Transcript VII ANNUAL CONFERENCE OOTR

PNEUMO TRIESTE 2012
THE PERSONALIZED THERAPY OF NSCLC
Giampietro Gasparini
Oncology - San Filippo Neri Hospital Rome, Italy
Trieste, 27 March 2012
www.professorgasparini.com
CANCER THERAPY ERAS
• Locoregional treatments
yrs ’40 -’50
• Chemotherapeutic- based
systemic treatments
yrs ’60 -’80
• Targeted treatments
current yrs
• Genomic-based treatments
the era is beginning
EVOLUTION OF SYSTEMIC THERAPY IN
ADVANCED NSCLC
Docetaxel
2003
First-line
Maintenance
Third-line
Paclitaxel
Gemcitabine
1998
Not approved
Erlotinib
2005
Pemetrexed
2004
Docetaxel
2000
Second-line
Gefitinib
2004
Bevacizumab
2007
Pemetrexed
2008
Vinorelbine
1997
Median
overall
survival,
months
Cisplatin
1978
1970
12+
Carboplatin
1989
Pemetrexed
2009
~8–10
~6
~2–4
1980
Gefitinib
2009
1990
2000
Erlotinib
2010
2010
Bevacizumab + PC
Best supportive care
Single-agent platinum
Doublets
Histology-direct therapy
European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp
IMPACT OF SYSTEMIC THERAPY ON OS
IN STAGE IV NSCLC OVER 10 YEARS
• PROPORTION OF PTS TREATED
at least 1 line
2 - 3 lines
1988
2008
20%
7%
42%
60%
8%
0.3%
37%
15%
4,6
5,1
• SURVIVAL RATES
1 yr survival
2 yrs survival
• MEDIAN OS (mos)
data from 987 pts followed at the Princess Margaret Hospital & Sannybrook Odette Cancer
Ctr – Toronto. The Oncologist, 16:1307, 2011
NSCLC
Different histotypes: Different treatments
Squamous cell
Non Squamous cell
( NO Bevacizumab)
(Pemetrexed)
CHARACTERISTICS OF THE NSCLC TUMORS
ACCORDING TO THE VASCULAR
PATTERNS
(a vascular pattern)
ALVEOLAR PATTERN
The only vessels evident in this pattern arise from the alveolar
septa
NSCLC MAIN FEATURES ACCORDING TO THE
VASCULAR PATTERNS
ANGIOGENESIS PATTERNS
BASAL
PAPILLARY
DIFFUSE
ALVEOLAR
Reproduced
Reproduced
Absent
Absent
Destroyed
Destroyed
Destroyed
Preserved
Present
Present
Present
Absent
Present
Present
Present
Absent
Lower incidence
Higher incidence
Expected incidence
Expected incidence
Squamous
Adenocarcinoma
None
None
None
Well differentiated
Poorly differentiated
Poorly differentiated
BCL-2, laminin
receptor
-
-
BCL-2
-
BCL-2, p53,
EGFR
BCL-2, laminin
receptor
-
Pezzella, Gasparini et al Am J Pathol 151: 1417, 1997
THE TUMOR OF EACH SINGLE PATIENT
IS UNIQUE BECAUSE THE GENOME OF
HIS/HER CANCER IS UNIQUE
THE SWITCH FROM HISTOLOGIC TYPE TO
MOLECULAR CLINICAL ONCOLOGY:
THERAPEUTIC IMPLICATIONS
OLD PARADIGM
DISEASEDRIVEN
THERAPY
HISTOLOGY
DRIVEN
THERAPY
NEW PARADIGM
SUBCLASSIFICATION BY
TARGET IDENTIFICATION
HISTOLOGY
DRIVEN THERAPY
PRESUMED
PRESUMED HOMOGENEOUS
HOMOGENEOUS
GROUP
GROUP OF
OF PTS
PTS
UNDERSTANDING THE
PRESUMED
HOMOGENEOUS
MOLECULAR
TAXONOMY:
GROUP OFDRIVEN
PTS
MOLECULAR
THERAPY
SAME THERAPEUTIC REGIMEN
SAME THERAPEUTIC REGIMEN
SAME THERAPEUTIC REGIMEN
PERSONALIZED THERAPY
THE PARADIGM OF PERSONALIZED CANCER CARE:
WHAT DOES IT MEAN?
THE ASPIRATION TO BASE A TREATMENT ON THE UNIQUE
BIOLOGICAL FEATURES OF A PATIENT’S DISEASE THROUGH THE
IDENTIFICATION OF VALIDATED TOOLS OF
RESPONSE/RESISTANCE TO THERAPY
AIMS
 TO IMPROVE DRUG EFFICACY
 TO AVOID INAPPROPRIATE DRUG
RESISTANT TUMORS)
 TO MAXIMIZE QUALITY OF LIFE
 TO SPARE UNNECESSARY COSTS
EXPOSURE
(PRIMARY
THERAPEUTIC TARGETING OF THE HALLMARKS OF
CANCER
Hanahan  Weinberg, Cell, 144:646, 2011
MULTISTEP PATHOGENESIS OF
INVASIVE LUNG ADENOCARCINOMA
Invasive
ADC
Poor
Prognosis
ADC
Cancer J Clinicians,61:91,2011
DRIVER MUTATIONS IN LUNG ADENOCARCINOMA
15%
8%
Infrequent
NF1
EGFR
KRAS
NTRK
10%
25%
STK11
17%
PIK3CA 4%
BRAF
HER-4 5%
ErbB2
EML4-ALK
3%
6%
Paik et Al,JCO 29: 2046. 2011
3%
PERSONALIZED THERAPY: EGFR NSCLC
IPASS TRIAL
Eligibility Criteria
•
≥ 18 years of age
•
Stage IIIB/IV NSCLC
•
ADC/Bronchoalveolar
•
Non/light smokers
•
No prior systemic Tx
•
Measurable disease by
RECIST
•
ECOG PS of 0 or 1
•
Adequate organ function
(N=1217)
R
A
N
D
O
M
I
Z
A
T
I
O
N
(n=607)
GEFITINIB
250 mg PO daily
Primary Endpoint : PFS
(n=589)
CARBOPLATIN/TAXOL
(6 cycles)
Secondary Endpoints : OS,
RR, QoL, Safety, EGFR
status
WJTOG0203 TRIAL
Eligibility Criteria
•
≥ 18 years of age
•
Stage IIIB/IV NSCLC
•
No prior systemic Tx
•
Measurable disease by
RECIST
•
ECOG PS of 0 or 1
•
Adequate organ function
RA
N
D
O
(N=604) M
I
Z
A
T
I
O
N
(n=301)
(n=302)
PLATINUMDOUBLETS
(6 cycles)
PLATINUMDOUBLETS
(3 cycles)
Takeda K, et al. J Clin Oncol; 28 (5):753-60, 2010
Primary Endpoint : OS
Secondary Endpoints :
PFS, RR, QoL, Safety
GEFITINIB
250 mg PO
daily
Mok TS, et al. N Engl J Med; 361 (10):947-57, 2009
IPASS TRIAL
WJTOG0203 TRIAL
Gefitinib
CBDCA/Taxol
CT only
ORR
43.0%
32.2%
ORR
M+
patients
71.2%
47.3%
WT
patients
1.1%
23.5%
18.6
17.3
34.2%
M+
patients
ND
ND
WT
patients
ND
ND
P:NS
OS
12.9
13.7
P:NS
P:NS
PFS M+
Gefitinib
29.3%
p < 0.001
OS
CT
9.5
6.3
P < 0.001
PFS
Takeda K, et al. J Clin Oncol; 28 (5):753-60, 2010
4.3
4.6
P < 0.001
Mok TS, et al. N Engl J Med; 361 (10):947-57, 2009
EGFR-TKIs AND EGFR MUTATION -DIRECTED
FRONT - LINE STUDIES
Study
Entry Criteria
HR for PFS
(EGFR mut +)
HR for OS
(EGFR mut +)
IPASS
Mok
NEJM 2009
Asiatic, never- & light –
smokers, adenocarcinoma
(EGFR mut + 59.7%)
0.48
(0.36-0.66)
0.91 *
(0.76-1.10)
*overall population
First – SIGNAL
Proc. IASLC
2009
Adenocarcinoma, Neversmokers
(EGFR mut + 44%)
0.61
(0.30-1.22)
0.82
(0.35-1.92)
NEJM 2010
Proc. ASCO 2011
EGFR Mutation + (all)
0.35
(0.25-0.50)
0.88
(0.634-1.241)
WJTOG3405
Lancet Onc. 2010
EGFR Mutation + (all)
0.48
(0.336-0.710)
EURTAC (EU)
EGFR Mutation + (all)
0.42
(0.27-0.64)
?
OPTIMAL (China)
EGFR Mutation + (all)
0.16
(0.10-0.26)
?
PROGRESS IN THE TREATMENT OF METASTATIC
LUNG CANCER
Pao W. et al. Nat. Rev. Cancer 2010;
10;760
THERAPEUTIC RESISTANCE TO KINASE INHIBITORS
• Gatekeeper mutations near to kinase active site
• Additional mutations in the target oncogene
• Gene amplification
• Upstream mutations
oncoproteins
activating
the
target
• Bypass mechanisms involving alterations that
dysregulate a cellular effector acting in parallel to
the drug target
Wagle et al, JCO;29:3085, 2011
FREQUENCIES OF INTRINSIC RESISTANCE TO EGFR-TKIS
RELATIVE TO SENSITIVITY/RESISTANCE IN NSCLC
DIAGNOSTIC FEATURES OF EML4-ALKPOSITIVE NSCLC
H&E
FISH
ALK HIC
•The frequency of EML4-ALK ranges from 1.5% - 6.7% (Asian) to 13% (White) to 33%
(never/light smokers without EGFR mutation)
•EML4-ALK pts are more likely to be men (23% vs 9%)
•EML4-ALK pts are significantly younger than EGFR or WT/WT pts
•EML4-ALK–positive tumors appear histologically distinct from EGFR mutant and WT/WT tumors
Shaw, AT, et al. J Clin Oncol; 27:4247-53 2009
PERSONALIZED THERAPY:
EMLA4-AKT NSCLC
NSCLC (Adenocarcinoma histology):
Suggested algorithm for molecular testing before treatment
with oral TKIs
(*) "Other" includes BRAF, MEK1, AKT1, PIK3CA…
Horn L, et al. J Clin Oncol, 27 (26):4232-5, 2009
BEVACIZUMAB IN NON SQUAMOUS NSCLC
KEY RESULTS
ECOG 4599
RR
PCB
PC
CGB (7.5)
CGB (15)
CG
35%
15%
34.1%
30.4%
20.1%
P value
PFS, months
HR / P value
OS, months
HR / P value
AVAIL
<.0001 (7.5)
.0023 (15)
<.001
6.2
4.5
6.7
10.3
0.79 (.003)
6.1
0.75 (.003) / 7.5
0.82 (.03) / 15
0.66 (<.001)
12.3
6.5
13.6
13.4
13.1
0.93 (ns) / 7.5
1.03 (ns) / 15
Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550.
Reck M, et al. J Clin Oncol. 2009;27(8):1227-1234.
SQUAMOUS CELL CARCINOMA OF THE LUNG
Gene
Event Type
Frequency
FGFR1
Amplification
20-25%
FGFR2
Mutation
5%
PIK3CA
Mutation
9%
PTEN
Mutation/Deletion
18%
CCND1
Amplification
8%
CDKN2A
Deletion/Mutation
45%
PDGFRA
Amplification/Mutation 9%
EGFR
Amplification
10%
MCL1
Amplification
10%
BRAF
Mutation
3%
DDR2
Mutation
4%
ERBB2
Amplification
2%
In 63% of lung SCCs
we can now identify a
possible therapeutic
target
Targets will need to
be validated
in pre-clinical models
FGFR1/2, PIK3CA and
DDR2
inhibitor trials are
planned or ongoing
Hammerman P. et al. Proc. IASLC
2011
WHICH STRATEGY FOR SEQUENTIAL
TREATMENTS TO MAKE A TUMOR A
CHRONIC DISEASE
STEPS FOR MATCHING EACH CANCER WITH
INDIVIDUALLY TARGETED THERAPY
Haber et al, Cell, 145: 19, 2011
SEQUENTIAL THERAPY OF ADVANCED DISEASE
EMPIRIC APPROACH
PHARMACOGENOMIC APPROACH
Use presumed
non-cross
resistant cytotoxic
agents
Biopsy-obtained updated genomic
characterization (eg, secondary
mutations, gene amplification,
epigenetic alterations, …)
NSCLC
1st line Cisplatinum-based Therapy
2nd
line Therapy
Docetaxel
Pemetrexed
Vinorelbine
1st line Gefinitib/Erlotinib in EGFR m
tumors
2nd
line Therapy
Selective agents to T790 mutation-WZ4002
c-MET inhibitors
Irreversible anti-EGFR agents
THE BATTLE TRIAL: PERSONALIZING THERAPY FOR
LUNG CANCER – STUDY DESIGN
Kim et al, Cancer Discovery, 1:43, 2011
THE BATTLE TRIAL: PERSONALIZING THERAPY FOR
LUNG CANCER – RESULTS
PHARMACOGENETICS and clinical
utility
Individualized drug
Minimize
Toxicity
Genetics
PHARMACOGENETICS
AIM
Maximize
Efficacy
Pharmacology
Individualized dosing
A FLIGHT ON FUTURE YEARS
• NEW STRATEGIES FOR KILLING CANCER STEM CELLS
1
• ULTRA-SELECTIVE ANTICANCER DRUG DELIVERY BY
NANOTECHNOLOGIES (Nanoporous particle-supported
by lipid bilayers) 2
• NEW COMPREHENSIVE CLASSIFICATION OF NSCLC BASED ON
GENOMIC ABNORMALITIES ACCOUNTING FOR ALL THE
MUTATED CANCER GENES PRESENT IN A SINGLE TUMOR
• PIVOTAL TRIALS IN GENOTYPE – DEFINED SUBGROUPS
1
Lang, Cancer Cell, 20: 341,2011
2 Ashley,
Nature Materials,10: 389, 2011