TKIs in NSCLC

1
TKIs in NSCLC

• Giuseppe Giaccone, MD PhD
• Chief, Medical Oncology Branch

TRACO 2009 September 14, 2009
2
Lung Cancer Demographics

• Second most frequently diagnosed cancer in the
  United States
• 12 of all new diagnoses
• 173,770 individual cases in 2004
• Median age at diagnosis is approximately 70 years
• Over 1/3 of all diagnoses are made in patients
  over 75 years of age
• Leading cause of cancer deaths in the
  United States
• 160,440 patients will die in 2004
• 32 and 25 of all cancer deaths in American men
  and women, respectively

Jemal et al. CA Cancer J Clin. 2004548. SEER
Cancer Statistics Review, 1975-2001. At
http//seer.cancer.gov/csr/1975_2001/. Accessed
October 22, 2004.
3
U.S. Cancer Mortality
Men
Women
CA Cancer J Clin 2006
4
NSCLC United States Survival Over 3 Decades.
The 5 year was13.9 in 197515.0 in
197815.1 in 198115.5 in 198415.1 in
198715.8 in 199016.3 in 199316.9 in 1997
5
Lung cancer in never smokersThe 7th leading
cause of cancer deaths in the world
Sun, Schiller, Gazdar Nat Rev Cancer 07
6
Activated proto-oncogenes in lung cancer
7
Inactivated tumor suppressor genes in lung cancer
8
Tyrosine kinases within the kinome
From Cell Signaling
9
TK and relative hazard to develop metastases in
early NSCLC
Muller-Tidow C et al. Cancer Res 65 1778, 2005
10
Approved molecularly targeted agents in advanced
NSCLC

• Erlotinib and gefitinib in patients who received
  prior chemotherapy
• No patient selection
• Gefitinib for EGFR mutants (EMEA)
• Bevacizumab in first line with carbo-taxol (FDA)
  or with a platinum-based regimen (EMEA)
• Non-squamous, no hemoptysis, no brain metastases

11
Phase III Trial of Bevacizumab in Non-Squamous
NSCLC ECOG 4599N855 (eligible)
(PC)Paclitaxel 200 mg/m2Carboplatin AUC
6(q 3 weeks) x 6 cycles (PCB)PC x 6 cycles
Bevacizumab (15mg/kg q 3 wks) to PD
12
E4599 Overall Survival. The 12 and 24 month
survival for PC was 44.4 and 15.4 respectively.
The 12 and 24 month survival for BV/PC was 51.0
and 22.0 respectively.
1.0
0.8
Proportion surviving
0.6
0.4
0.2
0.0
0
6
42
48
18
30
12
24
36
Patients at risk
444
318
1
0
104
9
190
36
5
PC
BV/PC
434
340
3
0
127
25
216
54
8
Survival (months)
13
Characteristics of selected VEGFR TKIs being
tested for NSCLC
Biochemical IC50 values were determined using
slightly different methods between the studies
and are not directly comparable. Adapted from
Lee and Heymach, Clin Lung Ca 2006 Wedge SR,
Cancer Res 624645-55, 2002 Mendel DB, Clin
Cancer Res 9327-37, 2003 Wilhelm SM, Cancer Res
647099-109, 2004 Hess-Stumpp ChemBioChem 2005
14
Waterfall Plots of VEGFR TKIs
BIBF 1120
15
Efficacy of VEGFR TKIs in advanced NSCLC
Weeks
Many previously untreated pts and many
previously resected pts
16
Phase II Study of Sorafenib in Patients With
Relapsed NSCLC

• Sorafenib potent inhibitor of Raf, PDGFR,
  VEGFR-1, -3, c-Kit
• Eligibility criteria Pts with recurrent NSCLC
  with measurable disease who have received no more
  than one prior chemotherapy regimen for
  metastatic disease, ECOG 0-2.
• Exclusion criteria Brain metastasis and
  therapeutic anticoagulation.
• Sorafenib is administered at a starting dose of
  400 mg bid continuously on 28-day cycles.
• Major endpoint response rate
• If gt 1 response in 12 patients --gt 37 patients
• Correlative studies
• Dynamic contrast enhanced MRI (DCE-MRI) performed
  before cycle 1 and at C1day 15 to study early
  changes in tumor vascularity.
• FDG-PET every 2 cycles
• PK
• Cyp3A4/5 genotyping
• K-ras mutations
• VEGF, IL6, and IL8 in plasma

17
Phase II Study of Sorafenib in Patients With
Relapsed NSCLC

• Eligibility criteria Pts with recurrent NSCLC
  with measurable disease who have received no more
  than one prior chemotherapy regimen for
  metastatic disease, ECOG 0-2, and adequate organ
  function.
• Exclusion criteria Brain metastasis and
  therapeutic anticoagulation.
• Sorafenib is administered at a starting dose of
  400 mg bid continuously on 28-day cycles.
• Responses are evaluated every 8 weeks according
  to RECIST criteria. Dynamic contrast enhanced MRI
  (DCE-MRI) is performed before cycle 1 and at
  C1day 15 to study early changes in tumor
  vascularity.

Gutierrez M et al. ASCO 2008
18
DCE-MRI results

• Reduction in the parameters of permeability, with
  decreased values in ktrans and kep, associated
  with reductions in the tumor size.

Before
2 wks after
19
Response

• Fifteen patients evaluable for response
• (gt8 weeks of treatment) before amendment (Aug
  08)
• 2 PR (13)
• 7 SD (46)
• Present accrual 28 patients 2 PR, 9 NC, 16 PD,
  1 TE
• Main side effects hypertension, head and foot
  syndrome, diarrhea, mucositis

20
ErbB family of receptor tyrosine kinases (RTKs)
and ligands. The ErbB1 or EGFR binds
EGF,TGFa,Amphiregulin,b-cellulin, HB-EGFand
Epiregulin. The ErbB2 or HERR is an orphan
receptor with no ligands. The ErbB3 of HER3R
binds Heregulins. The ErbB4 or HER4R binds NRG2,
NRG3, Heregulins and b-cellulin.
21
EGFR inhibitors in NSCLC-The EGFR tyrosine
kinase inhibitors (erlotinib and gefitinib) have
clinical activity in about 10 of metastatic
NSCLC patients -But no survival advantage has
been obtained by the combination with standard
chemotherapy-Activity has been associated with
activating EGFR mutations

22
EGFR mutations and response to EGFR-TKI in
advanced NSCLC

• Mutation frequency approximately 12 in
  Caucasians
• More frequent in never-smokers, women,
  adenocarcinoma, BAC and Asians
• Rare or absent in other tumor types
• Presence of a mutation predicts response to small
  molecules EGFR inhibitors
• Presence of EGFR mutations confers distinct
  survival advantage (20 m vs 8 m) upon treatment
  with EGFR TKIs
• Early event in lung carcinogenesis

23
EGFR in H3255 cells is more sensitive to
gefitinib in vitro than EGFR in NCI-H441, H1666
or H1781 cells
24
BR.21 erlotinib phase III study in advanced,
relapsed NSCLC. stage IIIB/IV, relapsed NSCLC PS
03failed one or two prior regimensDaily oral
erlotinib150mg/day n731 patients Primary
objective overall survivalSecondary objectives
response rate, stable-disease rate, duration of
response, time to disease progression, and QoL

25
Overall Survival. The erlotinib median is 6.7
months and the 1 yr survival is 31. The placebo
median is 4.7 months and the 1 yr survival is 21

26
Tumor Response in Selected Subsets
27
First line erlotinib in advanced NSCLC Response
(n53) 1 patient had a complete response
lasting 183 days. 11 patients had a Partial
response lasting 256 days. 17 patients had
stable disease lsting 84 days. 12 patients had
Progressive disease and 12 patients were Not
evaluable at 6 weeks.

28
Correlation of smoking status and tumor type with
responseIn patients who Never smoked, 3 females
with adenocarcinoma had PR and 1 had SD. In
females with BAC 3 had a PR. In females with
other histology 2 had SD. In males with BAC 1
had PR.In former or current smokers, females
with adenocarcinoma had 2 PR and 6 SD. Females
with SCC and LCC each had 1 SD. Males with
adenocarcinoma had 1 CR and 1SD. Males with SCC
had 2 PR and 1 SD. Males with LCC or BAC had 3
and 1 SD respectively.
29
MO17426 mutation analysisOf 28 patients
mutations of the EGFR occurred in 4/5 responders,
1/12 with SD and 0/11 non-responders. Of 28
patients with PI3K mutations, 0/3 were
responders, 1/11 with SD, and 0/11 nonresponders.
Of patients with K-ras mutations, 0/4 responded/
3/10 had SD and 7/11 were non-responders.
30
Survival based on EGFR status
31
Survival based on kras status
32
Incidence of EGFR gene mutations (global data
from literature n2880).EGFR mutations occur in
Asian females who smoke and get adenocarcinoma


33
IPASSPatients are Chemonaïve and Age 18 years.
Patients should have Adenocarcinoma histology and
a smoking history of Never or light ex-smokers.
The Life expectancy should be greater than 12
weeks and the tumor stage should be Measurable
stage IIIB / IV disease. Patients are treated
with gefitinib (250 mg/day) or carboplatin (AUC 5
or 6) with paclitaxel (200 mg/m2) 3 times weekly.
Primary endpoints are Progression-free survival
, whereas secondary endpoints are Objective
response rate, Overall survival, Quality of
life, Disease-related symptoms Safety and
tolerability. Exploratory Biomarkers include
EGFR mutation,EGFR-gene-copy number and EGFR
protein expression.
Endpoints

34
Study conduct

• 87 centres in 9 countries in Asia
• China, Hong Kong, Indonesia, Japan, Malaysia,
  Philippines, Singapore, Taiwan, Thailand
• 1217 patients randomised
• Randomisation period March 2006 to October 2007
• Data cut-off 14 April 2008
• 950 PFS events observed in ITT population (78
  maturity)
• Mean time on treatment
• gefitinib, 6.4 months
• carboplatin / paclitaxel, 3.4 months (median
  number of cycles 6)
• Final survival data (944 events) expected mid-2010

Hong Kong
Myanmar
limited to a maximum of 6 cycles PFS,
progression-free survival ITT, intent-to-treat
35
Demography (ITT population)
Gefitinib Carbo/pacliAge lt65 years 73 74Med
ian age (range), years 57 57Femalea 79 79
WHO PS 0 / 1 / 2a 26/64/10 26/63/11Never
smokera 94 94Light ex-smokera 6 6Mean
smoking duration, years 11.5 14.5Mean time
since cessation, years 24.6 23.4Metastatic
disease 75 76Time since diagnosis lt6
months 96 94Chinese ethnicity 52 50Japanese
ethnicity 19 20
36
Attrition rates in biomarker analysis 1217
randomisedpatients (100) 1038biomarker consent
(85) 683 provided samples (56) Evaluable
forEGFR mutation 437 (36)EGFR gene copy
number 406 (33)EGFR expression 365 (30)

37
EGFR Mutation Rate (Asian, Non-/Light Smoker,
Adenocarcinoma)

• 59.7 (261 / 437)

38
Tumor Response According to EGFR Mutation
Status.Responders (71.2) to TKI have EGFR
mutations
39
Prospective Studies of Patients with EGFR
mutations treated with EGFR TKIs. The relative
response to gefitinib ranges from 55-82. The
time to progression ranges from 9.4 to 13.3
months.
40
IPASS Objective tumour response.The odds ratio
is 1.59 with a p value of 0.0001
41
Estimated Tumor Response Rate and Actual Response
Rate
42
IPASS EGFR Mutation and Progression-free survival
EGFR mutation positive
EGFR mutation negative
Gefitinib (n132)Carboplatin / paclitaxel
(n129)
Gefitinib (n91)Carboplatin / paclitaxel (n85)
1.0
1.0
HR (95 CI) 0.48 (0.36, 0.64) plt0.0001 No.
events gefitinib, 97 (73.5)No. events C / P,
111 (86.0)
HR (95 CI) 2.85 (2.05, 3.98) plt0.0001 No.
events gefitinib , 88 (96.7)No. events C / P,
70 (82.4)
0.8
0.8
0.6
0.6
Probability of progression-free survival
Probability of progression-free survival
0.4
0.4
0.2
0.2
0.0
0.0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Months
Months
At risk
132
31
11
3
0
108
Gefitinib
91
2
1
0
0
21
71
4
129
37
7
2
1
0
103
C / P
85
14
1
0
0
0
58
Treatment by subgroup interaction test, plt0.0001
ITT populationCox analysis with covariates
Mok et al ESMO LBA 2, 2008
43
Comparison of PFS by mutation status within
treatment arms
Gefitinib EGFR M (n132)Gefitinib EGFR M-
(n91)Carboplatin / paclitaxel EGFR M
(n129) Carboplatin / paclitaxel EGFR M- (n85)
Probabilityof PFS
1.0
Gefitinib, HR0.19, 95 CI 0.13, 0.26,
plt0.0001No. events M 97 (73.5)No. events M-
88 (96.7) Carboplatin / paclitaxel, HR0.78,
95 CI 0.57, 1.06, p0.1103No. events M 111
(86.0)No. events M- 70 (82.4)
0.8
0.6
0.4
0.2
0.0
0
4
8
12
16
20
24
Time from randomisation (months)
Hazard ratio lt1 implies a lower risk of
progression in the M group than in the M- group
44
Progression-free survival in a population with
60 EGFR mutation rate
Carboplatin / paclitaxel
Gefitinib
N Events
609 453 (74.4)
608 497 (81.7)
HR (95 CI) 0.741 (0.651, 0.845) plt0.0001
Gefitinib demonstrated superiority relative to
carboplatin / paclitaxel in terms of PFS
Primary Cox analysis with covariates HR lt1
implies a lower risk of progression on gefitinib
Mok et al ESMO LBA 2, 2008
45
Overall survival in ITT population (follow-up
ongoing)
Gefitinib
Carboplatin / paclitaxel
Probabilityof survival
1.0
N Events
609 223 (36.6)
608 227 (37.3)
HR (95 CI) 0.91 (0.76, 1.10)
0.8
Median OS (months)6 month OS12 month OS
18.68468
17.38664
0.6
0.4
0.2
0.0
0
4
8
12
16
20
28
Months
24
At risk
609
239
118
38
0
514
Gefitinib
0
423
608
401
212
104
32
0
524
Carboplatin / paclitaxel
1
Cox analysis with covariatesHR lt1 implies a
lower risk of death on gefitinibOS, overall
survival
46
Gefitinib first-line in mutant EGFR
47
Acquired EGFR mutations confer resistance to
gefitinib, but not all EGFR inhibitors
48
Summary of EGFR Inhibitors Tested Against
EGFRL858R/T790MCompound IC50, nMCI-1033 23EKB-
569 33HKI-272 51SU-11464 450ZD6474 1900GW57
2016 3500Gefitinib 6600PKI-166 7700Erlotinib
10000
49
PF-00299804
50
PF-00299804, found to have activity in Exon 20
mutations (i.e. T790M)
51
PF-00299804in vitro Activity against EGFR, HER2
and KRASmut NSCLC Cell Lines (IC50,
uM).Gefitinib PD00299804A549 gt10 gt10 WT H441
gt10 4 WT Calu-3 1.4 .0063 WT H1819 .42
.0029 WT H1781 gt10 .28 WT GCC827 ,008 .002
Deletions CC4006 .050 .004 Deletions PC-9 .02
3 .002 Deletions H3255 .075 .007 L858R H1975
gt10 .44 T790M
52
Trial Design and Dosing Regimen
MulticenterNon-randomizedOpen
label PF-00299804 45 mg once daily
self-administered orally on an empty stomach
without planned breaks (i.e. continuously)Treatme
nt cycle 21 days
53
Maximum percentage change in target lesions per
RECIST in 41 patients with both a baseline and at
least one on-study measurement (March 31, 2009)
P. Janne.G.Giaccone, ASCO 2009
54
Treatment-related adverse events occurring in
15 of patients in the overall study population
P. Janne.G.Giaccone, ASCO 2009
55
PF-00299804 skin toxicities
56
Case Presentation 52 y/o AA male Never
smokerDiagnosed with NSCLC adenocarcinomaStage
IV, multiple lesions in LLL and RULNo Past
Medical HistoryNo Family HistoryTreatment
carboplatin/paclitaxel/bevacizumab8 cycles,
initial Partial Response (PR) then Progressive
Disease (PD)erlotinib 150 mg PO daily, (6 weeks)
PDReferred for evaluation at NCI
57
Treatment Course Screened for PF-00299804
trial KRAS wild type (wt)EGFR wtEnrolled
on trial PF-00299804 for patients who have failed
EGFR TKIsStarted on PF-0029980445 mg PO daily
58
Pretreatment and after 4 cycles of PF-00299804
59
Serum HER-2 levels at baseline and through 4
cycles of PF-00299804 therapy
60
Stain Tumor for Her2/Neu

• HER2/Neu FISH

• PATHOLOGY

• IHC 2
• Her2/Neu Amplified
• Cells counted 20
• HER2 10.3
• CEP17 2.4
• HER2/CEP17 Ratio 4.3

61
Durable SD (62 weeks)
Patient J adenocarcinoma, female, never-smoker,
1 prior chemotherapy regimen, 6.5 months of prior
erlotinib completed 6 months previously
62
EGFR mutations
63
Therapeutic targeting of EGFR in NSCLC Not
all the mutations have the same phenotypical
consequences How to circumvent TKI resistance
associated to certain types of mutation?
64
YFP-tagged EGFR intracellular domain
YFP-tagged EGFR intracellular domain
EGFR
1
YFP EGFR-ICD
688
TK
TK
Regulatory
Regulatory
1210
1116
65
Setting up and characterizing the assay system
66
Testing exon 20 mutations
67
Testing exon 21 mutations
68
MET amplification leads to gefitinib resistance
in lung cancer through activated ERBB3 signaling
MET
Gefitinib resistant
Baseline
30
Engelman JA, et al. Science 20073161039-43.
69
Patient population

• 51 NSCLC patients treated with gefitinib were
  retrospectively analyzed.
• The expression of c-MetpY1003 was also analyzed
  in tumors of
• 71 NSCLC patients treated with radical surgery,
• 16 NSCLC patients treated with erlotinib in
  first-line,
• 11 NSCLC patients treated with EGFR TKIs out of
  trials.
• Overall frequency of c-MetpY1003 expression
  6 (9/149)

Zucali PA, et al. Ann Oncol 2008191605-12.
70
Met copy number and survival in resected NSCLC
(n435)

• gt 5 copies 11.1
• Amplification 4.1
• Multivariate analysis
• P.04

Cappuzzo F et al. JCO 27, 1667, 2009
71
Current trials with MET inhibitors in NSCLC
Major issue no patient selection
72
Hepatocyte Growth Factor/Scatter Factor and c-MET
receptor
s
S?
S?
C

Ig
Ig
Ig
Ig
n
P
Y
P
Y
73
A Role for c-Met in Cancer Clinical Evidence

• Hereditary human renal papillary carcinomas
  causally related to germline activating MET
  mutations
• Overexpression of HGF/c-Met, genomic
  amplification and somatic mutations of MET seen
  in many cancer types
• Examples MET genomic amplification in gastric
  cancer and gefitinib-resistant NSCLC
• Poor prognostic marker in a number of
  malignancies, including gastric cancer, NSCLC,
  SCCHN, glioma and others
• 10-15 of adenocarcinoma and small cell carcinoma
  of the lung have a somatic mutation in the
  semaphorin or the juxtamembrane domain (not the
  TK domain)

74
PHA665752, a small molecule inhibitor of c-Met
inhibits growth in lung cancer xenografts
Puri et al Cancer Re. 67, 3529, 2007
75
Inhibitors of c-Met signaling - SPECIFIC
Genentech OA-5D5 c-Met receptor
AbAmgen AMG-102 HGF ligand Ab
Schering AV-299 HGF ligand AbNovartis
BJF475 c-Met receptor AbArqule ARQ197 non-ATPJ
ohnson Johnson JNJ-388 ATP SGX SGX-523
ATPPfizer X ATP
76
Inhibitors of c-Met signaling
NONSPECIFICPfizer PF-2341066 Ron, Axl, Alk,
Tie-2Exelixis XL-880 VEGFR, PDGFR, c-kit,
Flt3, Tie-2Exelixis XL-184
VEGFRAngion ANG-797 Ron, Tie-2MethylGene MGCD26
5 Ron, Tie-2, VEGFRBMS BMS-777607 Ron,
AxlBMS BMS-796302 Ron, Axl, VEGFR2, Flt3,
Tyro3, MerMerck Compound 1 FGFR,
Flt3SuperGen MP-470 PDGFR, c-Kit

77
Causes of EGFR resistance

• Resistant EGFR mutations
• Met amplification
• Her2 mutations
• Others
• K-Ras mutations
• Other receptor kinases (e.g. IGF1R)
• EMT

78
Patient selection for EGFR TKIs

• Positive selection
• Patient characteristics
• never-smoking, female, adenocarcinoma, East Asian
• EGFR mutations
• EGFR FISH
• Negative selection
• KRAS mutations
• Resistant EGFR mutations (e.g. T790M)
• C-Met amplification

79
Strategies for EGFR resistance

• Second generation EGFR inhibitors
• Met inhibitors
• Hsp90 inhibitors

80
Clinical Activity of the Oral ALK and MET
Inhibitor PF-02341066 in Non-Small Cell Lung
Cancer (NSCLC) with EML4-ALK Translocations

• Shaw AT1, Costa DB2, Iafrate AJ1, Dezube BJ2,
  Shapiro GI3, Bang YJ4, Janne PA3, Lynch TJ1, Maki
  RG5, Camidge DR6, Solomon B7, Kwak EL1, Tan W8,
  Chen I8, Christensen J8, Wilner K8, Clark JW1,
  Salgia R9

81
PF-02341066

• Potent selective ATP competitive oral inhibitor
  of MET and ALK kinases and their oncogenic
  variants

Cytoplasmic Fusion Variants of ALK
MET/HGFR
ALK
b a
SEMA
Extracellular
TM
TM
TM
TM
Intracellular
P
P
P
P
Kinase
Y
Y
Y
Y
P
P
P
P
Y
Y
Y
Y
NPM-ALK
EML4-ALK
P
P
Y
Y
P
P
Y
Y
P
P
Y
Y
P
P
Y
Y
P
P
P
P
Y
Y
Y
Y
P
P
P
P
Y
Y
Y
Y
82
EML4-ALK Translocations in NSCLC
EML4-ALK frequency 4 (64/1709)
Primarily lung adenocarcinoma
Soda et al., Nature 448 561-566, 2007
83
Break-Apart FISH Assay for ALK Fusion Genes
84
Study Status NSCLC ALK Patients

• 38 Patients Dosed Data Collection Ongoing
• 29 Patients Evaluable for Response

85
Clinical and Demographic Features of NSCLC
Patients with ALK Fusion
86
Tumor Responses to PF-02341066 for Evaluable
NSCLC ALK Patients
Two patients had clinical progression and
discontinued without radiographic confirmation.
87
48 yo Female Never Smoker with Stage IV NSCLC
Positive for EML4-ALK
88
43 yo Male Never Smoker with Stage IV NSCLC
Positive for EML4-ALK
89
Clinical Activity of PF-02341066 in NSCLC
Patients with ALK Translocations

• Overall Response Rate (ORR) 59 (17/29 pts)
• Disease Control Rate (PRSD) 83 (24/29 pts)
• Median Duration of Treatment 18 weeks
• 5 patients had progression at first evaluation

95 CI (39, 76)
95 CI (64, 94)
90
PF-02341066 Future Directions

• For the Current Phase I Clinical Trial
• Continue to enroll ALK patients in the enriched
  cohort to obtain mature PFS and OS data
• Conduct genetic characterization of ALK fusion
  partners and ALK variants in responders and
  non-responders
• Continue efforts to identify patients with MET
  amplification or mutations
• Clinical Development of PF-02341066 in NSCLC
• Conduct a randomized phase 3 registration
  clinical trial of PF-02341066 versus chemotherapy
  (pemetrexed/docetaxel) in NSCLC patients
  harboring ALK translocations after failure of 1st
  line therapy (A8081007)

91
Oncogene addiction may explain clinical
responses to many kinase-targeted therapeutics

NSCLC EGFR gefitinib/erlotinib
CML BCR-ABL imatinib/dasatanibGIST c-Kit/PDGF
R imatinib/sunitinibCMML PDGFR-b imatinibBrea
st cancer Her2 trastuzumab/lapatanibGastric
cancer c-MET PHA-665752Gastric cancer
FGFR2 AZD2171Melanoma B-Raf AZ628/CI-1040

92
Primary activating mutations. 10-15 of NSCLC
patients in the West about 20,000 cases/year.
30-35 of NSCLC patient in Asia about 100,000
cases/year
93
Significantly mutated genes in adenocarcinoma of
the lung
Ding et al. Nature 455, 1069, 2008
94
Significantly mutated pathways in adenocarcinoma
of the lung
Ding et al. Nature 455, 1069, 2008
95
Biomarker discovery and molecular
characterizationstudies in clinical specimens
96
Prospective Molecular ProfilingBackground

• The treatment of lung cancer and thymic
  malignancies is based on histopathology and
  clinical stage.
• Existing classifications and staging systems have
  reached their limit in providing information that
  may influence management or improve outcome.
• Molecular characterization of tumors has the
  potential ability to classify more accurately
  than histology and indicate specific treatments
  for subsets of patients.

97
Prospective Molecular ProfilingGeneral Outline

• Prospective collection of fresh frozen and PEFF
  tumor and circulating tumor material from
  patients with lung cancer and thymic malignancies
  coming to the clinical center.
• Extensive molecular profiling
• Limited profile for treatment decision
• Exploratory investigations
• Allow treatment based on molecular profiling
• Set up mechanism for access to experimental drugs
  for single patient studies

98
Subgroups of specific interestLung cancer in
never-smokersLung cancer in womenLung cancer in
younger than 40Familial forms of lung
cancerRare histological forms of lung cancer
Lung cancer in HIV patientsThymomasThymic
carcinoma
99
TKIs in NSCLC

• Strong evidence that specific genetic alterations
  (mutations and fusion genes) may be targeted by
  TKIs
• Patient selection is key
• Molecular profiling is promising
• Further understanding of genetic background will
  help develop better therapies