4EML4-ALK fusionChr 2pSoda et al. Nature 448, (2 August 2007)
5Tumor cell proliferation ALK PathwayOrInversionTranslocationALKALK fusion protein*Cell survivalPI3KBADAKTSTAT3/5mTORS6KRASMEKErKPLC-YPIP2IP3Tumor cell proliferation*Subcellular localization of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,21. 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.55
6FISH Assay for ALK Rearrangement* Telomere2p23 regionCentromerep25.2p25.2ALK 29.3p24.3p24.3t(2;5) ALK genebreakpoint regionp24.1p24.1p23.2p23.2p22.3p22.3p22.1p22.1EML4 42.3p16.3p16.3p16.1p16.13’5’p14p14p13.2p13.2p12p12~250 kb~300 kbq12.1q12.1q12.3q12.3Break-apart FISH assay for ALK-fusion genes1q14.1q14.1q14.3q14.3q21.2q21.2q22.1q22.1q23.2q22.2q22.2q23.2q24.1q24.1q24.3q24.3q31.3q31.3q32.1q32.3q33.2q32.1q32.3q33.2Non-split signalq34q34Split signalq36.1q36.3 q37.2q36.1q36.3 q37.2ALK 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 hybridization1Shaw AT et al. J Clin Oncol 2009;27:4247–42536
7Clinico-pathologic features of EML4-ALK mutant lung cancer. 141 patients screened (selected population)18 (13%) were ALK mutant31 (22%) were EGFR mutant,92 (65%) were wild-type (WT) for bothALK:Majority adenocarcinoma, signet ring cell typeResistant to EGFR TKIsYoungerNever/light smokersShaw et al. ASCO 2009 #11021
8Patients with ALK-positive NSCLC Do not Appear to Respond to EGFR TKIs Platinum-based chemotherapyEGFR TKIALK (N=10)EGFR (N=23)WT/WT* (N=23)Response rate, %7013TTP, months5166ALK (N=12)EGFR (N=8)WT/WT* (N=34)Response rate, %255035TTP, months91081008060402010080604020TTP for EGFR TKI1TTP for chemotherapy1%%EGFRWT/WTEGFREML4–ALKWT/WTEML4–ALK12243648601224364860MonthsMonths*WT/WT = wild type: no ALK fusion or EGFR mutation1Shaw AT et al. J Clin Oncol 2009;27:4247–42538
9Original 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 MedVolume 363(18):October 28, 2010
10Demographic and Clinico-pathological Characteristics - 82 Patients Male – 52%42% - > 3 prior therapies96% adenocarcinoma76% never smokers18% < 10 pack years6% > 10 pack yearsKwak EL et al. N Engl J Med 2010;363:
11Response to ALK Inhibition RR 57%SD 33%8 week disease control rate 87%7% PDKwak EL et al. N Engl J Med 2010;363:
12Duration of TherapyKwak EL et al. N Engl J Med 2010;363:
13Adverse Events in the 82 Patients Kwak EL et al. N Engl J Med 2010;363:
14Phase I updated results 143 evaluable ALK + patients were enrolledRR 60.8 %Median duration of response 49.1 weeksMedian PFS 9.7 monthsEstimated 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
15Original 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 MedVolume 368(25):June 20, 2013
16Progression-free Survival. Shaw AT et al. N Engl J Med 2013;368:
17Patient-Reported Outcomes. Shaw AT et al. N Engl J Med 2013;368:
18Summary of ResponsesShaw AT et al. N Engl J Med 2013;368:
19Adverse Events of Any Cause Shaw AT et al. N Engl J Med 2013;368:
20DRAFTClinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLCAlice 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. Engelman11Massachusetts 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
21Crizotinib-resistant H2228 tumor model with ALK C1156Y mutation LDK378 - CeritinibLDK378 is a potent and selective oral ALK inhibitor1Potent activity in enzymatic and cell based assays1,2LDK378 provides durable responses in EML4-ALK NSCLC xenografts, including crizotinib-resistant models)1AssayLDK378IC50 (nM)CRZEnzymaticALKIGF-1Rc-Met0.15832003400Cell-based3EML4-ALK- L1196M- G1269S- G1202R- C1156Y206014049013012081016001020350Crizotinib-resistant H2228 tumor model with ALK C1156Y mutationCRZ, 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.
22Study Design NCT01283516 Completed N=59 Additional N=71 enrolled‡ Any advanced ALK+ cancerProgression on standard therapy(dose escalation)NCTMTD* (50 mg/day starting dose)Continuous oral dosing; 21-day cyclesCompleted N=59Continuous oral dosing 21 day cyclesALK+ lung cancerPrior ALKi therapyALK+ lung cancernaïve to ALKiNon-lung ALK+ tumorsAdditional N=71 enrolled‡LDK378 ≤2 months after prior ALKi and progression during prior ALKiLDK378 >2 months after prior ALKi or progression after prior ALKiPrimary objective: determination of MTD (*750 mg/day)Secondary objectives: safety, pharmacokinetics and preliminary antitumor activityALKi, ALK inhibitor; MTD, maximum tolerated dose.‡Enrolled on or before 19 October 2012
23Patient EligibilityAdult patients with locally advanced or metastatic diseaseGenetic alterations of ALK as determined by FISH (ALK+ in ≥15% of tumor cells) in NSCLC, and by FISH, PCR or IHC in other cancersUntreated CNS metastases permitted if asymptomatic; treated CNS metastases permitted if neurologically stableECOG performance status ≤2Strong inhibitors/inducers of CYP3A4/5 and substrates of CYP3A4/5 or CYP2C9 with narrow therapeutic index excludedFISH fluorescence in situ hybridization; IHC, immunohistochemistry; PCR, polymerase chain reaction.
24Patient Demographics and Disease Characteristics* Patient CharacteristicAll patients, n (%)N=130Median age (range)53 (22–80)Female78 (60)ECOG Performance Status0 1≥225 (19)89 (69)16 (12)Cancer typeNSCLCBreastOther/missing121 (93)4 (3)5 (4)Prior ALK inhibitor (NSCLC)ALK inhibitor naïve (NSCLC)Non-NSCLC82 (63)40 (31)8 (6)*All patients with at least 18 weeks follow-up or discontinued earlier; data cut-off 28 Feb 2013
26Grade 3 and 4 Adverse Events (≥5%), Regardless of Study Drug Relationship Preferred term,n (%)50–300 mg n=10400 mg n=14500 mg n=10600 mg n=10700 mg n=5750 mg* n=81All patients N=130ALT increased0 (0)1 (7)2 (20)4 (80)18 (22)25 (19)AST increased2 (14)3 (60)8 (10)13 (10)Diarrhea1 (10)6 (7)11 (8)Lipase increased5 (6)7 (5)Hypokalemia1 (20)6 (5)Nausea4 (5)3 (2%) patients discontinued due to AEs*MTD
27Marked Activity of LDK378 in Patients with Advanced ALK+ NSCLC 100Best % change from baseline in target lesionsLDK –750 mg/day8060Prior crizotinibCrizotinib- naïve4020Best % change from baseline–20–40–60–80PFS event–100Patients with at least 1 post-baseline assessment of target lesions (investigator assessment)
30Prolonged Duration of Response and PFS in ALK+ NSCLC EndpointEstimate95% CIDORMedian DOR ≥400 mg/day (n=66 responders)8.2 months6.9–NE6 month DOR rate at 750 mg/day (n=47 responders)60.6%34.9–78.8PFSMedian PFS (≥400 mg/day) (n=114)8.6 months5.7–9.96 month PFS rate at 750 mg/day (n=78)*60.7%46.1–72.4CI, confidence interval; DOR, duration of response; PFS, progression-free survival.Median PFS at 750 mg/day not reached.
31Typical Responses to LDK378 BaselineAfter 3 months of LDK378
32Continued response in the CNS at 6 mos Responses in the CNST1- postT1- postFlairFlairContinued response in the CNS at 6 mosBaselineAfter 6 weeks of LDK378
33Updated Results of a First-in-Human Dose-Finding Study of the ALK/EGFR Inhibitor AP26113 in Patients with Advanced MalignanciesD 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 GettingerWCLC 2013, Sydney, AustraliaAbstract 2400
34AP26113 Phase 1/2 Study Study Design Cohort 1, NSCLC: N=20ALK+ and ALK inhibitor naïvePhase 1Cohort 2, NSCLC: N=20ALK+ and crizotinib-resistantDose Escalation,3+3 Design: N=30 to 60Advanced malignancies(all histologies except leukemia) until MTD and RP2D establishedCohort 3, NSCLC: N=20Documented T790M and resistant to 1 prior EGFR TKICohort 4: N=20Other cancers with AP26113 targets(eg, ALK, ROS1, EGFR ineligible for Cohort 3, and others)Cohort 5, NSCLC: N=25ALK+ and naïve or resistant to crizotinib with active brain metsAddedMay 2013
35Adverse Events Treatment Emergent, Grades ≥3 Preferred term(≥2 patients)30,60 mgN=690 mgN=8120 mgN=18180 mg*N=45240 mgN=12300 mgN=2TotalN=91Dyspnea1 (6)1 (2)1 (8)1 (50)4 (4)Fatigue1 (17)2 (17)Pneumonia3 (17)Hypoxia3 (3)Lung infection2 (2)PneumonitisLipase increasedDiarrheaHyponatremia1 (13)*Preferred terms ranked by incidence at 180 mgTreatment-related Grade ≥3 AEs in ≥2 patients: dyspnea (4%), fatigue (3%), diarrhea (2%), hypoxia (2%), and pneumonitis (2%)Data as of 6 Sept 2013
36Early Onset Pulmonary Symptoms Early onset (typically day 1 or 2) shortness of breath, O2 desaturation and patchy GGOObserved 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 criteriaReversible, 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 premedication180 mg AP26113 re-challengeO2 as neededData in graph from single patient
37ALK+ 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+ weeks14 confirmed, 4 awaiting confirmation, 4 not confirmedAll 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-intolerantData as of 6 Sept 2013
38Brain Metastases Activity 8 of 10 ALK+ NSCLC patients with active brain lesions at baselinea had evidence of radiographic improvement in brainDuration of CNS benefitb ranging from 8+ to 40+ weeksauntreated or progressing at baseline; bFirst dose to last scan with evidence of radiographic improvementData as of 6 Sept 2013
39Summary 61% objective response rate post-crizotinib (n=31) AP26113 exhibited robust anti-tumor activity in patients with ALK+ NSCLC61% 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 durationEarly onset pulmonary symptoms observed in some patients. RP2D 180 mg QD, preceded by 90 mg QD for 1 weekPhase 2 registration trial in crizotinib-resistant ALK+ NSCLC to begin shortlyData as of 6 Sept 2013
42Toxicities 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.
50Acquired Resistance in ALK+ NSCLC ALK-rearranged (ALK+) NSCLC is sensitive to crizotinib1–3ORR 60%Median PFS 8–10 monthsMost patients develop resistance to crizotinib4,5Usually within 1–2 yearsCNS relapses are common6Mechanisms of resistance are diverse4,5ALK resistance mutationsAlternative signaling pathwaysAmplifiedL1196MALKampALKmutG1269AS1206YG1202RNo ALK amp or mutL1152RC1156Yamp, 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.
51DRAFTAntitumor Activity in Patients with ALK+ NSCLC Regardless of Baseline ALK Mutation StatusPFS eventBest % change from baseline in target lesionsAll previously treated with crizotinibBest % change from baseline–100–80–60–40–2060402080100WTL1196MAmpG1269A 1151TinsS1206YCrizotinib received as last therapy:NoYesAmp, 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)
52AP26113 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 exposure1Systemic progression through diverse mechanisms, including multiple ALK mutations1,2,3In vitro, AP26113 has low nM activity against ALK (13 nM) and broadest range of activity against known resistance mutations in class1Weickhardt 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..
53Ongoing Trials Trial Phase Crizotinib vs. Plat/pem III Not recruiting LDK378 vs. Pem or DocIII – 2nd lineLDK378II, after chemo and crzLDK378 vs. plat/pemIII – first lineETPLDK378 + AUY922IbAP26113I/IICH542802I/II – prior chemo and crzASP3026I