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
Slide 2
The Targets ALK ROS1 BRAF C-Met RET PI3KCA
Slide 3
ALK
Slide 4
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:
Slide 5
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
Slide 6
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)
Slide 7
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
Slide 8
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%
Slide 9
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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[TITLE]
Slide 19
Slide 20
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
Slide 21
ROS1
Slide 22
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:
Slide 23
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
Slide 24
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
Slide 25
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
Slide 26
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
Slide 27
BRAF
Slide 28
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
Slide 29
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)
Slide 30
Genotypes Identified in the LCMC Analysis of ~1000
Adenocarcinomas
Slide 31
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
Slide 32
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
Slide 33
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
Slide 34
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
Slide 35
C-MET
Slide 36
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
Slide 37
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
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
Slide 40
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
Slide 41
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
Slide 42
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
Slide 43
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
Slide 44
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
Slide 45
RET
Slide 46
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
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
(