Advances in the Management of Non Small Cell Lung Cancer

1
Advances in the Management of Non Small Cell Lung
Cancer

• Thierry M. Jahan, MD
• Thoracic Oncology Program
• UCSF Diller Family Comprehensive Cancer Center

2
Presenter Disclosures

• Personal financial relationships with commercial
  interests relevant to this presentation during
  the past 12 months
• Research support Eli Lilly, Genetech, OSI
  pharmaceuticals

Personal financial relationships with
non-commercial interests (e.g., government or
other nonprofit funding) relevant to this
presentation, within past 12 months Relevant
institutional financial interests Personal
financial relationships with tobacco industry
entities within the past 3 years No
relationship to disclose
3
NSCLC Epidemiology
Statistics for 2008

• Cancer Incidence Deaths
• Colon 108,070 49,960
• Breast 184,450 40,930
• Prostate 186,320 28,660
• Total 478,840 119,550

Lung 215,020
161,840
Jemal, CA Cancer J Clin 2008 58 71
4
NSCLC Stage at Diagnosis
Stage I 10
Stage IV 40
Stage II 20
Stage IIIA 15
Stage IIIB 15
Ettinger et al. Oncology. 19961081-111.
5
We had reached a Ceiling for Improved Benefit of
Cytotoxic Chemotherapy in Advanced NSCLC
ECOG 1594
1.0
Cisplatin/Paclitaxel Cisplatin/Gemcitabine Cisplat
in/Docetaxel Carboplatin/Paclitaxel

• 1 yr survival plateau at about 35-40
• No clear efficacy benefit for non-platinum
  combinations or triplet combinations
• New paradigm is needed

0.8
Stage IIIB/IVPatientSurvival,
0.6
0.4
0.2
0.0
0
5
10
15
20
25
30
Months
Adapted with permission from Schiller JH et al. N
Engl J Med. 2002
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Platinum Doublet Chemotherapy in Advanced NSCLC1
Failed Paradigms Triplet Cytotoxic
Chemotherapy2,3 Non-Platinum Chemotherapy Single
Agent Chemotherapy
1. NCCN Non-small Cell Lung Cancer Clinical
Practice Guideline, v.2.2008. Available at
http//www.nccn.org/professionals/physician_gls/PD
F/nscl.pdf 2. Frasci et al. J Clin Oncol.
1999172316-2325 3. Kelly et al. Clin Cancer
Res. 200063474-3479.
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Strategies to improve treatment effectiveness

• Better Patient Selection
• What criteria?
• Better Predictive Markers
• Which ones?
• Better Treatments
• Less toxic
• More specific

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Role of Histology in Patient Selection JMDB
Trial Pemetrexed-Cisplation vs
Gemcitabine-Cisplatin in Adv NSCLC

• RandomizationFactors
• Stage
• PS
• Gender
• Histo vs cyto dx
• Brain mets hx

Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500
mg/m2 d 1
Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250
mg/m2 d 1 8
Vitamin B12, folate, and dexamethasone given in
both arms
Scagliotti Gandara JCO, 2008
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1st-line NSCLC Preplanned Analysis
Squamous (n473)
Nonsquamous (n1252)
HR1.229 (95 CI 1.001.51) p0.051
HR0.844 (95 CI 0.710.98) p0.011
Gemcitabinecisplatin Median OS 10.9 mos
Pemetrexedcisplatin Median OS 12.6 mos
Survival Probability
Survival Probability
Gemcitabinecisplatin Median OS 10.9 mos
Pemetrexedcisplatin Median OS 9.4 mos
Survival Time (months)
Survival Time (months)
Non-squamous adenocarcinoma, large cell
carcinoma, and other/indeterminate NSCLC histology
Scagliotti, et al. J Clin Oncol 2008
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JMDB Trial Cisplatin-Pemetrexed (CP) vs.
Cisplatin-Gemcitabine (CG) in Adv NSCLC
No difference in overall PFS or Survival
between study arms
CP improves Survival over CG in Non-SCCA (HR
0.81, p0.005)
CG improves Survival over CP in SCCA (HR 1.23,
p0.05)
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Insulin/IGF Receptor System
4

N
N
N
N
IGF-IIR
RAS /MAPK? mitogenesis PI3K/AKT? survival
(M6P-receptor)
C
C
C
C
Hybrid Receptors
IGF-IR

• Ligand IGF-I, IGF-II. Local bioavailability
  subject to regulation by binding with IGF-BP and
  release by IGF-BP protease
• IGF-IR binds to IGF-I, II
• IGF-IR/IR-A Hybrids with preferential binding to
  IGF-1 gtgt insulin.
• IR exists in two isoforms
• IR-B traditional insulin receptors.
• IR-A preferentially binds IGF-II (a fetal form
  re-expressed in some tumors)
• IGF-IIR non-signaling receptor, acting as a
  sink for IGF-II.

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IGF-I and risk of Cancers
prospective population-based case-control studies
0,1
1
10
Adjusted Relative Risk
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IGF1R Inhibitor Therapy Randomized Phase II
Trial Paclitaxel/Carboplatin /-CP-751,871 in
advanced NSCLC
TCI paclitaxel 200 mg/m2, carboplatin (AUC6),
Stage 1 CP-751,871 10 mg/kg Stage 2
CP-751,871 20 mg/kg
CP-751,871 Single agent
n97
21 randomization N150, 2 stagesof 73 and 77 pts
TCI
Optional upon progression on TC alone
TC paclitaxel 200 mg/m2, carboplatin (AUC6)
n53
CP-751,871 Single agent
Stage 3 single-arm, post-study extension in
SCC n30, 14 pts evaluable
TCI paclitaxel 200 mg/m2, carboplatin (AUC6)
CP-751,871 20 mg/kg
Karp ASCO 08
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Response Rate by Dose and Histology
Karp ASCO 08
15
Major Responses of TCI in Bulky SquamousRR 78
vs 57
40.0
20.0
0.0
-20.0
Change in Lesion size
-40.0
-60.0
-80.0
-100.0
October 2005
August 2007
November 2007
February 2006
October 2007
April 2008
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• Choice of treatment according to histology
• Adenocarcinoma Pemetrexed based
• Squamous cell carcinoma
• Gemcitabine based
• Pac/carbo IGF inhibitor CP 27181

?
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Histology will ultimately prove to be Suboptimal
for Selecting Chemotherapy (or Targeted Therapy)

• Histological sub typing groups tumors based on
  microscopic pattern recognition by a pathologist
  (using 18th century technology)
• At best, Histology is the phenotypic expression
  of complex genetic and molecular interactions
• 21st century approach will refine choice at the
  molecular level

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Thymidylate Synthtase Expression in Lung Cancer
Small Cell
Squamous
Normal lung
Bhattacharjee PNAS 2001
Adenocarcinoma

• SCLC High TS
• Squamous High TS
• Adeno Low TS

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Possible explanation to SQCCA sensitivity to CP
721871

• De-regulation of the IGFR pathway seems a
  possibility in squamous cell carcinoma
• ILGF binding protein 3 levels, which regulates
  activity of IGF-1, are low in SQCCA
• IGF-R appears to be expressed more in SQCCA
• IGF-IIR gene which codes for a negative regulator
  of the IGF-IR pathway is mutated in up to 60 of
  SQCCA

Karp JCO 2009
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Strategies to improve treatment effectiveness

• Better Patient Selection
• What criteria?

• Better Predictive markers
• Which Ones?

• Better Treatments
• Less Toxic
• More Specific

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HGF mAb AMG102 OA5D5
IGF-1 mAb CP721871 AMG479 IMC-A12 R1507 BIIB022
Anti-PI3k PI103 BGT226 BEZ235 XL765 XL147
Anti-IGF-1R XL228 OSI906 NDGA
Anti-HER Lapatinib BMS599626 BMS690514 PF00299804
XL647 BIBH2992 ARRY334543
UCN01
Anti-Ras Tipifarnib Lonafarnib BMS214662
Anti-Src Bosutinib XL999 AZD0530 KX010107
Apoptosis
Anti-cMET XL880 ARQ197 PF02341066 JNJ388 MGCD265 S
U11274 PHA665752
Anti-Akt Perifosine GSK690693
Anti-Raf Sorafenib RAF265 XL281 PLX4032
Transcription
Anti-mTOR Everolimus Deforolimus
Anti-MEK AZD6244 RDEA119 XL518
Cell Cycle Progression Proliferation Differentiati
on
Angiogenesis
Protein Translation
Anti-HDAC SNDX275 CI994 Apicidin Desipeptide Trapo
xin Depeudecin SK7068 vorinostat
Anti-DNMT 5-azacitadine 5-aza-2-deoxycitidine
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• The trick is
• To pick right target
• To have the right agent
• To have the right pairing

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Many Targeted Therapies Failed to Show Additional
Benefit when Combined with Platinum Based CT
Courtesy E. Vokes
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Bevacizumab Blocks Angiogenesis
Recombinant humanized monoclonal antibody to
VEGF-A

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E4599. Ph III RCT Bevacizumab and CP vs CP in
non-squamous NSCLC
RANDOMIZE
Paclitaxel 200 mg/m2 IV Carboplatinum AUC 6 q
21d X6 cycles
IIIB and IV non-squamous No brain mets No
hemoptysis No prior chemotherapy
Paclitaxel 200 mg/m2 IV Carboplatinum AUC 6 q
21d X6 cycles Bevacizumab 15mg/kg q3 wk
til PD

• Stratification by
• Stage (IIIB or IV)
• Geographic region

Sandler. NEJM 2006 355 2542
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Phase III ECOG 4599 trial Paclitaxel/Carboplatin
Bevacizumab
Non-Squamous histology, no hemoptysis, brain
metastases
1.0
12 mo 24 mo
Pac/carbo bev, n434 51 23
0.8
Pac/carbo, n444 44 15
0.6
12.3
Proportion surviving
HR 0.79, 0.67-0.92P .003
10.3
0.4
0.2
0.0
0
6
42
48
18
30
12
24
36
Months
37 of patients with advanced NSCLC are eligible
to receive bevacizumab, lt20 if also exclude age
70 years
Sandler AB, et al. New Engl J Med.
20063552542-2550.
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ECOG Trial (E4599) Treatment Related Deaths
Sandler AB, et al. New Engl J Med.
20063552542-2550.
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• Just when you think youve got it right..

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AVAIL Study design
Bevacizumab
RANDOMI ZE
Bevacizumab 7.5mg/kg Cis/Gem (CG)
2
PD
Previously untreated, stage IIIb, IV or recurrent
non-squamous NSCLC N1050
1
Placebo 7.5 CG
PD
1
Placebo 15 CG
Bevacizumab
Bevacizumab 15mg/kg CG
2
PD
Positive for primary endpoint PFS Negative for
Overall Survival
Manegold, et al. ASCO 2007, LBA 7514
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AVAIL Efficacy
The 1o endpoint for the trial PFS So that this
was reported as a positive trial But is it really
clinically significant?
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Epidermal Growth Factor Receptor (EGFR)
Inhibitors in NSCLC Status of Predictive
Biomarkers
Gefitinib Erlotinib Single Agent EGFR
mutpredictive EGFR FISHpredictive KRAS
mutpredictive TKIs Chemo are
negative (INTACT I/II TRIBUTE, TALANT all
negative)
Cetuximab Single Agent Biomarkers
Unclear Cetux Chemo (FLEXpositive)
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Cetuximab Mechanism of Action

• IgG1 monoclonal antibody
• Binds to EGFR and competitively inhibits ligand
  binding (e.g. EGF)
• Mechanisms different from TKI
• Receptor Internalization
• Antibody-Dependent Cellular Cytotoxicity (ADCC)
• Combinations with Radiation or Chemotherapy
  effective in other tumor types
• Radiation H N Cancer
• Chemotherapy Colon Cancer

Cetuximab
ADCC
IgG1 MAb
EGFR
Harari Clin Cancer Res, 2004
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FLEX Pivotal Trial Cetuximab Chemotherapy in
1st-Line Advanced NSCLC
Up to 6 cycles of chemotherapy patients not
progressing continue on cetuximab maintenance
RANDOMIZE
Cetuximab 400 mg/m2 d1 wk1, then 250 mg/m2, QW
Vinorelbine 25 mg/m2 d1,8 cisplatin 80 mg/m2
d1, Q3W
n557
Chemotherapy-naïve advanced NSCLC

• Stratified by
• IIIB or IV
• ECOG PS 0,1or 2

Vinorelbine 25 mg/m2 d1,8 cisplatin 80 mg/m2
d1, Q3W
n568

• Primary endpoint OS
• Secondary endpoints PFS, ORR, DCR, QoL, Safety,
  PK

• All histologic subtypes included
• ECOG PS 02
• No known brain metastases
• EGFR expression by IHC (1 positive tumor cells)

Pirker R, et al. Lancet 373(9674) 1525 1531,
2009.
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FLEX Results
OS ()
HR 0.871 P0.044
Months
NSnot significant TTFtime to treatment failure.
Pirker R, et al. Lancet 373(9674) 1525 1531,
2009.
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FLEX Differences in Ethnicity
Pirker R, et al. Lancet 373(9674) 1525 1531,
2009.
36
FLEX Asian Subgroup (N121)
Cannot draw definitive conclusions because of
small sample size (10 of total), differences in
histology and differences in post-study EGFR TKI
treatment
Pirker R, et al. Lancet 373(9674) 1525 1531,
2009.
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FLEX OS Caucasians (N946)Prespecified
Analysis
Overall Survival ()
P value stratified log-rank test (2-sided)
Months
CVcisplatin/vinorelbine.
Pirker R, et al. Lancet 373(9674) 1525 1531,
2009.
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FLEX OS Early Acne-Like RashPre-Planned Analysis
Any grade CT Cetuximab (N290) Grade 0 CT
Cetuximab (N228) HR0.631 (95 CI
0.515-0.774) Plt0.001
Overall Survival ()
Months
Patients at Risk Grade 0 228
145 88 54 15
0 Any Grade 290 238
163 101 38 3
Landmark analysis.
Gatzemeier et al, JTO 2008, Vol 3, No. 11, S4
(abstract 8)
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Cetuximab Platinum-Based Chemotherapy in 1st
line NSCLC Consistent Efficacy
Randomized to concurrent vs sequential
cetuximab Randomized to pac/carbo q3w vs pac
qw/carbo q4wPac qw/carbo q4w Press release
Aug 2008
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Structure of the EGFR-ATP Binding Site
Exons 18, 19, 20 and 21- Tyrosine kinase
domain In frame deletions and missense
mutations
Red deletions Light blue missense
mutations Dark blue gefitinib
From Lynch TJ et al. N Engl J Med.
20043502129-2139.
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Individualizing Anti-EGFR Therapy Methodology

• EGFR mutation status by gene sequencing
• EGFR gene copy number by fluorescence in situ
  hybridization (FISH)
• EGFR protein expression by immunohistochemistry
  (IHC)
• Serum Proteomics by MALDI MS

GGCGGGCCAAACTGCTGGGTGCG
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NCIC-C BR.21 TRIAL
NSCLC 1 prior combination regimen (no
more than 2) Elderly may have had
single-agent No requirement for PD
RANDOM I ZE
Erlotinib 150 mg daily n488
Placebo n243
Shepherd et al.NEJM, 2005
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BR-21 Overall survival all patients
1.00 0.75 0.50 0.25 0
42.5 improvement in median survival
HR0.73, Plt0.001
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Survival distribution function
TarcevaTM Placebo
21
0 5 10 15 20 25 30
Survival time (months)
HR and P-value adjusted for stratification
factors at randomization plus HER1/EGFR status.
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BR.21 Survival According to EGFR Mutation
EGFR mutation
No mutation
100 80 60 40 20 0
100 80 60 40 20 0
Erlotinib Placebo
Erlotinib Placebo
Log-rank p0.13HR0.73 (0.49, 1.10)
Log-rank p0.45HR0.77 (0.40, 1.50)
Percentage
Percentage
0 6 12 18 24 30
0 6 12 18 24 30
Months
Months
p value for interaction 0.97
EGFR Mutation is NOT a Prognostic Marker
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BR.21 EGFR FISH predicts Survival
BR21 FISH -
BR21 FISH
Log-rank p0.59HR0.85 (0.48, 1.51)
Log-rank p0.008HR0.44 (0.23, 0.82)
FISH positivity is a prognostic marker
Tsao NEJM, 2005
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Biomarkers for EGFR-directed Therapy Summary of
Current Status

• EGFR TKIs
• EGFR protein (IHC) equivocal for predictive value
• EGFR mutation predicts response
• EGFR FISH predicts survival (BR.21)
• KRAS mutation predicts lack of activity
• Cetuximab
• EGFR protein (IHC) selection factor for FLEX
• EGFR mutation not predictive (preclinical)
• EGFR FISH conflicting data (S0342, BMS-099)
• KRAS mutation not predictive (S0342, BMS-099)

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N0723 Predictive Marker Study Design
NCCTG (Study Chair Alex Adjei) CALGB, ECOG,
SWOG, NCIC Others C-Path industry partners,
Pharma
Initial Registration
Strata
Randomize
Outcome
EGFR FISH ( 30)
Erlotinib
2nd line NSCLC with specimen
1 PFS 2 OS, ORR
FISH Testing
Pemetrexed
1-2 years minimum additional follow-up
EGFR FISH - ( 70)
Erlotinib
Pemetrexed
4 years accrual, 1196 patients
957 patients

• Power validation of EGFR FISH as predictive
  biomarker
• 90 to detect 50 PFS improvement favoring
  erlotinib in FISH
• 90 to detect 30 PFS improvement favoring
  pemetrexed in FISH-
• gt 90 to detect interaction
• SWOG Tumor repository EGFR pathway analysis

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Possible Selection Factors for Individualizing
Therapy of NSCLC
from Gandara CLC, 2008
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Iressa Pan Asian Study (IPASS) Phase III Trial
Gefitinib vs Carboplatin/Paclitaxel in Selected
Patients With Advanced NSCLC
Never or light ex-smoker with adenocarcinoma hist
ology PS 0-2 Stage IIIB or IV chemotherapy-naïve
NSCLC N1217
Gefitinib (250 mg/day) Offered
carboplatin/paclitaxel on progression
R A N D O M I Z E
Carboplatin (AUC 5 or 6) Paclitaxel (200
mg/m2) 3 times weekly up to 6 cycles
Primary endpoint PFS (noninferiority) Secondary
endpoints ORR, OS, QOL, disease-related
symptoms, safety, and tolerability Exploratory
biomarkers EGFR mutation, gene copy number, and
protein expression
Never smokersmoked lt100 cigarettes in lifetime
light ex-smokerstopped 15 years ago and smoked
10 pack-years.
Mok. ESMO. 2008 (abstr LBA2).
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Progression-Free Survival in ITT Population
Carboplatin / paclitaxel
1.0
Probabilityof PFS
Gefitinib
N Events
609 453 (74.4)
608 497 (81.7)
0.8
HR (95 CI) 0.741 (0.651, 0.845) plt0.0001
0.6
5.874487
Median PFS (months)4 months progression-free6
months progression-free12 months progression-free
5.7614825
0.4
Gefitinib demonstrated superiority relative to
carboplatin / paclitaxel in terms of PFS
0.2
0.0
0
4
8
12
16
20
24
Months
At risk
Gefitinib
609
212
76
24
5
0
363
Carboplatin / paclitaxel
608
118
22
3
1
0
412
Primary Cox analysis with covariates HR lt1
implies a lower risk of progression on gefitinib
51
Progression-Free Survival in EGFR Mutation
Positive and Negative Patients
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 population Mutation rate 60Cox analysis
with covariates
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CONCLUSIONS

• Treatment paradigm are evolving due to
• Molecular characterizations of disease and agents
  to pick best fit
• Realization that all populations with this
  disease are not the same
• Realization that lung cancer is quite
  heterogeneous

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