Impact of Overall Survival in Advanced NSCLC EGFR+ · Impact of Overall Survival in Advanced NSCLC EGFR+ ... American Cancer Society Cancer Facts and Figures 2012. 2. ... SEER Cancer

01

Impact of Overall Survival in Advanced NSCLC EGFR+Dr. E. Omar Macedo PérezThoracic Tumors Clinic; INCan

02

Topics

• Review of OS data for chemotherapy:– Doublet with platinum– Histology-based therapy

• Review of OS data with bevacizumab

• Review of OS data with first-generation TKIs

• Review of OS for afatinib (2nd-Generation TKI): OS analysis of LUX-Lung 3 and 6

• Future of OS in NSCLC with EGFR mutated

• Conclusions

Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications.

03

1. American Cancer Society Cancer Facts and Figures 2012.2. Epidemiology of Lung Cancer. Chest. 2007;132:29S-55S.3. GLOBOCAN 2012 (IARC).

Lung Cancer: First Cause of Death Due to Cancer Worldwide

• 1.8 million new cases/year

• 1.62 million deaths/year

• 226,000 new cases

• 160,000 deaths

04

GLO

BO

CA

N 2

012

8439 / 5.7% 7608 / 9.7%

147,985 78,719

Lung Cancer Is the Leading Cause of Cancer-relatedDeath in Mexico

05

0

10

20

30

40

50

60

70

80

90

Stages I and II Stage III Stage IV

USA Mexico

15%

1.2%

25%

16.8%

82%

60%

SEER Cancer Statistics Review, 1975-2008.Macedo EO and Arrieta O. INCan Data 2009-2014.

85% will require palliative treatment!!

NSCLC: Stages at Diagnosis (USA vs Mexico)

06

AJCC 7th edition.

OS in Advanced Stages

07

Review of OS Data for Chemotherapy (First-Line)

08

Karnofsky DA, et al. Cancer. 1948;1:634-656.Kennedy BJ. Cancer. 1998;82:801-803.

1948

09

Progress in Lung Cancer Research

1995CT vs BSC:CT standard

2006QT +

Bevacizumab

010

NSCLC Collaborative Group. BMJ. 1995;311:899-909.

1995

Meta-analyses Confirm Survival Benefit With Chemotherapy in Advanced NSCLC

• N=778 patients

• 11 clinical trials

• Cisplatin plus etoposide or vinca alkaloids

• At 1 year, an absoluteimprovement in OS of 10%

• An increased median survivalof 1.5 months (P<0.0001)

011

New Drugs for Treatment of NSCLC

012

HR 0.77 (CI 95% 0.71 to 0.83)P<0.0001

A Second Meta-analysis Confirms Survival Benefit With Chemotherapy in Advanced NSCLC

2008

NSCLC Meta-Analysis Collaborative Group. J Clin Oncol. 2008;26:4617-4625.

• N=2,714 patients

• 16 clinical trials

• At 1 year, an absoluteimprovement in OS of 9% (20 vs 29%)

• Benefit with platinum-based CT

• Doublets with cisplatin: absolutebenefit in OS of 3 months

013

N = 1,207

ECOG 2002 Trial: Four Different Platinum-based Doublets With Similar OS

Schiller JH, et al. N Engl J Med. 2002;346:92-98.

014

CT OS(m)

1 Year (%)

PC 7.8 31

GC 8.1 36

DC 7.4 31

PCb 8.1 34

CT OS(m)

1 Year (%)

PCb 9.9 43

GC 9.8 37

CV 9.5 37

Pacli + carbo (PCb)Cis + vin (CV)

Ove

rall

surv

ival

%

100

80

60

40

20

00

Months Months

Ove

rall

surv

ival

30

Pacli + cis (PC)Gem + cis (GC)Doc + cis (DC) Pacli + carbo (PCb)

5 10 15 20 25

Pacli + carbo (PCb)Gem + cis (GC) Cis + vin (CV)

Months0

1.0

0.9

0.6

0.5

0.4

0.3

0.8

0.7

0.2

0.10

1.00.9

0.6

0.5

0.4

0.3

0.8

0.7

0.2

0.10

Ove

rall

surv

ival

305 10 15 20 250305 10 15 20 25

Several Combinations With Cisplatin:Reaching a Plateau in Efficacy

Kelly K, et al. J Clin Oncol. 2001;19:3210-3218. Schiller JH, et al. N Engl J Med. 2002;346:92-98. Scagliotti GV, et al. J Clin Oncol. 2002;20:4285-4291.

CT OS (m)

1 Year (%)

PCb 8.6 38

CV 8.1 36

015

Chemotherapy NumberPFS

(months)OS

(months)1-year survival

(%)ORR(%)

CDDP-Vinorelbine 202 4 months 8 months 36% 28

Carbo-Paclitaxel 208 4 months 8 months 38% 26

Paclitaxel-Carboplatin 299 3.1 months 7.8 months 34% 29

CDDP-Gemcitabine 301 4.2 months 8.1 months 36% 26

CDDP-Docetaxel 304 3.7 months 7.4 months 31% 31

CDDP-Paclitaxel 303 3.4 months 8.1 months 31% 29

CDDP-Vinorelbine 404 5.2 months 10.1 months 41% 30

CDDP-Docetaxel 408 5.2 months 11.3 months 46% 32

Carbo-Docetaxel 406 5.0 months 9.4 months 40% 26

CDDP-Vinorelbine 201 4.6 months 9.5 months 37% 29

CDDP-Gemcitabine 205 5.3 months 9.8 months 37% 28

Carboplatin-Paclitaxel 201 5.5 months 9.9 months 43% 31

Efficacy of CT in First Line Treatment of Advanced NSCLC

Kelly K, et al. J Clin Oncol. 2001;19:3210-3218. Schiller JH, et al. N Engl J Med. 2002;346:92-98.Fossella F, et al. J Clin Oncol. 2003;21:3016-3024.Scagliotti G, et al. J Clin Oncol. 2002;20:4285-4291.

≈5 months ≈8-10 months ≈40% ≈30%

016

Review of OS Data With Bevacizumab

017

Sandler A, et al. N Engl J Med. 2006;355:2542-2550.Reck M, et al. J Clin Oncol. 2009;27:1227-1234.Crinò L, et al. Lancet Oncol. 2010;11:733-740.

Bevacizumab in NSCLC

http://www.google.com.gt/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=OqcaWK8JCpSEYM&tbnid=witq8i4k4sFlPM:&ved=0CAUQjRw&url=http://www.scientistlive.com/content/roche%E2%80%99s-avastin-approved-japan&ei=EE-FUpK6CMzIkAfF6IDQAQ&bvm=bv.56343320,d.eW0&psig=AFQjCNG-ALWniSzCWczznKGMA2jC8H7ihg&ust=1384554622167535

http://www.google.com.gt/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=OqcaWK8JCpSEYM&tbnid=witq8i4k4sFlPM:&ved=0CAUQjRw&url=http://www.scientistlive.com/content/roche%E2%80%99s-avastin-approved-japan&ei=EE-FUpK6CMzIkAfF6IDQAQ&bvm=bv.56343320,d.eW0&psig=AFQjCNG-ALWniSzCWczznKGMA2jC8H7ihg&ust=1384554622167535

018

2 months OS:12.3 vs 10.3 mo

HR 0.79P=0.003

PFS:6.2 vs 4.5 mo

HR 0.66P<0.001

ECOG 4599: Paclitaxel–Carboplatin Alone or WithBevacizumab for Non–Small-Cell Lung Cancer

Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

019

12.313.5*

14.613.3‡

Med

ian

OS

(mon

ths)

18

12

6

0E45991 AVAiL2 SAiL3 ARIES4

15 mg/kg 7.5/15 mg/kg 7.5 or 15 mg/kg 7.5 or 15 mg/kg

CT + Bevacizumab: Median OS >1 Year

1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550; 2. Reck M, et al. Ann Oncol. 2010;21:1804-1809; 3. Crinò L, et al. Lancet Oncol. 2010;11:733-740; 4. Wozniak AJ, et al. ASCO 2010.

020

3

7

10

12.5

0

2

4

6

8

10

12

14

BSC Monotherapy Doublets withcisplatin

CT + Bevacizumab

Med

ian

OS

(mon

ths)

1975 1990 2000 2006

OS in Advanced NSCLC: Urgent Need for New Treatment Options

NSCLC Cooperative Group, Meta-analysis. J Clin Oncol. 2008;26:4617-4625; Kelly K, et al. J Clin Oncol. 2001;19:3210-3218; Schiller JH, et al. N Engl J Med. 2002;346:92-98; Scagliotti G, et al. J Clin Oncol. 2002;20:4285-4291; Sandler A, et al. N Engl J Med. 2006;355:2542-2550.

021

Histology-based Therapy

022

Non-small-cell Lung Cancers: A Heterogeneous Set of Diseases

Chen Z, et al. Nat Rev Cancer. 2014;14;535-546.

023

TS

• SCLC – High expression of TS• Squamous (SQ) – High expression of TS• Adeno – Low expression of TS

Thymidylate Synthetase in Lung Cancer

Bhattacharjee A, et al. Proc Natl Acad Sci U S A. 2001;98:13790-13795.

024

Low Expression of Thymidylate Synthetase in Adenocarcinoma: Better Response to Pemetrexed?

Ceppi P, et al. Cancer. 2006;107:1589-1596.Gronberg BH, et al. J Thorac Oncol. 2013;8:1255-1264.

025

Noninferiority study, 1725 patients

Phase III Study Comparing Cisplatin Plus GemcitabineWith Cisplatin Plus Pemetrexed in Chemotherapy-NaivePatients With Advanced-Stage NSCLC

Scagliotti V, et al. J Clin Oncol. 2008;26:3543-3551.

026

OS Squamous(n=172; 130 events)

Adj HR=1.563(95% CI: 1.079-2.264)

P=0.0182DocetaxelMedian = 7.4 months

PemetrexedMedian = 6.2 months

PemetrexedMedian = 9.3 months

DocetaxelMedian = 8.0 months

OS Nonsquamous(n=399; 279 events)

Adj HR=0.778(95% CI: 0.607-0.997)

P=0.0475

JMEI Study: Pemetrexed vs Docetaxel in Second-line (Retrospective Analyisis)

Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.Peterson et al. ECCO. 2007.

027

ECOG 4599: Bevacizumab in Advanced nonsquamos NSCLC (OS)

ECOG 4599: Bevacizumab in Advanced Adenocarcinoma (OS)

Adenocarcinoma:Pemetrexed + Bevacizumab?

Adenocarcinoma: Better Results With Bevacizumab

2.3 months

3.9 months

028

Censoring rate for Pem+Cb+Bev was 27.8%; for Pac+Cb+Bev was 27.2%

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 3 6 9 12 15 18 21 24 27 30 33 36 39

Time (months)

OS

prob

abili

ty

Pem+Cb+Bev

Pac+Cb+Bev

ASCO 2013.

POINTBREAK, a Randomised Phase III Trial: OS Since Induction Therapy (ITT)

Pem+Cb+Bev Pac+Cb+BevMedian OS (months) 12.6 13.4

HR (95% CI)P value

1.00 (0.86–1.16)

P=0.949

029

3

7

10

12.5 11.8

0

2

4

6

8

10

12

14

BSC Monotherapy Doublets withcisplatin

CT +Bevacizumab

CT byhistology

Med

ian

OS

(mon

ths)

1975 1990 2000 20082006

OS in Advanced NSCLC: Urgent Need for New Treatment Options

030

Target Therapy: Personalised Medicine

031

CPCP(≈15%)

Squamous cell(≈25%)

Adenocarcinoma(≈45-50%)

BAV(≈5%)

Large cell(≈5%)

Other (Not specified)

(≈10%)

Molecular Differences in Subtypes of Lung Cancer

Sun S, et al. Nat Rev Cancer. 2007;7:778-790.Lindeman NI. Arch Pathol Lab Med. 2013;137:828.

032

Molecular Alterations in NSCLC

Davidson MR. J Thorac Dis. 2013;5:S463-S478.

033

Adeno CG/CPNE Squamous cell CPCP

EGFR mutation ALK ROS/RET

HER2

BRAF KRAS

KRAS

Treatment According to Therapeutic Targets

034

OS According to Driver Mutations and Type of Treatment

Johnson B, et al. ASCO 2013. Abstract 8019.

Mutation + target therapy (n=313)Mutation without target therapy (n=265)No mutations CT (n=361)

100

80

60

40

20

0

Ove

rall

Surv

ival

(%)

0 1 2 3 4 5

Years

035

Review of OS Data With First-Generation EGFR TKIs

036

EGFR TKIs

Yu HA, et al. Clin Cancer Res. 2014;20:5898-5907.Janne. Mini Symposium MS27, WCLC 2013.

Drug Status FDACovalent-binding

Activity in T790M Structure Generation

Gefitinib Approved No No Quinazoline First

Erlotinib Approved No No Quinazoline First

Dacomitinib Phase III Yes No Quinazoline Second

Afatinib Approved Yes ± Quinazoline Second

AP26113 Phase I/II No ? Pyrimidine Third

CO-1686 Phase I Yes Yes Pyrimidine Third

AZD9291 Phase II Yes Yes Pyrimidine Third

037

IRESSA Registry in

Japan

ISEL

INTEREST

2002 200920072005

ISEL, INTEREST: non selective patients with previous treatment

2003Expression of EGFR protein

EGFR gene copy number

2004 2006 2008

History of Gefitinib

038

Randomisation

IRESSA® (250 mg) + BSC

Placebo + BSC

Primary endpoint:

SURVIVAL2:1 ratio

1692 patients in 210 centers across 28 countries stratified for histology, gender, intolerant/refractory disease, and smoking history

ISEL (IRESSA® Survival Evaluation in Lung Cancer)

Thatcher et al. 2005.

039

0 1 2 3 4 6 8 9 10 11 12 13 14 1

MonthsAt risk: 1692 1348 876 484 252 103 31

Patie

nts

surv

ivin

g (%

)

—— IRESSA®

------ Placebo

ORR: 7.1% vs 0.5%

ISEL Trial: Overall Population–Survival


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 2 4 6 8 10

040

PFS in overall population

Hazard ratio and 95% CI

Favours IRESSA® Favours placebo

Survival Response rate

Non-adenocarcinoma 4.6%

Never smoked 17.2%Ever smoked 5.2%

Refractory 7.8%

1 prior chemo 7.4%2 prior chemos 8.0%

PS 0,1 8.3%PS 2,3 6.6%

Male 4.9%

All patients 7.7%0.4 0.6 0.8 1 1.5

Adenocarcinoma 11.4%

Female 14.0%

ISEL Study: Effects in Subsets (1)


Intolerant 7.2%

041


Survival Response ratePrior docetaxel

All patients

Asian ethnicity

Time since Dx: >12 mo

Time since Dx: <6 mo

<65 yrs

No prior docetaxel

≥65 yrs

Time since Dx: 6-12 mo

Non-Asian ethnicity

Hazard ratio and 95% CI

Favours IRESSA® Favours placebo

Prior chemo response: PD/NE

Prior chemo response: CR/PRPrior chemo response: SD

10.3%

7.7%

12.0%

9.3%

6.8%

7.1%

6.7%

8.7%

6.9%

6.5%

7.0%

8.9%8.0%

0.4 0.6 0.8 1 1.5

Effects in Subsets (2)


042O

S (%

)

0 2 4 6 8 10 12 14 160.0

1.0

0.8

0.6

0.4

0.2

HR 0.67; 95% CI 0.49, 0.92; P=0.012Never smokers (n=375)

GefitinibPlacebo

0 2 4 6 8 10 12 14 16

Ever smokers (n=1317)HR 0.92; 95% CI 0.79, 1.06; P=0.242

1.0

Time (Months)

0.0

0.8

0.6

0.4

0.2

0 2 4 6 8 10 12 14 16

HR 0.66; 95% CI 0.48, 0.91; P=0.010

Cox Regression Analysis

0 2 4 6 8 10 12 14 16

Nonasian Origin (n=1350)HR 0.92; 95% CI 0.80, 1.07; P=0.294

OS

(%)

Asian origin (n=342)

ISEL Study: OS by Smoking History and Ethnic Origin


043

044

EGFR expression

+n=189

EGFR FISH +n=117

EGFR mutation +n=39

+++ n=24

4

3

n=16

n=73

n=84

n=8

Douillard. 2010.Soulières. ASCO 2011.

ISEL Trial: Overlap of Biomarkers (n=249) EGFR Gene Copy Number (FISH), IHC, or EGFR Mutation?

045

IPASS

IPASS: enrichment population, naive-treatment

Mutations in EGFR

History of Gefitinib

IRESSA Registry in

Japan

ISEL

INTEREST

2002 200920072005

ISEL, INTEREST: non selective patients with previous treatment

2003Expression of EGFR protein

EGFR gene copy number

2004 2006 2008

046

Lynch et al. 2004 (New Eng J Med. 350:2129-2139)

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib

Paez et al. 2004 (Science. 304:1497-1500)

EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

Mitsudomi T et al. J Clin Oncol. 2005;23(11):2513-2520

Mutations of the Epidermal Growth Factor Receptor Gene Predict Prolonged Survival After Gefitinib Treatment in Patients With Non-Small-Cell Lung Cancer With Postoperative Recurrence

EGFR Mutations: First Observed in 2004

047

Gefitinib250 mg/day

Carboplatin AUC 5 or 6 and Paclitaxel 200 mg/m2 3 wkly

×6 cycles

1:1 randomisation

Patients• Adenocarcinoma

histology

• Never smokers or light ex-smokers*

• PS 0-2

• Provision of tumour sample for biomarker analysis strongly encouraged

EndpointsPrimary• Progression-free survival

(non-inferiority)Secondary• Objective response rate• Quality of life• Disease-related symptoms• Overall survival• Safety and tolerabilityExploratory• Biomarkers

EGFR mutation EGFR gene copy number EGFR protein expression

*Never smokers: <100 cigarettes in lifetime; light ex-smokers: stopped ≥15 years ago and smoked ≤10 pack-years.Carboplatin/paclitaxel was offered to IRESSA patients upon progression.PS = performance status; EGFR = epidermal growth factor receptor.Mok T, et al. N Engl J Med. 2009;361:947-957.

IPASS: Phase III Study of Gefitinib vs Doublet Chemotherapy in First-line NSCLC

• 1217 patients from East Asian countries

048

IPASS: EGFR Mutation Is a Strong Predictor for Differential PFS Benefit Between Gefitinib and Doublet Chemotherapy (L858R, Del exon 19)

Mok T, et al. N Engl J Med. 2009;361:947-957.

EGFR M+HR=0.48, 95% CI 0.36, 0.64 P<0.0001EGFR M-HR=2.85, 95% CI 2.05, 3.98 P<0.0001Treatment by subgroup interaction test, P<0.0001

0 4 8 12 16 20 24

Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty o

f PFS

Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin/paclitaxel EGFR M+ (n=129)Carboplatin/paclitaxel EGFR M- (n=85)3.4 months

049

Treatment by subgroup interaction test P value

P=0.0437 for EGFRgene copy number

P=0.2135 for EGFRexpression

P<0.0001 for EGFRmutation

Favours gefitinib Favours carboplatin/paclitaxel

Known mutation status

EGFR Mutation+

EGFR Mutation-

Known expression status

EGFR +

EGFR -

Known FISH status

EGFR FISH+

EGFR FISH-

0.25 0.5 1.0 2.0 4.0Hazard Ratio (Gefitinib: Carboplatin/Paclitaxel) and 95% CI

IPASS: PFS by Biomarkers (ITT)

Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2871.

050

N=329 with known biomarker status for all 3 biomarkers

EGFR Mutation+ n=261

EGFR FISH+ n=249

+++ = 132

2551

13

28

1534

EGFRexpression +

n=266

IPASS: Overlap of Biomarkers

Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2871.

051

Higher RR with CT in EGFR mutated vs EGFR WT 4 or 6 cycles of CT?

IPASS: ORR

Mok T, et al. N Engl J Med. 2009;361:947-957.

EGFR+ EGFR- PORR with CT 47.3% 23.5% <0.001ORR with TKI 71.2% 1.1% <0.00001

052

Seven prospective trials; NSCLC patients with EGFR mutations

RRs were 76% vs 24.6% (P<0.001)4.7 months

Combined Survival Analysis of Prospective Clinical Trials of Gefitinib for NSCLC EGFR+

Satoshi M, et al. Clin Cancer Res. 2009;15:4493-4498.

053

Common mutations (Del. Exon 19/L858R)

4.5 months

CT for 3-4 Cycles

EURTAC, A Randomised Phase III Trial: Erlotinib vs CT in First Line

Rosell R, et al. Lancet Oncol. 2012;13:971-973

054

8.5 months

An open-label, randomised, phase 3 trial at 22 centres in China (N=154)CT × 4 cycles

Erlotinib vs CT as First-line Treatment for Patients With Advanced EGFR+ NSCLC (OPTIMAL, CTONG-0802)

Zhou C, et al. Lancet Oncol. 2011;12:735-742.

055

×6

×4

Summary of Phase III Trials of First-Generation TKI vs CT in First-line in Advanced NSCLC EGFR+

×6

×6

×4

×4

056

Day 0 Day 14Advantages:

1. High Response Rate1:*60-80% vs 20-30%

2. Rapid Responses2: *2 Ws vs 6 Ws.

3. Quality of Life3:*<adverse events

4. > PFS4: *10-13 vs 5-6 months

5. < progression to CNS5

TKI vs CT in First-line (NSCLC EGFR+)

1. Jancarikova D, et al. Anticancer Res. 2007;27:1879-1882; 2. Mok TS, et al. N Engl J Med. 2009;361:947-957; 3. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388; 5. Rosell R, et al. Lancet Oncol. 2012;13:239-246.

057

PFS

How do they compare?

GefitinibClinical Trial A vs C9.5 Months

(4 C of CT 6.3) 3.2 monthsQT

ErlotinibClinical Trial B vs C9.7 Months


AfatinibClinical Trial D vs C13.6 Months


Gefitinib Erlotinib

QT QT

Indirect comparison: A vs B; A vs D and B vs D

Afatinib

QT

058

Absolute difference in PFS(months)

orHR

Absolute difference in ORR(%)with

95% CI

Advantage in OS(months)

orHR

1. CT vs TKI

2. TKI vs TKI

Confounders variables: 1. Scheme of CT: is Gemcitabine a bad drug?

2. # Cycles of CT: EGFR+ high ORR to CT (4 or 6)?

3. Type of EGFR mutations4. % of Crossover

5. Asian vs Non-Asian patients

How We Should Analyze the Different Studies?

059

Review of OS for Afatinib(2nd-Generation TKI): OS Analysis of LUX-Lung 3 and 6

060

PFS

Impact of EGFR Inhibitor in NSCLC on Progression-Free and Overall Survival: A Meta-Analysis

Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605.

061

Overall Survival

Not including LUX-Lung 3 and 6

Impact of EGFR Inhibitor in NSCLC on Progression-Free and Overall Survival: A Meta-Analysis

Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605.

062Network Meta-analysis

AfatinibErlotinib

Gefitinib

How do they compare?

063

Including Seven eligible trials (1,649 patients)

Treatment with EGFR TKI compared with CT was associated with a 63%reduction in the risk of progressive disease (HR 0.37, 95% CI 0.32 to 0.42, P<0.001)

Impact of Specific EGFR Mutations and Clinical Characteristics on Outcomes After Treatment With TKIs vs Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis

Lee CK, et al. J Clin Oncol. 2015;33:1958-1965.


065

OS With TKIS vs CT in Common Mutations:A Meta-analysis

• Multiple phase 3 trials with first-generation TKIs have evaluated OS: – None showed an OS benefit (neither in ITT or in EGFR mutational subgroup

analysis)


066

Advanced NSCLC EGFR+

Treatment A

Treatment B

EVENT

Classic Randomised Clinical Trial

EVENT

Treatment A

Treatment B

PD

Treatment B

Treatment AAdvanced NSCLC

EGFR+

Crossover Randomised Clinical Trial

PD

No Benefit in OS With TKIs: Really?

067

Afatinib: Structure and Binding

Li D, et al. Oncogene. 2008;27:4702-4711. Solca F, et al. J Pharmacol Exp Ther. 2012;343:342-350.

ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib

068

ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib

Li D, et al. Oncogene. 2008;27:4702-4711; Solca F, et al. J Pharmacol Exp Ther. 2012;343:342-350; Yang JC, et al. Lancet Oncol. 2012;13:539-548.

Afatinib: An Irreversible ErbB Family Blocker

069

Afatinib: Preclinica Data

Li D, et al. Oncogene. 2008;27:4702-4711.Solca F, et al. J Pharmacol Exp Ther. 2012;343:342-350.

*ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib

*

070

AFATINIB: Good Activity in Resistant Cells to Gefitinib and Erlotinib

1. Li D, et al. Oncogene. 2008;27:4702-4711.2. Solca F, et al. Proceedings, AACR-NCI-EORTC International Conference on MolecularTargets and Cancer Therapeutics. 2005;118:Abstract A242.

Mutation WT Sensitivity Resistance

Wild-typeH1666

L858RH3255

L858R+T790MNCI1975

Target Type of Interaction

Afatinib1 60 0.7 99 EGFR/HER2 Irreversible

Gefitinib1 157 5 >4000 EGFR Reversible

Erlotinib1 110 40 >4000 EGFR Reversible

Lapatinib1 534 63 >4000 EGFR/HER2 Reversible

CP 714,7242 >4000 561 >4000 HER2 Reversible

EC50 values for the inhibitory activities of different compounds on the proliferation of NSCLC cells with EGFR mutations

071

LUX-Lung 3 and 6: Study Rationale

• EGFR+ Lung cancer: subgroup with sensivity to TKI, including PFS benefit compared with first-line CT in randomised trials1-5

• Afatinib demonstrated efficacy in lung adenocarcinoma patients with EGFR+ (LUX-Lung 2)6:

– ORR: 66%, median PFS 12 months (first-line; independent review)– Median PFS: 13.7 months among Del19/L858R (independent review)

• Cisplatin/pemetrexed is a highly effective and well-tolerated first-line CT to advanced lung adenocarcinoma,7 but it has not been compared with TKI in EGFR mutation-positive patients

• Cisplatin/gemcitabine is the approved standard CT in China8

072

Afatinib 40 mg/db

Cisplatin + Pemetrexed75 mg/m2 + 500 mg/m2

IV q21d, up to 6 cycles

Stage IIIB/IV Lung adenocarcinoma with EGFR mutation(central lab testing; TheraScreen® EGFR29a RGQ PCR)

Cisplatin + Gemcitabine75 mg/m2 + 1000 mg/m2 D1, D8

IV q21d, up to 6 Cycles

Randomised 2:1 Stratification: type of mutation (Del19/L858R/otros)

Primary Objective: PFS (RECIST 1.1, independent review)c

Secondary Objectives: OS, PROd, ORR, DCR, DOR, tumour shrinkage, securityaEGFR29: 19 deletions in exon 19, 3 insertions in exon 20, L858R, L861Q, T790M, G719S, G719A and G719C (or G719X), S768I.bDose escalated to 50 mg if limited AE observed in cycle 1. Dose reduced by 10-mg decrements in case of related G3 or prolonged G2 AE.cTumour assessments: q6 weeks until week 48 and q12 weeks thereafter until progression/start of new therapy. dPatient-reported outcomes: EQ-5D, EORTC QLQ-C30 and LC 13 at randomisation and q3 weeks until progression or new anticancer therapy. Note: 24 patients in LUX-Lung 3 and 28 patients in LUX-Lung 6 were still on treatment as of December 2013.RGQ = rotor-gene Q; PCR = polymerase chain reaction; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours; ORR = objective response rate; DCR = disease control rate; DOR = duration of response; OS = overall survival.1. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334; 2. Wu YL, et al. Lancet Oncol. 2014;15:213-222.

LUX-Lung 62(n=364; Asians pts)

LUX-Lung 3 and 6

LUX-Lung 31(n=345; Asians & Caucasian pts)

073

LUX-Lung 3 and 6: Patient Demographics and Clinical Characteristics

1. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.2. Wu YL, et al. Lancet Oncol. 2014;15:213-222.

074

Meta-analyisis: Demographic Characteristics


075

6.7 months

LUX-Lung 3: Progression-Free Survival(Common Mutations: L858R, Del Exon 19)

Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.

076

47%

22%

54%

2%

LUX-Lung 3 and LUX-Lung 6: Primary End Point PFS in Patients With Common Mutations by Independent Review

Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334.Wu YL, et al. Lancet Oncol. 2014;15:213-222.

077

LUX-Lung 3: PFS Subgroup Analysis


078

LUX-Lung 6: PFS Subgroup Analysis

Wu YL, et al. Lancet Oncol. 2014;15:213-222.

079

LUX-Lung 3 and 6: ORR(Combined Analysis in Common Mutations)


080

LUX-Lung 3 and 6: Most Frequent AEs


081

LUX-Lung 3 and 6: Summary of AEs


082

LUX-Lung 3: Quality of Life


083

LUX-Lung 3 and 6: OS in Common Mutations

• Multiple phase 3 trials with first-generation TKIs have evaluated OS: – None showed an OS benefit (neither in ITT or in EGFR

mutational subgroup analysis)


084

LUX-Lung 3: Overall Survival

Yang JC, et al. Lancet Oncol. 2015;16:141-151.

085

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

Cam

bio

máx

imo

vs b

asal

(%) Exon 20 insertions (n=20)

T790M de novo (n=14):T790M alone, T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X

Others (n=33):L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R, S768I, L861P, R776H+L858R, L861Q+Del19, K739_1744dup6

T790M Exon 20 insertions

Others

ORR (%) 14.3 8.7 71.1

RCD (%) 64.2 65.2 84.2

PFS (months) 2.9 2.7 10.7

OS (months) 14.9 9.4 18.6

120 -

100 -

80 -

60 -

40 -

20 -

0 -

–20 -

–40 -

–60 -

–80 -

–100 -

Uncommon Mutations: Heterogeneous SubgroupM

axim

um C

hang

e vs

Bas

elin

e (%

)

086

Common mutations

Afatinib (n=419)

Chemo(n=212)

Median OS (months) 27.3 24.3

HR (95% CI) P

0.81 (0.66-0.99)P=0.0374

Common mutations (Del19/L858R) (n=631)

Time of overall survival (months)

Estim

ated

OS

prob

abili

ty

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

No. at risk:Afatinib 419 411 390 371 343 320 284 251 225 201 181 141 77 58 33 9 1 0Chemotherapy 212 199 185 173 162 141 124 110 101 83 70 52 34 23 10 5 1 0

AfatinibChemotherapy

Presented by Yang et al. ASCO 2014. Abstract 8004.

3 months

LUX-Lung 3 and 6: Overall Survival(Combined Analysis in Common Mutations)

087

LUX-Lung 3

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

prob

abili

ty

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months)

203 197 188 181 171 162 143 133 121 108 101 90 58 49 32 9 1 0

104 98 92 86 81 71 63 55 52 47 40 35 26 20 10 5 1 0

Afatinib

Cis/Pem

No of patients

1.0

0.8

0.6

0.4

0.2

0Es

timat

ed O

S pr

obab

ility

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (months)

216 214 202 190 172 158 141 118 104 93 80 51 19 9 1 0

108 101 93 87 81 70 61 55 49 36 30 17 8 3 0 0

Afatinib

Cis/Gem

No of patients



Afatinib (n=203)

Cis/Pem(n=104)

Median, months 31.6 28.2HR (95% CI),

P value0.78 (0.58-1.06),

P=0.1090


Afatinib (n=216)

Cis/Gem (n=108)

Median, months 23.6 23.5HR (95% CI),

P value0.83 (0.62-1.09),

P=0.1756

LUX-Lung 6

AfatinibCis/Gem

AfatinibCis/Pem

LUX-Lung 3 and 6: Common Mutations

3 months

088

Yang et al. ASCO 2014. Abstract 8004.1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213; 3. Mok et al. N Engl J Med. 2009;361:947; 4. Fukuoka et al. J Clin Oncol. 2011;29:2866; 5. Yang et al. Eur J Cancer. 2011;(suppl 1):S633; 6. Maemondo et al. N Engl J Med. 2010;362:2380; 7. Inoue et al. Ann Oncol. 2013;24:54; 8. Mitsudomi et al. Lancet Oncol. 2010;11:121; 9. Rosell et al. Lancet Oncol. 2012;13:239; 10. TARCEVA® (erlotinib) prescribing information, 2013; 11. Zhou et al. Lancet Oncol. 2011;12:735; 12. Wu et al. J Thorac Oncol. 2013;8(suppl 2):P1.11-021.

Study PFSHR (95% CI)

LUX-Lung 31

Del19 0.28 (0.18–0.44)L858R 0.73 (0.46–1.17)

LUX-Lung 62

Del19 0.20 (0.13–0.33)L858R 0.32 (0.19–0.52)

IPASS3–5

Del19 0.38 (0.26–0.56)L858R 0.55 (0.35–0.87)

NEJ0026,7

Del19 0.35 (0.23–0.52)L858R 0.32 (0.20–0.50)

WJTOG34058

Del19 0.45 (0.27–0.77)L858R 0.51 (0.29–0.90)

EURTAC9,10

Del19 0.30 (0.18–0.50)L858R 0.55 (0.29–1.02)

OPTIMAL11

Del19 0.13 (0.07–0.25)L858R 0.26 (0.14–0.49)

ENSURE12

Del19 0.20 (0.12–0.33)L858R 0.54 (0.32–0.90)

Favorece QuimioterapiaFavorece TKIFavorece QuimioterapiaFavorece TKI10.50 1.5 0 1 2 3

OSHR (95% CI)

0.54 (0.36–0.79)1.30 (0.80–2.11)

0.64 (0.44–0.94)1.22 (0.81–1.83)

0.79 (0.54–1.15)1.44 (0.90–2.30)

0.83 (0.52–1.34)0.82 (0.49–1.38)

NANA

0.94 (0.57–1.54)0.99 (0.56–1.76)

NANA

NANA

HRs for PFS and OS in Patients With Del19 and L858R

089

L858RDel19

No. at risk:Afatinib 40 236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0Chemotherapy 119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0

0 6 9 12 15 18 21 24 27

0.4

0.6

0.8

1.0


Estim

ated

OS

prob

abili

ty

0.0

3 30 33 36 39 42 45 48 51

0.2

0.4

0.6

0.8

1.0

Estim

ated

OS

prob

abili

ty

0.0

0 6 9 12 15 18 21 24 273 30 33 36 39 42 45 48 51

0.2

No. at risk:Afatinib 40 183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0Chemotherapy 93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0




Del19 L858RAfatinib (n=236)

Chemo(n=119)

Afatinib (n=183)

Chemo (n=93)

Median, months 31.7 20.7 22.1 26.9

HR (95% CI), P value 0.59 (0.45-0.77), P=0.0001 1.25 (0.92-1.71), P=0.1600

11 months

LUX-Lung 3 and 6: OS, Combined Analysis


090

LUX-Lung 6LUX-Lung 3

112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0

57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0

Afatinib

Cis/Pem

No of patients:124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 0

62 58 53 49 44 35 30 28 26 21 18 11 4 3 0 0

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

OS

prob

abili

ty

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (months)

1.0

0.8

0.6

0.4

0.2

0Es

timat

ed O

S pr

obab

ility

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (months)

Afatinib

Cis/Gem

No of patients:


Afatinib (n=112)

Cis/Pem (n=57)

Median, months 33.3 21.1

HR (95% CI) P value

0.54 (0.36–0.79)P=0.0015

AfatinibCis/Pem

AfatinibCis/Gem

OS: Subgroup Del Exon 19

12.2 months 13 months



Afatinib (n=124)

Cis/Gem (n=62)

Median, months 31.4 18.4

HR (95% CI) P value

0.64 (0.44–0.94)P=0.0229

091

Afatinib

Chemotherapy

PD

Chemotherapy

TKIAdvanced Lung

Adenoca EGFR+

LUX-Lung 3 Study

71%

75%

Afatinib

Chemotherapy

PD

Chemotherapy

TKI

LUX-Lung 6 Study

58.8%

56.5%Advanced LungAdenoca EGFR+

LUX-Lung 3 and 6: Crossover (%)

092

Study TKI CT after TKI TKI after CT

Subsequent Treatments at PD in Others Studies


093

LUX-Lung 3 LUX-Lung 6Afatinib(n=203)

Cis/Pem(n=104)

Afatinib(n=216)

Cis/Gem(n=108)

Discontinued treatment, n (%) 184 (100) 104 (100) 194 (100) 108 (100)

Subsequent systemic therapy, n (%)a 144 (78) 88 (85) 123 (63) 70 (65)

Chemotherapy, n (%) 131 (71) 49 (47) 114 (59) 29 (27)

EGFR TKI, n (%)

Erlotinib Gefitinib Afatinib AZD9291DacomitinibIcotinibEGFR TKI combinations

81 (44)

61 (33)28 (15)

2 (1)2 (1)

––

5 (3)

78 (75)

46 (42)44 (42)

7 (7)1 (1)1 (1)

–9 (9)

50 (26)

21 (11)19 (10)

–––

11 (6)5 (3)

61 (56)

22 (20)39 (36)

–––

3 (3)3 (3)

Other systemic therapyb, n (%) 5 (3) 2 (2) 3 (2) 4 (4)

Radiotherapy, n (%) 32 (17) 21 (20) 4 (2) 0 (0)aCollection of data on subsequent therapies still ongoing. bIncludes investigational agents, monoclonal antibodies, non-EGFR targeting protein kinase inhibitors etc.

LUX-Lung 3 and 6: Subsequent Treatments at PD


094

OS in Patients With Del 19 Mutations in Countries With Reimbursement Policies


095

Exon19

Afatinib: Mechanism of Action

Bronte G, et al. Crit Rev Oncol/Hematol. 2014;89:300-313.

096

Cys773 and Cys 805

Erlo/Gefitinib/AfatinibY1173 and Y1068

Afatinib, a Different Drug: Action Mechanism

Nelson V, et al. Onco Targets Ther. 2013;6:135-143.Solca F, et al. J Pharmacol Exp Ther. 2012. 343:342-350.

097

Sensitivity and Kinase Activity of Epidermal Growth Factor Receptor (EGFR) Exon 19 and Others to EGFR Tyrosine Kinase Inhibitors

Furuyama K, et al. Cancer Sci. 2013;104:584-589.

098

Primary objective: OSSub-analysis: Type of EGFR mutation

LUX-Lung 7

099

Future of OS in NSCLC With EGFR Mutations

0100

Drug FDA StatusCovalent Binding

Activity in T790M Structure

Gefitinib Approved No No QuinazolineErlotinib Approved No No QuinazolineDacomitinib Phase III Yes No QuinazolineAfatinib Approved Yes ± QuinazolinaAP26113 Phase I/II No ? PyrimidineCO-1686 Phase I Yes Yes PyrimidineAZD9291 Phase II Yes Yes Pyrimidine

Janne. Mini Symposium MS27, WCLC 2013.

Third-generation compounds selectively block EGFR-T790M and are 30-100 times more potent vs EGFR-T790M and are 100 times less active vs EGFR-WT in comparison to quinazoline-based inhibitors

EGFR TKIs

0101

A Randomised Phase II Trial (JO25587): Erlotinib ± Bevacizumab

0102

AZD 9291 (AURA Study)

0103

AZD 9291

0104

0105

Rociletinib After Gefitinib or Erlotinib: Best ORR (All Doses) in 243 Patients T790M+

0106

Rociletinib After Gefitinib or Erlotinib: PFS in 270 Confirmed T790M+ Patients

0107

Quantitative and Sensitive BEAMing Test(Sysmex Inostics) Used for Plasma EGFR Mutation Testing

0108

Plasma Testing for T90M Has Good Sensitivity and Likely Good Specificity

• Plasma testing: goodoption

• T790M tissue plasma are not false positives. -790M was confirmed in plasma on subsequent testing in 5/7 samples

Tissue as reference T790M Activating mutationsPositive percent agreement 81% (155/192) 87% (193/221)

0109

32% 25%

PFS 4.7 months

Janjigian Y, et al. Cancer Discov. 2014;4:1036-1045.

Phase I/II Study of Afatinib + Cetuximab

0110

Source: Compiled by Neeta Somaiah & George Simon.

Approved/Launched SRC inhibitors

Inh. of PI3K, mTOR, AKT, MAPK/ERK

Apoptosis agonists

Anti-FGFR

DNA replication inhibitors

Antiangiogenics

Inhibitors of Mitosis/Topoisomerases

Others

Alkylating agents

Protein degradation

Anti-IGFR

Immunostimulants/Vaccines

TKI-EGFR

Anti-VEGFFosbretabulin (CA4P)

ABT-751

ANG-615

NPI-2358

ASA404

AfliberceptIVandetanib

ARamucirumabIXL-647

IAV-951

CT-322

ABevacizumab

Ixabepilone

BI-2536

ARRAY520

Vorinostat

RetaspimycinEtinostat

AUY922

Everolimus (RAD-001)Sirolimus (Rapamycin)

Temsirolimus (CCI-779)Enzostaurin

Deforolimus (AP23573)

AZD-6244 PX-866

OSI-027

AZD-8055

I XL-184

Figitumumab (CP-751871)

AVE-1642A Cixutumumab

A AMG-479

OSI-906

= IV & PO= PO= IV= 1st-line

= 2nd-line= 1st and 2nd line

= 3rd-line

= Undeclared

PF-2341066

MetMab

BHB022

Dulanermin (AMG-951)A Mapatumumab

AApomabAMG655

LCL-161

YM-155

I Dasatinib (Sprycel)AZD-0530

KX2-391

IBrivanibAV-370

ITKI-258

AG-014699ABT-888

CS-7017

Phase III

Phase II

Phase I

Stem Cell (PPAR, Hedgehog)

IPI-926

XL-281

BMS833923

BIBW2992

I PF-00299804

IBMS-690514

Cisplatin

CarboplatinIfosfamide

ACetuximabI Erlotinib

Docetaxel

Antimetabolites

= SCLC

Etoposide

Gemcitabine

Irinotecan

Paclitaxel

Pemetrexed

Vinorelbine/ Vinblastine

Paclitaxel (Albumin B.)

Liposomal Cisplatin

Panobinostat

GDC0449

AMG102

AEG35156

A Bavituximab

I Cediranib

APanitumumabANimotuzumab

Matuzumab

Gefitinib

I Sunitinib

SorafenibI Axitinib

I Motesanib

A R-1507

XL-228

MKC-1Oblimersen

Cilengitide

TalactoferrinSapacitabine

ReolysinIrvalec (Custirsen)

Mage-A3Stimuvax

PF-3512676 (agatolimod)

Tremelimumab

Imprime PGG

GVAX

CimaVax EGF

AVE-8062

Pralatrexate

ARQ197Apricoxib

IABT-869

ARRY-886

ARC-100

AS-1411

BI-6727

Decitabine

Cositecan

Glufosfamide

Eribulin

I Bosutinib

Kahalalide F

IMO-2055

EC-145

AF-50035

GI4000

KOS-1584A Lexatumumab

ARQ-621

Lip. PaclitaxelCamptothecin

ISIS-23722

PEG-Irinotecan

MDX-1105

AIntetumumab

IE-7080

AMP-001

IMGN-242

IDanusertib

JNJ-26854165

Vical-2 vaccine

A

Itipifarnib

Pertuzumab

INeratinib

A Naptumomab

MGCD-0103

AMORab-009

MP-470

V-930VX-001

Vinorelbine (emulsion)

V-935

Crinobulin

Registered

XL-999IBIBF-1120

I

XL-184 II BMS-690514

I Pazopanib

SNX5542

TemozolomidePicoPt

Obatoclax

AT-101

Zibotentan

Amrubicin

PF-00299804 I

Topotecan

ABT-263

INeratinib

BEZ-235 / BTGT226 / BKM

Inh. of Bcl-2

obatoclax

A

I

BSI-201

Auristatin PE

ADH-1 (Exherin)I = TKIA = Antibody

Zometa

bexarotene

LucanixNOV-002

belinostat

CYT-997

AMG-386

Retaspimycin

ABT-263

BNC-105

rebimastat

Treatment Options in NSCLC110

http://novartis-pipeline.citeline.com/CpViewAccess.aspx?B=5998&C=0&D=9&E=18558














































































































































































































































































http://novartis-pipeline.citeline.com/CpViewAccess.aspx?B=25065&C=0&D=9
















0111

OS in Advanced EGFR-Mutated Lung Cancer

3 7

10 13

36

48

60

0

10

20

30

40

50

60

70

Palliative Care(PC)

Single-agent PC Platinum-basedCT

CT +Bevacizumab

TKI + PreviousTx

New TKI +Previous Tx

Inmunotherapy+ Previous Tx

Med

ian

Sur

viva

l (m

onth

s)

19751990

20002006

2010

2014

2016

0112

Conclusions [1]

• Important advances in treatment of NSCLC: – Chemotherapy time: median OS 10 months– CT plus bevacizumab time: median OS 12.3 months– First-generation EGFR TKIs : median PFS 10 months, OS 27 months,

without benefit in OS compared with Chemotherapy arm (includedDel exon and L858R)

• Afatinib: first TKI that improved OS compared with CT in EGFR Del 19:

– LUX-Lung 3: median 33.3 vs 21.1 mo, HR=0.54, P=0.0015– LUX-Lung 6: median 31.5 vs 18.4 mo, HR=0.64, P=0.0229

• Del 19 and L858R: two different populations Studies withdifferent design

• Afatinib in first-line: standard of care in patients with EGFR Del19 and good option in other EGFR mutations (L858R)

0113

Conclusions [2]

• Del 19 and L858R are two different populations:– Studies with different designs– Afatinib: different mechanism of action

• Afatinib in first-line: standard of care in patients withEGFR Del19 and good option in other EGFR mutations (L858R)

• New TKIs (AZD 9291, rociletinib): – Excellent option after PD to TKI (first or second

generation)

0114

Dr. E. Omar Macedo PérezThoracic Tumors Clinic

(INCan)[email protected]

Thank You

Impact of Overall Survival in Advanced NSCLC EGFR+ · Impact of Overall Survival in Advanced NSCLC EGFR+ ... American Cancer Society Cancer Facts and Figures 2012. 2. ... SEER Cancer

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