ALK and Other Evolving Targets in Advanced NSCLC Mark A. Socinski, MD Professor of Medicine and...

ALK and Other Evolving Targets in Advanced NSCLC Mark A. Socinski, MD Professor of Medicine and Thoracic Surgery Director, Lung Cancer Section, Division of Hematology/Oncology Clinical Associate Director, Lung SPORE Co-Director, UPMC Lung Cancer Center of Excellence and Lung and Thoracic Malignancies Program University of Pittsburgh

The Targets ALK ROS1 BRAF C-Met RET PI3KCA

ALK Rearrangement in Cancer Or Inversion Translocation NSCLC EML4-ALK, KIF5B- ALK, TFG-ALK (3-5%) Anaplastic large cell lymphoma NPM-ALK Inflammatory myo-fibroblastic tumor TPM3-ALK, TPM4-ALK Other solid tumors ALK-POSITIVE CANCERS:

Demographics of ALK Population 1.Shaw AT et al, J Clin Oncol :27:4247-53, 2009 2.Rodig SJ et al, Clin Cancer Res;15:5216-23, 2009 3.Yoshida A et al, Lung Cancer:72:309-15, 2011 4.Inamura K et al, Mod Pathol:22:508-15, 2009 5.Zhang X et al, Mol Cancer:9:188, 2010 6. Wong DW et al, Cancer:115:1723-33, 2009 7. Kwak EL et al, N Engl J Med:363:1693-703, 2010

Diagnostic features of EML4-ALKpositive NSCLC Shaw A T et al. JCO 2009;27:4247-4253 2009 by American Society of Clinical Oncology Break-apart FISH ALK IHC H&E (split of red and green probes) (arrows denote signet ring cells)

Crizotinib: A Small Molecule Tyrosine Kinase Inhibitor of c-MET, ALK and ROS1 Kinase IC 50 (nM) mean* Selectivity ratio c-MET8 ALK40-605-8X ROS1607X RON8010X Axl 29434X 32237X Tie-244852X Trk A58067X Trk B39946X Abl1,159166X IRK2,887334X Lck2,741283X Sky>10,000>1,000X VEGFR2>10,000>1,000X PDGFR >10,000>1,000X Co-crystal structure of crizotinib (PF-02341066) bound to c-MET Cui et al. J Med Chem 54: 6342-63, 2011 and Pfizer data on file

Updated Phase I Results: Crizotinib in ALK+ NSCLC Camidge DR et al Lancet Oncology 13:1011-19, 2012 ORR 60.8% Med PFS 9.7 mos Est OS at - 6 mos 87.9% - 12 mos 74.8%

Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC Phase II (PROFILE 1005) Response Evaluable population, N=123 (excludes patients with early death and indeterminate response). CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. *Per RECIST v1.1, percent change from baseline for subjects with best overall response of CR can be

First and Second Generation ALK TKIs in Clinical Development NameCompanyStatusComments CrizotinibPfizer 1 st and 2 nd line registration trials are ongoing. 2 nd line trial is >75% accrued Accelerated approval granted August 26, 2011 LDK378Novartis Phase 1 dose escalationActivity observed at 400 mg. Enrolling in the US and Europe AF802Chugai Phase 1/2 in Japan and starting in US Activity observed in crizotinib-nave pts AP26113Ariad Phase 1 starting this fallSome activity against EGFR T790M. Enrolling in the US ASP3026Astellos Phase 1Similar to TAE684. Enrolling in Japan CEP-28122Cephalon Preclinical NMS-E628Nerviano Preclinical X276/396Xcovery Preclinical

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Clinical Activity of Hsp90 Agents in Advanced NSCLC # ptsORR (%)ORR/DCR (%) by genotype EGFR mtKRAS mtALK + IPI-504 1 7674/210/4267/100 AUY922 2 1201420/570/3929/57 Ganetespib 3 9940/130/650/87 1.Sequist LV et al. J Clin Oncol 28:4953-4960, 2010 2.Garon EB et al. J Clin Oncol 30: ASCO 2012, abstr # 7543 3.Wong K et al. J Clin Oncol 29: ASCO 2011, abstr # 7500

ROS Rearrangement in Cancer Translocation NSCLC SLC34A2-ROS, CD74-ROS (1-2%) Glioblastoma multiforme FIG- ROS Cholangiocarcinoma FIG-ROS Other solid tumors ? ROS-POSITIVE CANCERS:

Brock TG, Receptors and Tyrosine Kinases http://www.caymanchem.com/app/template/Article.vm/article/2187 http://www.caymanchem.com/app/template/Article.vm/article/2187 ROS1 Encodes a Receptor Tyrosine Kinase

Crizotinib: A Small Molecule Tyrosine Kinase Inhibitor of c-MET, ALK and ROS1 Kinase IC 50 (nM) mean* Selectivity ratio c-MET8 ALK40-605-8X ROS1607X RON8010X Axl 29434X 32237X Tie-244852X Trk A58067X Trk B39946X Abl1,159166X IRK2,887334X Lck2,741283X Sky>10,000>1,000X VEGFR2>10,000>1,000X PDGFR >10,000>1,000X Co-crystal structure of crizotinib (PF-02341066) bound to c-MET Cui et al. J Med Chem 54: 6342-63, 2011 and Pfizer data on file

Summary of Tumor Responses in Patients with Advanced ROS1+ NSCLC (N=14*) *Response-evaluable population. Tumor ROS1 FISH-positive, but negative for ROS1 fusion gene expression. Crizotinib held for >6 wks prior to first scans which showed PD. +, Treatment ongoing. Data in the database as of April 19, 2012. Decrease or Increase From Baseline (%) 100 80 60 40 20 0 20 40 60 80 100 PDSDPRCR 4+ 12+ 22+ 18 44+ 20+ 35+48+ 15+ 16+ 18+ 8+ dose to last available on treatment

Crizotinib Response in ROS1-positive Non-squamous 4 th Line 2/1/2012 On O 2, wheelchair-bound, PS 3 3/19/2012 Fully ambulatory, PS 1

Overview of the MAPK signaling pathway Giroux S et al. BMCL Digest 2012 2002 Cancer Genome Project identified BRAF mutations Occur in ~50% of melanomas (90% V600E) Serine/threonine kinase RAF family member (ARAF, BRAF and CRAF) RAF kinases located downstream of RAS GTPases and upstream of MEK and ERK in MAPK signaling pathway Mutated BRAF constitutively activates the MAPK pathway

BRAF in NSCLC (Adeno) Paik PK et J Clin Oncol 29:2046-51, 2011 697 adenos tested for BRAF mutations: 18 found (3%) All were current or former smokers (median pack yrs, 38, range 14-75) Mutually exclusive of EGFR, KRAS and EML4-ALK 50% V600E (6/10 advanced vs 3/8 early) Marchetti A et al. J Clin Oncol 29:3574-79, 2011 1046 NSCLC tested 36 (4.9%) adeno, 1 (0.3%) squamous 57% were V600E (more common in females) Mostly smokers (particularly non-V600E)

Genotypes Identified in the LCMC Analysis of ~1000 Adenocarcinomas

Relative frequency of BRAF mutations in (A) lung adenocarcinoma versus (B) melanoma. Paik P K et al. JCO 2011;29:2046-2051 2011 by American Society of Clinical Oncology

Figure 8 (A) Representative chemical structures of BRAF inhibitors; (B) Combination therapies involving MEK and HSP90 inhibitors given in combination with BRAF inhibitors in clinical trials for melanomas. Simon Giroux Overcoming acquired resistance to kinase inhibition: The cases of EGFR, ALK and BRAF Bioorganic & Medicinal Chemistry Letters Volume 23, Issue 2 2013 394 - 401 http://dx.doi.org/10.1016/j.bmcl.2012.11.037

Figure 8 (A) Representative chemical structures of BRAF inhibitors; (B) Combination therapies involving MEK and HSP90 inhibitors given in combination with BRAF inhibitors in clinical trials for melanomas. Simon Giroux Overcoming acquired resistance to kinase inhibition: The cases of EGFR, ALK and BRAF Bioorganic & Medicinal Chemistry Letters Volume 23, Issue 2 2013 394 - 401 http://dx.doi.org/10.1016/j.bmcl.2012.11.037 ASCO 2013

73 year old women with stage IV adenocarcinoma (BRAF V600E mutation) Recd 6 cycles of Carbo/pemetrexed/bevacizumab followed by 9 cycles of maintenance pemetrexed Dabrafenib Baseline 8 weeks later

c-MET Receptor Tyrosine Kinase Implicated in tumor cell migration, invasion, proliferation, and angiogenesis 1 The only known high-affinity receptor for hepatocyte growth factor (HGF) 1 Amplification is assoc. with: Poor prognosis in NSCLC 2 Resistance to EGFR kinase inhibitors in EGFR mutation-positive NSCLC 3,4 1.Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:40410 2.Cappuzzo F et al. JCO 2009;27:166774 3.Engelman JA et al. Science 2007;316:103943 4.Bean J et al. PNAS 2007;104:209327

Activation of Met in Cancer 37 MUTANT MET LUNG HCC (Childhood) PAPIL. RENAL (Hereditary & Sporadic) AUTOCRINE HGF GLIOMA OSTEOSARCOMA PANCREATIC GASTRIC INCREASED MET BREAST COLORECTAL ESOPHAGEAL GASTRIC GLIOMA HNSCC LUNG MELANOMA MESOTHELIOMA OVARIAN PANCREATIC RENAL OtherFocal Amp GASTRIC LUNG Met CRC High Met expression corresponds with higher Met activity Paracrine HGF

HGF/MET Pathway Inhibitors CompoundCompanyTarget(s)MechanismPhase METMetMAbGenentechMETOne-Arm AntibodyII ARQ197ArQuleMETSmall molecule inhibitorIII BMS-777607BMSMETSmall molecule inhibitorI/II INCB-28060Incyte/NovartisMETSmall molecule inhibitorI/II JNJ-38877605J&JMETSmall molecule inhibitorI MGCD-265MethylgeneMET, VEGFRs, Flt3, TIE-2 Small molecule inhibitorI MK-2461MerckMETSmall molecule inhibitorI/II PF02341066)PfizerMET, ALKSmall molecule inhibitorIII PF4217903PfizerMETSmall molecule inhibitorI SGX523SGXMETSmall molecule inhibitorDiscontinued XL184ExelixisMET, VEGFR2, C-kit, Flt-3, TIE-2 Small molecule inhibitorIII XL880, (GSK1363089) Exelixis / GSKMET, VEGFR2, C-kit, Flt-3, TIE-2 Small molecule inhibitorII HGFAMG102AmgenHGFMonoclonal antibodyII AV-299AVEOHGFMonoclonal antibodyI/II AntibodyTKI

Tivantinib: Phase III NSCLC Study MARQUEE Study 39 Inoperable locally adv or metastatic NSCLC Non-squamous histology 1-2 regimens prior chemo (no prior EGFR TKI) Prior adjuvant/ maintenance therapy allowed Erlotinib 150 mg PO QD + Placebo 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle 1Endpoint OS (ITT population) 2/Exploratory Endpoints include: PFS (ITT population) OS and PFS in EGFR WT patients Safety and toxicity QOL/FACT-L Biologic sub-groups 988 patients (~ 120 pts enrolled, Aug 2011)* Stratify by EGFR and KRAS mutation status Interim analysis performed at 50% of events Erlotinib 150 mg PO QD +ARQ 197 360 mg PO BID 28-day cycle Erlotinib 150 mg PO QD +ARQ 197 360 mg PO BID 28-day cycle Reference: Sequist et al. ESMO 2010 RANDOMIZERANDOMIZE

Tivantinib: Phase III NSCLC Study MARQUEE Study 40 Inoperable locally adv or metastatic NSCLC Non-squamous histology 1-2 regimens prior chemo (no prior EGFR TKI) Prior adjuvant/ maintenance therapy allowed Erlotinib 150 mg PO QD + Placebo 28-day cycle Erlotinib 150 mg PO QD + Placebo 28-day cycle 1Endpoint OS (ITT population) 2/Exploratory Endpoints include: PFS (ITT population) OS and PFS in EGFR WT patients Safety and toxicity QOL/FACT-L Biologic sub-groups 988 patients (~ 120 pts enrolled, Aug 2011)* Stratify by EGFR and KRAS mutation status Interim analysis performed at 50% of events Erlotinib 150 mg PO QD +ARQ 197 360 mg PO BID 28-day cycle Erlotinib 150 mg PO QD +ARQ 197 360 mg PO BID 28-day cycle Reference: Sequist et al. ESMO 2010 RANDOMIZERANDOMIZE Negative

MetMAb (15 mg/kg IV Q3W) + erlotinib (150 mg daily) Phase II: Erlotinib +/- MetMAb in 2 nd/ 3 rd -line NSCLC *128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010 Data presented includes >5 additional months of follow-up RANDOMIZATIONRANDOMIZATION 1:1 n=137* n=69 n=68 Arm A Arm B PD n=27 Must be eligible to be treated with MetMAb Key eligibility: Stage IIIB/IV NSCLC 2 nd /3 rd -line NSCLC Tissue required PS 02 Stratification factors: Tobacco history Performance status Histology Placebo (IV Q3W) + erlotinib (150 mg daily) Add MetMAb Co-primary objectives: PFS in Met Diagnostic Positive patients (est. 50%) PFS in overall ITT population Other key objectives: OS in Met Diagnostic Positive pts OS in overall ITT patients Overall response rate Safety/tolerability 5

Met Diagnostic Positive was defined as majority (50%) of tumor cells with moderate or strong staining intensity Met IHC as a companion diagnostic Met diagnostic status was assessed after randomization and prior to unblinding 93% of patients had adequate tissue for evaluation of Met by IHC 52% patients with evaluable tissue were Met Diagnostic Positive Negative Weak StrongModerate 6 Ventanas CONFIRM (SP44 mAb clone) IHC: immunohistochemistry Additional biomarker data are discussed in abstract # 7529

MetMAb plus erlotinib in Met Dx+ patients Time to progression (months) 0369121518 Probability of progression free 0.0 0.2 0.4 0.6 0.8 1.0 Placebo + erlotinib 3.8 26 MetMAb + erlotinib 12.6 16 Median (mo) HR (95% CI) Log-rank p-value No. of events Overall survival (months) 036912151821 Probability of survival 0.0 0.2 0.4 0.6 0.8 1.0 Placebo + erlotinib 1.5 27 Median (mo) HR (95% CI) Log-rank p-value No. of events PFS: HR=0.53OS: HR=0.37 9 MetMAb + erlotinib 2.9 20 0.53 (0.280.99) 0.04 0.37 (0.190.72) 0.002

44 OAM4971g Global Phase III Clinical Trial NSCLC Inoperable locally adv/metastatic dz. MET diagnostic positive 1-2 regimens prior chemo (no prior EGFR TKI) Prior adjuvant/ maintenance therapy allowed RANDOMIZERANDOMIZE 1 Endpoint OS 2/Exploratory Endpoints incl: -PFS -OS -Safety and toxicity -QOL/PRO -PK and immunogenicity 480 patients Stratify by MET score, prior rx, histology, and EGFRmutation status Interim analysis at 67% of events Erlotinib 150 mg PO QD +MetMab 15 mg/kg D1 21-day cycle Erlotinib 150 mg PO QD + Placebo 21-day cycle

RET ASSOCIATED DISEASES PAPILLARY THYROID CARCINOMA Multiple RET fusion genes Gain of function MULTIPLE ENDOCRINE NEOPLASIA MEN 2A & 2B Familial Medullary Thyroid Cancer Gain of function HIRSHPRUNGS DISEASE Loss of function

KIF5B EXON 1 1234567981011 2328329 12131415161718 19 2021222324 25 914915963 COILED-COIL KINESIN MOTOR TAIL KIF5B-RET RET 123456798101112131415 COILED-COIL KINESIN MOTOR 2575587879978 1213 141516 17 TYROSINE KINASE 18 19 328329 1213 17 TYROSINE KINASE 18 14 1516 19 1016 1114 724 CADHERIN 34 168 272

RET Fusions in NSCLC Surgical series of 936 patients examined by PCR (with IHC and FISH validation) 13 cases found (1.4%) - 11 adenos, 2 adenosquamous - 7 women, 6 men - 9 KIF5B-RET, 3 CCDC6-RET, 1 NCOA4-RET - More often poorly differentiated, young (

ALK and Other Evolving Targets in Advanced NSCLC Mark A. Socinski, MD Professor of Medicine and...

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