Lung Cancer Genotyping in
Colombia
Mauricio Lema Medina MD
Clínica de Oncología Astorga Medellín
Acknowledgments
Dr. Andrés Felipe Cardona Zorrilla M.D
Globocan, 2008
Registro Poblacional de Cáncer, Cali – Colombia
Registro Poblacional de Cáncer, Antioquia – Colombia, 2007-2009
Registro Poblacional de Cáncer, Antioquia – Colombia, 2007-2009
Registro Poblacional de Cáncer, Antioquia – Colombia, 2007-2009
http://rpcc.univalle.edu.co/
Colombia
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2010
Globocan, 2008
Cisplatin-based CT in advanced NSCLC
100
Supportive care + CT
Supportive care
80
Survival (%)
60
40
Meta-Analysis
Modest improvement in
OS
20
0
0
6
12
18
24
Time from randomisation (months)
Cisplatin-Based chemotherapy for advanced NSCLC
NSCLC Collaborative Group.
BMJ 1995;311:899–909
Platinum-Based Doublets in Advanced NSCLC
Probabilidad de supervivencia
1.0
Cisplatin / paclitaxel
Cisplatin / gemcitabine
Cisplatin / docetaxel
Carboplatin / paclitaxel
0.8
0.6
0.4
0.2
0.0
0
5
10
15
20
25
30
Meses
ECOG trial 1594
ECOG, Eastern Cooperative Oncology Group
Schiller et al. N Engl J Med 346:92, 2002
Schiller, et al. NEJM 2002
NSCLC Outcomes in Bogotá, Colombia
n=345
n=176
Stage IIIB / IV NSCLC
Received anti cancer agents
Male
64%
PS 0/1
45%
Adeno
60%
Squamous
24%
Weight loss
61.5%
1st Line therapy
Platinum-doublets
71%
Gem/Vin mono
19%
Erlotinib
4.5%
Cardona AF. Rev Venez Oncol 2010; 22(1):66-83
NSCLC Outcomes in Bogotá, Colombia
PFS
Cisplatin: 4.7 m
Carboplatin: 3.2 m
OS
Median: 9.2 m
1-yr OS: 26%
3.4
Cardona AF. Rev Venez Oncol 2010; 22(1):66-83
Molecular subtypes of lung carcinoma
Recently described
LKB1
MEK1
ROS fusion gene
EGFR
PDGFR amp
ERK
BIM
MET
Lung cancer 2010 – USA
219,000 new cases
Small-cell lung cancer (13%)
EGFR mutated (10% NSCLC )
Other
NSCLC
KRAS mutated (25% of adenocarcinoma)
Yearly incidence of cancers with driver mutations
KRAS-mutated NSCLC
36.000 cases/year
Pao W. ASCO 2010.
EGFR-mutated NSCLC
18.000 cases/year
EML4-ALK NSCLC
9.000 cases/year
CML
5.000 cases/year
EGFR mutations around the world
Overall 17%
E19 62%
E21 37%
E20 38%
Overall 14%
E19 60%
E21 30%
E20 8% - 38%
Overall 32.8%
E19 54.3%
E21 44.5%
E20 2.2%
Overall 40% - 50%
E19 51%
E21 42%
E20 2%
Overall 15.8%
E19 64.3%
E21 24.7%
IPASS: Carboplatin + Paclitaxel vs Gefitinib in metastatic
NSCLC adenocarcinoma (very low smoking burden)
Adenocarcinoma, Stage IV,
PS 0-2, very low smoking
burden
(n=1217)
Carboplatin + Paclitaxel (PC)
(n=608)
Gefitinib
(n=609)
PC: Carboplatin AUC 5-6 d1 + Paclitaxel 200 mg/m2 d1. q21 days x6. Gefitinib: 250 mg vía PO qd. Crossover allowed
Median OS (months)
PC
Gefitinib
P
All
17.3
18.6
NS
HR for progression
HR
P
Wild type EGFR
2.85
0.0001
Mutated EGFR
0.48
0.0001
Mok T, et al. ESMO 2008
EURTAC: CT vs Erlotinib in mEGFR
NSCLC
Chemotherapy
(n = 87)
Chemo-naive metastastic
NSCLC with mEGFR
(n = 173)
Erlotinib 150 mg PO qd
(n = 86)
Primary End-Point: Overall survival.
Rosell R, et al. ASCO 2011. Abstract 7503.
EURTAC: Response and Safety
Erlotinib
(n = 86)
Chemo
(n = 87)
• CT-treated patients had increased
frequency of:
58
15
– Grade 3/4 AEs (81% vs 45%)
 CR
2
0
 PR
56
15
Disease control rate
79
66
– Dose modification or interruption
due to treatment-related AE (47%
vs 23%)
SD
21
51
PD
7
13
No response
assessed
14
22
Response
Outcome, %
Objective response
Rosell R, et al. ASCO 2011. Abstract 7503.
– Discontinuation due to treatmentrelated AE (14%
vs 5%)
– Treatment-related serious AEs
(16% vs 7%)
Clinical Care Options.
EURTAC: Erlotinib vs Chemo in EGFR
Mutation-Positive, Stage IIIB/IV NSCLC
• Phase III; significant benefit in PFS and with erlotinib vs chemotherapy
1.0
Erlotinib (n = 86)
Chemotherapy (n = 87)
PFS Probability
0.8
0.6
5.2
HR: 0.37 (95% CI: 0.25-0.54;
log-rank P < .0001)
9.7
0.4
0.2
0
0
3
Patients at Risk, n
Erlotinib
86
63
Chemo
87
49
6
9
12
15
18
21
24
27
30
33
9
3
7
1
4
0
2
0
2
0
0
0
Mos
54
20
32
8
21
5
17
4
Rosell R, et al. ASCO 2011. Abstract 7503. Reprinted with permission.
Clinical Care Options.
EURTAC: OS and PFS Across Patient
Subgroups
•
•
No significant difference in OS at interim analysis; data immature with high rate of crossover (HR
= 0.80; 95% CI: 0.47-1.37; P = .4170)
No PFS benefit of erlotinib vs chemotherapy among former smokers
HR (95% CI)
0.37 (0.25-0.54)
0.44 (0.25-0.75)
0.28 (0.16-0.51)
0.38 (0.17-0.84)
0.35 (0.22-0.55)
0.26 (0.12-0.59)
0.37 (0.22-0.62)
0.48 (0.15-1.48)
0.56 (0.15-2.15)
1.05 (0.40-2.74)
0.24 (0.15-0.39)
0.30 (0.18-0.50)
0.55 (0.29-1.02)
All
< 65 yrs
≥ 65 yrs
Male
Female
PS 0
PS 1
PS 2
Current smoker
Former smoker
Never smoker
Exon 19 deletion
L858R mutation
0.1
0.2
0.4 0.6 0.8 1.0 1.5 2.0
Favors Erlotinib
Rosell R, et al. ASCO 2011. Abstract 7503.
HR
n
173
85
88
47
126
57
92
24
19
34
120
115
58
4.0
Favors Chemotherapy
Clinical Care Options.
Study design
Between subjects factorial design
Target population
Colombia incident
cases of LAC
EGFR+
Accesible population
LAC cases analized in a
centralized laboratory
10
BRAF
KRAS/EGFRWt
20
Study sample
LAC cases with complete
genotipification
10
Random
allocation
Control
Her2
KRAS+
PI3K
Main objective
•To establish the frequency of driver mutations in NSCLC in LATAM population.
Methods
•Direct sequencing in patients from Argentina, Colombia, Mexico, and Peru was performed at each site.
Measurement of clinical outcomes
Alk
Main study schedule - Colombia
Test for
ALK/ELM4
Translocation
+
N=1
N=26
Test BRAF
-
Test Her2
-
N=322
Test for
KRAS
mutation
N=205
Test for
EGFR
mutation
N=322
N=80
No further
molecular
testing
+
N=1
N=36
Test PI3k
+
N=20
N=35
No further
molecular
testing
+
N=0
N=60
N=170
N=242
+
Patients with available data
concerning the use of erlotinib
(N=41)
+
N=1
Main characteristics of EGFR mutant population
Variable
Number of pts treated with
erlotinib
(follow-up available data)
Mean age (SD)
Stratified age
>65 yrs
<65 yrs
ND
Sex
Male
Female
Tobacco exposure
Never smoker
Former smoker
Current smoker
Main metastasis (site)
Pleuropulmonary
Brain
Liver
Bone
ND
N (%)
41 (51%)
63 yrs (±12)
13 (31.7)
24 (58.5)
4 (9.8)
9 (22.0)
32 (78.0)
30 (73.2)
10 (24.4)
1 (2.4)
26 (63.4)
4 (9.8)
3 (7.3)
2 (4.9)
6 (14.6)
Hormonal receptor status
(tumor tissue)
Positive
Negative
ND
TTF1 status
Positive
Negative
ND
Mutation type
delE19
L858R
T790M basal
Positive
Negative
ND
Line of treatment
1
2
3
ND
Response
Stable disease
Partial response
Complete response
Progressive disease
ND
Overall response rate
Clinical benefit
22 (53.7)
11 (26.8)
8 (19.5)
22 (53.7)
11 (26.8)
ND 8 (19.5)
26 (63.4)
15 (36.6)
2 (4.9)
23 (56.1)
16 (39.0)
17 (41.5)
14 (34.1)
9 (22.0)
1 (2.4)
7 (17.1)
30 (73.2)
2 (4.9)
1 (2.4)
1 (2.4)
32 (78.1)
39 (95.2)
Colombia (ONCOLGroup study)
Median 14.7 mo
IC95% (11.8-17.6)
Colombia
IC95% (11.8-17.6)
Survival
Survival
P = 0.093
México
IC95% (8.8-13.1)
Time (months)
Time (months)
Progresion free survival
Cardona AF, et al. ASCO 2011.
Outcomes in Latin American NSCLC patients harboring wild-type
or activating mutations of EGFR (CLICaP Registry) - submitted to
ASCO 2012
PFS: 13 months
mEGFR
(n=175)
Stage IV NSCLC
- CLICaP Registry (n=589)
OS: 36 months
RR: 70%
PFS: 3 months
Non-EGFR
mEGFR
%
Female
57%
Adenocarcinoma
89%
Exon 19 mutations
58%
L858R mutation
36%
(n=414)
PFS: 14 months
RR: 29%
Arrieta O, Cardona AF, Bramuglia G, Campos AD, Becerra H, Martín C, Richardet
E, Serrano S, Y powazniak, Rosell R, on behalf of the CLICaP.
Main study schedule - Colombia
Test for
ALK/ELM4
Translocation
+
N=1
N=26
Test BRAF
-
Test Her2
-
N=322
Test for
KRAS
mutation
N=205
Test for
EGFR
mutation
N=322
N=80
No further
molecular
testing
+
N=1
N=36
Test PI3k
+
N=20
N=35
No further
molecular
testing
+
N=0
N=60
N=170
N=242
+
Patients with available data
concerning the use of erlotinib
(N=41)
+
N=1
ALK/ELM4
Juxtaposed the 5’ end of the EML4 gene with the 3’end of the ALK gene
MET
Cytoplasmic Fusion Variants
of ALK
ALK
b a
SEMA
Extracellular
TM
TM
Extracellular
TM
TM
P
Intracellular
Kinase
Kinase
Intracellular
YY
YY
P
P
Kinase
YY
YYP
YY P
P
YYP
P
P
YY
P
YYP
P
P
YY
YY
YYP
YY
NPM-ALK
YY
P
YY
Soda S, et al. Nature 2007.; Perner, et al. Neoplasia 2009.; Soda S, et al. PNAS 2008.
P
Kinase
YY
P
YY
YYP
P
YY
EML4-ALK
ALK/EML4 mutation around the world
4.2%
8.0%
2.7%
3.7%
J Clin Oncol 2009;27:4232–4235.
J Thorac Oncol .2009;4:1450-1454.
Tumor responses to crizotinib by patient
PROFILE 10011
PROFILE 10052
Median time to response: 8 wk
30
1. Camidge et al., ASCO 2011; Abs #2501.
2. Riely et al., IASLC 2011; Abs #O31.05.
Survival in ALK-positive NSCLC with crizotinib
versus crizotinib-naive controls
WT/WT
Control
(n=125)
ALK Crizotinib ALK Control
(n=30)
(n=23)
100%
80%
Median Survival, mo
NR
6
11
1-yr Survival, %
70
44
47
2-yr Survival, %
55
12
32
60%
From 2nd/3rd line crizotinib
HR = 0.49, p=0.02
40%
20%
0%
0
31
1
2
3
4
Overall survival (years)
Shaw et al., ASCO 2011; Abs #7507.
Adenocarcinoma de pulmón en mujer no fumadora T3N2(multinivel)M1(hueso) G2LxVx
ALK/EML4+ NSCLC
NPA (Female/53 yo)
Lung adenocarcinomaT3N2(multilevel)M1(bone) G2LxVx
Stage IV
EGFR 19 - L858R - T790M basal Wt/BCRA1 (T1)/RAP80 (T1)/ERCC1 (bajos niveles)/NKX2 (T1)/ ALK/ELM4 (V1+)
8 months
14 months
Diagnosis
24.10.09
1st line
Cis/Pem x 6 cycles
02.12.09 d
OS
3 months
OS 2.4 years
Manteinance
Pem x 4 cycles
27.05.10
2nd line
CBP/Gem/Bev
21.07.10
Manteinance
Bev x 13 cycles
27.05.10
3rd line
Doc x 3 cycles
03.07.11
PD 14.06.11
(Pleural)
PD 22.08.11
(Pericardial)
+
RT 6.000 cGy
PD 25.06.10
(one lesion brain)
Radiosurgery
02.07.10
4th line
Crizo x 1 cycles
13.10.11
NSCLC in Colombia
Relatively low incidence compared to
other countries: 15/100.000
High letality
Other mutations
ALK/EML4 and others have been found
They hold the promise of individualized care
Outcomes with CT
At first glance (and with very
limited data): Similar to other
countries
EGFR mutations
In mEGFR enriched samples: 32%
PFS/OS with 1st-line anti EGFR TKI appear to
be non-inferior to other cohorts
When should we perform genotyping in NSCLC?
SCENE
4
Different sub-types of NSCLC
Never
At progression
EGF/ALK
Mutation
At diagnosis
When should we perform genotyping in NSCLC
Different sub-types of NSCLC
Never
At progression
EGFR/ALK
Mutations
At diagnosis
When should we perform genotyping in NSCLC
Different sub-types of NSCLC
Never...
Never
 All patients are candidates to anti-EGFR therapy
 1st Line (EURTAC)
 Maintenance (Saturn-trial)
 2nd / 3rd Line (BR.21)
 No proven increase in OS with 1st Line TKI in mEGFR
 Likelihood of driver mutations other than EGFR, low
 No anti ALK/EML4 therapy in Colombia (at this time)
When should we perform genotyping in NSCLC?
Different sub-types of NSCLC.
Post-progression
Progression
 After chemotherapy progression
 To define anti EGFR vs 2nd Line Chemotherapy
 To identify other driver mutations (ie, ALK+ NSCLC)
 Not supported by clinical evidence
 May be reasonable
 Whom?
 All
 EGFR/ALK enriched populations?
When should we perform genotyping in NSCLC?
Different sub-types of NSCLC.
At diagnosis
Diagnosis
 In mEGFR patients may delay Chemotherapy initiation
 No benefit in OS for mEGFR (non-asiatic) patients with 1st
Line TKIs
 May help identify other driver mutations (ie, ALK+)
 But, should we treat those 1st or after conventional Rx?
 Whom?
 Restrict to non/light-smokers with adenocarcinoma?