Lung Cancer Genotyping in Colombia Mauricio Lema Medina MD Clínica de Oncología Astorga -...
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Transcript of Lung Cancer Genotyping in Colombia Mauricio Lema Medina MD Clínica de Oncología Astorga -...
Lung Cancer Genotyping in Colombia
Mauricio Lema Medina MDClínica 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
Colombia
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2010
http://rpcc.univalle.edu.co/
Globocan, 2008
Cisplatin-based CT in advanced NSCLC
Meta-AnalysisModest improvement in
OS
NSCLC Collaborative Group. BMJ 1995;311:899–909
Supportive care + CTSupportive care
Cisplatin-Based chemotherapy for advanced NSCLC
100
80
60
40
20
0
Surv
ival
(%)
0 6 12 18 24Time from randomisation (months)
Platinum-Based Doublets in Advanced NSCLC
Schiller, et al. NEJM 2002
Meses
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0
Carboplatin / paclitaxelCisplatin / docetaxelCisplatin / gemcitabineCisplatin / paclitaxel
Prob
abili
dad
de s
uper
vive
ncia
ECOG trial 1594ECOG, Eastern Cooperative Oncology GroupSchiller et al. N Engl J Med 346:92, 2002
NSCLC Outcomes in Bogotá, Colombia
Cardona AF. Rev Venez Oncol 2010; 22(1):66-83
n=345n=345
n=176n=176
Stage IIIB / IV NSCLCReceived anti cancer agents
Male64%Male64%
PS 0/145%
PS 0/145%
Adeno60%
Adeno60%
Squamous24%
Squamous24%
Weight loss61.5%
Weight loss61.5%
Platinum-doublets71%
Platinum-doublets71%
Gem/Vin mono19%
Gem/Vin mono19%
Erlotinib4.5%
Erlotinib4.5%
1st Line therapy
NSCLC Outcomes in Bogotá, Colombia
Cardona AF. Rev Venez Oncol 2010; 22(1):66-83
PFSCisplatin: 4.7 m
Carboplatin: 3.2 m
PFSCisplatin: 4.7 m
Carboplatin: 3.2 m
3.4
OSMedian: 9.2 m1-yr OS: 26%
OSMedian: 9.2 m1-yr OS: 26%
Molecular subtypes of lung carcinomaMolecular subtypes of lung carcinoma
PIK3CAPIK3CAH
ER2H
ER2
EGFREGFR
EML4-ALK
EML4-ALK
BRAFBRAF
K-ra
sK-
ras
FGFR4
FGFR4
Recently described Recently described
MEK1MEK1
ROS fusion geneROS fusion gene
PDGFR ampPDGFR amp
LKB1LKB1
ERKERK
BIMBIM
METMET
Lung cancer 2010 – USALung cancer 2010 – USA219,000 new cases219,000 new cases
KRAS-mutated NSCLC 36.000 cases/year
EGFR-mutated NSCLC 18.000 cases/year
EML4-ALK NSCLC 9.000 cases/year
CML5.000 cases/year
Yearly incidence of cancers with driver mutationsYearly incidence of cancers with driver mutations
Small-cell lung cancer (13%)
EGFR mutated (10% NSCLC )
KRAS mutated (25% of adenocarcinoma)
OtherNSCLC
Pao W. ASCO 2010.
EGFR mutations around the worldEGFR mutations around the world
Overall 40% - 50%E19 51%E21 42%E20 2%
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 15.8%
E19 64.3%E21 24.7%
IPASS: Carboplatin + Paclitaxel vs Gefitinib in metastatic NSCLC adenocarcinoma (very low smoking burden)
Mok T, et al. ESMO 2008
Adenocarcinoma, Stage IV, PS 0-2, very low
smoking burden(n=1217)
Carboplatin + Paclitaxel (PC)(n=608)
Gefitinib(n=609)
Median OS (months) PC Gefitinib P
All 17.3 18.6 NS
PC: Carboplatin AUC 5-6 d1 + Paclitaxel 200 mg/m2 d1. q21 days x6. Gefitinib: 250 mg vía PO qd. Crossover allowed
HR for progression HR P
Wild type EGFR 2.85 0.0001
Mutated EGFR 0.48 0.0001
EURTAC: CT vs Erlotinib in mEGFR NSCLC
Chemo-naive metastasticNSCLC with mEGFR
(n = 173)
Chemotherapy(n = 87)
Erlotinib 150 mg PO qd(n = 86)
Rosell R, et al. ASCO 2011. Abstract 7503.
Primary End-Point: Overall survival.
EURTAC: Response and Safety
• CT-treated patients had increased frequency of:– Grade 3/4 AEs (81% vs 45%)
– Dose modification or interruption due to treatment-related AE (47% vs 23%)
– Discontinuation due to treatment-related AE (14% vs 5%)
– Treatment-related serious AEs (16% vs 7%)
Response Outcome, %
Erlotinib(n = 86)
Chemo(n = 87)
Objective response 58 15
CR 2 0
PR 56 15
Disease control rate 79 66
SD 21 51
PD 7 13
No response assessed
14 22
Rosell R, et al. ASCO 2011. Abstract 7503.Clinical Care Options.
Rosell R, et al. ASCO 2011. Abstract 7503. Reprinted with permission.
EURTAC: Erlotinib vs Chemo in EGFR Mutation-Positive, Stage IIIB/IV NSCLC
• Phase III; significant benefit in PFS and with erlotinib vs chemotherapy
Erlotinib (n = 86)Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-0.54; log-rank P < .0001)
PFS
Prob
abili
ty
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33
Mos
5.2 9.7
Patients at Risk, nErlotinibChemo
8687
6349
5420
328
215
174
93
71
40
20
20
00
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
Rosell R, et al. ASCO 2011. Abstract 7503.
0.1 0.2 0.4 0.6 0.8 1.0 1.5 2.0 4.0
Favors Erlotinib HR Favors Chemotherapy
All< 65 yrs≥ 65 yrs
MaleFemale
PS 0PS 1PS 2
Current smokerFormer smoker
Never smokerExon 19 deletionL858R mutation
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)
n173858847
1265792241934
12011558
Clinical Care Options.
Study designStudy design
Between subjects factorial design
20
Target populationColombia incident cases of LAC
Accesible populationLAC cases analized in a centralized laboratory
Study sampleLAC cases with complete genotipification
10
10
EGFR+
KRAS+
KRAS/EGFRWt
Alk
BRAF
Her2
PI3K
Random allocation Control
Mea
sure
men
t of c
linic
al o
utco
mes
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.
+N=1
+N=0
Main study schedule - Colombia
-
+
-
+
+
N=322N=322
N=322N=80
N=26
N=205
N=242
N=35
N=170
N=1
N=60
N=36
+N=1
N=20
Variable N (%)Number of pts treated with erlotinib(follow-up available data)
41 (51%)
Mean age (SD) 63 yrs (±12)Stratified age >65 yrs <65 yrs ND
13 (31.7)24 (58.558.5)
4 (9.8)Sex Male Female
9 (22.0)32 (78.078.0)
Tobacco exposure Never smoker Former smoker Current smoker
30 (73.273.2)10 (24.4)
1 (2.4)Main metastasis (site) Pleuropulmonary Brain Liver Bone ND
26 (63.4)4 (9.8)3 (7.3)2 (4.9)
6 (14.6)
Hormonal receptor status (tumor tissue) Positive Negative ND
22 (53.753.7)11 (26.8)8 (19.5)
TTF1 status Positive Negative ND
22 (53.753.7)11 (26.8)
ND 8 (19.5)Mutation type delE19 L858R
26 (63.463.4)15 (36.6)
T790M basal Positive Negative ND
2 (4.94.9)23 (56.1)16 (39.0)
Line of treatment 1 2 3 ND
17 (41.5)14 (34.1)9 (22.0)1 (2.4)
Response Stable disease Partial response Complete response Progressive disease ND
7 (17.117.1)30 (73.273.2)
2 (4.94.9)1 (2.4)1 (2.4)
Overall response rate 32 (78.1)Clinical benefit 39 (95.2)
Main characteristics of EGFR mutant populationMain characteristics of EGFR mutant population
Colombia (ONCOLGroup study)Colombia (ONCOLGroup study)
Cardona AF, et al. ASCO 2011.
ColombiaIC95% (11.8-17.6)
MéxicoIC95% (8.8-13.1)
P = 0.093
Time (months)
Surv
ival
Surv
ival
Progresion free survival
Time (months)
Median 14.7 mo IC95% (11.8-17.6)
Outcomes in Latin American NSCLC patients harboring wild-type or activating mutations of EGFR (CLICaP Registry) - submitted to
ASCO 2012
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.
Stage IV NSCLC- CLICaP Registry -
(n=589)
mEGFR
Non-EGFR
(n=175)
(n=414)
PFS: 13 months
OS: 36 months
PFS: 3 months
PFS: 14 months
RR: 70%
RR: 29%mEGFR %
Female 57%
Adenocarcinoma 89%
Exon 19 mutations 58%
L858R mutation 36%
+N=1
+N=0
Main study schedule - Colombia
-
+
-
+
+
N=322N=322
N=322N=80
N=26
N=205
N=242
N=35
N=170
N=1
N=60
N=36
+N=1
N=20
ALK/ELM4ALK/ELM4
MET ALK
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
SEMA
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPPYYPPYYPP
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
TMExtracellular
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
NPM-ALK EML4-ALK
Soda S, et al. Nature 2007.; Perner, et al. Neoplasia 2009.; Soda S, et al. PNAS 2008.
Juxtaposed the 5’ end of the EML4 gene with the 3’end of the ALK gene
ALK/EML4 mutation around the worldALK/EML4 mutation around the world
J Clin Oncol 2009;27:4232–4235. J Thorac Oncol .2009;4:1450-1454.
30
Tumor responses to crizotinib by patientTumor responses to crizotinib by patient
Median time to response: 8 wk
1. Camidge et al., ASCO 2011; Abs #2501.2. Riely et al., IASLC 2011; Abs #O31.05.
PROFILE 10052PROFILE 10011
31
Survival in Survival in ALKALK-positive NSCLC with crizotinib -positive NSCLC with crizotinib versus crizotinib-naive controlsversus crizotinib-naive controls
0
0%
20%
40%
60%
80%
100%
Overall survival (years)1 2 3 4
Shaw et al., ASCO 2011; Abs #7507.
ALKALK Crizotinib Crizotinib(n=30)(n=30)
ALKALK Control Control(n=23)(n=23)
Median Survival, mo NRNR 66
1-yr Survival, % 7070 4444
WT/WT WT/WT ControlControl(n=125)(n=125)
1111
4747
From 2From 2ndnd/3rd line crizotinib/3rd line crizotinib
2-yr Survival, % 5555 1212 3232
HR = 0.49, p=0.02HR = 0.49, p=0.02
ALK/EML4+ NSCLCALK/EML4+ NSCLC
NPA (Female/53 yo)
Adenocarcinoma de pulmón en mujer no fumadora T3N2(multinivel)M1(hueso) G2LxVx
Lung adenocarcinomaT3N2(multilevel)M1(bone) G2LxVx Stage IVStage IV
Diagnosis24.10.09
1st lineCis/Pem x 6 cycles
02.12.09 d
++RT 6.000 cGy
ManteinancePem x 4 cycles
27.05.10
PD 25.06.10(one lesion brain)
Radiosurgery 02.07.10
2nd lineCBP/Gem/Bev
21.07.10
ManteinanceBev x 13 cycles
27.05.10
PD 14.06.11(Pleural)
3rd lineDoc x 3 cycles
03.07.11
PD 22.08.11 (Pericardial)
4th lineCrizo x 1 cycles
13.10.11
8 months 14 months 3 months
OS
OS 2.4 years OS 2.4 years
EGFR 19 - L858R - T790M basal Wt/BCRA1 (T1)/RAP80 (T1)/ERCC1 (bajos niveles)/NKX2 (T1)/ ALK/ELM4 (V1+)
NSCLC in Colombia
Outcomes with CT
ALK/EML4 and others have been foundThey hold the promise of individualized care
At first glance (and with very limited data): Similar to other countries
Other mutationsRelatively low incidence compared to
other countries: 15/100.000
High letality
In mEGFR enriched samples: 32%PFS/OS with 1st-line anti EGFR TKI appear to
be non-inferior to other cohorts
EGFR mutations
At progressionNever
EGF/ALKMutation
At diagnosis
SCENE4
When should we perform genotyping in NSCLC?
Different sub-types of NSCLC
At progressionNever
EGFR/ALKMutations
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)
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)
Never
When should we perform genotyping in NSCLC
Different sub-types of NSCLC
Post-progressionPost-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?
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?
Progression
When should we perform genotyping in NSCLC?
Different sub-types of NSCLC.
At diagnosisAt 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?
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?
Diagnosis
When should we perform genotyping in NSCLC?
Different sub-types of NSCLC.