1. 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

2. Oncogenic Drivers in NSCLC
KRAS 24%1
EGFR 13%1
PIK3CA 4%1
RET ~1%5
ALK 3%2
MET ~1%4
HER2 2%3
1Sequist et al., Ann Oncol 22:2616, 2011
2Takeuchi et al., Nat Med, Feb
3Shaw et al., NEJM 365:158, 2011
4Kris et al., WCLC 2011
5Takeuchi et al., Nat Med, Feb
NRAS 1%1
BRAF 2%1
AKT ~1%3
ROS ~1%2

3. The Promise of Genotype-Directed Therapy
Treatment A
Treatment B
NSCLC
Treatment C
Treatment D

4. The Promise of Genotype-Directed Therapy
ALK (or ROS)
Crizotinib, other ALK TKIs
EGFR mutation
Erlotinib or gefitinib
NSCLC
Treatment C
Treatment D

5. NCCN Guidelines for the Management of Stage IV NSCLC

6. Crizotinib
an update

7. Crizotinib: A Dual MET/ALK Tyrosine Kinase Inhibitor
IC50 (nM)
mean*
Selectivity ratio
c-MET 8 –
ALK
40-60
5-8X
ROS 60 7X
RON 80
10X
Axl
294
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
PDGFR
Co-crystal structure of crizotinib (PF ) bound to c-MET
Cui et al. J. Med. Chem. 2011;54: and Pfizer data on file

8. Marked Activity of Crizotinib in ALK+ NSCLC Update of the Phase 1 Study
ORR = 60.8%* in 143 evaluable patients
(133 evaluable patients shown)
Median response duration = 49.1 wks
Median PFS = 9.7 mos
*Higher ORR in Asians vs non-Asians
-30
Camidge et al., Lancet Onc, in press

9. Phase 2 Study: PROFILE 1005 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
Crizotinib 250 mg BID
administered PO on a
continuous dosing
schedule
N=250
>1000
NCT

10. Decrease or increase from baseline (%)
Marked Activity of Crizotinib in ALK+ NSCLC Update of the Phase 2 Study
100 PD SD PR CR 80 60 40 20
Decrease or increase from baseline (%)
–20
–40
–60 + +
–80
–100 + +
–120
*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
Kim et al., ASCO 2012

11. Probability of survival without progression
Marked Activity of Crizotinib in ALK+ NSCLC Update of the Phase 2 Study
1.0
Median PFS 8.1 months (95% CI: 6.8–9.7)
28% patients in follow-up for progression
0.8
+ Censored % Hall-Wellner Band
0.6
Probability of survival without progression
0.4
0.2
Time (months)
n at risk
Kim et al., ASCO 2012

12. PROFILE 1005: Any-Grade Treatment-Related AEs in ≥10% of Patients
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 Rare instances of fatal pneumonitis and fatal hepatotoxicity were reported in crizotinib clinical trial program

13. Phase 3 Study: PROFILE 1007 Crizotinib 250 mg BID Endpoints
administered PO on
a continuous dosing
schedule
(N=159)
Endpoints
Primary
- PFS (RECIST 1.1,
independent review)
Secondary
- ORR, DR, DCR
- OS
- Safety
- Patient reported
outcomes (PROs)
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
R A N D O M I Z E
Pemetrexed 500 mg/m2 or
Docetaxel 75 mg/m2
infused IV on day 1
of a 21-day cycle
(N=159)
Make arrows equal length going to each arm.
N=318
NCT

14. Next Generation ALK TKIs
LDK378

15. Mechanisms of Crizotinib Resistance
Target gene
alteration (28%)
Bypass track
activation (45%) * ??
No loss of ALK (26/26)
No EGFR or KRAS mutations (21/21)

16. LDK378: A Potent and Selective ALK Inhibitor
2,4-diaminopyrimidine derivative. MW:
Potent, ATP-competitive inhibitor of ALK
Assays
LDK378
IC50 (μM)
Crizotinib
ALK (enzymatic)
MET (enzymatic)
3.2
0.003
0.008
BaF3/ALK
BaF3/MET
0.027
1.3
0.11
0.028
Li et al., AACR-NCI-EORTC, 2011; Mehra et al., ASCO 2012

17. 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 LDK mg/kg/day
Li et al., AACR-NCI-EORTC, 2011
LDK378 caused complete tumor regression when dosed at 25 mg/kg/day or 50 mg/kg/day in mouse xenograft tumor model derived from NCI-H2228 (EML4-ALK, NSCLC) after 14 days of treatment.
Remission was maintained for more than 4 months after 14 days of treatment with LDK mg/kg/day.

18. Preclinical Evaluation of LDK378 Activity
Crizotinib-resistant xenograft models
ALK C1156Y mutation
No ALK mutation
• LDK378 at mg/kg/day has antitumor activity in different crizotinib-resistant models
Li et al., AACR-NCI-EORTC, 2011

19. Resistant to prior ALKi LDK378 continuous oral dosing
Phase I study of LDK378
ALK+ lung cancer
Resistant to prior ALKi
MTD
ALK+ lung cancer
Naive to prior ALKi
Any ALK+ cancer
Non-lung ALK+ tumors
LDK378 continuous oral dosing
Primary objective: Determine the MTD
Secondary objectives: Safety, pharmacokinetics, and antitumor activity
NCT

20. Baseline Patient Characteristics
All patients, n (%)
N=56
Age (median), yrs (range)
53 (22–78)
Sex (male)
19 (34)
ECOG Performance Status
10 (18)
39 (70)
7 (12)
Cancer type
NSCLC
Breast
Rectal
Alveolar rhabdomyosarcoma
50 (89)
4 (7)
1 (2)
Prior crizotinib
Crizotinib naive
37 (66)
Mehra et al., ASCO 2012

21. 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

22. Antitumor Activity of LDK378 in ALK+ NSCLC
Initial dose (mg)
Patients (n)
Responses
NSCLC
<400 8
2 (25)
≥400 33
22 (67)
Other diseases
50–600 6
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)
Mehra et al., ASCO 2012

23. Typical Responses to LDK378
Baseline
After 6 weeks on LDK378
Mehra et al., ASCO 2012

24. Typical Responses to LDK378
Baseline
After 6 weeks on LDK378
Mehra et al., ASCO 2012

25. CNS Activity of LDK378 Baseline After 6 weeks on LDK378
Mehra et al., ASCO 2012

26. 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

27. Other Next Generation ALK TKIsCH
AP26113

28. CH5424802 is a Potent and Selective ALK TKIB
Sakamoto et al., Cancer Cell 2011;19:679-90

29. AP26113 is a Potent and Selective ALK TKI
Crizotinib
AP26113
ALK-negative cells
EML4-ALK
-L1196M
Relative Cell Viability
EML4-ALK
Drug Concentration (nM)
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

30. Phase 1/2 Study of AP26113 Phase I/ II Schema Cohort 1: N=20
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
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

31. 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 •

32. 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 - • - • •