Crizotinib a8081001 asco 2010 slides

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  • Finally, I’d like to acknowledge contributing investigators from Karmanos Cancer Center, The Mayo Clinic, The University of Alabama-Birmingham, and The Ireland Cancer Center, Case Western Reserve.
    I’d also like to acknowledge the efforts of colleagues advancing the MEK inhibitor program at Pfizer…
    Click….
    And most importantly, I’d like to acknowledge the patients without whose support this ambitious study would not have been possible.
    Thank you for your attention.
  • Crizotinib a8081001 asco 2010 slides

    1. 1. Clinical Activity of the Oral ALK Inhibitor,Clinical Activity of the Oral ALK Inhibitor, Crizotinib (PF-02341066), in Patients withCrizotinib (PF-02341066), in Patients with ALKALK-positive Non-small Cell Lung Cancer-positive Non-small Cell Lung Cancer Bang Y,1 Kwak EL,2 Shaw A,2 Camidge DR,3 Iafrate AJ,2 Maki RG,4 Solomon B,5 Ou SI,6 Salgia R,7 Clark J2 1 Seoul National University, Seoul, Korea; 2 Massachusetts General Hospital, Boston, MA, USA; 3 University of Colorado Cancer Center, Aurora, CO, USA; 4 Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5 Peter MacCallum Cancer Centre, East Melbourne, Australia; 6 University of California at Irvine, Irvine, CA, USA; 7 University of Chicago Cancer Center, Chicago, IL, USA Abstract 3ASCO Annual Meeting 2010
    2. 2. Potential Oncogenic “Drivers” inPotential Oncogenic “Drivers” in Non-small Cell Lung Cancer (NSCLC)Non-small Cell Lung Cancer (NSCLC) ALK (~5%) Other Adenocarcinoma Massachusetts General Hospital, data on file. [AT Shaw, personal communication] ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; Her2 = human epidermal growth factor receptor 2; PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide
    3. 3. ALKALK PathwayPathway 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 PI3KPI3K BADBAD AKTAKT STAT3/5STAT3/5 mTORmTOR S6KS6K RASRAS MEKMEK ErKErK PLC-PLC-YY PIPPIP22 IPIP33
    4. 4. Soda M et al. Nature 2007;448:561–567 Reprinted by permission from Macmillan Publishers Ltd: Nature, © 2007 EML4–ALKEML4–ALK is a Potent “Oncogenic” Driveris a Potent “Oncogenic” Driver 3T3 Nude mice Tumor/ injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2 Vector EML4 ALK EML4–ALK K589M NPM–ALK v-Ras Inhibition of ALK leads to dramatic in vivo tumor regression EML4 = echinoderm microtubule-associated protein-like 4; NPM = nucleophosmin
    5. 5. ~250 kb ~300 kb t(2;5) ALK gene breakpoint region 2p23 regionTelomere Centromere 3’ 5’ FISH Assay forFISH Assay for ALKALK Rearrangement*Rearrangement* Break-apart FISH assay for ALK-fusion genes1 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
    6. 6. TTP for EGFR TKI1 1 Shaw AT et al. J Clin Oncol 2009;27:4247–4253 ALK (N=12) EGFR (N=8) WT/WT* (N=34) Response rate, % 25 50 35 TTP, months 9 10 8 TTP for chemotherapy1 Platinum-based chemotherapy EGFR TKI Patients withPatients with ALKALK-positive NSCLC-positive NSCLC Do not Appear to Respond to EGFR TKIsDo not Appear to Respond to EGFR TKIs ALK (N=10) EGFR (N=23) WT/WT* (N=23) Response rate, % 0 70 13 TTP, months 5 16 6 Months 0 12 24 36 48 60 100 80 60 40 20 0 EML4–ALK EGFR WT/WT % Months 0 12 24 36 48 60 100 80 60 40 20 0 % EML4–ALK EGFRWT/WT *WT/WT = wild type: no ALK fusion or EGFR mutation
    7. 7. Selectivity findings • Crizotinib – ALK and c-MET inhibition at clinically relevant dose levels • Crizotinib – low probability of pharmacologically relevant inhibition of any other kinase at clinically relevant dose levels Cellular selectivity on 10 of 13 relevant hits Upstate 102 kinase 13 kinase “hits” <100X selective for c-MET Kinase % Inhibition Met(h) 94 Tie2(h) 103 TrkA(h) 102 ALK(h) 100 TrkB(h) 100 Abl(T315I)(h) 98 Yes(h) 96 Lck(h) 95 Rse(h) [SKY] 94 Axl(h) 93 Fes(h) 93 Lyn(h) 93 Arg(m) 91 Ros(h) 90 CDK2/cyclinE(h) 87 Fms(h) 84 EphB4(h) 80 Bmx(h) 79 EphB2(h) 77 Fgr(h) 73 Fyn(h) 68 IR(h) 64 CDK7/cyclinH/MAT1(h) 58 cSRC(h) 58 IGF-1R(h) 56 Aurora-A(h) 54 Syk(h) 52 FGFR3(h) 50 PKCµ(h) 50 BTK(h) 35 CDK1/cyclinB(h) 25 p70S6K(h) 24 PRK2(h) 22 PAR-1Bα(h) 21 PKBß(h) 21 Ret(h) 21 GSK3ß(h) 18 Flt3(h) 17 MAPK1(h) 17 ZAP-70(h) 17 Abl(h) 16 c-RAF(h) 16 PKD2(h) 15 ROCK-II(h) 14 Rsk3(h) 14 GSK3α(h) 11 CDK5/p35(h) 10 PDGFRα(h) 10 Rsk1(h) 7 SGK(h) 6 CHK1(h) 5 ErbB4(h) 5 Rsk2(h) 5 JNK1α1(h) 4 PKBα(h) 4 Blk(m) 3 CDK3/cyclinE(h) 3 PKCι(h) 3 PKCθ(h) 3 CDK2/cyclinA(h) 2 PAK2(h) 2 PKCßI(h) 2 Pim-1(h) 1 PKCη(h) 1 SAPK4(h) 1 CaMKII(r) 0 MKK7ß(h) 0 CaMKIV(h) -1 CHK2(h) -1 CK2(h) -1 JNK2α2(h) -1 MKK6(h) -1 CK1δ(h) -2 PKCα(h) -2 MAPK2(h) -3 MEK1(h) -3 PKCδ(h) -3 PKCε(h) -3 Plk3(h) -3 PKCßII(h) -5 MSK1(h) -6 PDGFRß(h) -6 PKCζ(h) -6 SAPK3(h) -6 MAPKAP-K2(h) -7 PKA(h) -7 AMPK(r) -9 CDK6/cyclinD3(h) -9 CSK(h) -9 SAPK2a(h) -9 JNK3(h) -10 PKBγ(h) -10 IKKα(h) -11 NEK2(h) -11 *The cellular kinase activities were measured using ELISA capture method Kinase IC50 (nM) mean* Selectivity ratio c-MET 8 – ALK 20 2X RON 298 34X 189 22X 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 >10,000 >1,000X PDGFRβ >10,000 >1,000X Pfizer Inc. Data on file Crizotinib (PF-02341066) Crizotinib Selectivity ProfileCrizotinib Selectivity Profile
    8. 8. 0.0001 0.01 0.1 1 10 Crizotinib: cell growth inhibition and apoptosis induction in H3122 cells Crizotinib concentration (mM) 125 100 75 50 25 0 –25 –50 %control IC50 = 96 nM Crizotinib: Induction of Apoptosis inCrizotinib: Induction of Apoptosis in ALKALK-positive NSCLC Cells-positive NSCLC Cells Crizotinib: cell growth inhibition in NSCLC cell lines 1,000 800 600 400 200 0 H1993 H3122 H23 H1734 H82 H520 H526 SKMES1 H2347 H1975 H1838 H226 H1703 H647 H1755 CALU6 CALU1 H358 H1581 H2087 H1651 HCC827 HCC2935 H1355 H1573 H1650 H1666 H2405 A549 IC50value(nM) Crizotinib demonstrated potent growth inhibitory activity against H3122 (ALK fusion) cells Activated caspase-3 Untreated 50 nM 500 nM Cell death Pfizer Inc. Data on file IC50 = 50% inhibitory concentration *MET amplification *
    9. 9. Part 2: Molecularly enriched cohorts (ALK and c-MET) Enrolling patients with ALK-positive NSCLC after preliminary observation of impressive activity in a few patients • Data from database April 7, 2010 • Data presented for 82 patients, study ongoing Part 1: Dose escalation Crizotinib: First-in-human/Patient TrialCrizotinib: First-in-human/Patient Trial 1 DLT: grade 3 ALT elevation 2 DLTs: grade 3 fatigue Cohort 1 (n=3) 50 mg QD Cohort 2 (n=4) 100 mg QD Cohort 3 (n=8) 200 mg QD Cohort 4 (n=7) 200 mg BID Cohort 5 (n=6) 300 mg BID Cohort 6 (n=9) 250 mg BID MTD/RP2D ALT = alanine aminotransferase
    10. 10. Crizotinib Overview of Pharmacokinetics:*Crizotinib Overview of Pharmacokinetics:* All Patients Enrolled in Dose EscalationAll Patients Enrolled in Dose Escalation ● t1/2 ~53 hours at 250 mg BID ● No evidence of non-linearity in PK ● No food effect on PK ● Moderate CYP3A4 inhibitor Ceff = efficacious concentration; CYP = cytochrome P450; t1/2 = terminal elimination half-life; PK = pharmacokinetics *Please refer to (abstract 2596): Pharmacokinetics (PK) of PF-02341066, a dual ALK/c-MET inhibitor after multiple oral doses to advanced cancer patients. (9:00 AM, Monday, June 7) 500 400 300 200 100 0 Medianplasmaconcentration, cycle1day15(ng/mL) 0 2 4 6 8 Time (hours) 50 mg QD 200 mg BID 100 mg QD 250 mg BID 200 mg QD 300 mg BID Target Ceff (ALK)
    11. 11. Clinical and Demographic Features ofClinical and Demographic Features of Patients withPatients with ALKALK-positive NSCLC-positive NSCLC N=82 Mean (range) age, years 51 (25–78) Gender, male/female 43/39 Performance status,* n (%) 0 24 (29) 1 44 (54) 2 13 (16) 3 1 (1) Race, n (%) Caucasian 46 (56) Asian 29 (35) Smoking history, n (%) Never smoker 62 (76) Former smoker 19 (23) Current smoker 1 (1) Histology, n (%) Adenocarcinoma 79 (96) Squamous 1 (1) Other 2 (2) Prior treatment regimens, n (%) 0 5 (6) 1 27 (33) 2 15 (18) ≥3 34 (41) Not reported 1 (1) *Performance status = Eastern Cooperative Oncology Group
    12. 12. 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximumchangeintumorsize(%) –30% Tumor Responses to Crizotinib for PatientsTumor Responses to Crizotinib for Patients withwith ALKALK-positive NSCLC-positive NSCLC *Partial response patients with 100% change have non-target disease present *
    13. 13. 77% of Patients with77% of Patients with ALKALK-positive NSCLC-positive NSCLC Remain on Crizotinib TreatmentRemain on Crizotinib Treatment 0 3 6 9 12 15 18 21 Treatment duration (months) N=82; red bars represent discontinued patients Individualpatients • Duration of treatment (median: 5.7 months) 0–3 mo 13 pts >3–6 mo 29 pts >6–9 mo 24 pts >9–12 mo 9 pts >12–18 mo 4 pts >18 mo 3 pts • Reasons for discontinuation – Related AEs 1 – Non-related AEs 1 – Unrelated death 2 – Other 2 – Progression 13
    14. 14. Clinical Activity of Crizotinib inClinical Activity of Crizotinib in Patients withPatients with ALK-ALK-positive NSCLCpositive NSCLC ● Objective response rate (ORR): 57% (95% CI: 46, 68%) – 63% including 5 as yet unconfirmed PRs – 57% (8/14) for patients with performance status 2 or 3 No. prior regimens* ORR % (n/N) 0 80 (4/5) 1 52 (14/27) 2 67 (10/15) ≥3 56 (19/34) * Unknown for 1 patient ● Response duration: 1 to 15 months ● DCR† (CR/PR/SD at 8 weeks): 87% (95% CI: 77, 93%) † Disease control rate
    15. 15. Median PFS has Not been ReachedMedian PFS has Not been Reached 70% of Patients in Follow-up for PFS70% of Patients in Follow-up for PFS 1.00 0.75 0.50 0.25 0.00 Progression-freesurvivalprobability 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Progression-free survival (months) PFS probability at 6 months: 72% (95% CI: 61, 83%) Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands
    16. 16. Treatment-related Adverse Events inTreatment-related Adverse Events in ALKALK-positive NSCLC (≥10%)-positive NSCLC (≥10%) Adverse event Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Total n (%) Nausea 43 (52) 1 (1) 0 0 44 (54) Diarrhea 38 (46) 1 (1) 0 0 39 (48) Vomiting 35 (43) 1 (1) 0 0 36 (44) Visual disturbance* 34 (42) 0 0 0 34 (42) Constipation 18 (22) 2 (2) 0 0 20 (24) Peripheral edema 13 (16) 0 0 0 13 (16) Dizziness 12 (15) 0 0 0 12 (15) Decreased appetite 11 (13) 0 0 0 11 (13) Fatigue 8 (10) 0 0 0 8 (10) *Changes in light/dark accommodation (no abnormalities on ophthalmologic exam)*Changes in light/dark accommodation (no abnormalities on ophthalmologic exam) N=82
    17. 17. Treatment-related Grade 3/4 Adverse EventsTreatment-related Grade 3/4 Adverse Events inin ALKALK-positive NSCLC-positive NSCLC Adverse event Grade 3 n (%) Grade 4 n (%) Any adverse event 10 (12) 1 (1) ALT elevation* 4 (5) 1 (1) AST elevation 5 (6) 0 Lymphopenia 2 (2) 0 Hypophosphatemia 1 (1) 0 Neutropenia 1 (1) 0 Hypoxia 1 (1) 0 Dyspnea 1 (1) 0 Pulmonary embolism 1 (1) 0 *Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4% (In preclinical toxicology studies, no histologic changes in the liver were observed) 1 patient discontinued for ALT elevation
    18. 18. SummarySummary ● Treatment with crizotinib resulted in impressive clinical activity in patients with ALK-positive advanced NSCLC – ORR: 57% – DCR at 8 weeks: 87% – PFS probability at 6 months: 72% ● Crizotinib was well tolerated – The most frequent adverse events were mild and moderate gastrointestinal events and mild visual disturbances
    19. 19. ConclusionsConclusions ● These results are an example of rapid clinical development from target identification, to clinical validation, and supports a personalized approach to NSCLC treatment ● For patients with ALK-positive NSCLC, crizotinib may offer a potential new standard of care
    20. 20. Current Crizotinib Clinical TrialsCurrent Crizotinib Clinical Trials PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451 Key entry criteria ● Positive for ALK by central laboratory ● 1 prior chemotherapy (platinum-based) N=318 PROFILE 1007 Crizotinib 250 mg BID (N=250) administered on a continuous dosing schedule Key entry criteria ● Positive for ALK by central laboratory ● Progressive disease in Arm B of study A8081007 ● >1 prior chemotherapy PROFILE 1005 R A N D O M I Z E N=250 Crizotinib 250 mg BID (n=159) administered on a continuous dosing schedule Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 (n=159) infused on day 1 of a 21-day cycle
    21. 21. AcknowledgmentsAcknowledgments Massachusetts General Hospital ● John Iafrate,* Jeffrey Clark, Eunice Kwak, Alice Shaw, Eunice Kwak, Thomas Lynch, Panos Fidias, Jeffrey Engelman, Marguerite Parkman Dana-Farber Cancer Institute ● Geoffrey Shapiro, Pasi Janne,* James Butrynski, Leena Gandhi, Andrew Wolanski Suzanne Hitchcock-Bryan, Charles Lee Beth Israel Deaconess Medical Center ● Bruce Dezube, Daniel Costa, Myles Clancy Memorial Sloan Kettering Cancer Center ● Robert Maki, Suresh C. Jhanwar,* Linda Ahn, Lindsey Burge Seoul National University ● Woo-Ho Kim,* Dong-Wan Kim, Se-Hoon Lee, Do Youn Oh, Sae-Won Han, Tae-Min Kim Peter MacCallum Cancer Centre ● Benjamin Solomon, Alex Dobrovic,* Stephen Fox,* Hongdo Do*, Toni-Maree Rogers,* Allison Lamb University of Colorado ● Ross Camidge, Marileila Garcia,* S. Gail Eckhardt, Wells Messersmith University of California – Irvine ● Sai-Hong Ou, Antonio Sanchez, Katie Gottbreht University of Chicago ● Ravi Salgia, Mark Ratain, David Geary, Leonardo Faoro, Rajani Kanteti Pfizer ● James Christensen, Victoria Cohan, Gina Emory, Paulina Selaru, Martin Shreeve, Jamey Skillings, Sreesha Srinivasa, Patricia Stephenson, Weiwei Tan, Greg Wei, Keith Wilner *Molecular profiling contributor ● We would like to thank all of the participating patients and their families, as well as the global network of investigators, research nurses, study coordinators, and operations staff ● This study was supported by funding from Pfizer Inc. Editorial Support was provided by Jessica Stevens at ACUMED® (Tytherington, UK) with funding from Pfizer Inc.
    22. 22. Permissions for Use of FiguresPermissions for Use of Figures ● Break-apart FISH assay for ALK-fusion genes, slide 5; TTP graphs, slide 6 – AT Shaw et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247–4253. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved ● Figure on slide 4 – Soda M et al. Identification of the transforming EML4–ALK fusion gene in non- small-cell lung cancer. Nature 2007;448:561–567. Reprinted by permission from Macmillan Publishers Ltd: Nature, © 2007

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