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incorporating novel data in the molecular features of lung cancer into the treatment paradigm

In association with Translational Research in Oncology

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

This program is supported by educational grants from

about these slides
About These Slides
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  • These slides may not be published or posted online without permission from Clinical Care Options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 Faculty

Program Director

Dennis J. Slamon, MD, PhD

TRIO ChairmanChief, Division of Hematology/OncologyDavid Geffen School of Medicine at UCLALos Angeles, California

Faculty

Bruce Johnson, MD

Professor of MedicineDepartment of MedicineHarvard Medical SchoolProgram DirectorLowe Center for Thoracic OncologyDana-Farber Cancer InstituteBoston, Massachusetts

faculty disclosures
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.

incorporating novel data in the molecular features of lung cancer into the treatment paradigm1
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm
  • 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
epidermal growth factor receptor mutations
Epidermal Growth Factor Receptor Mutations

13 of 14 patients with

response to gefitinib

had EGFR mutation

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

incorporating novel data in the molecular features of lung cancer into the treatment paradigm2
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

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

egfr mutant nsclc cell lines are dependent on egfr for their survival
EGFR-Mutant NSCLC Cell Lines Are Dependent on EGFR for Their Survival

30

25

Control

Gefitinib

20

15

Apoptosis (%)

10

5

0

A549

HI666

H3255

DFCILU-011

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

gefitinib vs combination chemotherapy for nsclc with mutated egfr
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

Gefitinib

(n = 160)

  • NSCLC with sensitive EGFRmutations
  • Stage IIIb/IV
  • No previous chemo
  • PS 0-1
  • 20-75 yrs of age
  • Primary endpoint
  • PFS
  • Secondary endpoints
  • OS
  • Response
  • Adverse events
  • QoL

R

Balanced: institution sex stage

CBDCA + TXL

(n = 160)

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

gefitinib vs combination chemotherapy pfs
Gefitinib vs Combination Chemotherapy: PFS

100

Gefitinib: median PFS 10.8 mos

Chemotherapy: median PFS 5.4 mos

HR: 0.30 (95% CI: 0.22-0.41; P < .001)

80

60

PFS (%)

40

Gefitinib(n = 114)

Standard chemotherapy(n = 110)

20

P < .001

0

0

3

6

9

12

15

18

21

24

27

Mos Since Randomization

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

prospective clinical trials in japan and china egfr tkis vs chemotherapy
Prospective Clinical Trials in Japan and China: EGFR-TKIs vs Chemotherapy

*12-mo rate of PFS.

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.

incorporating novel data in the molecular features of lung cancer into the treatment paradigm3
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm

Unknown

EGFR

KRAS

MET

Amplification

ALK

PIK3CA

MEK1

ERBB2 Amplification

ERBB2

BRAF

potential druggable molecular targets
Potential “Druggable” Molecular Targets?

Emerging “Druggable” Targets in NSCLC-Squamous Subtype

Lung Cancer Molecular Consortium Lung Adenocarcinomas

No mutationdetected

KRAS22%

AKT1

NRAS

EGFR17%

MEK1

EML4-ALK7%

MET AMP

HER2

PIK3CA 2%

BRAF 2%

Doublemutants 3%

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

incorporating novel data in the molecular features of lung cancer into the treatment paradigm4
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm
  • 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
alk rearrangement in nsclc
ALK Rearrangement in NSCLC

Identification of the Transforming EML4-ALK Fusion Gene in NSCLC

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

alk inhibitor tae684 affects growth of eml4 alk containing nci h3122 cells in vivo
ALK Inhibitor TAE684 Affects Growth of EML4-ALK–Containing NCI-H3122 Cells in Vivo

3500

ControlErlotinibTAE684 10 mpkTAE684 25 mpk

3000

2500

2000

Mean Tumor Volume

1500

1000

500

0

0

4

7

11

15

18

21

25

28

32

35

39

42

46

49

53

Days

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

survival of alk positive nsclc patients treated with crizotinib
Survival of ALK-Positive NSCLC Patients Treated With Crizotinib

100

Median OS: not reached

1-yr OS: 74%; 2-yr OS: 54%

61% of patients in follow-up for OS

with median follow-up of 18 mos

80

74%

60

OS From First Crizotinib Dose (%)

From first crizotinib dose

54%

40

20

0

0

1

2

3

4

Yrs

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

study a8081007 phase 3 study of crizotinib vs pemetrexed or docetaxel
Study A8081007: Phase 3 Study ofCrizotinib vs Pemetrexed or Docetaxel

RANDOMIZE

  • Key Entry Criteria
  • Positive for ALK gene translocation
  • Brain mets allowed
  • 1 previous chemo(platinum based)(N = 318)

Crizotinib

(n = 159)

Pemetrexed or Docetaxel(n = 159)

50 yr old woman with alk positive nsclc treated with crizotinib1
50-Yr-Old Woman With ALK-Positive NSCLC Treated With Crizotinib

September 2011

April 2012

alk positive timeline
ALK-Positive Timeline

EML4-ALK chromosomal rearrangements reported in NSCLC[1]

Crizotinib antitumor activity in advanced cancers with EML4-ALK rearrangement[4]

FDA approves crizotinib for treatment of ALK+ NSCLC[6]

2011

2007

2009

2008

2010

Preclinical studies document antitumor activity of ALK inhibitors in lung cancer cell lines and xenografts[2,3]

Crizotinib produces a response in 47/82 ALK+ patients and a 6-month PFS of 72%[5]

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.

lung adenocarcinoma 2012
Lung Adenocarcinoma: 2012

Unknown

EGFR

KRAS

MET

Amplification

ALK

PIK3CA

MEK1

ERBB2 Amplification

ERBB2

BRAF

incorporating novel data in the molecular features of lung cancer into the treatment paradigm5
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm
  • 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
incorporating novel data in the molecular features of lung cancer into the treatment paradigm6
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm
  • 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

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

phase ii randomized oam4558g study erlotinib metmab onartuzumab in stage iiib iv nsclc
Phase II Randomized OAM4558g Study: Erlotinib ± MetMAb (Onartuzumab) in Stage IIIB/IV NSCLC

Stratified by tobacco use, performance score, histology

Primary objective

  • PFS in overall ITT population

Other key objectives

  • OS in “MET-high” patients
  • OS in overall ITT patients

Arm A

Erlotinib 150 QD PO +

Onartuzumab 15 mg/kg IV q3w

(n = 64)

Patients with stage IIIB/IV NSCLC who failed first- or second-line treatment, ECOG PS 0-2

(n = 128)

Arm B

Erlotinib 150 QD PO +

Placebo IV q3w

(n = 64)

PD

  • Enrollment from 3/2009 to 3/2010
  • Data cutoff: June 8, 2010

Addition of Onartuzumab*

(n = 23)

*If eligible.

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

development of met ihc as a diagnostic
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+

“MET high” was defined prior to unblinding as

≥ 50% tumor cells with a staining intensity of 2+ or 3+

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

oam4558g study of erlotinib metmab onartuzumab in stage iiib iv nsclc pfs and os itt
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

PFS HR: 1.09

OS HR: 0.8

Placebo + Erlotinib

MetMAb + Erlotinib

Placebo + Erlotinib

MetMAb + Erlotinib

1.0

1.0

Median, mosHR95% CILog-rank P valueEvents, n

2.656

1.090.73-1.62.69

2.248

Median, mosHR95% CILog-rank P valueEvents, n

7.441

0.800.50-1.28.34

8.934

0.8

0.8

0.6

0.6

Probability of Progression Free

Probability of Survival

0.4

0.4

0.2

0.2

0

0

0

3

6

9

12

15

18

0

3

6

9

12

15

18

21

TTP (Mos)

OS (Mos)

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

metmab plus erlotinib in met dx patients

1.0

1.0

0.8

0.8

0.6

0.6

0

3

6

9

12

15

18

0

3

6

9

12

15

18

21

0.4

0.4

0.2

0.2

0.0

0.0

MetMAb Plus Erlotinib in Met Dx+ Patients

PFS: HR = 0.53

OS: HR = 0.37

Placebo +erlotinib

1.5

27

MetMAb +erlotinib

2.9

20

Placebo +erlotinib

3.8

26

MetMAb +erlotinib

12.6

16

Median (mo)

HR

(95% CI)

Log-rank p-value

No. of events

Median (mo)

HR

(95% CI)

Log-rank p-value

No. of events

0.37

(0.19–0.72)

0.002

0.53

(0.28–0.99)

0.04

Probability of survival

Probability of progression free

Time to progression (months)

Overall survival (months)

incorporating novel data in the molecular features of lung cancer into the treatment paradigm7
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm
  • 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
erlotinib entinostat for adv nsclc progressing on prior chemo phase ii
Erlotinib ± Entinostat for Adv NSCLC Progressing on Prior Chemo: Phase II

Open-label Extension

  • 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)

Erlotinib250 mg/day PO +

Entinostat 10 mg/day PO

Days 1, 15 of 28-day cycle

(n = 67)

Option to continue combination therapy

If no PD

Erlotinib150 mg/day PO +

Placebo daily PO

Days 1, 15 of 28-day cycle

(n = 65)

Option of crossing over to combination therapy

If no PD

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

subpopulations of nsclc pts who may be effectively treated with hdac inhibitors
Subpopulations of NSCLC Pts Who May Be Effectively Treated With HDAC Inhibitors

EGFR Interacting Molecules

ATP

ErbB3

EGFR

E-CAD

HDACi

x

HDAC

Snail

ZEB1

ECAD

AGGTG

CACCT

ErbB3

Courtesy of Paul Bunn, Jr, MD.

erlotinib entinostat for adv nsclc pfs and os in full patient population
Erlotinib ± Entinostat for Adv NSCLC: PFS and OS in Full Patient Population

PFS

OS

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

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)

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)

1.00

1.00

0.75

0.75

0.50

0.50

Probability of OS

Probability of PFS

0.25

0.25

0

0

0

6

12

18

24

30

0

2

4

6

8

10

12

14

16

Mos

Mos

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

PlaceboEntinostat

30/6524/67

16/3516/40

8/1814/22

5/100/7

0/10/1

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

erlotinib entinostat for adv nsclc effect of e cadherin status on os and outcome
Erlotinib ± Entinostat for Adv.NSCLC: Effect of E-cadherin Status on OS and Outcome

PFS: E-cadherinHIPatients*

OS: E-cadherinHI Patients†

  • High E-cadherin expression levels at diagnosis correlated with Increased sensitivity to HDACi/EGFR-TKI
  • Results warrant further biomarker-driven validation

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)

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)

1.00

1.00

0.75

0.75

0.50

PFS (probability)

0.50

Probability of OS

0.25

0.25

0

0

0

2

4

6

8

10

12

14

16

0

6

12

18

24

30

Time (months)

Mos

PlaceboEntinostat

7/125/14

3/54/9

1/21/4

0/01/2

0/01/1

0/00/0

0/00/0

0/00/0

PlaceboEntinostat

7/124/14

3/54/9

1/13/5

0/00/2

0/00/0

*IHC intensity score +3

†IHC intensity score +3

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

subpopulations of nsclc patients who may be effectively treated with hdac inhibitor
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
incorporating novel data in the molecular features of lung cancer into the treatment paradigm8
Incorporating Novel Data in the Molecular Features of Lung Cancer Into the Treatment Paradigm
  • 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
go online for more cco coverage of chicago 2012
Go Online for More CCO Coverage of Chicago 2012!

Capsule Summariesof all the key data, plusCME-certified Slidesetsexploring the clinical implications of these findings

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

clinicaloptions.com/oncology