Targeting ALK in Advanced NSCLC A New Treatment Paradigm

Alice T. Shaw, MD PhD

Massachusetts General Hospital Cancer Center

Harvard Medical School

August 25, 2012

Oncogenic Drivers in NSCLC

KRAS 24%1

EGFR 13%1

PIK3CA 4%1

ALK 3%2

HER2 2%3

BRAF 2%1

ROS ~1%2

RET ~1%5

MET ~1%4

NRAS 1%1

AKT ~1%3

1Sequist et al., Ann Oncol 22:2616, 20112Takeuchi et al., Nat Med, Feb 12 20123Shaw et al., NEJM 365:158, 20114Kris et al., WCLC 20115Takeuchi et al., Nat Med, Feb 12 2012

The Promise of Genotype-Directed Therapy

Treatment B

Treatment C Treatment D

Treatment A

NSCLC

The Promise of Genotype-Directed Therapy

ALK (or ROS)

Crizotinib, other ALK TKIs

Treatment C Treatment D

EGFR mutation

Erlotinib or gefitinib

NSCLC

NCCN Guidelines for the Management of Stage IV NSCLC

Crizotinib

an update

Crizotinib: A Dual MET/ALK Tyrosine Kinase Inhibitor

KinaseIC50 (nM)mean*

Selectivity ratio

c-MET 8 –

ALK 40-60 5-8X

ROS 60 7X

RON 80 10X

Axl294 34X

322 37X

Tie-2 448 52X

Trk A 580 67X

Trk B 399 46X

Abl 1,159 166X

IRK 2,887 334X

Lck 2,741 283X

Sky >10,000 >1,000X

VEGFR2 >10,000 >1,000X

PDGFR >10,000 >1,000X

Co-crystal structure of crizotinib (PF-02341066) bound to c-MET

Cui et al. J. Med. Chem. 2011;54:6342-63 and Pfizer data on file

Marked Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase 1 Study

-30

ORR = 60.8%* in 143 evaluable patients(133 evaluable patients shown)Median response duration = 49.1 wksMedian PFS = 9.7 mos*Higher ORR in Asians vs non-Asians

Camidge et al., Lancet Onc, in press

Phase 2 Study: PROFILE 1005

NCT00932451

Crizotinib 250 mg BID administered PO on a

continuous dosing schedule

Key entry criteria

● Positive for ALK by central laboratory (local testing subsequently allowed on case-by-case basis)

● Progressive disease in Arm B of PROFILE 1007 study

● >1 prior chemotherapy

● ECOG PS 0-3

● Stable/controlled brain mets allowed

N=250

>1000

100

80

60

40

20

0

–20

–40

–60

–80

–100

–120

De

cre

as

e o

r in

cre

as

e f

rom

ba

se

lin

e (

%)

*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

PD

++

++

Marked Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase 2 Study

SD PR CR

Kim et al., ASCO 2012

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

Pro

bab

ilit

y o

f su

rviv

al w

ith

ou

t p

rog

ress

ion

0 5 10 15 20Time (months)

+ Censored 95% Hall-Wellner Band

n at risk 261 175 95 26 2

Marked Activity of Crizotinib in ALK+ NSCLCUpdate of the Phase 2 Study

Kim et al., ASCO 2012

PROFILE 1005: Any-Grade Treatment-Related AEs in ≥10% of Patients

AEMature 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 diplopiaRare instances of fatal pneumonitis and fatal hepatotoxicity were reported in crizotinib clinical trial program

Key entry criteria

● Positive for ALK by central FISH testing

● Stage IIIB/IV NSCLC

● 1 prior chemotherapy

(platinum-based)

● ECOG PS0-2

● Measurable disease

● Treated brain metastases allowed1

N=318

RANDOMIZE

Crizotinib 250 mg BID administered PO on a continuous dosing

schedule(N=159)

Pemetrexed 500 mg/m2 or

Docetaxel 75 mg/m2 infused IV on day 1of a 21-day cycle

(N=159)

NCT00932893

Endpoints

● Primary

- PFS (RECIST 1.1,

independent review)

● Secondary

- ORR, DR, DCR

- OS

- Safety

- Patient reported

outcomes (PROs)

Phase 3 Study: PROFILE 1007

Next Generation ALK TKIs

LDK378

ALK amplificationALK mutationEGFR activationCKIT amplificationUnknown

Mechanisms of Crizotinib Resistance

??No loss of ALK (26/26)No EGFR or KRAS mutations (21/21)

Target gene alteration (28%)

Bypass trackactivation (45%)

*

*

LDK378: A Potent and Selective ALK Inhibitor

2,4-diaminopyrimidine derivative. MW: 558.14

Potent, ATP-competitive inhibitor of ALK

Assays LDK378IC50 (μM)

CrizotinibIC50 (μM)

ALK (enzymatic)MET (enzymatic)

0.000153.2

0.0030.008

BaF3/ALKBaF3/MET

0.0271.3

0.110.028

Li et al., AACR-NCI-EORTC, 2011; Mehra et al., ASCO 2012

Preclinical Evaluation of LDK378 Activity

NCI-H2228 sensitive xenograft models

• LDK378 caused complete tumor regression after 14 days of treatment• No growth of tumors for >4 months in mice treated with LDK378 50 mg/kg/day

Li et al., AACR-NCI-EORTC, 2011

Preclinical Evaluation of LDK378 Activity

Crizotinib-resistant xenograft models

ALK C1156Y mutation No ALK mutation

• LDK378 at 50-100mg/kg/day has antitumor activity in different crizotinib-resistant models

Li et al., AACR-NCI-EORTC, 2011

Any ALK+ cancer MTD

ALK+ lung cancerResistant to prior ALKi

LDK378 continuous oral dosing

Non-lung ALK+ tumors

ALK+ lung cancerNaive to prior ALKi

NCT01283516

Primary objective: Determine the MTDSecondary objectives: Safety, pharmacokinetics, and antitumor activity

Phase I study of LDK378

CharacteristicAll patients, n (%)

N=56

Age (median), yrs (range) 53 (22–78)

Sex (male) 19 (34)

ECOG Performance Status 0 1 2

10 (18)39 (70)7 (12)

Cancer type NSCLC Breast Rectal Alveolar rhabdomyosarcoma

50 (89)4 (7)1 (2)1 (2)

Prior crizotinibCrizotinib naive

37 (66)19 (34)

Baseline Patient Characteristics

Mehra et al., ASCO 2012

Adverse events associated with LDK378

• SAEs related to LDK378 have occurred in 5 patients– Transaminase elevation (400 mg), vomiting (500 mg),

dehydration (600 mg), and interstitial lung disease (750 mg)• All SAEs were reversible upon cessation of LDK378

– Two patients resumed treatment with LDK378 a lower dose level

– Two had simultaneous progressive disease• Common AEs included

– Nausea (59%), vomiting (54%), and diarrhea (48%), fatigue (21%), and dyspnea (16%)

• Only one patient has discontinued treatment because of an AE

Mehra et al., ASCO 2012

Antitumor Activity of LDK378 in ALK+ NSCLC

• Response rate 81% (21/26) in NSCLC patients treated at ≥400 mg who progressed following crizotinib– Responses include confirmed + unconfirmed per RECIST 1.0

(6 patients with PR awaiting confirmatory scans)

Initial dose(mg) Patients (n) Responses

NSCLC <400 8 2 (25)

≥400 33 22 (67)

Other diseases 50–600 6 0

Mehra et al., ASCO 2012

Typical Responses to LDK378

After 6 weeks on LDK378Baseline

Mehra et al., ASCO 2012

After 6 weeks on LDK378Baseline

Typical Responses to LDK378

Mehra et al., ASCO 2012

After 6 weeks on LDK378Baseline

CNS Activity of LDK378

Mehra et al., ASCO 2012

Summary of LDK378

• The MTD of LDK378 is 750 mg PO qd• The most common AEs are nausea, vomiting and

diarrhea• LDK378 exhibits potent antitumor activity in

patients with ALK+ NSCLC, particularly in those who have progressed following crizotinib

• LDK378 is active in brain metastases

Other Next Generation ALK TKIs

CH5424802AP26113

CH5424802 is a Potent and Selective ALK TKI

A

B

C

Sakamoto et al., Cancer Cell 2011;19:679-90

Crizotinib

1 10 100 1000 100000

25

50

75

100

1 10 100 1000 100000

25

50

75

100

AP26113

EML4-ALK-L1196M

EML4-ALK

ALK-negative

cells

Drug Concentration (nM)

Rel

ativ

e C

ell V

iabi

lity

> Ba/F3 cells (ALK-negative) engineered to express EML4-ALK or the L1196M mutant> AP26113, but not crizotinib, inhibits viability of the L1196M mutant with high

selectivity> Similar results obtained with multiple other mutants, including G1269S, S1206R,

C1156Y, F1174C, F1245C, I1174T and L1152V

Zhang et al, AACR 2010

AP26113 is a Potent and Selective ALK TKI

Dose Escalation Cohorts

N=30 to 50

Advanced malignancies

All histologies except leukemia

ECOG 0-2

CNS mets allowed if stable for 8 wks

Oral AP26113, 30 mg once daily

(QD) starting dose

→

Dose level cohorts escalating until

RP2D is established

Cohort 1: N=20

NSCLC: ALK rearrangement and

ALK inhibitor naïve

* Cohort 2: N=20

NSCLC: ALK rearrangement and

resistant to at least 1 prior ALK inhibitor

* Cohort 3: N=20

NSCLC: EGFR activating mutation and

resistant to at least 1 prior EGFR inhibitor

Cohort 4: N=20

Other cancers with abnormal targets

eg, ALK, ROS, and others* Tissue must be obtained after development of resistance to ALK (cohort 2) or EGFR (cohort 3) TKI therapy

Phase I/ II SchemaPhase 1/2 Study of AP26113

Summary

Crizotinib is now a standard therapy for patients with advanced, ALK+ NSCLC

- ORR 60%

- Median PFS 8-9 months

- Phase 3 studies

More potent ALK TKIs like LDK378 may be effective salvage therapies for the majority of patients who relapse on crizotinib

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•

Future Directions

Timing of next generation ALK TKIs

Front-line use of next generation ALK TKIs

Mechanism of action

Overcoming resistance vs more potent target inhibition

Resistance to next generation ALK TKIs

Developing combination strategies

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