Targeted Therapy in Oncology
SUNY Upstate Medical University
Targeted Therapy in Oncology
The goal in the approach to therapy for
patients with malignant disease is to
understand the underlying biology,
drivers of the malignant state
 Through understanding the drivers of the
malignant state, the hope is that we can
individualize therapy

SUNY Upstate Medical University
Targeted Therapy in Oncology
Outline
Review some important examples of how
targeted therapy has impacted the care of
patients
 Use Lung Cancer as a model for the
change in our approach to cancer
therapy

SUNY Upstate Medical University
Prognostic vs Predictive
Factors
Prognostic markers are patient or tumor
factors that predict patient survival
independent of treatment
 Predictive markers are factors that may
influence and predict the outcome of
treatment in terms of either response or
survival benefit

SUNY Upstate Medical University
Prognostic Factors

Acute Leukemia
– Cytogenetics

Head and Neck Cancer
– Human Papilloma Virus

Breast Cancer
– Her2 expression

Chronic Lymphocytic Leukemia
– P53 mutations
SUNY Upstate Medical University
Examples of Targeted Therapy
in Oncology




Breast Cancer
– Herceptin for Her2 + patients
Colon Cancer
– K-ras wild type patients benefit from
cetuximab
Chronic Myelogenous Leukemia
– Imatinib, dasatinib and nilotinib target
BRC-ABL
B-Cell Lymphomas
– Rituximab SUNY Upstate Medical University
Chronic Myelogenous Leukemia
CML
Myeloproliferative disorder associated
with the Philadelphia chromosome
t(9q34:22q11)
 Results in the BCR-ABL fusion gene and
protein
 A constitutively active tyrosine kinase
which causes deregulation

SUNY Upstate Medical University
CML

IRIS trial established imatinib as the
standard of care
– Imatinib
– Interferon/cytarabine
Complete hematologic response 97%
 Complete cytogenetic response 87%
 Major molecular response 39%
 5 year survival >90%

SUNY Upstate Medical University
SUNY Upstate Medical University
Background Information –
HER2/neu Over-Expression
1.
HER2 is a human epidermal growth factor receptor encoded
by the HER2 gene
also referred to as ErbB2
2.
HER2 is amplified in approximately 20% to 25% of metastatic
breast cancers
3.
Adverse prognostic factor
4.
Confers aggressive form of disease with significantly shortened
disease-free survival and overall survival
SUNY Upstate Medical University
The HER-2 Pathway
Lin, N. U. et al. Clin Cancer Res 2007;13:1648-1655
Copyright ©2007 American Association for Cancer Research
SUNY Upstate Medical University
SUNY Upstate Medical University
Schema
ASCO Presentation 2005 – E. Romond, M.D.
SUNY Upstate Medical University
Disease Free Survival
ASCO Presentation
2005 – E. Romond, M.D.
SUNY Upstate Medical University
Overall Survival
ASCO Presentation 2005 – E. Romond, M.D.
SUNY Upstate Medical University
Conclusions:
 Addition
of HERCEPTIN to
chemotherapy in adjuvant treatment
of HER2 (+) pts reduces FIRST
BREAST CANCER EVENT by 52%
at 3 years
SUNY Upstate Medical University
Advances in the Treatment of
Colon Cancer
SUNY Upstate Medical University
Approach to Lung Cancer Goals
Review recent trends in lung cancer
epidemiology, incidence and mortality
 Review the importance of histology and
molecular profiling in directing therapy
 Review current clinical trials available at
SUNY Upstate Medical University

SUNY Upstate Medical University
CANCER INCIDENCE 2012

PROSTATE
 BREAST
242,000
229,000
LUNG
226,000

COLORECTAL
143,000
SUNY Upstate Medical University
CANCER MORTALITY 2012
LUNG
160,000
COLORECTAL
 BREAST
 PANCREAS

52,000
40,000
37,000
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
Trends for death rates from
lung cancer by gender
Males
Females
1992-2005
2005-2008
-1.9%/year
-2.8%/year
1992-2002
2002-2008
+0.6%/year
-0.9%/year
SUNY Upstate Medical University
Changing epidemiology of SCLC
Govindan et al. 2006;24:4539.
SUNY Upstate Medical University
Histopathologic Classification
of Lung Cancer

Non-small cell lung cancer
– Adenocarcinoma (50%)
– Squamous cell carcinoma (25%)
– Large cell anaplastic carcinoma (10%)
Small cell lung cancer (13%)
 Other (5%)

– Adenosquamous, carcinoid, misc
SUNY Upstate Medical University
Trends in Lung Cancer
More adenocarcinoma
 Less small cell lung cancer
 Death rates falling for men since 1992
 Death rates falling for women since
2005

SUNY Upstate Medical University
SUNY Upstate Medical University
Approach to Lung Cancer Goals
Review recent trends in lung cancer
epidemiology, incidence and mortality
 Review the importance of histology and
molecular profiling in directing therapy
 Review current clinical trials available at
SUNY Upstate Medical University

SUNY Upstate Medical University
Personalized Therapy for
Lung Cancer – Old Paradigm
Small cell versus non-small cell lung
cancer
 Stage
 Performance Status
 Pretreatment weight loss

SUNY Upstate Medical University
Personalized Therapy for
Lung Cancer – New Paradigm
Small cell versus non-small cell lung
cancer, stage, performance status
 Histological Subtype (adenocarcinoma
versus squamous cell carcinoma)
 Smoking versus non-smoking related
 Molecular markers (EGFR mutation and
ALK translocation)

SUNY Upstate Medical University
Chemotherapy based on
Histology
For non-squamous cell cancer, consider
use of bevacizumab
 For Adenocarcinoma, consider
pemetrexed in front-line settting
 For Squamous cell cancer, consider
gemcitabine or another agent

SUNY Upstate Medical University
Bevacizumab in Advanced NSCLC: ECOG
4599 Trial
Stage IIIB w/ effusion,
Stage IV, or recurrent
NSCLC
Non-squamous cell
No previous
chemotherapy
No hemoptysis
No CNS mets
Paclitaxel 200 mg/m2, day 1
Carboplatin AUC 6, day 1
Q 3 weeks*
vs
No crossover to
bevacizumab
allowed
N = 878
Paclitaxel 200 mg/m2, day 1
Carboplatin AUC 6, day 1
Bevacizumab 15 mg/kg, day 1
Q 3 weeks†
Stratified by:
*Maximum of 6 courses
†Maximum of 6 cycles of chemotherapy; bevacizumab until
• RT vs no RT
progression
• Stage IIIB or IV vs recurrent
• Wt loss < 5% vs ≥ 5%
• Measurable vs non-measurable disease
Oral Presentation by Alan B. Sandler at the 42nd Annual Meeting of the American Society of Clinical Oncology. Clinical Science Session:
Angiogenesis Inhibitors in Lung Cancer. June 4, 2006. SUNY
Atlanta,Upstate
Georgia.Medical
Submitted
to N Engl J Med.
University
Bevacizumab with Chemotherapy in
NSCLC: Overall Survival
1.0
BPC
(305
events/ 417
Median survival: 12.3 vs
10.3
months;
P cases)
= 0.003
PC (344 events/ 433 cases)
— PCB (305 events / 417 cases)
--- PC (344 events / 433 cases)
Probability
Probability of Survival
0.8
P = 0.003
0.6
Medians:
Medians:10.3,
10.3,12.3
12.3months
0.4
0.2
0.0
0
6
12
18
24
30
36
42
Months
Months
Oral Presentation by Alan B. Sandler at the
Annual Meeting of the American
Society of Clinical Oncology. Clinical Science Session:
SUNY
Upstate
Medical
University
Angiogenesis Inhibitors in Lung Cancer. June 4, 2006. Atlanta, Georgia. Submitted
to N Engl J Med.
42nd
Bevacizumab Patient Selection

Patients with non-squamous histology

Stage IIIB, IV, or recurrent NSCLC

Exclude patients if:
– Major hemoptysis
– Significant cardiovascular disease
– Uncontrolled hypertension
– CNS metastasis
– Require therapeutic anticoagulation
SUNY Upstate Medical University
SUNY Upstate Medical University
Chemotherapy based on
Histology
For non-squamous cell cancer, consider
use of bevacizumab
 For Adenocarcinoma, consider
pemetrexed in front-line setting and
maintenance
 For Squamous cell cancer, consider
gemcitabine or another agent

SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
Lancet 2009;374:1432-1440/
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
Chemotherapy based on
Histology
For non-squamous cell cancer, consider
use of bevacizumab
 For Adenocarcinoma, consider
pemetrexed in front-line setting and
maintenance
 For Squamous cell cancer, consider
gemcitabine or another agent

SUNY Upstate Medical University
SUNY Upstate Medical University
Clinical Factors Associated with
EGFR mutations
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
Case - JR








78 YOF presented with dyspnea; CXR and CT scan
showed a large right sided pleural effusion in 12/07
Never smoked, husband a non-smoker
Thoracentesis performed 1/8/08
Cytology positive for adenocarcinoma (TTF-1 +,
mammoglobin -, c/w lung primary)
PET scan showed mass right infrahilar region and
multiple bilateral pulmonary nodules
Stage IV, T4/N0/M1
Pleurx catheter placed 1/24/08 with relief of her SOB
Excellent performance status (1) and no weight loss
SUNY Upstate Medical University
Case - JR



Cell block of the pleural fluid tested for EGFR
Results: Positive for high EGFR copy number
(FISH +)
Offered participation in CALGB 30406 and
she agreed to participate and signed consent
form
– Erlotinib
– Chemotherapy + Erlotinib
SUNY Upstate Medical University
Phase II randomized study of erlotinib +/- carboplatin/paclitaxel in
pts with previously untreated adenocarcinoma of the lung who
never smoked or were former light smokers.
CALGB 30406
SUNY Upstate Medical University
Case - KE






68 YOF developed cough, CT done 5/07 showed
bilateral ground-glass opacities
Bronchoscopy done 6/07 negative for infection or
malignancy
Repeat CT chest done 8/07 unchanged
CT guided core biopsy done 8/07 and pathology
showed well-differentiated adenocarcinoma
(reviewed by Dr. Katzenstein)
Smoked 5-6 cigarettes per day for 30 years, quit 1990
– estimated about 10 pack years
Excellent performance status (0) and no weight loss
SUNY Upstate Medical University
Case - KE

Offered participation in CALGB 30406 and
she agreed to participate and signed consent
form
– Erlotinib
– Chemotherapy + Erlotinib


Randomized to erlotinib alone
Started on erlotinib in September 2007
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
Crizotinib Selectivity Profile
Upstate 102
kinase
Kinase
Met(h)
Tie2(h)
TrkA(h)
ALK(h)
TrkB(h)
Abl(T315I)(h)
Yes(h)
Lck(h)
Rse(h) [SKY]
Axl(h)
Fes(h)
Lyn(h)
Arg(m)
Ros(h)
CDK2/cyclinE(h)
Fms(h)
EphB4(h)
Bmx(h)
EphB2(h)
Fgr(h)
Fyn(h)
IR(h)
CDK7/cyclinH/MAT1(h)
cSRC(h)
IGF-1R(h)
Aurora-A(h)
Syk(h)
FGFR3(h)
PKCµ(h)
BTK(h)
CDK1/cyclinB(h)
p70S6K(h)
PRK2(h)
PAR-1Bα(h)
PKBß(h)
Ret(h)
GSK3ß(h)
Flt3(h)
MAPK1(h)
ZAP-70(h)
Abl(h)
c-RAF(h)
PKD2(h)
ROCK-II(h)
Rsk3(h)
GSK3α(h)
CDK5/p35(h)
PDGFRα(h)
Rsk1(h)
SGK(h)
CHK1(h)
ErbB4(h)
Rsk2(h)
JNK1α1(h)
PKBα(h)
Blk(m)
CDK3/cyclinE(h)
PKCι(h)
PKCθ(h)
CDK2/cyclinA(h)
PAK2(h)
PKCßI(h)
Pim-1(h)
PKCη(h)
SAPK4(h)
CaMKII(r)
MKK7ß(h)
CaMKIV(h)
CHK2(h)
CK2(h)
JNK2α2(h)
MKK6(h)
CK1δ(h)
PKCα(h)
MAPK2(h)
MEK1(h)
PKCδ(h)
PKCε(h)
Plk3(h)
PKCßII(h)
MSK1(h)
PDGFRß(h)
PKCζ(h)
SAPK3(h)
MAPKAP-K2(h)
PKA(h)
AMPK(r)
CDK6/cyclinD3(h)
CSK(h)
SAPK2a(h)
JNK3(h)
PKBγ(h)
IKKα(h)
NEK2(h)
% Inhibition
94
103
102
100
100
98
96
95
94
93
93
93
91
90
87
84
80
79
77
73
68
64
58
58
56
54
52
50
50
35
25
24
22
21
21
21
18
17
17
17
16
16
15
14
14
11
10
10
7
6
5
5
5
4
4
3
3
3
3
2
2
2
1
1
1
0
0
-1
-1
-1
-1
-1
-2
-2
-3
-3
-3
-3
-3
-5
-6
-6
-6
-6
-7
-7
-9
-9
-9
-9
-10
-10
-11
-11
Cellular selectivity on 10 of 13
relevant hits
13 kinase “hits”
<100X selective
for
c-MET
IC50
(nM)
mean*
Selectivit
y ratio
c-MET
8
–
ALK
20
2X
298
34X
189
22X
294
34X
322
37X
Tie-2
448
52X
Trk A
580
67X
Trk B
399
46X
Abl
1,159
166X
IRK
2,887
334X
Kinase
RON
Axl
SUNY Upstate Medical University
Lck
2,741
283X
Crizotinib
(PF-02341066)
Selectivity findings
• Crizotinib – ALK and
c-MET inhibition at clinically
relevant dose levels
• Crizotinib – low probability of
pharmacologically relevant
inhibition of any other kinase
at clinically relevant dose
levels
Pfizer Inc. Data on file
Summary

Treatment with crizotinib resulted in impressive clinical
activity in patients with ALK-positive advanced NSCLC
– ORR: 57%
– DCR at 8 weeks: 87%
– PFS probability at 6 months: 72%

Crizotinib was well tolerated
– The most frequent adverse events were mild and
moderate gastrointestinal events and mild visual
disturbances
SUNY Upstate Medical University
Tumor Responses to Crizotinib for
Patients with ALK-positive NSCLC
Maximum change in tumor size (%)
60
Progressive disease
Stable disease
40
Confirmed partial response
Confirmed complete response
20
0
–20
–30%
–40
–60
–80
–100
*
*Partial response patients with 100% change have
non-target
disease
present
SUNY
Upstate
Medical
University
Potential Oncogenic “Drivers” in
Non-small Cell Lung Cancer
(NSCLC)
Adenocarcinoma
K-ras
EGFR
B-raf
Her2
Other
PIK3CA
ALK
MET
Other
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth
factor receptor; Her2 = human epidermal growth factor receptor 2;
PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide
SUNY Upstate Medical University
ALK (~5%)
Massachusetts General Hospital, data on file.
[AT Shaw, personal communication]
Crizotinib in Lung Cancer
ALK + Patients
SUNY Upstate Medical University
FISH Assay for ALK Rearrangement*
p25.2
p25.2
p24.3
p24.1
p23.2
p22.3
p22.1
p16.3
ALK 29.3
p24.3
EML4 42.3
p16.3
Telomere
2p23 region
p24.1
p23.2
p22.3
p22.1
p16.1
p16.1
p14
p13.2
p14
p13.2
p12
p12
q12.1
q12.3
q12.1
q12.3
q14.1
q14.1
q14.3
q21.2
q14.3
q21.2
q22.1
q22.2
q23.2
q22.1
q22.2
q23.2
q24.1
q24.1
q24.3
q24.3
q31.3
q31.3
q32.1
q32.1
q32.3
q32.3
q33.2
q33.2
q34
q34
q36.1
q36.3
q37.2
q36.1
q36.3
q37.2
Centromere
t(2;5) ALK gene
breakpoint region
3’
~250 kb
5’
~300 kb
Break-apart FISH assay
for ALK-fusion genes1
Non-split signal
Split signal
ALK break-apart FISH assay
[Courtesy John Iafrate, Massachusetts General Hospital]
*Assay is positive if rearrangements can be detected in ≥15% of cells
FISH = fluorescence in situ hybridization
SUNY Upstate Medical University
1Shaw
AT et al. J Clin Oncol
2009;27:4247–4253
Case - MD






58 YOF presented to multidisciplinary thoracic clinic
in 12/10 with persistent cough, CXR showed a right
hilar mass
CT of chest showed a right hilar mass but also liver
and bone metastases
ROS 5 lb weight loss and back pain, PS 1
Never smoked, but had second hand smoke
exposure (father and ex-husband)
CT guided biopsy of the liver showed poorly
differentiated adenocarcinoma c/w lung primary (TTF1 and CK7 +), EGFR mutation negative
Stage IV, T2/N2/M1
SUNY Upstate Medical University
Case - MD




Treated with carboplatin and pemetrexed for
4 cycles through April 2011
In May 2011 developed worsening hip pain
and she underwent radiation to the hip and
LS spine
In June 2011, On restaging w/u had solitary
brain met and received gamma knife
radiosurgery
In January 2011, she agreed to participation
in phase II study of crizotinib and was
screened for ALK translocation and was +,
started therapy in July 2011
SUNY Upstate Medical University
Case - EH







51 YOM seen ROC 2/11; In 2006, while living in
Saudi Arabia, he developed a pathological fracture of
left femur
Underwent a rod stabilization procedure followed by
RT
Biopsy showed adenocarcinoma c/w lung primary
CT of chest showed a mass in the left lower lobe
He was treated with 6 cycles of carboplatin and
gemcitibine with stable disease
Moved to US and in August 2010 developed a
seizure and was found to have multiple brain lesions
and underwent WBRT
Repeat lung biopsy showed adenocarcinoma of the
lung and he was found to be EGFR and K-ras wildtype
SUNY Upstate Medical University
Case - EH



In August 2011, he had evidence of progressive
disease with enlargement of LLL mass and pleural
effusion
Started on carboplatin/pemetrexed in August,
received 4 cycles of therapy with stable disease and
then received maintenance pemetrexed through
January 2012
We attempted to test his tumor for ALK but there was
insufficient tissue so we did a repeat lung biopsy on
1/9/2012
SUNY Upstate Medical University
SUNY Upstate Medical University
SUNY Upstate Medical University
[TITLE]
SUNY Upstate Medical University
[TITLE]
SUNY Upstate Medical University
[TITLE]
SUNY Upstate Medical University
SUNY Upstate Medical University
Standard Chemotherapy
Regimens








A platinum compound (cisplatin or carboplatin) +
– paclitaxel
- docetaxel
– vinorelbine
- pemetrexed (consider for adeno)
– gemcitabine
4-6 cycles of chemotherapy
For non-squamous consider carbo/paclitaxel + bevacizumab
For EGFR mutated NSCLC, consider front-line erlotinib
For ALK rearranged NSCLC, consider front-line crizotinib
Can consider early maintenance with pemetrexed
(adenocarcinoma) or erlotinib
Second-line therapy can be considered-docetaxel, pemetrexed,
erlotinib
Third-line therapy: erlotinib or single agent chemotherapy
SUNY Upstate Medical University
Approach to Lung Cancer Goals
Review recent trends in lung cancer
epidemiology, incidence and mortality
 Review the importance of histology and
molecular profiling in directing therapy
 Review current clinical trials available at
SUNY Upstate Medical University

SUNY Upstate Medical University
Current Clinical Trials for
NSCLC – Stage IV/Recurrent


Stage IV
– SWOG S0819: A Randomized, Phase III Study Comparing
Carboplatin/Paclitaxel or Carboplatin/Paclitaxel/Bevacizumab
with or without Concurrent Cetuximab in Patients with
Advanced Non-Small Cell Lung Cancer (NSCLC)
– CALGB 30801-A Randomized Phase III Double Blind Trial
Evaluating Selective COX-2 Inhibition in COX-2 Expressing
Advanced Non-Small Cell Lung Cancer
– CALGB 30607: maintenance sunitinib/placebo p 4 cycles of CT
– Pfizer trial of crizotinib for ALK + patients
Second-Line
– Erlotinib +/- MetMab for Met+ NSCLC (Genentech)
– Axitinib vs erlotinib for squamous cell carcinoma (Boerhinger
Ingelheim)
SUNY Upstate Medical University
Current Clinical Trials for NSCLC
– Stage IV/Recurrent


Stage IV
– CALGB 30801-A Randomized Phase III
Double Blind Trial Evaluating Selective
COX-2 Inhibition in COX-2 Expressing
Advanced Non-Small Cell Lung Cancer
– Pfizer: For ALK + NSCLC, Phase III study
of crizotinib vs pemetrexed/platin
Second-Line
– Genentech: Phase III study of tarceva +/MetMAB for Met + NSCLC
SUNY Upstate Medical University
Current Clinical Trials for
NSCLC – Stage I - III
Stage IB-IIIA – E1505: CT +/bevacizumab
 Stage IIIA/IIIB unresectable
– CALGB 31102: Hypofractionated RT
+ carboplatin/paclitaxel

SUNY Upstate Medical University
CALGB 30801
SUNY Upstate Medical University
Study Design
Key entry criteria; N=334
●
ALK-positive locally
adv/metastatic non-squamous
NSCLC
●
No prior treatment for advanced
disease
R
A
N
D
O
M
I
Z
E
N=167
Crizotinib 250 mg BID
continuous dosing schedule
Crossover on PD
N=167
Pemetrexed/ cisplatin or
pemetrexed/ carboplatin
(Day 1/21)
Trial design
Endpoints
Stratification
World-wide
Multicenter
Randomized
Open-label
Focused screening
Primary: PFS*
Secondary: OS, ORR*, DR, safety, QoL,
Lung cancer-specific symptoms
ECOG PS (0/1 vs 2)
Ethnicity (Asian vs non-Asian)
Brain metastases
*Based on RECIST v 1.1 and confirmed by independent radiology review
www.clinicaltrials.gov (NCT01154140)
SUNY Upstate Medical University
[TITLE]
SUNY Upstate Medical University
[TITLE]
SUNY Upstate Medical University
Tissue is the
Issue
SUNY Upstate Medical University
Summary
Decline in incidence and death rates
from lung cancer
 Decrease in incidence of small cell lung
cancer and increase in adenocarcinoma
 New paradigm for lung cancer

– Smoking versus non-smoking cancer
– Importance of histological subtype
» To choose therapy based on toxicity and
efficacy considerations
SUNY Upstate Medical University
Summary

Importance of molecular markers,
particularly for adenocarcinomas
– EGFR mutation positive patients should
receive erlotinib first line
– Test for ALK translocations, ALK positive
patients should receive crizotinib
Clinical trials should be enriched for the
driver mutation or target
 Future targets - ?Braf, K-ras, met,
SUNY Upstate Medical University
arrays
