never-smoker with lung cancer in southern california
DESCRIPTION
Never-smoker with Lung cancer in Southern California. Never-smokers with lung cancer have distinct genetic changes. Chao Family Comprehensive Cancer Center at UCI Irvine offers cutting edge clinical trials. Please call 1-714-456-8000TRANSCRIPT
Lung cancer in Never-smokersA clinical entity with increasing clinical relevance in Southern
CaliforniaThe role of chemotherapy and updates from ASCO2009
Sai-Hong Ignatius Ou, MD PhDAssociate Clinical Professor
Chao Family Comprehensive Cancer CenterDepartment of Medicine, Division of Hematology-Oncology
University of California Irvine Medical Center, Orange, CA 92868
Genetic Epidemiology Research InstituteDepartment of Epidemiology School of Medicine
University of California Irvine, Irvine, CA92697
Patient case• 56 yo Chinese never-smoking female, mother of 2, no PMHx• Routine health check-up (asymptomatic) right chest opacity
on CXR• CT-PET fusion revealed RML mass 1.8 cm (SUV 5.2) and right
mediastinal and subcarinal LN involvement• VAT revealed pleural nodules (Lobectomy + mediastinal LN
resection aborted, RML mass wedge resection and pleural nodules biopsy performed)
• Lung mass & pleural nodules: well-differentiated adenocarcinoma with BAC features
• MRI of brain negative• Stage: T4 N2 M0 (current staging) or T1 N2 M1 (new staging)
Global Cancer deaths
Sun Nature Review cancer 2007; 7 : 778-790
Global distribution of never-smokers
Sun Nature Review cancer 2007; 7 : 778-790
NSCLC Epidemiology (Orange, San Diego, & Imperial County 1995 to 2003; N=11,969)
Variable Number Percent
Age 68.3 years +/- 0.1 SE ---
Gender Male Female
64705497
54.145.9
Smoking status Smoker Non-smoker
8762942
90.39.7
Stage Localized Regional Metastatic
239930715907
21.127.051.9
Characteristics of NSCLC according to smoking status
Characteristics of Asian subgroupsTotal
Ever-smoker Never-smoker PN (%)^ 891 (73.9) 314 (26.1)Median age [years] (95% CI) 68 (47-83) 66 (44-86) .0359*Sex Male Female
671 (75.3)220 (24.7)
83 (26.4)231 (73.6) < .0001
Histology Adenocarcinoma BAC Large cell Squamous cell Undifferentiated
361 (40.5)25 (2.8)55 (6.2)
183 (20.5)267 (30.0)
178 (56.7)23 (7.3)18 (5.7)16 (5.1)
79 (25.2) < .0001AJCC stage Stage 1 Stage 2 Stage 3 Stage 4 Unknown
92 (10.3)42 (4.7)
203 (22.8)420 (47.1)134 (15.0)
31 (9.9)5 (1.6)
49 (15.6)190 (60.5)39 (12.4) .0003
Proportion of NSCLC patients by gender & smoking status
*percentage calculated across the row*percentage calculated across the row
Percentages of Never-smokers in Southern California
Proportion of NSCLC who were never-smokers5 major Asian subgroups and period of diagnosis
Effect of Smoking on overall survival
Major EGFR signaling pathways
Expression pattern of EGFR in NSCLC
EFGR Expression by IHC and SurvivalMeta-analysis
Meert et al, Eur Respir J 2002; 20: 975-981
Gefitinib [Iressa® (ZD1839)]MW=446
CI
F
N
O NH
N
O
O
N
NH
N
O
O
N
Erlotinib [Tarceva™ (OSI-774)]MW=430
O
O
H3C
H3CO
O
NH
N
N
Structures of EGFR-TK Inhibitors (Quinazolines)
BR21 OS
Shepherd NEJM 2005; 353: 123-132
Erlotinib (N=488)
Placebo (N=243)
Median Survival
6.7 mo 4.7 mo
1-Year Survival
31.2% 21.5%
ISEL OS
At 7.2 months median follow-upOS: 5.6 months vs 5.1 months1 yr survival rate: 27% vs 21%HR 0.89, [0.77-1.02]; P = 0.087
At 10.2 months median follow-upHR 0.89, [0.79-1.01]; P = 0.074
Thatcher et al, Lancet 2005; 366: 1527-1537
ISEL Adenocarcinoma OS
At 7.2 months median follow-upOS: 6.3 months vs 5.4 months1 yr survival rate: 30% vs 18%HR 0.84, [0.68-1.03]; P = 0.089
At 10.2 months median follow-upHR 0.84, [0.70-1.02]; P = 0.072
Thatcher et al, Lancet 2005; 366: 1527-1537
Overall Survival of ISELAsian vs. non-Asian
Chang JTO 2006; 1: 847-855
1. Asians have higher proportion of never-smokers with lung
cancer2. Asian seems to response and have better survival to inhibitors
of Epidermal Growth Factor Receptor (EGFR)
Why?
Discovery of activating EGFR mutations in NSCLC
List of EGFR mutations in NSCLC
Sharma Nature Review Cancer 2007; 7: 169-181
Distribution of EGFR mutations
Shigematsu Gazdar Int J Cancer 2006; 118: 257-262
EGFR mutation incidence by cigarette-smoking status
Pham et al JCO 2006; 24: 1700-1704Pham et al JCO 2006; 24: 1700-1704
How would you treat the patient?
• Tarceva?• Chemotherapy?
– which combination?
• Screen for EGFR mutation?
Not all mutations are the same!!!
List of EGFR mutations in NSCLC
Sharma Nature Review Cancer 2007; 7: 169-181
Differential response of exon 19 deletions & L858R point mutation to TKIs
Riely et al, Clin Cancer Res 2006; 12: 839-844
Differential response of exon 19 deletions & L858R point mutation to TKIs
Exon 19 deletion L858R mutation P
N 22 10
CR 9% 0%
PR 64% 50%
ORR 73% 50% 0.25
Median OS 38 mo 17 mo 0.0384
Median TTP 24 mo 10 mo 0.04
Median Duration of Rx for CR/PR 16 mo 13 mo 0.46
Median duration of RX for SD 26 mo 10 mo 0.01
Jackman et al, Clin Cancer Res 2006; 12: 3908-3914
No K-ras mutation identifiedRR: gefitinib (78%) vs erlotinib (33%) (P = 0.035)
Acquired resistance to oral EGFR TKI
• T790M mutation (70%)• c-met over-expression (8%)
Arcila PASCO 2009
List of EGFR mutations in NSCLC
Sharma Nature Review Cancer 2007; 7: 169-181
BIBW2992
• Orally available• Irreversible inhibitor of EGFR1 and EGFR2
– Binds covalently to Cys773 within the catalytic cleft of the ATP-binding pocket of EGFR
• Inhibits to a significant level in vitro phosphorylation of EGFR in NSCLC cell lines with T790M mutation
EGFR-TKIsSelectivity
IC50 (nM)
EGFR-1 HER-2Erlotinib (Tarceva) 2 350Gefitinib (Iressa) 23 3700
BIBW2992 (Tovok) 0.5 14Lapatinib (GW572016) 11 9
EGFR-TKIsIn vitro EGFR activity
IC50 (nM)
Cell line BIBW2992 GefitinibNCI-H1666 (EGFR WT) 7 100
NCI-H3255 (L858R) 6 50NCI-H1975 (L858R + T790M) 93 resistant
1200.22 Patient 146 yo Hispanic Female Never-smoker
Exon19 deletion
8/20/2008 9/15/2008
1200.22 Patient 1 46 yo Hispanic Female Never-smoker
Exon19 deletion
3/2/2009
1200.22 Patient 263 yo Vietnamese Female Never-smoker
Exon19 deletion
12/16/2008 1/9/2009
1200.22 Patient 263 yo Vietnamese Female Never-smoker
Exon19 deletion
2/9/2009 3/9/2009
Global trial registration trial of BIBW2992
• EGFR mutation positive patients• BIBW2992 versus Pemetrexed/Cisplatin• Primary endpoint: Progression-Free survival
How would you treat the patient now?
• EGFR mutation analysis is negative (wild-type)
Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and
ALK Inhibitor PF-02341066
EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4, MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5
1. Massachusetts General Hospital 5. University of Chicago Cancer Center
2. University of Colorado Cancer Center 6. Peter MacCallum Cancer Centre
3. Dana-Farber Cancer Institute 7. Seoul National University4. Memorial Sloan-Kettering Cancer Center 8. University of California at Irvine
PF-02341066
Potent & selective ATP competitive inhibitor of MET and ALK kinases and their oncogenic variants
ON
N
Cl
F
Cl
NN
N
Kinase IC50 (nM)
Mean Selectivity
Ratioα
c-Met 8 ---
ALK 20 2X
RON 248 31X
Axl 308 39X
Tie-2 448 56X
Trk A 580 73X
Trk B 399 50X
PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.
PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.
MET/HGFRMET/HGFR ALKALK
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
SEMA
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPPYYPPYYPP
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
KinaseYY
PP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
Kinase
Cytoplasmic Fusion Variants of ALK
Cytoplasmic Fusion Variants of ALK
NPM-ALKNPM-ALK EML4-ALKEML4-ALK
Initial characterization of EML4-ALK fusion in NSCLC
Soda Nature 2007; 448:561-566 Soda Nature 2007; 448:561-566
Schema of EML4-ALk NSCLC translocations
Wong Cancer 2009; 115; 1723-1733Wong Cancer 2009; 115; 1723-1733
EML4-ALK NSCLC Adenocarcinoma comparisons (N = 209)
Wong Cancer 2009; 115; 1723-1733Wong Cancer 2009; 115; 1723-1733
EML4-ALK positive
EML4-ALK negative
Total P
Median age 59 (51-61)
64 (55-71)
64 (54.5-71)
0.018
Smoking status Never-smoker Ever-smoker
10 (90.9)1 (9.1)
117 (59.1)81 (40.9)
127 (60.8)82 (39.2) 0.053
EGFR Mutated Wildtype
0 (0)11 (100)
121 (61.1077 (38.9)
121 (57.9)88 (42.1) < 0.001
~250 kb ~300 kb
t(2;5) ALK genebreakpoint region
2p23 regionTelomere Centromere
3’ 5’
Break-Apart FISH Assay for ALK Fusion Genes
Potential Fusion Partners:
• EML4• KIF5B• TGF
EML4-ALK Patients: Waterfall PlotTumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK FusionsTumor Responses to PF-02341066 for NSCLC Patients with EML4-ALK Fusions
For 2 patients whose best response was PD, patients discontinued prior to first on-study scanFor 2 patients whose best response was PD, patients discontinued prior to first on-study scan
Tumor Size ChangeDuration of Response (Weeks)
-100
-80
-60
-40
-20
0
Blue - SD Black - PD Green - PR
% o
f Bes
t Cha
nge
from
B
asel
ine
2222 1616161620202020
40404040
8+8+8+8+ 121212124+4+4+4+
13+13+13+13+15+15+15+15+
8+8+8+8+23+23+23+23+ 15+15+15+15+
2+2+2+2+
48 YO Female Non-Smoker with EML4-ALK NSCLC
Pre-Treatment Pre-Treatment After 2 Cycles PF-02341066After 2 Cycles PF-02341066
My own pt51 yo Caucasian Male NSCLC
Failed Tarceva, on 6th line Rx before enrolling in c-met trialBefore and After c-met inhibitor
Before After 2 months of c-met
Planned Global registration trial for PF-02341066
• EML4-ALK positive NSCLC patients• PF-02341066 versus Pemetrexed/Cisplatin• Primary endpoint: PFS
1st & 2nd -line treatment for Never-smoker with NSCLC
EGFR Mutation Positive(~60%)
EML4-ALK translocation
Positive(~5%)
EGFR WTEGFR UnknownEGFR not tested
(~35%)
06-62
08-01
07-40
A8081007
A8081005
08-49PF-00299804
1200.32
1200.42
The End
Proportion of male NSCLC never-smokerBy period of diagnosis and 5 Asian subgroups
Proportion of female NSCLC never-smokerBy period of diagnosis and 5 ethnicities
1st & 2nd line Rx of NSCLC in ever-smokers• First line
– ATTRACT-1 (UCI-07-72)• Carboplatin/paclitaxel +/- ASA402
– CP13-0811 (UCI-09-05)• Carboplatin/gemcitabine/Erbitux +/- IMC-A12
• Second line– UCI-04-60
• Docetaxel or alimta +/- erbitux
– UCI-09-04• Tarceva +/- CP-751,871
– ATTRACT-2 (UCI-08-66)• Docetaxel +/- ASA404
Adjuvant Rx
• ECOG1505– Cisplatin + gemcitabine
/navelbine/alimta/taxotere +/- avastin
• MARGRIT (UCI-07-57)– Adjuvant MAGE vaccine
Never-smoker SmokerHR 95% CI P HR 95% CI P
Ethnicity* Caucasian Asian African-American Hispanic
1.0000.8661.1260.843
(0.751-0.999)(0.796-1.592)(0.714-0.996)
.0483
.8938
.0446
1.0000.8660.9870.981
(0.807-0.928)(0.901-1.081)(0.923-1.043)
< .0001.7800.5450
Gender Male Female
1.0000.786 (0.707-0.874) < .0001
1.0000.841 (0.814-0.868) < .0001
AJCC stage 1 2 3 4
1.002.7882.2423.033
(2.053-3.785)(1.784-2.818)(2.465-3.731)
< .0001< .0001< .0001
1.001.6752.0092.893
(1.537-1.826)(1.885-2.142)(2.729-3.068)
< .0001< .0001< .0001
Age 1.015 (1.011-1.019) < .0001 1.012 (1.010-1.013) < .0001
Cox models for Never-smokers and Smokers
Place of birth-North America
Smoker (%)* Never-smoker (%)*Canada All (N=176) Male Female
162 (92.1%)79 (95.2%)83 (89.2%)
14 (7.9%)4 (4.8%)
10 (10.8%)
Mexico All (N=647) Male Female
516 (79.8%)373 (91.6%)143 (59.6%)
131 (20.3%)34 (8.4%)
97 (40.4%)
Interplay between CA repeats and promoter polymorphism in EGFR gene
Nomura PLoS Med 2007; 4 (4):e125
California Cancer Registry
http://statecancerprofiles.cancer.gov/
Birthplace of Asian patients
Filipino Vietnamese Chinese Japanese Koreans
All Never-smoker
Smoker All Never-smoker
Smoker All Never-smoker
Smoker All Never-smoker
Smoker All Never-smoker
Smoker
N 446 113 333 396 114 282 137 47 90 148 22 126 78 18 60
Native-born Yes (%) No (%)
410 (91.9)
36 (8.1)
107 (94.7)
6 (5.3)
303 (91.0)
30 (9.0)
342 (86.4)
54 (13.6)
101 (88.6)
13 (11.4)
241 (85.5)
41 (14.5)
111 (81.0)
26 (19.0)
36 (76.6)
11 (23.4)
75 (83.3)
15 (16.7)
73 (49.3)
75 (50.7)
14 (63.6)
8 (36.4)
59 (46.8)
67 (53.2)
57 (73.1)
21 (26.9)
12 (66.7)
6 (33.3)
45 (75.0)
15 925.0)
Proportion of never-smokers by Asian subgroups
OS according to stage stratified by smoking status
Pharmodynamic blockade of EGFR pathway
Positions of Mutations Detected in HER1/EGFR Tyrosine Kinase Domain in NSCLC
747-750
Activation loop
L858
G719
TM K DFG Y Y Y Y
AutophosphorylationTyrosine kinaseEGF ligand binding
K R H DFGGXGXXG L L Y
718 745 776 835 858 861 869 964
18 19 20 21 22 23 24
757-750
Exon:
Paez:
Lynch:
Pao:
Tumor with point mutation (amino acid substitution)
Tumor with in-frame deletion
EGF = endothelial growth factor; TM = transmembrane. Adapted from: Pao et al. Proc Natl Acad Sci U S A. 2004;101:13306; Lynch et al. N Engl J Med. 2004;350:2129; Paez et al. Science. 2004;304:1497.
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