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

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Presentation on theme: "Management of ALK positive NSCLC – initial therapy and resistant disease Ranee Mehra, MD Fox Chase Cancer Center."— Presentation transcript:

1 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 CH5424802 – Alectinib ASP3026

4 EML4-ALK fusion Chr 2p Soda et al. Nature 448, 561-566 (2 August 2007)

5 ALK Pathway 1. Inamura K et al. J Thorac Oncol 2008;3:13–17 2. 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. *Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed. 1,2 Translocation Or ALK ALK fusion protein* Tumor cell proliferation Inversion Cell survival PI3K BAD AKT STAT3/5 mTOR S6K RAS MEK ErK PLC- Y PIP 2 IP 3

6 ~250 kb~300 kb t(2;5) ALK gene breakpoint region 2p23 regionTelomere Centromere 3’ 5’ FISH Assay for ALK Rearrangement* Break-apart FISH assay for ALK-fusion genes 1 ALK 29.3 EML4 42.3 ALK break-apart FISH assay [Courtesy John Iafrate, Massachusetts General Hospital] 1 Shaw AT et al. J Clin Oncol 2009;27:4247–4253 q36.1 q36.3 q37.2 q34 q32.1 q32.3 q33.2 q31.3 q24.3 q24.1 q23.2 q22.2 q22.1 q21.2 q14.3 q14.1 q12.3 q12.1 p12 p13.2 p14 p16.1 p16.3 p22.1 p23.2 p22.3 p24.1 p24.3 p25.2 q36.1 q36.3 q37.2 q34 q32.1 q32.3 q33.2 q31.3 q24.3 q24.1 q23.2 q22.2 q22.1 q21.2 q14.3 q14.1 q12.3 q12.1 p12 p13.2 p14 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

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 TTP for EGFR TKI 1 1 Shaw AT et al. J Clin Oncol 2009;27:4247–4253 ALK (N=12) EGFR (N=8) WT/WT * (N=34) Response rate, % 255035 TTP, months9108 TTP for chemotherapy 1 Platinum-based chemotherapyEGFR TKI Patients with ALK-positive NSCLC Do not Appear to Respond to EGFR TKIs ALK (N=10) EGFR (N=23) WT/WT * (N=23) Response rate, % 07013 TTP, months5166 Months 01224364860 100 80 60 40 20 0 EML4–ALK EGFR WT/WT % Months 01224364860 100 80 60 40 20 0 % EML4–ALK EGFR WT/WT *WT/WT = wild type: no ALK fusion or EGFR mutation

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):1693-1703 October 28, 2010

10 Demographic and Clinico-pathological Characteristics - 82 Patients Kwak EL et al. N Engl J Med 2010;363:1693-1703 Male – 52% 42% - > 3 prior therapies 96% adenocarcinoma 76% never smokers 18% < 10 pack years 6% > 10 pack years

11 Response to ALK Inhibition Kwak EL et al. N Engl J Med 2010;363:1693-1703 RR 57% SD 33% 8 week disease control rate 87% 7% PD

12 Duration of Therapy Kwak EL et al. N Engl J Med 2010;363:1693-1703

13 Adverse Events in the 82 Patients Kwak EL et al. N Engl J Med 2010;363:1693-1703

14 Phase I updated results Camidge et al. The Lancet Oncology, Volume 13, Issue 10, Pages 1011 - 1019, October 2012 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.

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):2385-2394 June 20, 2013

16 Progression-free Survival. Shaw AT et al. N Engl J Med 2013;368:2385-2394

17 Patient-Reported Outcomes. Shaw AT et al. N Engl J Med 2013;368:2385-2394

18 Summary of Responses Shaw AT et al. N Engl J Med 2013;368:2385-2394

19 Adverse Events of Any Cause Shaw AT et al. N Engl J Med 2013;368:2385- 2394

20 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. Engelman 1 1 Massachusetts General Hospital, Boston, MA; 2 Fox Chase Cancer Center, Philadelphia, PA; 3 Seoul National University Hospital, Seoul, Korea; 4 Vall d’Hebron University, Barcelona, Spain; 5 University of Washington, Seattle, WA; 6 University of Colorado, Denver, CO; 7 National Cancer Center, Singapore; 8 University Hospital KU Leuven, Leuven, Belgium; 9 Huntsman Cancer Institute, Salt Lake City, UT; 10 Instituto Europeo di Oncologia, Milan, Italy; 11 University Hospital Cologne, Cologne, Germany; 12 Massachusetts General Hospital, Boston, MA; 13 Novartis Pharmaceuticals, Cambridge, MA. DRAFT ASCO 2013

21 LDK378 - Ceritinib LDK378 is a potent and selective oral ALK inhibitor 1 – Potent activity in enzymatic and cell based assays 1,2 LDK378 provides durable responses in EML4-ALK NSCLC xenografts, including crizotinib-resistant models) 1 Assay LDK378 IC 50 (nM) CRZ IC 50 (nM) Enzymatic ALK IGF-1R c-Met 0.15 8 3200 3 400 8 Cell-based 3 EML4-ALK - L1196M - G1269S - G1202R - C1156Y 20 60 140 490 130 120 810 1600 1020 350 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. Crizotinib-resistant H2228 tumor model with ALK C1156Y mutation CRZ, crizotinib; IGF-1R, insulin-like growth factor 1 receptor.

22 Study Design ALK+ lung cancer naïve to ALKi Non-lung ALK+ tumors ALK+ lung cancer Prior ALKi therapy LDK378 ≤2 months after prior ALKi and progression during prior ALKi LDK378 >2 months after prior ALKi or progression after prior ALKi Any advanced ALK+ cancer Progression on standard therapy (dose escalation) ALKi, ALK inhibitor; MTD, maximum tolerated dose. NCT01283516 Continuous oral dosing 21 day cycles Primary objective: determination of MTD (*750 mg/day) Secondary objectives: safety, pharmacokinetics and preliminary antitumor activity MTD * (50 mg/day starting dose) Continuous oral dosing; 21-day cycles Completed N=59 Additional N=71 enrolled ‡ ‡ 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* *All patients with at least 18 weeks follow-up or discontinued earlier; data cut-off 28 Feb 2013 Patient CharacteristicAll patients, n (%) N=130 Median age (range)53 (22–80) Female78 (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)

25 Adverse Events (≥15%), Regardless of Study Drug Relationship *MTD 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 Nausea5 (50)10 (71)9 (90)10 (100)5 (100)56 (69)95 (73) Diarrhea3 (30)9 (64)7 (70)8 (80)4 (80)63 (78)94 (72) Vomiting4 (40)8 (57)5 (50)8 (80)4 (80)47 (58)76 (58) Fatigue3 (30)4 (29)4 (40)8 (80)0 (0)34 (42)53 (41) ALT increased0 (0)2 (14)3 (30)1 (10)4 (80)24 (30)34 (26) Decreased appetite2 (20)0 (0)3 (30)4 (40)3 (60)21 (26)33 (25) Constipation1 (10)1 (7)2 (20)3 (30)2 (40)22 (27)31 (24) Abdominal pain1 (10)1 (7)2 (20) 1 (20)23 (28)30 (23) AST increased0 (0)3 (21)2 (20)1 (10)3 (60)15 (19)24 (18) Asthenia3 (30)2 (14)1 (10)3 (30)3 (60)12 (15)24 (18) Cough0 (0)3 (21)3 (30)1 (10)0 (0)12 (15)19 (15) ALT, alanine aminotransferase; AST, aspartate aminotransferase.

26 Grade 3 and 4 Adverse Events (≥5%), Regardless of Study Drug Relationship 3 (2%) patients discontinued due to AEs *MTD 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 increased0 (0)1 (7)2 (20)0 (0)4 (80)18 (22)25 (19) AST increased0 (0)2 (14)0 (0) 3 (60)8 (10)13 (10) Diarrhea1 (10)1 (7)1 (10)2 (20)0 (0)6 (7)11 (8) Lipase increased1 (10)0 (0) 1 (10)0 (0)5 (6)7 (5) Hypokalemia0 (0) 1 (20)5 (6)6 (5) Nausea0 (0) 1 (10)0 (0)4 (5)6 (5)

27 Marked Activity of LDK378 in Patients with Advanced ALK+ NSCLC Patients with at least 1 post-baseline assessment of target lesions (investigator assessment) Best % change from baseline Best % change from baseline in target lesions LDK378 400–750 mg/day –100 –80 –60 –40 –20 0 60 40 20 80 100 PFS event Prior crizotinib Crizotinib- naïve

28 High Response Rate in Patients with ALK+ NSCLC: LDK378 400–750 mg/day Response 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 disease37 (32)27 (34)10 (29) Progressive disease6 (5)6 (8)0 (0) CR + PR + uPR86 (75)62 (78)24 (69) Overall response rate* (CR + PR)66 (58)45 (57)21 (60) *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 Response 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 disease23 (29)15 (31)8 (28) Progressive disease4 (5)4 (8)0 (0) CR + PR + uPR59 (76)38 (78)21 (72) Overall response rate* (CR + PR)47 (60)29 (59)18 (62) *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 EndpointEstimate95% CI DOR Median DOR ≥400 mg/day (n=66 responders)8.2 months6.9–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 months5.7–9.9 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 Responses in the CNS T1- post Flair T1- post Flair Baseline After 6 weeks of LDK378 Continued response in the CNS at 6 mos

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 34 Phase 1 Cohort 1, NSCLC: N=20 ALK+ and ALK inhibitor naïve Phase 2 Cohort 2, NSCLC: N=20 ALK+ and crizotinib-resistant 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) Dose Escalation, 3+3 Design: N=30 to 60 Advanced malignancies (all histologies except leukemia) until MTD and RP2D established 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 35 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 Dyspnea0 0 1 (6)1 (2)1 (8)1 (50)4 (4) Fatigue1 (17) 0 01 (2)2 (17)04 (4) Pneumonia 00 3 (17)1 (2) 0 04 (4) Hypoxia0 0 01 (2)1 (8)1 (50)3 (3) Lung infection0 0 1 (6)1 (2)002 (2) Pneumonitis0 0 1 (6)1 (2)002 (2) Lipase increased001 (6)02 (17)03 (3) Diarrhea0 00 02 (17)02 (2) Hyponatremia0 1 (13) 001 (8)02 (2) 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 *Preferred terms ranked by incidence at 180 mg

36 Early Onset Pulmonary Symptoms 36 60 mg prednisone QD premedication 180 mg AP26113 re-challenge O 2 as needed Data in graph from single patient Early onset (typically day 1 or 2) shortness of breath, O 2 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)

37 ALK+ NSCLC Anti-Tumor Activity Target Lesions (N=34) 37 All patients received prior crizotinib unless otherwise indicated; Doses ranged from 60-240 mg/d (23 pts ≥180mg/d); a TKI-naïve; b Received prior crizotinib and LDK378; c PD by RECIST 1.1 due to 2nd primary tumor of melanoma; d Crizotinib-intolerant Response duration 8+ to 40+ weeks 14 confirmed, 4 awaiting confirmation, 4 not confirmed Data as of 6 Sept 2013 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)

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

39 Summary 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 39 Data as of 6 Sept 2013

40 CH542802 - 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 AgentRRPFSTrialToxicities Crizotinib60% 65% 9.7 months 7.2 I III – 2 nd line Vision Transaminitis Nausea, diarrhea Peripheral edema LDK37860%8.7IAbdominal pain Nausea Diarrhea Transaminitis AP2611360% 100% (crz naïve) IPulmonary toxicity CH54280293%IGrade 1 vision, diarrhea

49 Relative frequencies of crizotinib resistance mechanisms Doebele R C et al. Clin Cancer Res 2012;18:1472-1482 ©2012 by American Association for Cancer Research

50 Acquired Resistance in ALK+ NSCLC L1196M G1269A G1202R C1156Y L1152R S1206Y ALK mut ALK amp No ALK amp or mut amp, amplification; CNS, central nervous system; mut, mutation; ORR, overall response rate; PFS, progression-free survival. Amplified 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. ALK-rearranged (ALK+) NSCLC is sensitive to crizotinib 1–3 – ORR 60% – Median PFS 8–10 months Most patients develop resistance to crizotinib 4,5 – Usually within 1–2 years – CNS relapses are common 6 Mechanisms of resistance are diverse 4,5 – ALK resistance mutations – Alternative signaling pathways

51 Antitumor Activity in Patients with ALK+ NSCLC Regardless of Baseline ALK Mutation Status Patients with baseline ALK mutation assessments (n=19) and at least 1 post-baseline assessment of target lesions (investigator assessment) 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 0 WT L1196M WTAmp L1196M G1269A 1151Tins WTAmp L1196M WT S1206Y WT Crizotinib received as last therapy: No Yes Amp, ALK amplification; WT, wild type ALK kinase domain. DRAFT

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

53 Ongoing Trials TrialPhase Crizotinib vs. Plat/pemIIINot recruiting LDK378 vs. Pem or DocIII – 2 nd line LDK378II, after chemo and crzNot recruiting LDK378 vs. plat/pemIII – first line LDK378ETP LDK378 + AUY922Ib AP26113I/II CH542802I/II – prior chemo and crz ASP3026I


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