eml4-alk translocations and crizotinib

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EML4-ALK translocations and crizotinib

Heather Wakelee, MD

Assistant Professor of Medicine, Oncology

Stanford University/Stanford Cancer Center

Soda et al. Nature 2007

ALK Pathway

TranslocationOr

ALK ALK fusion protein

Tumor cellproliferation

Inversion

Cell survival

PI3KPI3K

BADBAD

AKTAKT

STAT3/5STAT3/5

mTORmTOR

S6KS6K

RASRAS

MEKMEK

ErKErK

PLC-PLC-YY

PIPPIP22

IPIP33

With permission from Bang ASCO 2010

~250 kb ~300 kb

t(2;5) ALK genebreakpoint region

2p23 regionTelomere Centromere

3’ 5’

FISH Assay for ALK Rearrangement*

Break-apart FISH assay for ALK-fusion genes

ALK 29.3

EML4 42.3

ALK break-apart FISH assay[Courtesy John Iafrate, Massachusetts General Hospital]

q36.1

q36.3q37.2

q34

q32.1

q32.3

q33.2

q31.3

q24.3

q24.1

q23.2q22.2q22.1

q21.2q14.3

q14.1

q12.3q12.1

p12

p13.2p14

p16.1

p16.3

p22.1

p23.2

p22.3

p24.1

p24.3

p25.2

q36.1

q36.3q37.2

q34

q32.1

q32.3

q33.2

q31.3

q24.3

q24.1

q23.2q22.2q22.1

q21.2q14.3

q14.1

q12.3q12.1

p12

p13.2p14

p16.1

p16.3

p22.1

p23.2

p22.3

p24.1

p24.3

p25.2

Split signal

Non-split signal

*Assay is positive if rearrangements can be detected in ≥15% of cells

FISH = fluorescence in situ hybridization

With permission from Bang ASCO 2010

Crizotinib: First-in-human ALK Inhibitor

Potent and selective ATP competitive oral inhibitor of ALK

and MET tyrosine kinases and their oncogenic variants

Safety and activity of crizotinib examined in an expanded

cohort of patients with advanced ALK-positive NSCLC1

Crizotinib administered at the MTD of 250 mg PO twice daily

1Kwak et al. NEJM 2010;363:1693-703

Shaw ASCO 2011, Lancet Oncology 12:1004, 2011

Clinical and Demographic Features of ALK-Positive and ALK-Negative NSCLC Patients

ALK ControlsN=36

WT/WT ControlsN=253

p-value

Age, yrs Median 51 64 <0.001

Range 32–78 27–87

Sex, n M/F 16/20 108/145 0.86

Race, n (%) Caucasian 31 (86) 231 (92) 0.47

Asian 3 (8) 15 (6)

Smoking history, n (%) Never smoker 24 (67) 63 (25) <0.001

≤ 10 pack-years 7 (19) 32 (13)

> 10 pack-years 5 (14) 158 (62)

Histology, n (%) Adenocarcinoma 34 (94) 223 (88) 0.39

Squamous 1 (3) 10 (4)

Other 1 (3) 20 (8)

Brain metastases* No/Yes 19/17 147/105 0.59

* At any time


60

40

20

0

–20

–40

–60

–80

–100

Progressive disease

Stable disease

Confirmed partial response

Confirmed complete response

Max

imu

m c

han

ge

in t

um

or

size

(%

)

–30%

Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC

*

With permission from Bang ASCO plenary 2010 N= 76

Treatment-related Grade 3/4 Adverse Events in ALK-positive NSCLC

Adverse eventGrade 3

n (%)Grade 4

n (%)

Any adverse event 10 (12) 1 (1)

ALT elevation* 4 (5) 1 (1)

AST elevation 5 (6) 0

Lymphopenia 2 (2) 0

Hypophosphatemia 1 (1) 0

Neutropenia 1 (1) 0

Hypoxia 1 (1) 0

Dyspnea 1 (1) 0

Pulmonary embolism 1 (1) 0

* Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4%; 1 patient discontinued for ALT elevation

Bang ASCO 2010

Crizotinib Survival Analysis:Study Objectives

• Examine overall survival of crizotinib-treated ALK-positive NSCLC patients

• Compare the survival outcomes of crizotinib-treated vs crizotinib-naïve, ALK-positive NSCLC patients

• Explore the prognostic significance of ALK rearrangement by comparing the survival outcomes of crizotinib-naïve ALK-positive and ALK-negative NSCLC patients


Study PopulationsALK CRIZOTINIB

ALK-positiveCrizotinib-treated

N=82

US/AustraliaN=56

2nd/3rd lineN=30

ALK CONTROLS

US/AustraliaN=36

2nd lineN=23

Never/lightsmoker

AdenoCAN=21

ALK-positiveCrizotinib-naïve

WT/WT CONTROLS

US (MGH)N=253

2nd lineN=125

Never/lightsmoker

AdenoCAN=48

ALK-negativeEGFR-

wildtype

Never/lightsmoker

AdenoCAN=28


Clinical and Demographic Features of Crizotinib-Treated and Control ALK-Positive NSCLC Patients

ALK Crizotinib N=56

ALK ControlsN=36

p-value

Age, yrs Median 51 51 0.90

Range 28–78 32–78

Sex, n M/F 30/26 16/20 0.52

Race, n (%) Caucasian 48 (86) 31 (86) 1.00

Asian 4 (7) 3 (8)

Smoking history, n (%) Never smoker 46 (82) 24 (67) 0.25

≤ 10 pack-years 7 (13) 7 (19)

> 10 pack-years 3 (5) 5 (14)

Histology, n (%) Adenocarcinoma 54 (96) 34 (94) 0.64

Squamous 1 (2) 1 (3)

Other 1 (2) 1 (3)

Brain metastases* No/Yes 27/29 19/17 0.83

* At any time


Treatment Histories of Crizotinib-Treated and Control ALK-Positive NSCLC Patients

ALK Crizotinib N=56

ALK ControlsN=36

p-value

Lines of therapy* Median 2 2 0.68

Range 0–7 1–4

Types of therapies, n (%) Platinum 44 (79) 30 (83) 0.79

Pemetrexed 30 (54) 24 (67) 0.28

Erlotinib 27 (48) 16 (44) 0.83

* For metastatic disease


Pemetrexed may lead to prolonged PFS in ALK+ ptsCamidge et al. JTO 6:774, 2011

Balanced for age, gender, but more with smoking history in control group

ALK Crizotinib

(n=30)

ALK Control(n=23)

Median Survival, mo NR 6

1-yr Survival, % 70 44

WT/WT Control(n=125)

11

47

From 2nd/3rd line crizotinib

2-yr Survival, % 55 12 32

HR = 0.49, p = 0.02

Overall SurvivalOverall Survival22ndnd Line Subset Line Subset


Limitations of the Study

• Retrospective nonrandomized study design with potential imbalances among the study populations

• Potential confounding of survival outcomes by post-crizotinib therapies

• Small numbers in subset analyses


Resistance to Crizotinib

• Resistance to crizotinib develops, usually in < 1yr

• Cell line work of acquired resistance revealed1:

– Amplification of EML4-ALK, secondary mutation (L1196M - gatekeeper)

• Analysis of pts with secondary resistance revealed2:

– Secondary resistance mutations in ALK TK domain3

– Increase in ALK CNG

– Growth of other NSCLC clones (EGFR, KRAS)

• HSP90 inhibitors show promise

1-Katayama Proc NAS 108:7535, 20112-Doebele Clin Ca Res Epub, 20123-Choi NEJM 363:1734, 2010

Research To Practice could not obtain permission to reproduce this slide at the time of publication.

For further information, please see the following:

Ramalingam S et al. Heat Shock Protein 90 Inhibitors in Lung Cancer: Shock and Awe? Presentation.

ASCO 2011. No abstract available

Crizotinib Summary

• Crizotinib highly effective in pts w/ ALK FISH+ NSCLC

• Better diagnostics under development

• Survival benefit demonstrated

• Role as 1st line therapy under investigation

– Currently in NCCN guidelines

• Resistance in < 1 yr a major issue

– Mechanisms, 2nd mutations, growth of other clones

• HSP90 inhibitors, other strategies in development

Saturday, February 11, 2012Hollywood, Florida

Faculty

Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD

Co-Chair and ModeratorNeil Love, MD

Chandra P Belani, MDJohn Heymach, MD, PhDPasi A Jänne, MD, PhD

Thomas J Lynch Jr, MDHeather Wakelee, MD

eml4-alk translocations and crizotinib

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