1. Ranee Mehra, MD Fox Chase Cancer Center
Management of ALK positive NSCLC – initial therapy and resistant disease
Ranee Mehra, MD
Fox Chase Cancer Center

2. Disclosures Consulting – Novartis, Bristol Myers Squib
Spouse is employee of GSK

3. Current ALK inhibitors
Crizotinib
LDK378 - Ceritinib
AP26113
CH – Alectinib
ASP3026

4. EML4-ALK fusion
Chr 2p
Soda et al. Nature 448, (2 August 2007)

5. Tumor cell proliferation
ALK Pathway Or
Inversion
Translocation
ALK
ALK fusion protein*
Cell survival
PI3K
BAD
AKT
STAT3/5
mTOR
S6K
RAS
MEK
ErK
PLC-Y
PIP2
IP3
Tumor cell proliferation
*Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2
1. Inamura K et al. J Thorac Oncol 2008;3:13– Soda M et al. Proc Natl Acad Sci U S A 2008;105:19893–19897 Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614; and Data on file. Pfizer Inc. 5 5

6. FISH Assay for ALK Rearrangement*
Telomere
2p23 region
Centromere
p25.2
p25.2
ALK 29.3
p24.3
p24.3
t(2;5) ALK gene
breakpoint region
p24.1
p24.1
p23.2
p23.2
p22.3
p22.3
p22.1
p22.1
EML4 42.3
p16.3
p16.3
p16.1
p16.1 3’ 5’
p14
p14
p13.2
p13.2
p12
p12
~250 kb
~300 kb
q12.1
q12.1
q12.3
q12.3
Break-apart FISH assay for ALK-fusion genes1
q14.1
q14.1
q14.3
q14.3
q21.2
q21.2
q22.1
q22.1
q23.2
q22.2
q22.2
q23.2
q24.1
q24.1
q24.3
q24.3
q31.3
q31.3
q32.1
q32.3
q33.2
q32.1
q32.3
q33.2
Non-split signal
q34
q34
Split signal
q36.1
q36.3 q37.2
q36.1
q36.3 q37.2
ALK break-apart FISH assay [Courtesy John Iafrate, Massachusetts General Hospital]
*Assay is positive if rearrangements can be detected in ≥15% of cells FISH = fluorescence in situ hybridization
1Shaw AT et al. J Clin Oncol 2009;27:4247–4253 6

7. Clinico-pathologic features of EML4-ALK mutant lung cancer.
141 patients screened (selected population)
18 (13%) were ALK mutant
31 (22%) were EGFR mutant,
92 (65%) were wild-type (WT) for both
ALK:
Majority adenocarcinoma, signet ring cell type
Resistant to EGFR TKIs
Younger
Never/light smokers
Shaw et al. ASCO 2009 #11021

8. Patients with ALK-positive NSCLC Do not Appear to Respond to EGFR TKIs
Platinum-based chemotherapy
EGFR TKI
ALK (N=10)
EGFR (N=23)
WT/WT* (N=23)
Response rate, % 70 13
TTP, months 5 16 6
ALK (N=12)
EGFR (N=8)
WT/WT* (N=34)
Response rate, % 25 50 35
TTP, months 9 10 8
100 80 60 40 20
100 80 60 40 20
TTP for EGFR TKI1
TTP for chemotherapy1 % %
EGFR
WT/WT
EGFR
EML4–ALK
WT/WT
EML4–ALK 12 24 36 48 60 12 24 36 48 60
Months
Months
*WT/WT = wild type: no ALK fusion or EGFR mutation
1Shaw AT et al. J Clin Oncol 2009;27:4247–4253 8

9. Original Article Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Eunice L. Kwak, M.D., Ph.D., Yung-Jue Bang, M.D., Ph.D., D. Ross Camidge, M.D., Ph.D., Alice T. Shaw, M.D., Ph.D., Benjamin Solomon, M.B., B.S., Ph.D., Robert G. Maki, M.D., Ph.D., Sai-Hong I. Ou, M.D., Ph.D., Bruce J. Dezube, M.D., Pasi A. Jänne, M.D., Ph.D., Daniel B. Costa, M.D., Ph.D., Marileila Varella-Garcia, Ph.D., Woo-Ho Kim, M.D., Thomas J. Lynch, M.D., Panos Fidias, M.D., Hannah Stubbs, M.S., Jeffrey A. Engelman, M.D., Ph.D., Lecia V. Sequist, M.D., M.P.H., WeiWei Tan, Ph.D., Leena Gandhi, M.D., Ph.D., Mari Mino-Kenudson, M.D., Greg C. Wei, Ph.D., S. Martin Shreeve, M.D., Ph.D., Mark J. Ratain, M.D., Jeffrey Settleman, Ph.D., James G. Christensen, Ph.D., Daniel A. Haber, M.D., Ph.D., Keith Wilner, Ph.D., Ravi Salgia, M.D., Ph.D., Geoffrey I. Shapiro, M.D., Ph.D., Jeffrey W. Clark, M.D., and A. John Iafrate, M.D., Ph.D.
N Engl J Med
Volume 363(18):
October 28, 2010

10. Demographic and Clinico-pathological Characteristics - 82 Patients
Male – 52%
42% - > 3 prior therapies
96% adenocarcinoma
76% never smokers
18% < 10 pack years
6% > 10 pack years
Kwak EL et al. N Engl J Med 2010;363:

11. Response to ALK Inhibition
RR 57%
SD 33%
8 week disease control rate 87%
7% PD
Kwak EL et al. N Engl J Med 2010;363:

12. Duration of Therapy
Kwak EL et al. N Engl J Med 2010;363:

13. Adverse Events in the 82 Patients
Kwak EL et al. N Engl J Med 2010;363:

14. Phase I updated results
143 evaluable ALK + patients were enrolled
RR 60.8 %
Median duration of response 49.1 weeks
Median PFS 9.7 months
Estimated 12 month survival 75%
12 patients received therapy after documented progression for ongoing clinical benefit.
Camidge et al. The Lancet Oncology, Volume 13, Issue 10, Pages , October 2012

15. Original Article Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
Alice T. Shaw, M.D., Ph.D., Dong-Wan Kim, M.D., Ph.D., Kazuhiko Nakagawa, M.D., Ph.D., Takashi Seto, M.D., Lucio Crinó, M.D., Myung-Ju Ahn, M.D., Tommaso De Pas, M.D., Benjamin Besse, M.D., Ph.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Fiona Blackhall, M.D., Ph.D., Yi-Long Wu, M.D., Michael Thomas, M.D., Kenneth J. O'Byrne, M.D., Denis Moro-Sibilot, M.D., D. Ross Camidge, M.D., Ph.D., Tony Mok, M.D., Vera Hirsh, M.D., Gregory J. Riely, M.D., Ph.D., Shrividya Iyer, Ph.D., Vanessa Tassell, B.S., Anna Polli, B.S., Keith D. Wilner, Ph.D., and Pasi A. Jänne, M.D., Ph.D.
N Engl J Med
Volume 368(25):
June 20, 2013

16. Progression-free Survival.
Shaw AT et al. N Engl J Med 2013;368:

17. Patient-Reported Outcomes.
Shaw AT et al. N Engl J Med 2013;368:

18. Summary of Responses
Shaw AT et al. N Engl J Med 2013;368:

19. Adverse Events of Any Cause
Shaw AT et al. N Engl J Med 2013;368:

20. DRAFT
Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC
Alice T. Shaw,1 Ranee Mehra,2 Dong-Wan Kim,3 Enriqueta Felip,4 Laura Q. M. Chow,5 D. Ross Camidge,6 Daniel S. W. Tan,7 Johan Vansteenkiste,8 Sunil Sharma,9 Tommaso De Pas,10 Juergen Wolf,11 Ryohei Katayama,12 Yvonne Lau,13 Meredith Goldwasser,13 Anthony L. Boral,13 Jeffrey A. Engelman1
1Massachusetts General Hospital, Boston, MA; 2Fox Chase Cancer Center, Philadelphia, PA; 3Seoul National University Hospital, Seoul, Korea; 4Vall d’Hebron University, Barcelona, Spain; 5University of Washington, Seattle, WA; 6University of Colorado, Denver, CO; 7National Cancer Center, Singapore; 8University Hospital KU Leuven, Leuven, Belgium; 9Huntsman Cancer Institute, Salt Lake City, UT; 10Instituto Europeo di Oncologia, Milan, Italy; 11University Hospital Cologne, Cologne, Germany; 12Massachusetts General Hospital, Boston, MA; 13Novartis Pharmaceuticals, Cambridge, MA.
ASCO 2013

21. Crizotinib-resistant H2228 tumor model with ALK C1156Y mutation
LDK378 - Ceritinib
LDK378 is a potent and selective oral ALK inhibitor1
Potent activity in enzymatic and cell based assays1,2
LDK378 provides durable responses in EML4-ALK NSCLC xenografts, including crizotinib-resistant models)1
Assay
LDK378
IC50 (nM)
CRZ
Enzymatic
ALK
IGF-1R
c-Met
0.15 8
3200 3
400
Cell-based3
EML4-ALK
- L1196M
- G1269S
- G1202R
- C1156Y 20 60
140
490
130
120
810
1600
1020
350
Crizotinib-resistant H2228 tumor model with ALK C1156Y mutation
CRZ, crizotinib; IGF-1R, insulin-like growth factor 1 receptor.
1. Li N, et al. AACR-NCI-EORTC 2011; Abstr B232; 2. Shaw AT, et al. ESMO 2012; Abstr 440O.
3. Novartis, data on file.

22. Study Design NCT01283516 Completed N=59 Additional N=71 enrolled‡
Any advanced ALK+ cancer
Progression on standard therapy
(dose escalation)
NCT
MTD* (50 mg/day starting dose)
Continuous oral dosing; 21-day cycles
Completed N=59
Continuous oral dosing 21 day cycles
ALK+ lung cancer
Prior ALKi therapy
ALK+ lung cancer
naïve to ALKi
Non-lung ALK+ tumors
Additional N=71 enrolled‡
LDK378 ≤2 months after prior ALKi and progression during prior ALKi
LDK378 >2 months after prior ALKi or progression after prior ALKi
Primary objective: determination of MTD (*750 mg/day)
Secondary objectives: safety, pharmacokinetics and preliminary antitumor activity
ALKi, ALK inhibitor; MTD, maximum tolerated dose.
‡Enrolled on or before 19 October 2012

23. Patient Eligibility
Adult patients with locally advanced or metastatic disease
Genetic alterations of ALK as determined by FISH (ALK+ in ≥15% of tumor cells) in NSCLC, and by FISH, PCR or IHC in other cancers
Untreated CNS metastases permitted if asymptomatic; treated CNS metastases permitted if neurologically stable
ECOG performance status ≤2
Strong inhibitors/inducers of CYP3A4/5 and substrates of CYP3A4/5 or CYP2C9 with narrow therapeutic index excluded
FISH fluorescence in situ hybridization; IHC, immunohistochemistry; PCR, polymerase chain reaction.

24. Patient Demographics and Disease Characteristics*
Patient Characteristic
All patients, n (%)
N=130
Median age (range)
53 (22–80)
Female
78 (60)
ECOG Performance Status
0 1 ≥2
25 (19)
89 (69)
16 (12)
Cancer type
NSCLC
Breast
Other/missing
121 (93)
4 (3)
5 (4)
Prior ALK inhibitor (NSCLC)
ALK inhibitor naïve (NSCLC)
Non-NSCLC
82 (63)
40 (31)
8 (6)
*All patients with at least 18 weeks follow-up or discontinued earlier; data cut-off 28 Feb 2013

25. Adverse Events (≥15%), Regardless of Study Drug Relationship
Preferred term, n (%)
50–300 mg n=10
400 mg n=14
500 mg n=10
600 mg n=10
700 mg n=5
750 mg* n=81
All patients N=130
Nausea
5 (50)
10 (71)
9 (90)
10 (100)
5 (100)
56 (69)
95 (73)
Diarrhea
3 (30)
9 (64)
7 (70)
8 (80)
4 (80)
63 (78)
94 (72)
Vomiting
4 (40)
8 (57)
47 (58)
76 (58)
Fatigue
4 (29)
0 (0)
34 (42)
53 (41)
ALT increased
2 (14)
1 (10)
24 (30)
34 (26)
Decreased appetite
2 (20)
3 (60)
21 (26)
33 (25)
Constipation
1 (7)
2 (40)
22 (27)
31 (24)
Abdominal pain
1 (20)
23 (28)
30 (23)
AST increased
3 (21)
15 (19)
24 (18)
Asthenia
12 (15)
Cough
19 (15)
ALT, alanine aminotransferase; AST, aspartate aminotransferase.
*MTD

26. Grade 3 and 4 Adverse Events (≥5%), Regardless of Study Drug Relationship
Preferred term,
n (%)
50–300 mg n=10
400 mg n=14
500 mg n=10
600 mg n=10
700 mg n=5
750 mg* n=81
All patients N=130
ALT increased
0 (0)
1 (7)
2 (20)
4 (80)
18 (22)
25 (19)
AST increased
2 (14)
3 (60)
8 (10)
13 (10)
Diarrhea
1 (10)
6 (7)
11 (8)
Lipase increased
5 (6)
7 (5)
Hypokalemia
1 (20)
6 (5)
Nausea
4 (5)
3 (2%) patients discontinued due to AEs
*MTD

27. Marked Activity of LDK378 in Patients with Advanced ALK+ NSCLC
100
Best % change from baseline in target lesions
LDK –750 mg/day 80 60
Prior crizotinib
Crizotinib- naïve 40 20
Best % change from baseline
–20
–40
–60
–80
PFS event
–100
Patients with at least 1 post-baseline assessment of target lesions (investigator assessment)

28. High Response Rate in Patients with ALK+ NSCLC: LDK378 400–750 mg/day
All NSCLC
N=114
NSCLC
CRZ-pretreated n=79†
NSCLC CRZ-naïve n=35‡
Complete response (CR)
1 (1)
0 (0)
Partial response (PR)
65 (57)
44 (56)
21 (60)
Stable disease
37 (32)
27 (34)
10 (29)
Progressive disease
6 (5)
6 (8)
CR + PR + uPR
86 (75)
62 (78)
24 (69)
Overall response rate* (CR + PR)
66 (58)
45 (57)
*Confirmed per RECIST 1.0 (investigator assessment)
†1 response unknown; ‡4 response unknown
CRZ, crizotinib; uPR, unconfirmed PR

29. High Response Rate in Patients with ALK+ NSCLC: LDK378 750 mg/day
All NSCLC
N=78
NSCLC
CRZ-pretreated n=49†
NSCLC CRZ-naïve n=29‡
Complete response (CR)
0 (0)
Partial response (PR)
47 (60)
29 (59)
18 (62)
Stable disease
23 (29)
15 (31)
8 (28)
Progressive disease
4 (5)
4 (8)
CR + PR + uPR
59 (76)
38 (78)
21 (72)
Overall response rate* (CR + PR)
*Confirmed per RECIST 1.0 (investigator assessment)
†1 response unknown; ‡3 response unknown
CRZ, crizotinib; uPR, unconfirmed PR

30. Prolonged Duration of Response and PFS in ALK+ NSCLC
Endpoint
Estimate
95% CI
DOR
Median DOR ≥400 mg/day (n=66 responders)
8.2 months
6.9–NE
6 month DOR rate at 750 mg/day (n=47 responders)
60.6%
34.9–78.8
PFS
Median PFS (≥400 mg/day) (n=114)
8.6 months
5.7–9.9
6 month PFS rate at 750 mg/day (n=78)*
60.7%
46.1–72.4
CI, confidence interval; DOR, duration of response; PFS, progression-free survival.
Median PFS at 750 mg/day not reached.

31. Typical Responses to LDK378
Baseline
After 3 months of LDK378

32. Continued response in the CNS at 6 mos
Responses in the CNS
T1- post
T1- post
Flair
Flair
Continued response in the CNS at 6 mos
Baseline
After 6 weeks of LDK378

33. Updated Results of a First-in-Human Dose-Finding Study of the ALK/EGFR Inhibitor AP26113 in Patients with Advanced Malignancies
D Ross Camidge, Lyudmila Bazhenova, Ravi Salgia, Glen J Weiss, Corey J Langer, Alice T Shaw, Narayana I Narasimhan, David J Dorer, Victor M Rivera, Joshua Zhang, Tim Clackson, Frank G Haluska, Scott N Gettinger
WCLC 2013, Sydney, Australia
Abstract 2400

34. AP26113 Phase 1/2 Study Study Design
Cohort 1, NSCLC: N=20
ALK+ and ALK inhibitor naïve
Phase 1
Cohort 2, NSCLC: N=20
ALK+ and crizotinib-resistant
Dose Escalation,
3+3 Design: N=30 to 60
Advanced malignancies
(all histologies except leukemia) until MTD and RP2D established
Cohort 3, NSCLC: N=20
Documented T790M and resistant to 1 prior EGFR TKI
Cohort 4: N=20
Other cancers with AP26113 targets
(eg, ALK, ROS1, EGFR ineligible for Cohort 3, and others)
Cohort 5, NSCLC: N=25
ALK+ and naïve or resistant to crizotinib with active brain mets
Added
May 2013

35. Adverse Events Treatment Emergent, Grades ≥3
Preferred term
(≥2 patients)
30,60 mg
N=6
90 mg
N=8
120 mg
N=18
180 mg*
N=45
240 mg
N=12
300 mg
N=2
Total
N=91
Dyspnea
1 (6)
1 (2)
1 (8)
1 (50)
4 (4)
Fatigue
1 (17)
2 (17)
Pneumonia
3 (17)
Hypoxia
3 (3)
Lung infection
2 (2)
Pneumonitis
Lipase increased
Diarrhea
Hyponatremia
1 (13)
*Preferred terms ranked by incidence at 180 mg
Treatment-related Grade ≥3 AEs in ≥2 patients: dyspnea (4%), fatigue (3%), diarrhea (2%), hypoxia (2%), and pneumonitis (2%)
Data as of 6 Sept 2013

36. Early Onset Pulmonary Symptoms
Early onset (typically day 1 or 2) shortness of breath, O2 desaturation and patchy GGO
Observed in 3/26 patients (12%) at 180 mg QD in Ph 2 expansion (4/45 [9%]) overall)
Occurred at lower doses, but less common; not observed at these doses with narrowed eligibility criteria
Reversible, responsive to drug interruption and steroid support; documented recurrence with re-challenge, but some cases resolved with continued dosing w/o additional intervention; 1 case associated with fatality concurrent with progressive malignancy (Ph 1)
60 mg prednisone QD premedication
180 mg AP26113 re-challenge
O2 as needed
Data in graph from single patient

37. ALK+ NSCLC Anti-Tumor Activity Target Lesions (N=34)
65% (22/34) objective response rate (95% CI: 47-80%)
61% (19/31) post-crizotinib (incl. 1 criz intolerant)
100% (3/3) in TKI-naïve (incl. 1 CR)
Response duration 8+ to 40+ weeks
14 confirmed, 4 awaiting confirmation, 4 not confirmed
All patients received prior crizotinib unless otherwise indicated; Doses ranged from mg/d (23 pts ≥180mg/d); aTKI-naïve; bReceived prior crizotinib and LDK378; cPD by RECIST 1.1 due to 2nd primary tumor of melanoma; dCrizotinib-intolerant
Data as of 6 Sept 2013

38. Brain Metastases Activity
8 of 10 ALK+ NSCLC patients with active brain lesions at baselinea had evidence of radiographic improvement in brain
Duration of CNS benefitb ranging from 8+ to 40+ weeks
auntreated or progressing at baseline; bFirst dose to last scan with evidence of radiographic improvement
Data as of 6 Sept 2013

39. Summary 61% objective response rate post-crizotinib (n=31)
AP26113 exhibited robust anti-tumor activity in patients with ALK+ NSCLC
61% objective response rate post-crizotinib (n=31)
100% objective response rate in TKI-naïve patients (n=3)
AP26113 is active in ALK+ brain metastases, demonstrating frequent responses of clinically meaningful duration
Early onset pulmonary symptoms observed in some patients. RP2D 180 mg QD, preceded by 90 mg QD for 1 week
Phase 2 registration trial in crizotinib-resistant ALK+ NSCLC to begin shortly
Data as of 6 Sept 2013

40. CH Alectinib
Inoue, World Lung 2013

41. Phase I/II

42. Toxicities Interstitial pneumonia (Grade 1) was observed in 1 patient.
Visual disorders were rare.
Most treatment-related AEs were Grade 1 or 2 (94.7% of total treatment-related AEs).
The most common treatment-related AEs were dysgeusia, rash, AST increased, blood bilirubin increased, blood creatinine increased, and constipation.

43. Response

44. Treatment Duration - CNS

45. CNS Activity

46. PFS

47. ASP3026 Potent ALK inhibitor
Activity in EML4-ALK tumor xenografts, including a model with the gatekeeper mutation
Kuromitsu et al, AACR-NCI-EORTC International Conference-2011

48. Current data Agent RR PFS Trial Toxicities Crizotinib 60% 65%
9.7 months
7.2 I
III – 2nd line
Vision
Transaminitis
Nausea, diarrhea
Peripheral edema
LDK378
8.7
Abdominal pain
Nausea
Diarrhea
AP26113
100% (crz naïve)
Pulmonary toxicity
CH542802
93%
Grade 1 vision, diarrhea

49. Relative frequencies of crizotinib resistance mechanisms
Doebele R C et al. Clin Cancer Res 2012;18:
©2012 by American Association for Cancer Research

50. Acquired Resistance in ALK+ NSCLC
ALK-rearranged (ALK+) NSCLC is sensitive to crizotinib1–3
ORR 60%
Median PFS 8–10 months
Most patients develop resistance to crizotinib4,5
Usually within 1–2 years
CNS relapses are common6
Mechanisms of resistance are diverse4,5
ALK resistance mutations
Alternative signaling pathways
Amplified
L1196M
ALK
amp
ALK
mut
G1269A
S1206Y
G1202R
No ALK amp or mut
L1152R
C1156Y
amp, amplification; CNS, central nervous system; mut, mutation; ORR, overall response rate; PFS, progression-free survival.
1. Camidge DR, et al. Lancet Oncol 2012;13:1011–1019; 2. Kim D-W, et al. ESMO 2012 (Abstr 1230PD); 3. Shaw AT, et al. ESMO 2012 (Abstr LBA1_PR); 4. Katayama R, et al. Sci Transl Med 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res 2012;18:1472–1482; 6. Takeda M, et al. J Thorac Oncol 2013;8:654–657.

51. DRAFT
Antitumor Activity in Patients with ALK+ NSCLC Regardless of Baseline ALK Mutation Status
PFS event
Best % change from baseline in target lesions
All previously treated with crizotinib
Best % change from baseline
–100
–80
–60
–40
–20 60 40 20 80
100 WT
L1196M
Amp
G1269A 1151Tins
S1206Y
Crizotinib received as last therapy: No
Yes
Amp, ALK amplification; WT, wild type ALK kinase domain.
Patients with baseline ALK mutation assessments (n=19) and at least 1 post-baseline assessment of target lesions (investigator assessment)

52. AP26113 is a Potent ALK Inhibitor
Crizotinib is active in patients with ALK+ NSCLC, but most patients eventually progress
~46% of patients first progress in brain, suggesting inadequate CNS exposure1
Systemic progression through diverse mechanisms, including multiple ALK mutations1,2,3
In vitro, AP26113 has low nM activity against ALK (13 nM) and broadest range of activity against known resistance mutations in class
1Weickhardt et al, J Thorac Oncol, 2012;7:1807–1814; 2Doebele et al, Clin Cancer Res, 2012;18(5):1472–82; 3Katayama et al, Sci Transl Med, 2012;4(120). Data on file, ARIAD Pharmaceuticals, Inc. .

53. Ongoing Trials Trial Phase Crizotinib vs. Plat/pem III Not recruiting
LDK378 vs. Pem or Doc
III – 2nd line
LDK378
II, after chemo and crz
LDK378 vs. plat/pem
III – first line
ETP
LDK378 + AUY922 Ib
AP26113
I/II
CH542802
I/II – prior chemo and crz
ASP3026 I