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.