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Update on ALK Inhibitors

in NSCLC

Tianhong (Tina) Li, MD PhD

July 20th, 2012

UC Davis Comprehensive Cancer Center

Sacramento, CA

Disclosures

• Research Grant: Eli Lilly and Company, Astellas (previous

OSI Pharmaceuticals, INC)

• Consultant: Astellas (2011), Genentech (2010, 2011),

Daiichi Sankyo, Inc (2012).

• Non-Profits: IASLC, NCI, Addario Foundation, Chinese

American Hematologist Oncologist Network (CAHON)

Outlines: ALK Inhibitors in NSCLC

What is new since July 2011?

1. Crizotinib was granted US FDA accelerated approval with a companion diagnostic in August 2011.

2. Updates on clinical data supporting the FDA approval (i.e., crizotinib in PROFILE 1001 and 1005 studies)

3. Progress in identifying rare subsets of patients for ALK inhibitor therapy: from NSCLC to other tumor types

4. New insights in understanding the ALK+ tumor biology and resistance mechanisms to first-generation ALK inhibitor crizotinib

5. New ALK inhibitors and promising agents in clinical development

ALK Inhibitors in NSCLC:

“Milestones” at the ILCC Meetings

The Next

Generation of

Agents for

Lung Cancer

2010

State-of-the

Art Treatment

of Advanced

Lung Cancer

2011-2012

Personalized

Medicine or

Standard of

Care

2013- ?

Crizotinib was granted FDA accelerated approval concurrently

with an FDA-approved companion diagnostic test.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncement. Accessed on December 10, 2011.

Milestones for Crizotinib (PF-02341066) Development

Modified from online access to Pfizer’s submission to ODAC

NPM, nucleophosmin; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma;

IMT, inflammatory myofibroblastic tumor; NSCLC, non-small cell lung cancer; NBL, neuroblastoma

lymphoma

May 2012

FDA

approval*

August

Improved Drug-Biomarker Development Paradigms:

“Marriage” of Drug-Biomarker Development

~18 mo. ~18 mo. ~36 mo. ~18 mo.

Total Time ~90 mo.

(7.5 years)

N=30 N=300 N=1600 Drug

Approval

Confirm Target

Assay

Development

Integrate Biomarker

Assay

Performance

Phases of Development of New Biomarker Assay linked to New Drug

Biomarker Informative?

Assay

Validation

Clinical Validation

Co-Primary Endpoint

Companion Diagnostics

Approval

Phases of Development of a New Drug

Phase I Phase II Phase III Pre-clinical

Gandara, Li, Lara et al, Clin Lung Cancer, 2012

Clinical Implications

The NCCN clinical practice guidelines for NSCLC

have been updated to recommend :

1) First-line crizotinib in EML4-ALK-positive

disease

2) The Vysis ALK break FISH probe kit for

detection of ALK gene rearrangements.

Crizotinib: Overview

● Formulary name: PF-02341066

● Generic name: Crizotinib

● Trade name: XALKORITM

● Chemical formula: C21H22Cl2FN5O

● Mechanism of action: Competitive ATP inhibitor

● Main targets: ALK, c-Met, ROS

● Approved by US FDA for ALK-positive NSCLC on August 26, 2011

Pfizer, data on file

Crizotinib in the ALK ATP binding pocket

Crizotinib: mechanism of action

Ligand:

Pleiotrophin?

Midkine? ALK receptor

EXTRACELLULAR

INTRACELLULAR

Normal ALK signaling

EXTRACELLULAR

Constitutive

proliferation &

inhibition of

apotosis

EXTRACELLULAR

EML4-ALK fusion

protein

silenced by

crizotinib

Pathologic

ALK signalling

Crizotinib

mode of action

Proliferation &

survival

upon ligand binding

to ALK

ALK kinase domain abnormally

activated due to fusion with EML4

Crizotinib first-in-human phase I study design

(PROFILE 1001)

BID = twice daily; MTD = maximum tolerated dose; QD = once daily; RP2D = recommended phase 2 dose

Cohort 1

(n=3)

50 mg QD

Part 2: Molecularly enriched cohorts (n=250)

Part 1: Dose escalation (n=37)

Cohort 2

(n=4)

100 mg QD

Cohort 3

(n=8)

200 mg QD

Cohort 4

(n=7)

200 mg BID

Cohort 5

(n=6)

300 mg BID

Cohort 6

(n=9)

250 mg BID

MTD/RP2D

250 mg BID PO

1 DLT:

G3 ALT 2 DLTs:

G3 Fatigue

c-MET and ALK-positive NSCLC cohort added 2008

Phase II efficacy, safety, and QOL data

● PROFILE 1001 – Ongoing (NCT00585195)

● PROFILE 1005 – Ph 2 pretreated (NCT00932451)

● Analysis of crizotinib-naive controls

Clinical Efficacy and Safety Data

for Accelerated Approval of Crizotinib

Crizotinib first-in-human phase I study design

(PROFILE 1001)

BID = twice daily; MTD = maximum tolerated dose; QD = once daily; RP2D = recommended phase 2 dose

Cohort 1

(n=3)

50 mg QD

Part 2: Molecularly enriched cohorts (n=250)

Part 1: Dose escalation (n=37)

Cohort 2

(n=4)

100 mg QD

Cohort 3

(n=8)

200 mg QD

Cohort 4

(n=7)

200 mg BID

Cohort 5

(n=6)

300 mg BID

Cohort 6

(n=9)

250 mg BID

MTD/RP2D

250 mg BID PO

1 DLT:

G3 ALT 2 DLTs:

G3 Fatigue

PROFILE 1005: Study Design

N=400 (planned)

Riely et al., IASLC 2011; Abs #O31.05

Crizotinib 250 mg p.o. b.i.d.

continuous dosing schedule

Key eligibility criteria:

• ALK+ NSCLC by central

laboratory

• ECOG PS: 0–3

• ≥1 prior line of

chemotherapy

• Brain metastases that

were stable/controlled

were allowed

• Not eligible for Phase 3

study (PROFILE 1007)

Primary endpoints: ORR, Safety, Tolerability

Secondary endpoints: OS, TTR, DR, DCR, PK, biomarkers,

PRO/HRQoL (EORTC QLQ30-C30 and LC-13)

Treatment

PROFILE 10011

N=119

PROFILE 10052

N=136

Age, years Median

Range

51

(21–79)

52

(29–82)

Gender, % Male / Female 50 / 50 47 / 53

Race, % White / Asian / Other 62 / 29 / 9 63 / 32 / 5

Smoking status, %

Never smoker

Former / current

smoker

72

27 / 1 68

29 / 4

Histology, %

Adenocarcinoma

Other

97

3

96

4

ECOG PS, %

0

1

≥2

34

53

13

27

54

18

Prior systemic regimens, %

(advanced/metastatic

disease)

0

1

2

3

≥4

13

30

20

14

22

0

7

29

31

34

Clinical and Demographic Features

1. Camidge et al., ASCO 2011; Abs #2501

2. Riely et al., IASLC 2011; Abs #O31.05

PROFILE 10011

N=116

PROFILE 10052

N=133

Best overall response

Complete response 2 1

Partial response 69 67

Stable disease 31 45

Progressive disease 6 10

Other† 8 10

Objective response (CR+PR) rate 61% (95% CI: 52%, 70%) 51% (95% CI: 42%, 60%)

Duration of response3 48.1 weeks (median) 41.9 weeks (median)

Duration of treatment, median 32 weeks 22 weeks

Median PFS

10.0 months

(95% CI: 8.2, 14.7) Not mature

Clinical Efficacy



3. XALKORI® Package Insert

Independent Radiology Review 52% (95% CI: 42%, 62%) 41.9% (95% CI: 32.3%, 51.9%)

Tumor responses to crizotinib by patient

Median time to response: 8 wk



PROFILE 10052 PROFILE 10011

Objective Response Rate

Patient Subgroup PROFILE 10011

N=116

% (n/N)

PROFILE 10052

N=133

% (n/N)

Age: <65 years old

≥65 years old

60 (60/100)

69 (11/16)

50 (58/115)

56 (10/18)

Sex: Male

Female

61 (36/59)

61 (35/57)

44 (28/64)

58 (40/69)

ECOG PS:

0

1

2

54 (21/39)

63 (39/62)

79 (11/15)

56 (20/36)

53 (38/72)

40 (10/25)

No. prior systemic regimens:

(metastatic disease)

0

1

2

3

≥4

80 (12/15)

57 (16/28)

62 (13/21)

59 (13/22)

57 (17/30)

NA

44 (7/16)

58 (23/40)

55 (21/38)

44 (17/39)

Race: Asian

Non-Asian

82 (28/34)

52 (43/82)

62 (26/42)

46 (42/91)

Tumor responses to crizotinib

by patient characteristics



Clinical benefit has been seen across all subtypes of NSCLC patients.

Rapid responses could be seen !

● Example of a patient with a large tumor burden showing marked

response at 14 days

Camidge et al., ESMO 2010; Abs #366PD

Source: Dr SI Ou

PROFILE 1005: Clinical Efficacy and Best percent change from

baseline in size of target lesions by patient (mature population*)

*N=240 response-evaluable patients from the mature population, and excludes patients with early death,

indeterminate response and non-measurable disease

+Per RECIST 1.1, percent change from baseline for subjects with best overall response of CR can be less

than 100% when lymph nodes are included as target lesions.

100

80

60

40

20

0

–20

–40

–60

–80

–100

–120

% D

ec

rea

se

or

Inc

rea

se

Fro

m

Ba

se

lin

e

+

+

+ + PD SD PR CR

Variable Mature population (n=259) n (%)

Complete response 4 (1.5)

Partial response 151 (58.3)

Stable disease 69 (26.6)

Objective progression 19 (7.3)

Objective response (CR + PR) [95% CI] 155 (59.8) [53.6, 65.9]

Median duration of response, weeks [95% CI] 45.6 [35.3–53.6]

Median time to response, weeks [range] 6.1 [4.9–49.1]

Kim et al., ASCO 2012; Abs #7533

PROFILE 1005: Kaplan-Meier plot showing PFS

in the mature population (n=261)

Median PFS 8.1 months (95% CI: 6.8–9.7)

28% patients in follow-up for progression

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al D

istr

ibu

tio

n F

un

cti

on

0 5 10 15 20

Progression Free Survival time (months)

+ Censored 95% Hall-Wellner Band

n at risk 261 175 95 26 2


PROFILE 1005: Any grade treatment-related

adverse events in ≥10% of patients

Adverse event

Mature population, n=261

n (%)

Overall population, n=901

n (%)

Any AE 245 (93.9) 827 (91.8)

Vision disorder* 154 (59) 468 (51.9)

Nausea 148 (56.7) 423 (46.9)

Vomiting 116 (44.4) 352 (39.1)

Diarrhea 106 (40.6) 369 (41.0)

Constipation 86 (33.0) 249 (27.6)

Peripheral edema 72 (27.6) 211 (23.4)

Fatigue 64 (24.5) 163 (18.1)

Decreased appetite 59 (22.6) 167 (18.5)

Increased alanine aminotransferase 45 (17.2) 146 (16.2)

Dysguesia 43 (16.5) 149 (16.5)

Dizziness 40 (15.3) 95 (10.5)

Neutropenia 36 (13.8) 84 (9.3)

Increased aspartate aminotransferase 33 (12.6) 106 (11.8)

*includes visual impairment, photopsia, vision blurred, vitreous floaters, photophobia and diplopia

There were rare instances of fatal pneumonitis and fatal hepatotoxicity reported in crizotinib clinical trial program


PROFILE 1005: Mean change from baseline in

global QOL and lung cancer symptom scores

Global QOL

*p≤0.05

Clinically meaningful

improvement in QOL

Clinically meaningful

improvement in

symptoms

14

12

10

8

6

4

2

0

Me

an

Ch

an

ge

fro

m

Ba

se

lin

e

0

–5

–10

–15

–20

–25

Me

an

Ch

an

ge

fro

m

Ba

se

lin

e

Cycle

Fatigue

Cough

Dyspnea

* *

* * *

*

*

* *

* *

* *

* *

* *

*

*

* *

* *

*

*

* *

* *

* *

* *

* *

*

* * * * *

* *

* * *

* * * *

* * * *

*

2 4 6 8 10 12 14 16 18 20

2 4 6 8 10 12 14 16 18 20

* *

* *

*

* *

* * *

* *

*


PROFILE 10011

N=116

PROFILE 10052

N=133

PROFILE 10053

N=261

Best overall response

Complete response 2 1 4 (1.5%)

Partial response 69 67 151 (58.3%)

Stable disease 31 45 69 (26.6%)

Progressive disease 6 10 19 (7.3%)

Other† 8 10

Objective response

(CR+PR) rate (95% CI) 61% (52%, 70%) 51% (42%, 60%) 59.8% (53.6%, 65.9%)

Duration of response3 48.1 weeks

(median) 41.9 weeks (median) 45.6 (35.3, 53.6)

Duration of treatment,

median 32 weeks 22 weeks n/a

Median PFS

10.0 months

(95% CI: 8.2, 14.7) Not mature 8.1 months

Take Home Message 1: Summary of Efficacy Data



3. Kim et al, ASCO 2012; Abs #7533

PROFILE 1007 (N=318)

● ALK-positive by central laboratory

● 1 prior chemotherapy

(platinum-based)

R

A

N

D

O

M

I

Z

E

Crizotinib 250 mg BID (n=159)

[continuous]

Pemetrexed 500 mg/m2 or

docetaxel 75 mg/m2 (n=159)

infused on day 1 of a 21-day cycle

Other Ongoing Crizotinib PROFILE Program


[continuous]


● ALK-positive by central laboratory

● ≥1 prior chemotherapy and not

eligible for 1007


● ALK-positive locally advanced/

metastatic non-squamous NSCLC

● No prior treatment for advanced

disease

R

A

N

D

O

M

I

Z

E


[continuous]

Pemetrexed/cisplatin or

pemetrexed/carboplatin (n=167)

infused on day 1 of a 21-day cycle

Crossover on PD

Crossover on PD

Companion Diagnostics for Identifying

Appropriate Patients for ALK Inhibitor Therapy:

from NSCLC to other tumor types

Hypothesis: gain-of-function tyrosine kinase-activating

ALK gene expression by rearrangements is a valid

predictive biomarker for clinical response to ALK inhibitors.

Echinoderm microtubule associated protein like 4-anaplastic

lymphoma kinase (EML4-ALK) fusion oncogenes in NSCLC

Adapted from Soda Nature 2007 & Sasaki et al., Eur J Cancer 2010; 46:1773-1780

C.

KLC1-ALK

PTPN3-ALK

others?

Oncogenic Effect of Different ALK Fusion Genes

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

Tumor/

injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2

Vector EML4 ALK EML4–ALK K589M NPM–ALK v-Ras

3T3

Nude

mice

D.

Takeuchi et al., Clin Cancer Res 2009

Methods for Detection of ALK Overexperssion

Shaw, A. T. et al. J Clin Oncol; 27:4247-4253 2009

Hirsch F et al. Clin Cancer Res 2010;16:4909–4911

1. FISH

2. IHC

3. RT-PCR

4. Sequencing

Potential ALK

Fusion Partners:

•EML4

•KIF5B

•TFG

Fused (native) pattern:

Single green (5’) pattern:

Split pattern:

Single red (3’) pattern:

Negative patterns

Positive patterns

~250 kb ~300 kb

t(2;5) ALK gene

breakpoint region

2p23 region Telomere:

Centromer

e

3’ 5’

ALK EML4

Break-apart FISH Schematic: EML4-ALK as an example

Vysis LSI ALK Dual Color, Break Apart

Rearrangement Probe (Abbott Molecular)

Courtesy of Dr. Camidge; Garcia 2011 WCLC

Interpretation of FISH Results:

Positive and Negative

Cellular positivity is set by presence of split or single red (or mixed) patterns

Tumoral positivity is set by proportions of cellular positives (>15%)

Varella-Garcia M et al. ASCO 2010, Abs# 10533

Rodig et al, CCR 2009

Negative Positive: Split Red/Green Positive: Single Reds

Interpretation of FISH Results: >15% can eliminate the negatives

Camidge DR et al. Clin Cancer Res.

2010;16:5581–90.

Mean

% A

LK

-po

sit

ive c

ell

s

ALK-pos

tumor ALK-neg

tumor

15%

ALK-pos

non-tumor ALK-neg

non-tumor

Patient category ALK positive ALK negative

Histology Tumor Non-tumor Tumor Non-tumor

No. areas tested (range) 16 (7-20) 8 (5-15) 18 (8-20) 8 (5-10)

Mean no. cells scored

per area (range)

15 (12-16) 14 (11-19) 15 (14-16) 13 (11-15)

% cells positive for

rearrangement (range)

53.80

(22.25-

86.62)

6.81

(2.14 -

11.14)

5.98

(3.51 -

9.45)

5.26

(0.71-11.21)

Immunohistochemistry (IHC)

● Accumulating data using improved antibody and detection

systems indicate potential for IHC in screening for ALK

positivity

● Standardization needed: antibody, scoring system, cutoffs Mitsudomi et al., ASCO 2011; Abs #7534

Park et al., IASLC 2011; Abs #O05.07

0 1+ 2+ 3+ IHC score

Summary of recent data correlating IHC and FISH results

IHC FISH

0 Negative

1+ Equivocal – need confirmatory FISH

2+ Equivocal – need confirmatory FISH

3+ Positive

Reverse transcription-polymerase chain

reaction (RT-PCR)

● Multiplex RT-PCR can detect all EML4-ALK variants.1

● Technique developed to carry out RT-PCR even using RNA from

FFPE samples.2

● RT-PCR can also be used to screen for most common EML4-

ALK variants and other biomarkers simultaneously.3,4

1. Takeuchi et al., Clin Cancer Res 2008; 14:6618-6624

2. Dannenberg et al., ASCO 2010; Abs #10535

3. Li et al., ASCO 2011; Abs #10520

4. Li et al., ASCO 2012; Abs #7594

Comparison of FISH, IHC, and RT-PCR as

screening modalities for high ALK expression

Adapted from

Mitsudomi, IASLC 2011; Abs #MTE22.1

Hirsch, IASLC 2011; Abs #O05.08

FISH IHC RT-PCR

Current standard for ALK

detection Yes No No

Sensitivity Break-apart signal

can be subtle

*High with detection

enhancement High

Detection of unknown

variants Yes Yes No/Yes

Relative cost High Low Low

Labor intensive Yes No No

Highly specialized training

required Yes No No

Simultaneous visualization of

cell morphology No Yes No

Widely used outside of

specialized centers No Yes No

Subject 4 19 21 23 25 27 28 34 36 37 38 42 43 44 45 50 51 55 56 57 58 59 61 62 63 64 66 68 72 75 76

Response (%) +12 22 26 28 31 33 33 40 43 43 44 49 50 50 50 57 57 64 65 67 70 71 73 74 74 75 76 78 87 100 100

Treatment

duration (wks)

7 15 13 40 20 53+ 51+ 40+ 15+ 27 40+ 40+ 21 12+ 49+ 27+ 16+ 16+ 22 40+ 53+ 84+ 79+ 31+ 48+ 36+ 39 59+ 17+ 79+ 57+

Smoking

(PYrs)

0 0 0 0 5 0 0 1 0 9 5 0 5 3 0 6 9 0 0 35 3 0 0 0 0 0 5 10 0 0 0

ALK FISH + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

EML4–ALK

breakpoint

6 U 18 U U 13 13 13 U 6 U 13 U U 13 6 20 13 U U 13 13 6b 6 13 13 – 6 13 13 –

ALK IHC

expression

2+ 2+ 2+ 2+ 1+ – 1+ 1+ – 2+ 2+ 3+ 1+ – 2+ 3+ 3+ 1+ – – 2+ 2+ 2+ 3+ 1+ 2+ 2+ 2+ – 2+ 2+

-100

-80

-60

-40

-20

0

20

40

PD PR

SD CR

Molecular analysis of EML4–ALK breakpoints:

PROFILE 1001 (N=31)

Kwak et al. New Engl J Med. 2010;363:1693−03

● EML4 confirmed as fusion partner by RT-PCR in 20/29 analyzable samples

● ALK protein detected by IHC in 25/25 analyzable samples

Ch

an

ge f

rom

baselin

e (

%)

How to put this genomic information together for

individual tumors?

• Cancer is a disease of

clonal evolution within the

body

• Imperfect DNA replication

creates random variation

• The accumulation of

mutations over time can

eventually transform a

single cell

Gerlinger,

N Engl J Med 2012; 366:883-892

Intrapatient Heterogeneity of Tumors

Gerlinger, NEJM 2012

N=40 N=59 N=29

N=128

ALK Abnormalities: more than known

Mossé et al., Clin Cancer Res 2009;15(18):5609–14

TFG

KLC1

PTPN3

Others

ALK TKI in Multiple Tumor Types

McDermott U , Settleman J JCO 2009;27:5650-5659

Resistance Mechanisms and Strategies

to Overcome Resistance to Crizotinib

--An Evolving Story

ALK TKI resistance via kinase domain mutations

Choi et al., NEJM 2010

Sasaki et al., Can Res 2011

Doebele et al., Clin Can Res 2012

Katayama et al., Sci Trans Med 2012

continued need for unbiased mutation assessment

Mutations identified in this study All mutations identified in patients 9 separate

mutations in

12 patients

Doebele et al., ASCO 2012, Abs #7504

Emergence of ALK Resistance Mechanisms:

Rebiopsy of 19 ALK+ tumors at progression to crizotinib

Doebele et al, CCR 2012

ALK-independent ALK-dependent

Koivunen et al, CCR 2008 RT-PCR for EML4-ALK, DS for EGFR 1 of 8 (13%) ALK+ specimens was

EGFR mt (exon 19 del)

Zhang et al, Molecular Cancer 2010 RACE-coupled PCR for EML4-ALK, DS

for EGFR

1 of 12 (8%) ALK+ specimens was

EGFR mutated (exon 19 del)

Camidge et al, CCR 2010 Break-apart FISH for ALK, DS for EGFR 1 of 13 (8%) ALK+ specimens was

EGFR mutated (exon 20 S768I)

Kris et al, ASCO 2011 Break-apart FISH for ALK, SNaPshot or

sequenome for EGFR

2 of 38 (5%) ALK+ specimens were

EGFR mutated (mutations were not

described)

Sasaki et al, CCR 2011 Break-apart FISH for ALK, DS for EGFR

3 of 50 (6%) ALK+ specimens were

EGFR mutated (L858R, exon 19 del,

exon 20 ins)

Shaw et al, JCO 2009 Break-apart FISH for ALK, DS for EGFR 0 of 19 ALK+ specimens were EGFR

mutated

Simultaneous detection of both ALK fusion genes and

EGFR mutations in pre-treatment NSCLC samples

ALK Inhibitors in Clinical Development

Drug Company Clinical Stage

Crizotinib Pfizer Phase II-III for NSCLC

Phase I-II in neuroblastoma and other solid tumors

(Mosse et al, ASCO 2012, Abs#9500)

Phase I ALCL

LDK378 Novartis

Phase I NSCLC (ALKi-naïve, resistant) and other

tumors (Mehra et al, ASCO 2012)

CH5424802 Chugai Phase I (Kiura et al, ASCO 2012)

ASP3026 Astellas Phase I (ongoing accrual)

GSK2141795 GlaxoSmithKine Phase I, solid tumors or lymphomas

CEP-28122 Cephalon Preclinical

AP-26113

Ariad

Pharmacetical Preclinical

Xcovery X-277 Preclinical

Others: Eli Lilly,, Nerviano, etc.

TS Expression in ALK+ versus ALK- NSCLC

TS Expression N Median 95% CI Range p Value

ALK+ Patients 63 2.02 1.60-2.11 0.55-19.44 <0.0001

ALK- Patients 1698 3.32 3.15-3.45 0.36-53.51

0

5

10

15

20

AL

K+

TS

2

0

10

20

30

40

50

60

All

AL

K-n

eg

TS

2

TS in patients with ALK+ cancers TS in patients with ALK- cancers

Gandara et al, ASCO 2012, Abs#7582

Stratification Factors

• Number of prior chemotherapy (0 vs ≥1)

• Zubrod Performance status (0-1 vs 2)

• Prior history of brain metastases (yes, no)

• If known brain metastases whether all lesions are treated or not treated (by radiation or surgery) and, if treated, whether stable or not stable (defined by unequivocal growth post local therapy)

• Number of systemic sites of disease progressing on crizotinib at study entry (1, 2-4, >4), defining each lesion as a separate site unless contiguous

• Co-Primary Endpoint: PFS difference; ORR pemetrexed monotherapy arm

• Secondary Endpoints: Patterns of failure, ORR, OS, safety and tolerability

R

A

N

D

O

M

I

Z

E

Crizotinib 250 mg BID

continuous oral daily dosing

+ Pemetrexed 500 mg/m2 IV D1**

(1 cycle = 21 days)

Pemetrexed 500 mg/m2 IV D1

(1 cycle = 21 days)

*Pre-Study Rx, post-

randomization biopsy

of lesion growing on

crizotinib

1:1

• Non-squamous NSCLC

patients with ALK-positive

tumors by break-apart FISH

• Systemic progression on

crizotinib monotherapy after

clinical benefit, i.e., patients

with either ORR or SD ≥ 3 mos

• Starting treatment within 3-30

days after discontinuing

crizotinib

• Absent or asymptomatic

brain metastases

• Pemetrexed-naïve

*30%

Biopsy

each

arm

**Safety and tolerability

assessed in first 20 patients

each arm and combination

dose modified if needed

SWOG: A randomized, phase II trial of crizotinib plus pemetrexed versus

pemetrexed alone in ALK+ non-squamous NSCLC patients who have

progressed systemically after previous clinical benefit from crizotinib therapy Co-PIs: Camidge and Li

LDK378 is a potent and selective ALK inhibitor

Assay

LDK378

IC50 (μM)

Crizotinib

IC50 (μM)

Enzymatic

ALK

MET

0.00015

3.2

0.003

0.008

Cell-based

ALK

MET

0.027

1.3

0.11

0.028

Mehra R, et al. ASCO. 2012; Abstract 3007

Any ALK+ cancer (dose escalation)

ALK+ lung cancer

Resistant to prior ALKi

Non-lung ALK+ tumors

ALK+ lung cancer

Naive to prior ALKi

NCT01283516

Primary objective: Determine the MTD

Secondary objectives: Safety, pharmacokinetics, and antitumor activity

Phase I study of LDK378

LDK378 continuous oral dosing


The dose escalation phase is complete

• Patients with cancers carrying

genetic alterations of ALK

– NSCLC with ALK translocation

by FISH

– Amplification by FISH or IHC+ in

other cancers

• Dose escalation

– Bayesian logistic regression

model

• MTD is 750 mg

• Treatment duration 1–53 wks

(median 12 wks, 64% ongoing)

LDK378, mg/day

Patients treated by

dose

N = 59

50 2

100 2

200 3

300 3

400 14

500 10

600 10

700 5

750 10


LDK378 has antitumor activity in ALK+ NSCLC

• Of the 24 responding patients, 11 responses were confirmed, and 7

are awaiting confirmatory scans

• Response rate was 81% (21/26) in patients with NSCLC treated at

≥ 400 mg who progressed following crizotinib

Initial dose (mg)

Evaluable

Patients (n) Responses (PR)

NSCLC

< 400 8 2 (25%)

≥ 400 33 22 (67%)

Other diseases 50 - 600 6 0


Take Home Messages

1. Crizotinib offers a new standard of care for advanced NSCLC patients whose tumors harboring TK-activating ALK gene expression.

ORR ~60%, median PFS 8-10 months

2. ALK tumor biology is complex in lung cancer: clinical implication?

1) more diverse and heterogeneous molecular mechanisms have been reported to drive ALK gene overexpression

2) not all ALK “drivers” are the same

3) Interaction with other oncogenic drivers (and targeted therapies) in NSCLC

3. Emerging clinical efficacy of ALK inhibitors in a rare subset of patients in other tumor types and second generation ALK inhibitors

4. Unmet clinical needs: 1) To establish a cost-effective strategy to select candidate patients for the

treatment of ALK inhibitor crizotinib, expanding from NSCLC (2011) to other tumor types (2012)

2) To identify treatment strategies for those ALK-positive NSCLC patients

who have progressed on crizotinib monotherapy: It is getting more individualized in 2012 !

update on alk inhibitors in nsclce-syllabus.gotoper.com/_media/_pdf/ilc12_fri_02_li_final.pdf ·...

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