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Lucio Crinò, MD Silvestrini Hospital Perugia, Italy

ALK INHIBITORS IN LUNG CANCER THERAPY. Lucio Crinò, MD Silvestrini Hospital Perugia, Italy. Expressed in ALCL with t(2;5) chromosome rearrangement resulting in a fusion protein of two genes: the novel tyrosine kinase gene ( ALK ) and NPM 1

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Lucio Crinò, MD Silvestrini Hospital Perugia, Italy

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  1. ALK INHIBITORS IN LUNG CANCER THERAPY Lucio Crinò, MD Silvestrini Hospital Perugia, Italy

  2. Expressed in ALCL with t(2;5) chromosome rearrangement resulting in a fusion protein of two genes: the novel tyrosine kinase gene (ALK) and NPM1 Other chromosome translocations involving the ALK locus have also been identified in several different human cancers 2,3,4 Detection of phosphoprotein in an ALCL cell line in SCID mice compared with controls1 Identification of Aberrant Forms of the Anaplastic Lymphoma Kinase 1 2 3 4 5 6 7 80 kDa ALCL, anaplastic large-cell lymphoma; NPM, nucleophosmin; SCID, severe combined immunodeficiency. 1Shiota M & Mori S. Leuk Lymphoma. 1996;23:2532. 2Pulford K, et al. J Cell Physiol. 2004;199:33058. 3Palmer, et al. Biochem J. 2009;420:345–61. 4Mano. Cancer Sci. 2008;99:2349–55.

  3. Identification of the EML4-ALK Fusion in NSCLC 1 HELP 496 981 EML4 Basic WD 1 496 1059 EML4–ALK variant 1 1 1058 1620 ALK Kinase TM ALK EML4 ~3.6 kb Exon 13 Exon 21 297 bp EML4-ALK variant 1 EML, echinoderm microtubule-associated protein-like 4; HELP, hydrophobic echinoderm mizroxbule-associated protein-like protein Soda M, et al. Nature. 2007;448:561–67.

  4. See alternative slide in back-up (slide 28) Inversion Translocation ALK Pathway Or ALK fusion protein* ALK Partner gene product RAS PI3K PLC-Y STAT3/5 AKT MEK PIP2 mTOR ErK Cellsurvival BAD IP3 Tumour cellproliferation S6K *Subcellular localisation of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2 BAD, BCL2-associated agonist of death; STAT3, signal transducer and activator of transcription 3; S6K, ribosome protein S6 kinase; ERK, extracellular signal-regulated kinase. 1Inamura K, et al. J Thorac Oncol. 2008;3:13–17. 2Soda M, et al. Proc Natl Acad Sci. U S A. 2008;105:19893–97.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):5609–14; and Pfizer Inc, data on file.

  5. EML4–ALK Is a Potent Oncogenic Driver1 • Other fusion partners for ALK have also been identified, including NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC2 Vector EML4 ALK EML4–ALK K589M NPM–ALK v-Ras 3T3 Nude mice tumour/ injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2 TPM3, tropomyosin 3; ATIC, aminoimidazole-4-carboxamide ribonucleotide formyltransferase 11MP cyclohydrolase; TFG, TRK-fused gene; CARS, cysteinyl-tRNA synthetase; CLTC, clathrin, heavy chain. 1Soda M, et al. Nature. 2007;448:561–67. 2Zhang, et al. Mol Cancer. 2010;9:188.

  6. Retrospective Data ALK Fusion Prevalence in NSCLC Prospective Data Lung Cancer Mutation Consortium9Adenocarcinoma RT-PCR, reverse transcription-polymerase chain reaction; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. 1Takahashi, et al. 2010. 2Wong, et al. 2009. 3Perner, et al. 2008. 4Paik, et al. 2011. 5Boland, et al. 2009. 6Paik, et al 2011. 7Takahashi, et al. 2010.8Rodig, et al. 2009. 9Kris, et al. Presented at ASCO 2011. Abstract CRA7506.

  7. Status of Actionable Driver Mutations in Lung Adenocarcinoma Tumor Specimens No mutation detected NRAS<1% KRAS (22%) MEK1<1% EGFR (18%) MET AMP<1% EML4-ALK (7%) HER2 1% Double mutants (2%) PIK3CA 1% Alk Fusion Prevalence in NSCLC: Retrospective Data BRAF (2%) AKT1 1Takahashi, et al. 2010. 2Wong, et al. 2009. 3Perner, et al. 2008. 4Paik, et al. 2011. 5Boland, et al. 2009. 6Paik, et al 2011. 7Takahashi, et al. 2010.8Rodig, et al. 2009. Johnson D, et al. ECCO ESMO 2011. Abstract 9018.

  8. Patients with the ALK fusion gene may not benefit from agents such as EGFR TKIs ALK-positive patients display similar sensitivity to platinum-based chemotherapy compared with ALK-negative patients1 Patients With ALK Fusion Represent a Specific Molecular Subset of Adenocarcinoma TTP on EGFR-TKI monotherapyALK may predict sensitivity to EML4–ALK inhibition but resistance to EGFR TKIs 100 EGFR WT/WT EML4-ALK 80 60 Percent progression free P =.004 (ALK vs EGFR) 40 TTP on platinum-based chemotherapy 20 100 EGFR WT/WT EML4-ALK 80 0 12 24 36 48 60 Time (months) 60 Percent progression free Patients with ALK-positive disease (n=15): 5 months Patients with EGFR-positive disease (n=25): 16 months Patients with EGFRWT/WT disease (n=49): 6 months 40 20 0 12 24 36 48 60 Time (months) 1Shaw AT, et al. J ClinOncol. 2009;27:4247‒53.

  9. Clinical Impact of ALK Rearrangement: A Single Center, Retrospective, Case-match Study • 1100 patient cases with lung cancer of non-squamous histology were collected in the NSCLC database of Seoul National University Hospital • 257 samples which were EGFR wild type or unresponsive to prior EGFR TKI therapy underwent FISH for ALK testing • Each patient with an ALK-positive tumour was matched to: • Two patients with EGFR-mutation positive tumours and • Two patients with ALK WT/EGFR WTtumours (WT/WT) • Matching variables included: age at diagnosis, sex, and stage of disease (IIIB or IV) Kim DW, et al. Presented at ASCO 2011; Abstract 7515.

  10. Overall Survival and Progression-Free Survival by Genetic Characteristics OS PFS of EGFR-TKI treated patients 100 80 60 40 20 0 100 80 60 40 20 0 ALK+ (N=10) EGFR mut+ (N=40) WT/WT (N=24) ALK+ (N=22) EGFR mut+ (N=44) WT/WT (N=44) *Excludes ALK-positive patients enrolled due to previous non- response to EGFR TKIs PFS (%)* OS (%) 0 10 20 30 40 0 20 40 60 80 100 Months Months • Early investigations do not support ALK rearrangement as a favourable prognostic factor • ALK-positive patients might be more resistant to EGFR TKI treatment compared with WT/WT patients • Patients who had received an ALK inhibitor were not included in this study Kim DW, et al. Presented at ASCO 2011; Abstract 7515.

  11. Status of ALK Inhibitors in Clinical Development

  12. Kinase % Inhibition 94 Met(h) 103 Tie2(h) 102 TrkA(h) 100 ALK(h) 100 TrkB(h) 98 Abl(T315I)(h) 96 Yes(h) 95 Lck(h) 94 Rse(h) [SKY] 93 Axl(h) 93 Fes(h) 93 Lyn(h) 91 Arg(m) 90 Ros(h) 87 CDK2/cyclinE(h) 84 Fms(h) 80 EphB4(h) 79 Bmx(h) 77 EphB2(h) 73 Fgr(h) 68 Fyn(h) 64 IR(h) 58 CDK7/cyclinH/MAT1(h) 58 cSRC(h) 56 IGF-1R(h) 54 Aurora-A(h) 52 Syk(h) 50 FGFR3(h) 50 PKCµ(h) 35 BTK(h) 25 CDK1/cyclinB(h) 24 p70S6K(h) 22 PRK2(h) 21 PAR-1Bα(h) 21 PKBß(h) 21 Ret(h) 18 GSK3ß(h) 17 Flt3(h) 17 MAPK1(h) 17 ZAP-70(h) 16 Abl(h) 16 c-RAF(h) 15 PKD2(h) 14 ROCK-II(h) 14 Rsk3(h) 11 GSK3α(h) 10 CDK5/p35(h) 10 PDGFRα(h) 7 Rsk1(h) 6 SGK(h) 5 CHK1(h) 5 ErbB4(h) 5 Rsk2(h) 4 JNK1α1(h) 4 PKBα(h) 3 Blk(m) 3 CDK3/cyclinE(h) 3 PKCι(h) 3 PKCθ(h) 2 CDK2/cyclinA(h) 2 PAK2(h) 2 PKCßI(h) 1 Pim-1(h) 1 PKCη(h) 1 SAPK4(h) 0 CaMKII(r) 0 MKK7ß(h) -1 CaMKIV(h) -1 CHK2(h) -1 CK2(h) -1 JNK2α2(h) -1 MKK6(h) -2 CK1δ(h) -2 PKCα(h) -3 MAPK2(h) -3 MEK1(h) -3 PKCδ(h) -3 PKCε(h) -3 Plk3(h) -5 PKCßII(h) -6 MSK1(h) -6 PDGFRß(h) -6 PKCζ(h) -6 SAPK3(h) -7 MAPKAP-K2(h) -7 PKA(h) -9 AMPK(r) -9 CDK6/cyclinD3(h) -9 CSK(h) -9 SAPK2a(h) -10 JNK3(h) -10 PKBγ(h) -11 IKKα(h) -11 NEK2(h) Crizotinib: A Selective Inhibitor of ALK and c-MET Upstate 102 kinase panel Cellular selectivity on 10 of 13 relevant hits Crizotinib (PF-02341066) 13 ‘hits’ <100X selective for c-Met • Findings for crizotinib • High probability of ALK and c-Met inhibition at clinically relevant doses • Low probability of relevant inhibition of RON, Axl, Tie2, or Trk at clinical dose levels *Measured using ELISA capture method Pfizer Inc, data on file.

  13. Modified from: Tan, et al. J Clin Oncol. 2010;28:15S. Abstract 2596. Crizotinib: First-in-human/Patient Trial (A8081001) Cohort 5 (n=6) 300 mg BID Part 1: Dose escalation(n=37) Cohort 6 (n=9) 250 mg BIDMTD/RP2D Cohort 4 (n=7) 200 mg BID Cohort 3 (n=8) 200 mg QD Part 2: Molecularly defined cohorts Cohort 2 (n=4) 100 mg QD Cohort 1 (n=3) 50 mg QD BID, twice daily; QD, once daily; MTD, maximum tolerated dose; RP2D, randomised phase 2 dose.

  14. A8081001: Rapid Responses Reported Day 7 Day 14 Ou, et al. J Thorac Oncol. 2010;5(12):2044–46.

  15. A8081001: Progression-Free Survival (N=119) Median PFS=10.0 months (95% CI: 8.2, 14.7)50 events (42%; 40 PD events) 69 patients (58%) censored, 59/69 (86%) in follow-up for PFS 1.0 0.8 0.6 0.4 0.2 0 Censored 95% Hall-Wellner Band Survival distribution function 0 5 10 15 20 n at risk 119 73 29 8 1 Months Camidge DR, et al. Presented at ASCO 2011; Abstract 2501.

  16. A8081001: Overall Survival • Median OS had not been reached as of the data cut-off • 23 deaths (19%) • 2 patients (2%) censored (lost to follow-up) • 94 patients (79%) remain in follow-up for OS • No deaths were related to study treatment • Survival probabilities from first dose of crizotinib: • 6 months: 90% (95% CI: 82.7, 94.4) • 12 months: 81% (95% CI: 70.9, 87.2) Camidge DR, et al. Presented at ASCO 2011; Abstract 2501.

  17. Impact of ALK Inhibition on Overall Survival of Patients With Advanced, ALK–Positive NSCLC • Study background and rationale • The true impact of crizotinib on OS may be difficult to establish in ongoing randomised phase 3 studies due to crossover • In the absence of randomised data, determination of survival benefit requires a comparator population of ALK-positive, crizotinib-naïve patients • Study objectives • Examine OS of crizotinib-treated ALK-positive NSCLC patients • Compare the survival outcomes of crizotinib-treated vscrizotinib-naïve, ALK-positive NSCLC patients • Explore the prognostic significance of ALK rearrangement by comparing the survival outcomes of crizotinib-naïve ALK-positive and ALK-negative NSCLC patients Shaw AT, et al. Presented at ASCO 2011; Abstract 7507.

  18. Study Populations ALK CRIZOTINIB ALK CONTROLS WT/WT CONTROLS ALK-positive Crizotinib-treated N=82 ALK-positive Crizotinib-naïve ALK-negative EGFR-wild type US/Australia N=56 US/Australia N=36 US (MGH) N=253 2nd/3rd line N=30 2nd line N=23 2nd line N=125 Never/light smoker AdenoCA N=28 Never/light smoker AdenoCA N=21 Never/light smoker AdenoCA N=48 Shaw AT, et al. Presented at ASCO 2011; Abstract 7507.

  19. Overall Survival: 2nd Line Subset WT/WT Control(n=125) ALK Crizotinib(n=30) ALK Control(n=23) 100% Median Survival, mo NR 6 11 80% 1-yr Survival, % 70 44 47 2-yr Survival, % 55 12 32 60% From 2nd/3rd line crizotinib HR=0.49, P=.02 40% 20% 0% 0 1 2 3 4 Years Shaw AT, et al. Presented at ASCO 2011; Abstract 7507.

  20. Conclusions • Targeting the ALK fusion gene in NSCLC , a direct driver of oncogenesis, has resulted in promising clinical response rates and PFS in patients with advanced NSCLC treated with crizotinib • ORR: 61% • Median PFS: 10 months • The most frequent adverse events observed with crizotinib were mild and moderate gastrointestinal events and mild visual disturbances • Overall survival of patients with advanced, ALK-positive NSCLC treated with 2nd-/3rd- line crizotinib is significantly longer than that of clinically comparable, crizotinib-naïve controls • Safety and efficacy of a molecularly targeted agent may be assessed in molecularly defined cohorts directly following traditional phase 1 dose escalation • US FDA has approved crizotinib for ALK-positive NSCLC based on data from this study • Crizotinib has also been successfully filed with the EMA • These results are an example of rapid clinical development, from target identification to clinical validation, and support a personalised approach to NSCLC treatment

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