1 MAP2K2 MAPK1 MC1R MCL1 MEN1 MET MLH1 MLL MRE11A MSH2 MSH6 MYC MYCN NOTCH1 PAX5 PDGFRB PIK3CA PIK3R1 PMS2 PTEN RAF1 NKX2-1 SMO SRSF2 SUZ12 TET2

TYR VHL MITF ERCC2

Tier 3: Frequently Mutated

APC BAK1 BCL2 CCND1 CCNE1 CDH1 CDKN2A CREBBP CRLF2 CSF1R CTNNB1 EPHA3 EPHA5 EPHB6 ETV6 EZH2 FBXW7 FGFR3 GAB2 GATA1 GNAS GRIN2A HNF1A IKZF1 IL7R JAK1 MAP2K4 MDM2 MDM4 MUTYH MYCL1 NF1 STK11 NOTCH2 PBRM1 PRPF40B PTCH1 PTPN11 PTPRD RB1 RPS14 RUNX1 SF1 SF3B1 SMAD2 SMAD3 SMAD4 SMARCA4 SMARCB1 SPRY4 SRC TFG TGFBR2 TP53 TRRAP U2AF1 U2AF65 WT1 ZRSR2

Germline Pharmacogenomics

ABCB1 ABCC2 ABCC4 ABCG2 C1orf144 COMT CYP1B1 CYP2C19 CYP2C8 CYP2D6 CYP3A4 CYP3A5 DPYD EIF3A ESR1 ESR2 FCGR1A UMPS FCGR2A FCGR3A GSTP1 GUCY1A2 ITPA LRP2 MAN1B1 MTHFR NQO1

NRP2 SLC19A1 SLC22A2 SLCO1B3 SOD2 SULT1A1 TPMT TYMS UGT1A1

UW-OncoPlex™ v2

Genes Targeted: 194 DNA Sequenced: >850,000 bp

>500X Coverage

Next Generation Whole Exom DNA Sequencing

• Technology is here now • Costs are expensive but plummeting • Time to interpret results is long but

decreasing • The volume of data generated is vast,

especially over time • Emerging field of computational

biology

Treatment for Metastatic Melanoma 1980’s to 2011

• Node positive melanoma – alpha interferon only FDA-approved additional treatment

• Metastatic (distant sites) melanoma – DTIC (chemo) or Interleukin-2

• Clinical trials

Targeted Pathways in Melanoma

Fecher, et al JCO 25:1606, 2007

Modeling of Information Flow in Biological

Networks

Targeted Therapeutics and Cancer: Harder Than We Thought

Molecular Subtyping and

ID of RX Targets

Rx-Resistance via

Redundant Molecular Pathways

Initial Rx-Response to

Targeted Rx

B = 15 weeks Rx (Zelboraf®) C = 23 weeks Rx and emergence of MEK1C1215 mutant Wagle et al. (2011) JCO 29, 3085)

Courtesy of Dr. Carolyn Compton - AJCC

Emerging Immune and Molecular Strategies/Therapies in Melanoma • Targeted therapies:

– Mutated BRAF inhibitors – vemurafenib, dabrafenib

– C-kit inhibitors – Imatinib (Gleevec) – MEK inhibitors – trametinib

• Immunotherapy – immune checkpoint blockers: – Ipilimumab (Yervoy) - anti-CTLA-4 antibody – Anti –PD-1 – Nivolumab, Lambrolizumab

Pre-Rx

Post-Rx

Immunotherapy for Melanoma

The Path Forward

The Problem

“…there are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns -- the ones we don't know we don't know." --Donald Rumsfeld

http://www.youtube.com/watch?v=GiPe1OiKQuk

Slide courtesy of Dr. Richard Schilsky

What Do We Know?

• Targeted therapy makes clinical sense and is available now for some cancers

• Targeted therapy doesn’t always work or effectiveness is short-lived

• Tumors evolve in the patient, spontaneously and under selection pressure

• Costs of testing and targeted treatment must be addressed up front.

• Resurgence of promise for immunotherapy

What Don’t We Know? • How to optimally combine agents (dose,

schedule, sequence) • How to efficiently integrate data sets • How to quickly convert a lab assay to a clinical

test • How to navigate regulatory mazes • How to convey test results to physicians in a

useful format • How to define how individual tumors behave • How to present the economic case for targeted

therapy

Courtesy of Dr. Richard Schilsky

Costs of Genetic Sequencing

We are rapidly approaching availability of the $1,000 genome

The Patient of the Past

The Patient of the Future

DNA Sequence Barcode on

forehead

Doctor, what do we do about this?

“You want the Truth? You can’t handle the Truth.”

Jack Nicholson - A few Good Men

Linear Growth

Exponential Growth

Technology

Clinical Care

Gap

Rat

e of

Impr

ovem

ent

Doing One’s Best: 2013

Thank you!

Patient Panel

1:00 – 2:45 pm

Afternoon Break

Enjoy healthy smoothie samples from SCCA Nutrition in the Great Hall!

2:45 – 3:15 pm

Getting Involved

Tim Turnham, PhD Executive Director

Melanoma Research Foundation

Getting Involved

April 5, 2014

Tell Your Story

181

Melanoma is not widely recognized.

Oh, my friend had that. No, wait it was lymphoma, or was it mesothelioma, no maybe multiple myeloma….

Melanoma? That’s just skin cancer, right?

The consequence is a cavalier attitude toward risk, toward early detection, and even around treatment.

Tell Your Story: Primary Prevention

182

UV Radiation is a factor in the majority of cutaneous melanomas (maybe as high as 75%) in the United States. •Tanning salons

– More numerous than Starbucks/MacDonalds – Largely unregulated: bulb intensity, frequency of use, etc. – Often uses misleading marketing

•Culture of tanning – “Healthy glow” – Beauty/fashion/celebrity industries are selling a lie

Tell Your Story: Secondary Prevention

183

Early detection is key!

Tell Your Story: Patient Education

184

What about the patient in North Dakota who doesn’t look for information on the internet, won’t travel for care, and whose oncologist sees one or two melanomas a year?

– # of patients in clinical trials – # of patients treated with Dacarbazine/chemo

CME and general marketing won’t work; key is peer-to-peer communication.

Share Your Strength

185

MRF education and volunteer efforts are built on the absolute conviction that patients who are well informed and well supported live longer and better

• Support Groups •MPIP • Phone Buddies

Become a Lobbyist!

186

•Ongoing “asks” – Tanning legislation—federal and state – CDMRP – NIH/CDC

•Emerging Issues – Oral Parity – Specialty Tiering – Pricing policies (per mg)

•How to get started – MRF Hill Day – Virtual Advocacy Program

Invest In Better Solutions

•Miles for Melanoma •Host a fundraiser •Write a check •Consider an estate gift

187

Do Something!

Commit to doing two things in the next year: • Send an email to your member of Congress • Hold a dinner party and tell your story • Contact local media • Run in a Miles for Melanoma event • Speak at a school group • Write a check to some melanoma effort • Sign up to volunteer • Make at least one post on MPIP • Take patient or caregiver brochures to your dermatologist/oncologist • Create a fundraising event • Participate in a clinical trial • Become a Phone Buddy

188

Together we can change the world!

189

Step by step the longest march Can be won, can be won.

Many stones to build an arch; Singly none, singly none.

And by union what we will, can be accomplished still.

Drops of water turn the wheel sing we on, sing we on.

Thank you for joining us at the 2014 Melanoma Symposium!

(Video footage of the symposium will be available at the end of April at www.sccablog.org.)

http://www.sccablog.org/