Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

Bruce Johnson, MDProfessor of Medicine Department of MedicineHarvard Medical SchoolProgram DirectorLowe Center for Thoracic OncologyDana-Farber Cancer InstituteBoston, Massachusetts

Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

This program is supported by educational grants from

In association with Translational Research in Oncology

clinicaloptions.com/oncologyTranslational Research 2012

About These Slides

Our thanks to the presenters who gave permission to include their original data

Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent

These slides may not be published or posted online without permission from Clinical Care Options

DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.


Program Faculty

Program DirectorDennis J. Slamon, MD, PhDTRIO ChairmanChief, Division of Hematology/OncologyDavid Geffen School of Medicine at UCLALos Angeles, California

FacultyBruce Johnson, MDProfessor of Medicine Department of MedicineHarvard Medical SchoolProgram DirectorLowe Center for Thoracic OncologyDana-Farber Cancer InstituteBoston, Massachusetts


Faculty Disclosures

Bruce Johnson, MD, has disclosed that he has received consulting fees from Acceleron, AstraZeneca, Chugai, Genentech, Millennium, and Pfizer; has ownership interest (equity) in Celgene; and has received postmarketing royalties from Genentech for EGFR testing.

Dennis J. Slamon, MD, PhD, has disclosed that he has received consulting fees from Genentech, GlaxoSmithKline, and Roche.



EGFR mutation testing in initial assessment and treatment of lung cancer

ALK rearrangements and their role in therapeutic selection

MET as a therapeutic target in NSCLC

Subpopulations of NSCLC patients who may be effectively treated with HDAC inhibitors


January 2002 October 2004

Woman With Adenocarcinoma Treated With Gefitinib


Epidermal Growth Factor Receptor Mutations

13 of 14 patients withresponse to gefitinibhad EGFR mutation

Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139. Paez JG, et al. Science. 2004;304:1497-1500.



Paez JG, et al. Science. 2004;304:1497-1500.


EGFR-Mutant NSCLC Cell Lines Are Dependent on EGFR for Their Survival

Ap

op

tosi

s (%

)

Control

Gefitinib

Tracy S, et al. Cancer Research. 2004;64:7241-7244.

30

25

20

15

10

5

0A549 HI666 H3255 DFCILU-

011


Gefitinib vs Combination Chemotherapy for NSCLC With Mutated EGFR

Sample size was calculated to be 320 in total (alpha = 5%, power = 80%) to confirm the superiority of arm A (HR: 0.69)

Interim analysis to investigate PFS was planned 4 mos after 200 patients were entered

Maemondo M, et al. N Engl J Med. 2010;362:2380-2388.

NSCLC with sensitive EGFRmutations

Stage IIIb/IV No previous chemo PS 0-1 20-75 yrs of age

RBalanced: institution

sex stage

Gefitinib(n = 160)

CBDCA + TXL(n = 160)

Primary endpointPFSSecondary endpointsOSResponseAdverse eventsQoL


Gefitinib vs Combination Chemotherapy: PFS

Gefitinib: median PFS 10.8 mos Chemotherapy: median PFS 5.4 mosHR: 0.30 (95% CI: 0.22-0.41; P < .001)

Maemondo M, et al. N Engl J Med. 2010;362:2380-2388.

100

80

60

40

20

0

PF

S (

%)

0 3 6 9 12 15 18 21 24 27

Mos Since Randomization

Gefitinib(n = 114)

Standard chemotherapy

(n = 110)P < .001


Prospective Clinical Trials in Japan and China: EGFR-TKIs vs ChemotherapyAuthors Therapeutic Arms n Median PFS,

mosMedian OS,

mos

Mitsudomi[1] Gefitinib

Docetaxel/cisplatin

86

86

9.2

6.3

36

39

Maemondo[2] Gefitinib

Paclitaxel/carboplatin

114

110

10.8

5.4

30.5

23.6

Zhou[3] Erlotinib

Gemcitabine/carboplatin

82

72

13.1

4.6

NR

NR

1. Mitsudomi T, et al. ASCO 2012. Abstract 7521. 2. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 3. Zhou C, et al. Lancet Oncol. 2011; 12:735-742.

*12-mo rate of PFS.



EGFR

KRAS

Unknown

ALK

BRAF

PIK3CA

ERBB2

MEK1ERBB2 Amplification

MET Amplification


MET AMP

Gene Event Type Frequency, %

FGFR1 Amplification 20-25

FGFR2 Mutation 5

PIK3CA Mutation 9

PTEN Mutation deletion 18

CCND1 Amplification 8

CDKN2A Deletion/mutation 45

PDGFRA Amplification mutation

9

EGFR Amplification 10

MCL1 Amplification 10

BRAF Mutation 3

DDR2 Mutation 4

ERBB2 Amplification 2

Emerging “Druggable” Targets in NSCLC-Squamous SubtypeLung Cancer Molecular

Consortium Lung Adenocarcinomas

Mutations found in 54% (280/516)

Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01

Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

Potential “Druggable” Molecular Targets?

No mutationdetected KRAS

22%

EGFR17%

NRAS

Doublemutants 3%

AKT1

BRAF 2%

MEK1

HER2PIK3CA 2%

EML4-ALK7%


ALK Rearrangement in NSCLC

Soda M, et al. Nature. 2007;448:561-566.

Identification of the Transforming EML4-ALK Fusion Gene in NSCLC


Days

Koivunen JP, et al. Clin Cancer Res. 2008;14:4275-4283.

ALK Inhibitor TAE684 Affects Growth of EML4-ALK–Containing NCI-H3122 Cells in Vivo

Mea

n T

um

or

Vo

lum

e

3500

3000

2500

2000

1500

1000

500

0530 4 7 11 15 18 21 25 28 32 35 39 42 46 49

ControlErlotinibTAE684 10 mpkTAE684 25 mpk


July 2009 January 2012

72-Yr-Old Woman With ALK-Positive NSCLC Treated With Crizotinib


Shaw AT, et al. Lancet Oncol. 2011;12:1004-1012.

74%

54%

1 2 3 400

20

40

60

80

100

Yrs

OS

Fro

m F

irst

C

rizo

tin

ib D

ose

(%

)

Median OS: not reached 1-yr OS: 74%; 2-yr OS: 54%61% of patients in follow-up for OSwith median follow-up of 18 mos

From first crizotinib dose

Survival of ALK-Positive NSCLC Patients Treated With Crizotinib


Key Entry Criteria Positive for ALK gene

translocation Brain mets allowed 1 previous chemo

(platinum based)(N = 318)

Crizotinib (n = 159)

Trial Design Endpoints Stratification Study Sites FSFV

Multicenter, randomized open label

Primary: PFS

Secondary: ORR, DR, DCR, OS, safety, QoL,

biomarkers

ECOG status(0/1 vs 2)

Previous EGFRTKI treatment

Brain metastases

WW 3Q09

Pemetrexed or Docetaxel(n = 159)

Study A8081007: Phase 3 Study ofCrizotinib vs Pemetrexed or Docetaxel

RANDOMIZE


December 2010 May 2011




September 2011 April 2012


1. Soda M, et al. Nature. 2007;448:561-566. 2. McDermott U, et al. Cancer Res. 2008;68:3389-3395. 3. Koivunen JP, et al. Clin Cancer Res. 2008;14:4275-4283. 4. Kwak EL, et al. ASCO 2009. Abstract 3509. 5. Kwak EL, et al. N Engl J Med. 2010;363:1693-1703. 6. US Food and Drug Administration.

ALK-Positive Timeline

Preclinical studies document antitumor activity of ALK

inhibitors in lung cancer cell lines and xenografts[2,3]

2007 2009

EML4-ALK chromosomal rearrangements reported

in NSCLC[1]

2008 2010

2011

Crizotinib antitumor activity in advanced cancers with

EML4-ALK rearrangement[4]

Crizotinib produces a response in 47/82 ALK+

patients and a 6-month PFS of 72%[5]

FDA approves crizotinib for treatment of

ALK+ NSCLC[6]


Lung Adenocarcinoma: 2012

EGFR

KRAS

Unknown

ALK

BRAF

PIK3CA

ERBB2

MEK1ERBB2 Amplification

MET Amplification


Spigel DR, et al. ASCO 2011. Abstract 7505.


Rationale for targeting MET

– MET is amplified, mutated, overexpressed in many tumors

– MET expression is associated with a worse prognosis in many cancers including NSCLC

– MET activation is implicated in resistance to erlotinib/gefitinib in patients with activating EGFR mutations

MetMAb (onartuzumab):

– 1-armed format designed to prevent HGF-mediated stimulation of pathway

– Preclinical activity across multiple tumor models


Phase II Randomized OAM4558g Study: Erlotinib ± MetMAb (Onartuzumab) in Stage IIIB/IV NSCLC

Primary objective PFS in overall ITT population

Other key objectives OS in “MET-high” patients

OS in overall ITT patients

Addition of Onartuzumab*

(n = 23)

PD

*If eligible.

Arm AErlotinib 150 QD PO +

Onartuzumab 15 mg/kg IV q3w(n = 64)

Arm BErlotinib 150 QD PO +

Placebo IV q3w(n = 64)

Patients with stage IIIB/IV NSCLC who failed first- or second-line

treatment, ECOG PS 0-2

(n = 128)

Spigel D, et al. ASCO 2011. Abstract 7505.

Enrollment from 3/2009 to 3/2010

Data cutoff: June 8, 2010

Stratified by tobacco use, performance score, histology


Development of MET IHC as a Diagnostic

Intensity of MET staining on tumor cells scored on 0-3+ scale

Estimated that ~ 50% of patients would have “MET-high” tumors

Met by IHC was assessed after randomization

Tissue was obtained from 100% of patients

95% of patients had adequate tissue for evaluation of MET by IHC

54% patients had “MET-high” NSCLC

1+ 2+ 3+

Spigel D, et al. ESMO 2010. Abstract LBA15.

“MET high” was defined prior to unblinding as ≥ 50% tumor cells with a staining intensity of 2+ or 3+


OAM4558g Study of Erlotinib ± MetMAb (Onartuzumab) in Stage IIIB/IV NSCLC: PFS and OS (ITT)

-23 patients from the erlotinib + placebo arm crossed over to MetMAb

mPFS and mOS are consistent with previously reported findings in similar disease setting

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y o

f P

rog

ress

ion

Fre

e

TTP (Mos)

0 183 6 9 12 15

PFS HR: 1.09

Median, mosHR95% CILog-rank P valueEvents, n

2.6

56

2.2

48

1.090.73-1.62

.69

Placebo + Erlotinib

MetMAb + Erlotinib

1.0

0.8

0.6

0.4

0.2

0Pro

bab

ilit

y o

f S

urv

ival

OS (Mos)

0 213 6 9 12 15

OS HR: 0.8

Median, mosHR95% CILog-rank P valueEvents, n

7.4

41

8.9

34

0.800.50-1.28

.34

Placebo + Erlotinib

MetMAb + Erlotinib

18


MetMAb Plus Erlotinib in Met Dx+ Patients

Time to progression (months)

0 3 6 9 12 15 18

Pro

bab

ilit

y o

f p

rog

ress

ion

fre

e

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

3.8

26

MetMAb +erlotinib

12.6

16

Median (mo)HR

(95% CI)Log-rank p-value

No. of events

Overall survival (months)

0 3 6 9 12 15 18 21

Pro

bab

ilit

y o

f su

rviv

al

0.0

0.2

0.4

0.6

0.8

1.0

Placebo +erlotinib

1.5

27

Median (mo)HR

(95% CI)Log-rank p-value

No. of events

PFS: HR = 0.53 OS: HR = 0.37 MetMAb +erlotinib

2.9

20

0.53(0.28–0.99)

0.04

0.37(0.19–0.72)

0.002


Erlotinib ± Entinostat for Adv NSCLC Progressing on Prior Chemo: Phase II

Primary endpoint: 4-mo PFS

Secondary endpoints: 6-mo PFS, overall best objective response

Patients > 18 yrs of age with:

Stage IIIB/ IV NSCLC PD after 1 or 2

previous chemo or CRT regimen

(N = 132)

Erlotinib 250 mg/day PO +Entinostat 10 mg/day PODays 1, 15 of 28-day cycle

(n = 67)

Erlotinib 150 mg/day PO +Placebo daily PO

Days 1, 15 of 28-day cycle(n = 65)

Witta SE, et al. J Clin Oncol. 2012;[Epub ahead of print].

Open-label Extension

Option to continue

combination therapy

Option of crossing

over to combination

therapy

If no PD

If no PD


Subpopulations of NSCLC Pts Who May Be Effectively Treated With HDAC Inhibitors

ATP

EGFR ErbB3E-CAD

AGGTG CACCT

HDACZEB1 Snail

ECAD

HDACix

ErbB3

EGFR Interacting Molecules

Courtesy of Paul Bunn, Jr, MD.


Erlotinib ± Entinostat for Adv NSCLC: PFS and OS in Full Patient Population

Erlotinib + entinostat did not improve outcomes in the overall study population vs erlotinib monotherapy

Witta SE, et al. J Clin Oncol. 2012;[Epub ahead of print].

PFS OS

1.00

0.75

0.50

0.25

0

Pro

bab

ilit

y o

f P

FS

160 2 4 6 8 10 12 14

Mos

Placebo, median PFS: 1.88 mosEntinostat, median PFS: 1.97 mos

HR: 0.99 (95% CI: 0.68-1.44;P = .98 by stratified log-rank test)

PlaceboEntinostat

36/6532/67

12/2617/31

6/143/12

2/61/8

0/32/7

1/21/2

0/00/0

0/00/0

1.00

0.75

0.50

0.25

0

Pro

bab

ilit

y o

f O

S

300 6 12 18 24

Mos

Placebo, median OS: 6.7 mosEntinostat, median OS: 8.9 mos

HR: 0.85 (95% CI: 0.59-1.23;P = .39 by stratified log-rank test, 2 sided)

PlaceboEntinostat

30/6524/67

16/3516/40

8/1814/22

5/100/7

0/10/1


Erlotinib ± Entinostat for Adv.NSCLC: Effect of E-cadherin Status on OS and Outcome

High E-cadherin expression levels at diagnosis correlated with Increased sensitivity to HDACi/EGFR-TKI

Results warrant further biomarker-driven validationWitta SE, et al. J Clin Oncol. 2012;[Epub ahead of print].

PFS: E-cadherinHI Patients* OS: E-cadherinHI Patients†

†IHC intensity score +3*IHC intensity score +3

1.00

0.75

0.50

0.25

0

Pro

bab

ilit

y o

f O

S

300 6 12 18 24

Mos

Placebo, median OS: 5.4 mosEntinostat, median OS: 9.4 mos

HR: 0.35 (95% CI: 0.13-0.92; P = .03 by stratified log-rank test, 2 sided)

PlaceboEntinostat

7/124/14

3/54/9

1/13/5

0/00/2

0/00/0

1.00

0.75

0.50

0.25

0

PF

S (

pro

bab

ilit

y)

160 2 4 6 14

Time (months)

PlaceboEntinostat

7/125/14

3/54/9

1/21/4

0/01/2

0/00/0

Placebo, median PFS: 1.88 monthsEntinostat, median PFS: 3.68 months

HR: 0.55 (95% CI: 0.22-1.37; P = .19 by stratified log-rank test)

8 10 12

0/01/1

0/00/0

0/00/0


Subpopulations of NSCLC Patients Who May Be Effectively Treated With HDAC Inhibitor

Erlotinib plus entinostat did not improve the outcomes of patients in overall study population compared with erlotinib monotherapy

High E-cadherin expression levels at time of diagnosis are associated with a increased sensitivity to HDACi/EGFR-TKI inhibition

This may provide rationale for investigating a biomarker-driven validation study

Go Online for More CCO Coverage of Chicago 2012!

Capsule Summaries of all the key data, plus CME-certified Slidesets exploring the clinical implications of these findings

Downloadable slides: for use as a study resource or in your noncommericial presentations

clinicaloptions.com/oncology

http://www.clinicaloptions.com/oncology

Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

Documents

Transcript of Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm