ST101 Companion Diagnostics for Targeted Therapy in …handouts.uscap.org/2016_cm15_linde_1.pdf ·...

ST101 Companion Diagnostics for Targeted Therapy in CancerDavid G. Hicks, MD, FCAP, Jeffrey A. Kant, MD, PhD, FCAP and Neal I. Lindeman MD, FCAP

September 9, 2012

© 2012 College of American Pathologists. Materials are used with the permission of the faculty. Lindeman - 1

Molecular Diagnostics in Lung Cancer:Is it worth it?

Neal Lindeman, MD

Director, Molecular DiagnosticsBrigham and Women’s Hospital

Associate Professor of Pathology Harvard Medical School

American Society for Investigative PathologyCompanion Meeting, USCAP

March 12, 2016

Van Gogh, 1885

Introductions

2

I *DO* have conflicts of interest!

Astra Zeneca – consulting re: engaging pathologists in clinical trials(selumetinib in KRAS+ lung cancer)

Molecular Pathology: in the middle of a storm

4

Patients and Docs

Notas: Industry

Euros: Government

Boreas: Insurance

Zephyros:Academics


September 9, 2012


Academics: we started this� What is our true Conflict of Interest?

• Publications• Grants• Career development• Centers of excellence

� “Precision Medicine”• Optimism: better outcomes• Blurring of research and practice

• “n of one” experiments• “basket” trials

� Fun and Interesting 5

Industry: Fanning the flames� Venture Capital: quicker ROI than drugs

• Take loss build market sell� Tech manufacturers: Outpacing “Moore’s Law”

• Sell boxes/juice

� Dx companies: LDT “loophole”• Bypass FDA• [IP protection]• More flexibility than hospitals

� Pharma: more successful trials• Better outcomes• “Save” failed drugs 6

Insurance: Cooling it down

� Evidence-based medicine• Pessimism in medicine• Do no harm

� Cost containment• Tests are expensive• Drugs are really expensive

� Distinction between research and practice• If it’s unproven, it’s an experiment• Patients and payers don’t pay for research 7

Government: Braking wind

� Regulation of lab tests• CLIA/CMS: labs as medical practice• FDA: tests as devices• “LDTs”: tests unique to one lab

� FDA: LDTs are unsafe• No clinical validity or utility• Lack of standardization

� FDA proposal• Premarket approval vs. standards-based 8


September 9, 2012


Patients and their doctors:What should we do?

� Is there clinical benefit to molecular diagnostics in cancer?• Under what circumstances?• How big is the benefit?• Should we pay for it?

Fundamental conflict:Evidence-based medicine vs. Precision Medicine

9

Use case: lung cancer

� Why lung cancer?• Very common

• Rapidly & inexorably progressive disease• Can assess outcomes quickly• Patients more willing to try novel therapies

• Multiple molecular alterations• Differing levels of utility

10

Case Presentation:

� 52 yr old female � Symptoms (months):

• Headaches• Light/dark sensitivity• Chronic dry cough

� MRI: • Enhancing dural mass

� DDx: ???

11

Case Presentation:

� 52 yr old female � Symptoms (months):

• Headaches• Light/dark sensitivity• Chronic dry cough

� MRI: • Enhancing dural mass

� Differential Dx: • Tumor

• Meningioma• Lymphoma• Metastasis • Primary CNS tumor

• Granuloma• Sarcoidosis• Tuberculosis

• Chronic meningitis• Wegener’s

12


September 9, 2012


Case presentation:� Brain biopsy:

13

Case presentation:

� Brain biopsy:• Adenocarcinoma

• Lung• Colon• Other

14

Case Presentation

� Follow-up imaging studies• 5 cm lung mass• Additional masses:

• Lung (x2), liver (x2), bone

� Non-small Cell Lung Cancer, Stage IV

15

Lung Cancer is Bad

� Survival @ 18 months:• Stage I: 49 – 65% • Stage II: 39 - 55%• Stage III: 4 – 15%• Stage IV: 1%

� Median survival:• Stage I/II: 17 – 32 months• Stage III: 9 - 22 months• Stage IV: 16 – 36 weeks

Van Gogh, 1885 16


September 9, 2012


Lung Cancer is Bad for society

� 14% of cancers

� 28% of deaths

� 71% mortality

American Cancer Society, 2011

Cancer Mortality, 2011

ng

al

st

as

te

ia

ma

er

ry

er

ey

S

ma

ma

us

id

Deaths

LungColorectal

LeukemiaProstate

PancreasBreast

LymphomaLiver

OvaryBladderKidneyCNS

MelanomaEndometrium

Thyroid

Myeloma

20K20K

40K

60K

80K

100K

120K

140K

160K

U.S. Cancer Deaths, 2011

17

Lung Cancer Treatment: 2004

� Stage I: surgery� Stage II: surgery� Stage IIIA: surgery

• +/- XRT• +/- chemotherapy

� Stage IIIB: chemo + XRT� Stage IV: chemo, palliation

18

Return to Case:� History:

• Never smoked• Course:• 4/01: Carboplatin-Paclitaxel

• Response for 6 wks• Progression by 12/01

• 12/01: Cetuximab (Erbitux)• Stabilization for 4 mos• Progression by 7/02

8/02

5/03

19





• 8/02: Gefitinib (Iressa)• Sustained response for 30 mos

8/02

5/03

20


September 9, 2012






• 8/02: Gefitinib (Iressa)• Sustained response for 30 mos• Relapse in 2/05

8/02

5/03

2/05

21

Case summary:

� 52F nonsmoker with stage IV NSCLC• Expected survival: ~ 6 mos• Likelihood of being alive after 18 mos: ~1%

� Initial treatment with platinum chemo• Initial response, but quick relapse

� Tried two anti-EGFR study agents• Erbitux: progressed on therapy• Iressa: regression, 30 mos after Dx!

22

What is EGFR and why target it?

23

EGFR signaling simplified:

� Ligand binds� Receptor Dimerization � Phosphorylation� Downstream signaling

• RASRAFERK• JAKSTAT• PIK3CAAKTmTOR

� Cells proliferate, survive

Very commonly overexpressed in human carcinomas24


September 9, 2012


Iressa* worked really well… sometimes

� Phase II: Dramatic response in 10% of NSCLC • ~20,000 patients per year in US

� How to predict the responders?• Clinical Predictors• Surgical Pathology Predictors• Molecular Genetic Predictors

Miller, et al., J Clin Onc 200425

*Iressa is the tradename for gefitinib sold by Astra Zeneca, for whom I have done consulting on an unrelated project. Iressa is not available in the US

Why isn’t Iressa available in the US?� Old school phase III trials: Iressa failed

• Criteria for treatment: NSCLCTRIAL Drug n Survival Placebo

INTACT-1 Iressa 1093 9.9 10.9

INTACT-2 Iressa 1037 9.8 9.9

ISEL Iressa 1692 5.6 5.1

TRIBUTE Tarceva 1059 10.6 10.5

TALENT Tarceva 1172 43 wks 44.1 wks

BR.21 Tarceva 488 6.7 4.7

26Iressa: Astra Zeneca* Tarceva: Genentech

WHOM to treat?(Mutation was not the world’s first thought)

� Clinical criteria: inadequate predictors

IRisk Ratio

M-H, Random, 95% CI

0.01 0.1 1 10 100Mutant No Mutant/ Wild typ

GENDERRisk Ratio

M-H, Random, 95% CI


AGE

CIRisk Ratio

M-H, Random, 95% CI


TOBACCORisk Ratio

M-H, Random, 95% CI


ETHNICITY

<65

>65

F

M

No

Yes

Asia

West

Afr

27

IHCRisk Ratio

M-H, Random, 95% CI

0.02 0.1 1 10 50High Low

FISH

How to test for EGFR?Molecular Diagnosis!

CI

]]]]]]]]]]]

]]]]]]]

]]

Risk RatioM-H, Random, 95% CI

0.05 0.2 1 5 20High Low

IRisk Ratio

M-H, Random, 95% CI


Mol Dx

28


September 9, 2012


What hath EGFR wrought?Oncologic Transformation� Old School:

• Nonspecific therapy targets all replicating cells• High toxicity, low efficacy

• Stage, grade, histology determine therapy• Small cell / Non-small cell

� New Wave:• Target specific problematic molecule

• Less toxicity, ?higher efficacy?• Molecular classification helps determine therapy

29

Lung Cancer, c. 2005-2008� Horrible, lethal cancer from which most

patients died quickly, for decades, with no major improvements in outcome

� EGFR Hope• Pessimism: Evidence-based medicine

• Better definition of when EGFR helps

• Optimism: Personalized medicine• Search for other genes with similar effects

30

What is a favorable outcome?Radiographic Response Progression-free Survival

Overall Survival

Goss, ASCO, 2010

Evidence-based medicine:What is a response?

32

Gideon M. Blumenthal et al. JCO doi:10.1200/JCO.2014.59.0489

PFS vs ORR OS vs ORR/PFSSame data,

different display

Why not OS? Crossover


September 9, 2012


As a field, we have settled on PFS

Zhou, Lancet, 2011 Maemondo, NEJM, 2010

Evidence-based medicine:No clear benefit in early stage

34

Goss, et al., JCO, 2013BR.19 trial

Full analysis set.Median (m)

HR (95% CI) P valueE (N=623) P (N=350)

DFS 50.5 48.2 0.90 (0.741-1.104) 0.3235OS NR NR 1.13 (0.881-1.448) 0.3350

EGFR M+ subsetMedian (m)

HR (95% CI) P valueE (N=102) P (N=59)

DFS 46.4 28.5 0.61 (0.384-0.981) 0.0391*OS NR NR 1.09 (0.545-2.161) 0.8153

RADIANT trial, Kelly, et al., ASCO, 2014

Precision medicine today:EGFR resistance

35

Blakely and Bivona, Cancer Research, 2012

Should relapsed patients be rebiopsied to direct them to new molecularly targeted trials?

Precision Medicine: other genes

36Blakely and Bivona, Cancer Research, 2012


September 9, 2012


Evidence-based medicine, 2011:ALK fusion crizotinib response

Crizotinib and ALK FISH both approved by FDA, 2011Advanced stage patients

37

Mino-Kenudson, 2010Shaw, Lancet, 2011

Precision Medicine, 2015:Crizotinib resistance� Secondary mutations in ALK (~30%)

• L1196M, G1269A most common

� Activation of other oncogenes• KIT, KRAS, EGFR

Zhan

g, C

hem

Bio

l Dru

g D

esig

n, 2

011

38

Evidence-based medicine, 2014:ROS1 crizotinib response� ~1-2% of lung adenocarcinoma� Multiple fusion partners

� FDA approved crizotinib for ROS1-rearranged lung cancers this past Friday 39

Davies, Clin Cancer Res, 2012

KRAS:� GTP-binding signal transduction protein

• EGFRRASRAFERKproliferation� Mutations in ~30% of adenocarcinomas

• Point mutations in codons 12, 13• “Never” coexist with EGFR mutations, ALK rearrangements

� Therapy: no specific inhibitors• Farnesylation inhibitors (lonafarnib)?• Inhibition downstream (MEK1)?

� Diagnostics: “rule out” EGFR, ALK alterations• Most common oncogene mutated in lung adenocarcinoma• Technically much easier than EGFR, ALK testing• KRAS mutant cancers do NOT respond to erlotinib, crizotinib

40


September 9, 2012


BRAF� Downstream of EGFR, KRAS� ~3% of lung adenocarcinoma� V600E mutation common in thyroid, melanoma

• Additional mutations in lung in exon 11

� Treatment response complex: • Sorafenib: trial stopped prematurely

• Vemurafenib: response V600E

• Dabrafenib: ~30% response V600E• ASCO, 2015

• Dabrafenib+MEK inhibitor: ~60% response rate• (manuscript in preparation)

41

MEK1

� Mutations are rare (<1%)

� Rx: selumetinib*, trametinib• May be effective for

• KRAS mutation• BRAF mutation

Meng, PLoS One, 2010

Marks, Cancer Res, 2008

42

*Selumetinib is an Astra Zeneca drug, and I have received consulting fees for guidance in a selumetinib clinical trial.

MET� HGF receptor� Activates ERBB3PI3KAKTmTOR� “Amplified” in 5-20% EGFR resistant lung cancers

• Treatment: disappointing trials (bad biomarker?)

� Exon 14 skipping mutations in 3%• Intron mutations historically were missed• Small series: respond to crizotinib, cabozantinib

-Engelman, et al., Science 2007

43

-Robinson, Oncologist, 2013

-Paik, Cancer Disc, 2015

RET

� ~1-2% of lung adenocarcinomas� Inv 10p11.22–q11.21� KIF5B-RET very subtle FISH finding� Rx: cabozantinib?

Takeuchi, Nature Med, 2012

44

Drilon, Cancer Discov, 2013

Drilon, Cancer Discov, 2013


September 9, 2012


NTRK1

� ~3% of lung adenocarcinoma� Chromosomal rearrangements� Mutant Cell lines inhibited by pan-TKI

Vaishnavi, Nature Med, 2013

45

Evidence regression

46

EGFR: multiple Phase III RCTs, PFS

ALK: Phase II, ORR

RET: case reports

NTRK1: mice

MEK1: cell lines

The list goes on…� ERBB2� NRG1� RIT1� NF1� PIK3CA� AKT1� NRAS� mTOR

47

But wait, there’s more: Squamous carcinoma!� FGFR1 amplification: 20%

� DDR2 mutation: 5%

� KIT/PDGFRA amplification: 10%

Dutt, et al., PLoS ONE, 2011 Ramos, et al., Cancer Biol Ther, 2009

Hammerman, et al., Cancer Discovery, 201148


September 9, 2012


…and I have only talked about lung cancer

49

…and I have only talked about DNA

50

So, where do we draw the line between clinical practice and investigation?

51

Ariel Lopez-Chavez et al. JCO doi:10.1200/JCO.2014.58.2007 LCMC, ASCO, 2014

Do we view one gene at a time, or look at this holistically?

Has this really worked?

Year 1975 1980 1985 1990 1995 1999 2003 2007

5-Year Relative Survival 11.4% 12.5% 13.0% 13.3% 14.5% 15.2% 16.0% 18.2%

SEER 9 Incidence & U.S. Mortality 1975-2012, All Races, Both Sexes. Rates are Age-Adjusted.


September 9, 2012


CAMD volumes:Demand is growing

0

2000

4000

6000

8000

10000

12000

14000

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Germline genetics

Hematopathology

Solid Tumors

Infection

Profile

Many challenges to balance

IP

Information Management Hype

CostRegulatoryFramework Biotech

Is this all a fad?

55

Discuss

versus

Evidence-Based

Medicine

Promise of

Precision Medicine

ST101 Companion Diagnostics for Targeted Therapy in …handouts.uscap.org/2016_cm15_linde_1.pdf ·...

Documents

Transcript of ST101 Companion Diagnostics for Targeted Therapy in …handouts.uscap.org/2016_cm15_linde_1.pdf ·...