Slide 1 ___________________________________ ___________________________________ Targeting ALK Signaling in NSCLC ___________________________________ Tianhong (Tina) Li, MD/PhD August 14, 2011 ___________________________________ UC Davis Cancer Center Sacramento, CA ___________________________________ ___________________________________ ___________________________________ Slide 2 ___________________________________ Disclosure • No conflict of interest in this presentation. ___________________________________ Acknowledgement ___________________________________ • Drs. D. Ross Camidge, Fred Hirsch, Marileila Varella Carcia, Suresh Ramalingam, Robert Sweetman for providing their slides. ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 3 ___________________________________ Outlines: ALK Inhibitors in NSCLC • A case study ___________________________________ • Update on the results from PROFILE 1001 and 1005 studies • Unmet needs in clinical use of ALK inhibitors ___________________________________ • New insights in understanding the ALK signaling pathway and resistance mechanisms • Strategies to overcome the resistances to ___________________________________ first-generation ALK inhibitor crizotinib ___________________________________ ___________________________________ ___________________________________
Slide 4 ___________________________________ A 56-year-old female, never-smoker • A 56-year-old Caucasian female, never-smoker, who initially ___________________________________ presented with persistent cough in August 2006. • Workups revealed multiple lung masses with liver and bony metastases. Core needle biopsy of a liver mass revealed lung adenocarcinoma. • Summary of prior cancer treatment: Carbo/pac x 4, PD; ___________________________________ erlotinib x <1 mo, intolerability; bevacizumab and vinorelbine x 3, PD; nab paclitaxel x2, PD; pac weekly x 20 (5 mos.), PD; Pem 16 mos, PD; gem/docetaxel x 5 mos, PD; erlotinib 50 mg x 2 mos, PD; RT to right iliac bone (wheel chair-bound); Pem/Cis/Bev x3 mos then Pem/Bev x 5 mos, PD. • July 15, 2010: Liver biopsy (initial diagnosis): EML4-ALK ___________________________________ Break-Apart FISH positive (90% of cells). • Enrolled in PROFILE 1005, which is a phase II study of crizotinib monotherapy in refractory, metastatic NSCLC patients. She started the treatment on 12/1/2010. ___________________________________ ___________________________________ ___________________________________ Slide 5 ___________________________________ Crizotinib monotherapy: 250 mg po bid • Patient reports significant decrease in ___________________________________ nonproductive cough within one week after starting crizotinib. Right hip pain has also decreased and controlled. ___________________________________ • One level dose reduction of crizotinib at Cycle 3 for grade 2 peripheral neuropathy, which was resolved with dose reduction; no worsening symptoms since resuming original level dose of ___________________________________ crizotinib since cycle 10. Grade 1 vision changes has been stable. ___________________________________ ___________________________________ ___________________________________ Slide 6 ___________________________________ Baseline CT Scan Crizotinib: Post 2 cycles ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________
Slide 7 ___________________________________ Baseline CT Scan Crizotinib: Post 2 cycles ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ ___________________________________ Slide 8 ___________________________________ Echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion oncogenes in NSCLC ALK EML4-ALK ___________________________________ Extracellular TM TM TM TM Intracellular P P P P P P P P Y Y Y Y Y Y Y Y Kinase P P Kinase P P P P P P Y Y Y Y Y Y Y Y Y Y P P P P P P P P Y Y Y Y Y Y P P P P P P P P Y Y Y Y ___________________________________ Y Y Y Y EML4 – ALK NPM – ALK Vector EML4 ALK K589M v-Ras 3T3 ___________________________________ Nude mice Tumor/ injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2 Soda et al., Nature 448: 561-566, 2007 ___________________________________ ___________________________________ ___________________________________ Slide 9 ___________________________________ Crizotinib – a dual c-MET and ALK inhibitor at clinically relevant dose levels Upstate 102 Cellular selectivity on 10 of kinase 13 relevant hits Kinase % Inhibition Met(h) 94 103 Crizotinib Tie2(h) 102 IC 50 (nM) Selectivity ___________________________________ TrkA(h) ALK(h) 100 TrkB(h) 100 Abl(T315I)(h) 98 Kinase ratio (PF-02341066) Yes(h) 96 mean* Lck(h) 95 13 kinase Rse(h) [SKY] 94 Axl(h) 93 Fes(h) 93 Lyn(h) 91 93 “hits” <100X c-MET 8 – Ros(h) Arg(m) 90 CDK2/cyclinE(h) 87 Fms(h) 84 EphB4(h) 80 selective for Bmx(h) 79 EphB2(h) 77 ALK 20 2X Fgr(h) 73 Fyn(h) 68 c-MET IR(h) 64 CDK7/cyclinH/MAT1(h) cSRC(h) 58 58 IGF-1R(h) 56 298 34X Aurora-A(h) 54 Syk(h) 52 FGFR3(h) 50 RON PKCµ(h) 50 BTK(h) 35 189 22X CDK1/cyclinB(h) 25 p70S6K(h) 24 PAR-1Bα(h) PRK2(h) 22 21 PKBß(h) 21 Ret(h) 21 294 34X ___________________________________ GSK3ß(h) 18 Flt3(h) 17 Axl MAPK1(h) 17 ZAP-70(h) 17 Abl(h) 16 322 37X c-RAF(h) 16 PKD2(h) 15 14 ROCK-II(h) Rsk3(h) 14 GSK3α(h) 11 CDK5/p35(h) 10 Tie-2 448 52X PDGFRα(h) 10 Rsk1(h) 7 SGK(h) 6 CHK1(h) 5 Trk A 580 67X ErbB4(h) 5 JNK1α1(h) Rsk2(h) 5 PKBα(h) 4 4 Blk(m) 3 CDK3/cyclinE(h) 3 Trk B 399 46X PKCι(h) 3 PKCθ(h) 3 CDK2/cyclinA(h) 2 PAK2(h) 2 PKCßI(h) 2 Abl 1,159 166X Pim-1(h) PKCη(h) 1 SAPK4(h) 1 1 CaMKII(r) 0 MKK7ß(h) 0 CaMKIV(h) -1 IRK 2,887 334X CHK2(h) -1 ___________________________________ CK2(h) -1 JNK2α2(h) -1 MKK6(h) -1 CK1δ(h) PKCα(h) -2 Lck 2,741 283X MAPK2(h) -3 -2 MEK1(h) -3 PKCδ(h) -3 PKCε(h) -3 Plk3(h) -3 Sky >10,000 >1,000X PKCßII(h) -5 MSK1(h) -6 PDGFRß(h) -6 PKCζ(h) -6 SAPK3(h) -7 -6 VEGFR2 >10,000 >1,000X MAPKAP-K2(h) PKA(h) -7 AMPK(r) -9 CDK6/cyclinD3(h) -9 CSK(h) -9 PDGFR SAPK2a(h) -9 >10,000 >1,000X JNK3(h) -10 PKBγ(h) -10 IKKα(h) -11 NEK2(h) -11 *The cellular kinase activities were Pfizer Inc. Data on file measured using ELISA capture method ___________________________________ ___________________________________ ___________________________________
Slide 10 ___________________________________ Crizotinib: Induces Potent Growth Inhibition and Apoptosis in either c-Met amplified or EML4- ALK fusion oncogene-positive NSCLC cells ___________________________________ Crizotinib: cell growth inhibition Crizotinib: cell growth inhibition and apoptosis induction in H3122 cells in NSCLC cell lines 1,000 125 100 800 IC 50 value (nM) 75 600 ___________________________________ 50 % control IC 50 = 96 nM 400 25 0 200 – 25 0 – 50 0.0001 0.01 0.1 1 10 H23 H82 ___________________________________ H1993 H3122 H1734 H520 H526 SKMES1 H2347 H1975 H1838 H226 H1703 H647 H1755 CALU6 CALU1 H358 H1581 H2087 H1651 HCC827 H1355 H1573 H1650 H1666 H2405 A549 HCC2935 * Crizotinib concentration (mM) IC 50 = 50% inhibitory concentration *MET amplification Pfizer Inc. Data on file ___________________________________ ___________________________________ ___________________________________ Slide 11 ___________________________________ Milestones for Crizotinib (PF-02341066) Development ___________________________________ ___________________________________ May ___________________________________ NPM, nucleophosmin; ALK, anaplastic lymphoma kinase; ALCL, anaplastic large cell lymphoma; IMT, inflammatory myofibroblastic tumor; NSCLC, non-small cell lung cancer; NBL, neuroblastoma lymphoma Online access to Pfizer’s submission to ODAC ___________________________________ ___________________________________ ___________________________________ Slide 12 ___________________________________ PROFILE 1001: Phase 1 Safety, Pharmacokinetic And Pharmacodynamic Study Of Crizotinib, A c-Met/HGFR Selective Tyrosine Kinase Inhibitor, Administered Orally To Patients With Advanced Cancer (Began in 2006) N=175 Cohort 5 (n=6) 300 mg BID ___________________________________ Part 1: Cohort 6 (n=9) Dose escalation 250 mg BID (n=37) Cohort 4 (n=7) MTD/RP2D 200 mg BID Cohort 3 (n=8) ___________________________________ Part 2: 200 mg QD Molecularly defined cohorts ( ALK and c-MET ) Cohort 2 (n=4) Prescreening for patients with 100 mg QD ALK (non-lung) or MET activation ___________________________________ Discovery of ALK gene rearrange- Cohort 1 (n=3) ments in NSCLC in 2007 50 mg QD ALK -positive NSCLC cohort added 2008 BID, twice daily; QD, once daily; MTD, maximum tolerated dose; RP2D, randomized phase 2 dose Modified from Tan et al. J Clin Oncol 2010;28:15S abstract 2596 Soda, Nature 2007;448:561-6 ___________________________________ ___________________________________ ___________________________________
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