DATA PRIBADI

Nama Lengkap : dr. Jamal Zaini, PhD, Sp.P

Tempat/tanggal lahir : Jakarta, 29 Maret 1977

RIWAYAT PENDIDIKAN

Tahun 1983 - 1989 : SDN Petukangan Utara 07, Jakarta Selatan

Tahun 1989 - 1992 : SMP Negeri 110, Jakarta Selatan

Tahun 1992 - 1995 : SMA Negeri 6, Jakarta Selatan

Tahun 1995 - 2001 : Program Dokter Umum, FKUI, Jakarta

Tahun 2004 - 2009 : Program Doktor, Tohoku University, Jepang

Tahun 2002 - 2011 : Spesialis Paru, FKUI, Jakarta

Managing EGFR mutant NSCLC

Jamal Zaini Dept Pulmonology and Respiratory Medicine,

Faculty of Medicine Universitas Indonesia/

Persahabatan Hospital

IndonesiaSource: Globocan 2018

Summary statist ic 2018

Males Females Both sexes

Population 134 273 304 132 521 684 266 794 986

Number of new cancer cases 160 578 188 231 348 809

Age-standardized incidence rate (World) 134.8 139.6 136.2

Risk of developing cancer before the age of 75 years (%) 14.5 14.3 14.3

Number of cancer deaths 108 186 99 024 207 210

Age-standardized mortality rate (World) 94.2 76.1 84.1

Risk of dying from cancer before the age of 75 years (%) 10.0 8.2 9.1

5-year prevalent cases 308 850 466 270 775 120

Top 5 most frequent cancers excluding non-melanoma skin cancer

(ranked by cases)

Lung

Colorectum

Liver

Nasopharynx

Prostate

Breast

Cervix uteri

Ovary

Colorectum

Thyroid

Breast

Cervix uteri

Lung

Colorectum

Liver

Number of new cases in 2018, both sexes, all ages

Total: 348 809

Breast

58 256 (16.7%)

Cervix uteri

32 469 (9.3%)

Lung

30 023 (8.6%)

Colorectum

30 017 (8.6%)

Liver

18 468 (5.3%)

Other cancers

179 576 (51.5%)

Number of new cases in 2018, males, all ages

Total: 160 578

Lung

22 440 (14%)

Colorectum

19 113 (11.9%)

Liver

14 238 (8.9%)

Nasopharynx

13 966 (8.7%)

Prostate

11 361 (7.1%)

Other cancers

79 460 (49.5%)

Number of new cases in 2018, females, all ages

Total: 188 231

Geography

Numbers at a glance

Total population

266 794 986Number of new cases

348 809Number of deaths

207 210Number of prevalent cases (5-year)

775 120Data source and methods

Incidence

Country-specific data source: National

Method: "All sites" estimates from neighbouring countries

partit ioned using frequency data

Mortality

Country-specific data source: No data

Method: Estimated from national incidence estimates by

modelling, using incidence:mortality ratios derived from

cancer registry data in neighbouring countries

Prevalence

Computed using sex-; site- and age-specific incidence to

1-;3- and 5-year prevalence ratios from Nordic countries for

the period (2000-2009), and scaled using Human

Development Index (HDI) ratios.

The Global Cancer Observatory - All Rights Reserved - May, 2019. Page 1

IndonesiaSource: Globocan 2018

Incidence, Mortality and Prevalence by cancer site

New cases Deaths 5-year prevalence (all ages)

Cancer Number Rank (%) Cum.risk Number Rank (%) Cum.risk Number Prop.

Breast 58 256 1 16.7 4.61 22 692 2 11.0 1.96 160 653 121.23

Cervix uteri 32 469 2 9.3 2.58 18 279 3 8.8 1.64 84 201 63.54

Lung 30 023 3 8.6 1.47 26 095 1 12.6 1.30 28 937 10.85

Liver 18 468 4 5.3 0.88 18 148 4 8.8 0.87 14 383 5.39

Nasopharynx 17 992 5 5.2 0.73 11 204 6 5.4 0.52 48 401 18.14

Colon 15 245 6 4.4 0.72 9 207 7 4.4 0.40 32 595 12.22

Non-Hodgkin lymphoma 14 164 7 4.1 0.64 7 565 9 3.7 0.35 35 490 13.30

Rectum 14 112 8 4.0 0.66 6 827 10 3.3 0.31 32 069 12.02

Leukaemia 13 498 9 3.9 0.50 11 314 5 5.5 0.43 35 870 13.44

Ovary 13 310 10 3.8 1.06 7 842 8 3.8 0.69 32 818 24.76

Thyroid 11 470 11 3.3 0.47 2 119 19 1.0 0.07 34 249 12.84

Prostate 11 361 12 3.3 1.41 5 007 11 2.4 0.41 23 055 17.17

Corpus uteri 6 745 13 1.9 0.57 2 407 16 1.2 0.21 18 559 14.00

Bladder 6 716 14 1.9 0.36 3 375 14 1.6 0.17 17 151 6.43

Brain, nervous system 5 323 15 1.5 0.21 4 229 13 2.0 0.18 13 051 4.89

Lip, oral cavity 5 078 16 1.5 0.23 2 326 17 1.1 0.11 12 669 4.75

Pancreas 4 940 17 1.4 0.23 4 812 12 2.3 0.23 3 430 1.29

Larynx 3 188 18 0.91 0.16 1 564 20 0.75 0.07 7 845 2.94

Stomach 3 014 19 0.86 0.14 2 521 15 1.2 0.11 3 743 1.40

Multiple myeloma 2 717 20 0.78 0.14 2 250 18 1.1 0.12 5 884 2.21

Salivary glands 2 330 21 0.67 0.11 890 24 0.43 0.05 5 080 1.90

Kidney 2 112 22 0.61 0.09 1 225 21 0.59 0.06 4 910 1.84

Melanoma of skin 1 392 23 0.40 0.07 797 25 0.38 0.04 3 703 1.39

Testis 1 382 24 0.40 0.09 283 31 0.14 0.03 4 818 3.59

Oropharynx 1 303 25 0.37 0.06 626 26 0.30 0.03 3 582 1.34

Gallbladder 1 217 26 0.35 0.06 1 056 23 0.51 0.05 1 370 0.51

Oesophagus 1 154 27 0.33 0.05 1 058 22 0.51 0.05 1 079 0.40

Vulva 1 153 28 0.33 0.10 420 28 0.20 0.04 3 403 2.57

Hodgkin lymphoma 1 047 29 0.30 0.05 574 27 0.28 0.03 3 242 1.22

Penis 899 30 0.26 0.09 334 30 0.16 0.03 2 361 1.76

Anus 660 31 0.19 0.03 352 29 0.17 0.02 1 511 0.57

Vagina 412 32 0.12 0.04 208 32 0.10 0.02 1 074 0.81

Hypopharynx 229 33 0.07 0.01 134 34 0.06 0.01 324 0.12

Mesothelioma 206 34 0.06 0.01 171 33 0.08 0.01 216 0.08

Kaposi sarcoma 91 35 0.03 0.01 63 35 0.03 0.00 220 0.08

All cancer sites 348 809 - - 14.35 207 210 - - 9.07 775 120 290.53

Age-standardized (World) incidence rates per sex, top 10 cancers

01020304050 0 10 20 30 40 50

Breast

Lung

Cervix uteri

Liver

Nasopharynx

Colorectum

Prostate

Non-Hodgkin lymphoma

Leukaemia

Ovary

19.4

12.4

10.5

7.7

11.3

7.4

6.5

42.1

6.0

23.4

3.4

2.9

4.4

3.7

4.1

9.7

ASR (World) per 100 000

Males Females

Age-standardized (World) incidence and mortality rates, top 10 cancers

01020304050 0 10 20 30 40 50

Breast

Cervix uteri

Lung

Colorectum

Prostate

Ovary

Liver

Nasopharynx

Non-Hodgkin lymphoma

Leukaemia

42.1

23.4

12.4

12.1

11.3

9.7

7.6

6.6

5.5

5.3

17.0

13.9

10.9

6.9

5.7

6.0

7.5

4.3

3.0

4.4

ASR (World) per 100 000

Incidence Mortality

The Global Cancer Observatory - All Rights Reserved - May, 2019. Page 2

Indonesia, GLOBOCAN 2018

Hallmark of Cancer: the next generation

Cell 2011;144:646-74

•

•

••

•

•

•

•

•

•

•

•

•

Wild type AGTGA

Mutant AGAGA

Adapted from: Roychowdhury et al. Sci Transl Med; 20122

Timeline in understanding EGFR biology in NSCLC

Lancet Oncol 2015;16:e447.

NSCLC is Genomically Diverse

Li et al. J Clin Oncol. 2013;31:1039.

Personalizing NSCLC Treatment through

Genotype-Directed Treatment

Personalized Medicine 2013;11:3

Adenocarcinoma, targets and therapy

EGFR Sensitizing -Gefitinib4

-Erlotinib4

-Afatinib4

-Osimertinib4

-Necitumumab4

-Rociletinib3

ALK -Crizotinib4

-Alectinib4

-Ceritinib4

-Lorlatinib4

-Brigatinib4

MET -Crizotinib2

-Cabozantinib2

HER2 -Trastuzumab

emtansine2

-Afatinib2

-Dacomitinib2

ROS1 -Crizotinib4

-Cabozantinib2

-Ceritinib2

-Lorlatinib2

-DS-6051n2

BRAF -Vemurafenib2

-Dabrafenib2

RET -Cabozantinib2

-Alectinib2

-Apatinib2

-Vandetanib2

-Ponatinib2

-Lenvantinib2

NTRK1 -Entrectinib2

-LOXO-1012

-Cabozantinib2

-DS-6051b1

MEK1 -Trametinib2

-Selumetinib3

-Cobimetinib2

PIK3CA -LY30234142

-PQR 3091

FDA Approval

EGFR mutation

ALK rearrangement

ROS1 rearrangement

1. Phase I

2. Phase II

3. Phase III

4. Approved J Thorac Oncol 2016;11:613-38

Commercially available NGS

GUARDANT

Foundation One

Erb family

The ErbB Family of Receptors Members

ErbB = proto-oncogene B of the avian erythroblastosis virus.

1.Yarden and Pines. Nat Rev Cancer. 2012;12:553; 2. Hirsch and Bunn. Lancet Oncol. 2009;10:432; 3. Rosell et al. N Engl J Med. 2009;361:958; 4.Tzahar

et al. Mol Cell Biol. 1996;16:5276; 5. Stephens et al. Nature. 2004;431:525; 6. Shigematsu et al. Cancer Res. 2005;65:1642; 7. Hellyer et al. J Biol Chem.

2001;276:42153; 8. Rudloff and Samuels. Cell Cycle. 2010;9:1487; 9. Soung et al. Int J Cancer. 2006;118:1426.

EGFR (ErbB1)

•Mutation frequency in NSCLC: 10% of white

and 50% of Asian patients2

•Common mutations: exon 19 (deletion) and

exon 21 (point mutation L858R)3

HER2 (ErbB2)

•Preferred partner for dimerisation for all

receptors of the ErbB Family4

•Mutation frequency in NSCLC: 2%-4%5,6

ErbB3

•Acts as heterodimer with HER2 as the most

potent oncogene7

ErbB4

•Increasing relevance in dysregulation of the

ErbB Family signal cascade8

•Mutation frequency in NSCLC: 2%-5%8,9

Adapted from Yarden and Pines 2012.1

The receptors are responsible for essential functions in homeostasis of healthy tissues.

However, they can upregulate proliferation and metastasis of various tumours.1

Impaired

TKI domain

No known ligand

Ligand Binding and Receptor Dimerisation Lead to

Activation of Proliferation and Survival Pathways Homodimer Heterodimer

HER2 (ErbB2) lacks a ligand-binding domain, and it is the preferred dimerisation

partner for the other receptors.

Adapted from Yarden and Pines. Nat Rev Cancer. 2012;12:553; Hynes and Lane. Nat Rev Cancer. 2005;5:341.

Activation of

downstream

signaling pathways

N Engl J Med 2008;359:1367-80

EGFR

Locations and Types of the 134 EGFR Gene Mutations Detected in Lung Cancers

Shigematsu H et al. JNCI J Natl Cancer Inst 2005;97:339-346

Journal of the National Cancer Institute, Vol. 97, No. 5, © Oxford University Press 2005, all rights reserved.

L858R

Del 19

T790M

EGFR mutations

Nat Rev Cancer (2007)7:169

Clinically important : Exon 18, 19,21

There are several EGFR-sensitizing mutations (EGFRm) common mutation

There are several EGFR-sensitising activation

mutations that occur in the tyrosine kinase domain of

EGFR:1.

In-frame deletion in exon 19

L858R mutation in exon 21

G719 mutation in exon 18

L861Q mutation in exon 21

In-frame insertion in exon 19

These oncogenic mutations activate EGFR and lead to

stimulation of EGFR-mediated cell proliferation and survival pathways1

These activating mutations also decrease the affinity of EGFR for ATP and, therefore, sensitise the receptor to inhibition by small molecule EGFR-TKIs1

The most common mutations observed

involve L858R in exon 21 and an exon 19

deletion (accounting for up to 86% of

cases)2

22

EGFR-sensitising mutations*1,2 Exon 18 19 20 21

EGFR mutation

G719X insertions

deletions L861Q L858R

Frequency (%) 1–3% <1–1% 45–46% 1–2% 37–40%

*Data taken from two reviews discussing the frequency of EGFR mutations.

1. Jorge SEDC, et al. Braz J Med Biol Res 2014;47:929–939;

2. Siegelin MD & Borczuk AC. Lab Invest 2014;94:129–137.

GOLD standard : sequencing

NEJM (2004)350:2129

Pro : could detect ALL possible mutations Cons : Expensive, timeconsuming

© 2018 Syahruddin et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unpor ted, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work

you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).

Lung Cancer: Targets and T erapy Dovepress

submit your manuscript

Dovepress 25

open access t o scient ifi c and medical research

Open Access Full Text Article

http://dx.doi.org/10.2147/LCTT.S154116

EGFR

Purpose: We aimed to evaluate the distribution of individual epidermal growth factor receptor

(EGFR) mutation subtypes found in routine c ytological specimens.

Patients and methods: A retrospective audit was performed on EGFR testing results of 1,874

consecutive cytological samples of newly diagnosed or treatment-naïve Indonesian lung cancer

patients (years 2015–2016). Testing was performed by ISO15189 accredited central laboratory.

Results: Overall test failure rate was 5.1%, with the highest failure (7.1%) observed in pleural

effusion and lowest (1.6%) in needle aspiration samples. EGFR mutation frequency was 44.4%.

Tyrosine kinase inhibitor (TKI)-sensitive common EGFR mutations (ins/dels exon 19, L858R)

and uncommon mutations (G719X, T790M, L861Q) contributed 57.1% and 29%, respectively.

Approximately 13.9% of mutation-positive patients carried a mixture of common and uncommon

mutations. Women had higher EGFR mutation rate (52.9%) vs men (39.1%; p<0.05). In contrast,

uncommon mutations conferring either TKI responsive (G719X, L861Q) or TKI resistance (T790M,

exon 20 insertions) were consistently more frequent in men than in women (67.3% vs 32.7% or

69.4% vs 30.6%; p<0.05). Up to 10% EGFR mutation–positive patients had baseline single mutation

T790M, exon 20 insertion, or in coexistence with TKI-sensitive mutations. Up to 9% patients had

complex or multiple EGFR mutations, whereby 48.7% patients harbored TKI-resistant mutations.

One patient presented third-generation TKI-resistant mutation L792F simultaneously with T790M.

Conclusion: Routine diagnostic cytological techniques yielded similar success rate to detect

EGFR mutations. Uncommon EGFR mutations were frequent events in Indonesian lung cancer

patients.

Keywords: EGFR mutations, lung cancer, treatment naive, T790M, tyrosine kinase inhibitor,

Indonesia, cytology

IntroductionLung cancer in Indonesia ranks the fourth most common of all cancers.1 Majority of lung

cancer cases are found in late stages and cytological specimens are common sources of

diagnostic practices in tertiary hospitals.1 In addition to valuable diagnostic tools, cytologi-

cal specimens are useful sources of epidermal growth factor receptor (EGFR) mutation

testing. Specific guidelines of EGFR mutation testing in cytological specimens have

been issued and adopted widely.2,3 However, there are considerable concerns regarding

EGFR testing failure rates that may delay timeline of treatment decisions. Few or lack of

tumor cells, improper fixation procedures, poor extracted DNA quality, and/or absence

of or generation of nonspecific polymerase chain reaction (PCR) products have led to

testing failures.3

Journal name: Lung Cancer: Targets and Therapy

Article Designation: Original Research

Year: 2018

Volume: 9

Running head verso: Syahruddin et al

Running head recto: Uncommon EGFR mutations in Indonesian lung cancer patients

DOI: http://dx.doi.org/10.2147/LCTT.S154116

This article was published in the following Dove Press journal:

Lung Cancer: Targets and Therapy

First Generation EGFR TKI

Gefitinib (Iressa)

Erlotinib (Tarceva)

EGFR TKIs for EGFR Mutation (+) EGFR TKIs are recommended as 1st-line therapy for pts. with EGFR

M(+) NSCLC.

Randomized, 230 patients with metastatic, NSCLC and EGFR mutation

Who had not previously received chemotherapy to receive gefitinib or

carboplatin-paclitaxel

N Engl J Med 2010;362:2380-8

In selected inviduals: chemo or EGFR TKI as first line therapy?

N Engl J Med 2010;362:2380-8

Type of mutation

N Engl J Med 2010;362:2380-8

Erlotinib a first Generation EGFR Targeted TKI, in

the treatment in NSCLC: EURTAC study

Rossel R et al. Lancet Oncol 2012;13:239-246

EURTAC study : PFS

Rossel R et al. Lancet Oncol 2012;13:239-246

Erlotinib provides PFS of 15,3 Months in sub-patients in Exon 19 Deletion 1

A s i a n p a t i e n t s

( O P T I M A L s t u d y ) 1

Erlotinib (n=82) Chemotherapy (n=72)

HR=0.16 (95% CI:0.11–

0.26)

Log-rank

p<0.0001

4.6

13.7

1.0

0.8

0.4

0.2

0 0 5 10 15 20 25 30 35 45

0.6

PF

S E

ST

IMA

TE

TIME (MONTHS)

40

84% Reduce Risk of Progress

ion

1. Zhou, C., Wu, Y. & Chen, G. (2011). Lancet Oncol 12: 735-742

ITT = intention-to-treat.

[VALUE] Chemoterapy

[VALUE] (erlotinib Exon 19)

[VALUE] ( erlotinib ITT)

0 5 10 15 20

OPTIMAL

Median PFS (Months)

PFS (Months)

First-line treatment with erlotinib provides above 1 year (13.7 months) of survival in EGFR Mut+ advanced NSCLC

Nat Rev Cancer 2010;10(11):760.

Progress in the Treatment of

Metastatic NSCLC

EGFR TKIs: monotherapy treatment options_1st gen

RR defined as complete response + partial response.

RR = response rate; TKI = tyrosine kinase inhibitors.

1. Mok TS, et al. NEJM 2009;361:947957. 2. Fukuoka M, et al. J Clin Oncol 2011 29: 2866–7.

3. Han J-Y, et al. J Clin Oncol 2012;30:1122–8. 4. Mitsudomi T, et al. Lancet Oncol 2010;11:121–128. 5. Maemondo M, et al. NEJM

2010;362:2380–2388.

6. Zhou C, et al. Lancet Oncol; 2011;12:735–742. 7. Wu YL, et al. Ann Oncol 2015;26:1883–9. 8. Rosell R, et al. Lancet Oncol

2012;13:239–46.

EGFR TKI Chemotherapy Study N (EGFR

mutation

positive)

RR (study treatment

versus

chemotherapy)

Median PFS in patients

with EGFR-positive

mutations (study

treatment versus

chemotherapy)

Gefitinib

Carboplatin +

paclitaxel IPASS1,2 261 71.2 versus 47.3% 9.5 versus 6.3 months

Gemcitabine +

cisplatin First-SIGNAL3 42 84.6 versus 37.5% 8.0 versus 6.3 months

Cisplatin + docetaxel WJTOG 34054 177 62.1 versus 32.2% 9.2 versus 6.3 months

Carboplatin +

paclitaxel NEJGSG0025 114 73.7 versus 30.7% 10.8 versus 5.4 months

Erlotinib

Gemcitabine +

carboplatin OPTIMAL6 154 83 versus 36% 13.1 versus 4.6 months

Gemcitabine +

cisplatin ENSURE7 217 62.7 versus 33.6% 11.0 versus 5.5 months

Cisplatin +

docetaxel/gemcitab

ine

EURTAC8 173 58 versus 15% 9.7 versus 5.2 months

Second Generation EGFR TKI

Afatinib (Giotrif)

Dacomitinib

Pelitinib

Canertinib

Neratinib

Complete Blockade of the ErbB Family Enhances the Effect on

Important Signaling Pathways

Targeting the whole ErbB Family

enhances the effect on

important signaling pathways

Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342.

Phase IIb LUX-Lung 7: Afatinib vs Gefitinib in

EGFR-Mutated Advanced NSCLC

Coprimary endpoints: PFS, TTF, OS

Secondary endpoints: ORR, time to response, DoR, DCR, duration of disease control, tumor

shrinkage, QoL

Park K, et al. Lancet Oncol. 2016;17:577-589. Slide credit: clinicaloptions.com

Afatinib*† 40 mg PO QD (n = 160)

Gefitinib†‡ 250 mg PO QD (n = 159)

Treatment continued until PD or

unacceptable toxicity

Stratified by EGFR mutation (exon 19 deletion vs L858R) and brain metastases at baseline (yes vs no)

Treatment-naive patients with stage IIIB or IV lung adenocarcinoma,

exon 19 deletion or L858R EGFR mutations, ECOG PS 0/1,

adequate organ function (N = 319)

*Dose escalation to 50 mg allowed in absence of TEAEs. †Treatment interruptions ≤ 14 days allowed. ‡Dose modifications allowed.

Wu YL, et al. Lancet Oncol. 2017;18:1454-1466. Mok TS, et al. J Clin Oncol. 2018;36:2244-2250.

40 Park K, et al. Lancet Oncol 2016; 17: 577–589

Lux Lung 7 :No Difference PFS based on EGFR Mutation type

LUX-Lung 6 LUX-Lung 3

OS in Del19 Subgroup

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

Est

ima

ted

OS p

rob

ab

ility

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

0

Est

ima

ted

OS p

rob

ab

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:

PFS in overall population

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

PFS in overall population

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

Afatinib

Cis/Pem

Afatinib

Cis/Gem

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

Afatinib in Uncommon Mutation

Yang CH, et al. Lancet Oncol. 2015; 16: 830-838

Dacomitinib versus Gefitinib for the first-line treatment of

advanced EGFR mutation positive NSCLC (ARCHER 1050):

a Randomized open-label Phase III Trial

J Clin Oncol 2017;35(18): LBA9007

452 naive NSCLC EGFR mutation +

Dacomitinib (45mg) vs Gefitinib (250mg)

PFS 14.7 months vs 9.2 months (p<0.0001)

Median PFS in First-line phase Ⅲ EGFR M(+) studies

• Meta-Analysis of 3 EGFR TKIs

• 16 of Phase III Trials

• With 2,962 patient cases of EGFR Mut+

PLoS One 2016 : Meta-Analysis of Efficacy & Safety of 3 EGFR TKIs1

Efficacy Safety

Erlotinib High Moderate

Gefitinib Moderate Moderate

Afatinib High High

1. Optimized selection of three major EGFR-TKIs in advanced EGFR-positive non-small cell lung cancer: a network meta-analysis by Yaxiong Zhang

PFS : meta analysis of first line TKI

1. Paz-Ares, et al. J Cell Mol Med 2014; 2. Petrelli, et al. Clin Lung Cancer 2012 3. Haaland, et al. J Thorac Oncol 2014; 4. Greenhalgh, et al. Cochrane Database of Systematic

Reviews 2016

Time (months)

All lines

0 6 12 18

Erlotinib (n=731)

Gefitinib (n=1,802)

Chemotherapy (n=984)

A p o o l e d a n a l y s i s o f d a t a f r o m

> 9 0 p u b l i s h e d s t u d i e s 1

A n e t w o r k

a n a l y s i s o f

d a t a f r o m

p h a s e I I I

c l i n i c a l t r i a l s 3

0.05 0.1 0.25 0.5 1.0

Favours EGFR TKI

0.19

0.39

Erlotinib

Gefitinib

Favours chemotherapy HR

A m e t a - a n a l y s i s o f p a t i e n t s i n 9 r a n d o m i s e d ,

c o n t r o l l e d t r i a l s 2

HR

0.2 0.4 0.6 1.5

Favours

Erlotinib

Favours

afatinib

1.0

0.56

HR 0.2 0.4 0.6 1.5

Favours

Erlotinib

Favours

gefitinib

1.0

0.57

Erlotinib

Gefitinib

Afatinib

HR Favours

EGFR TKI

Favours

chemotherapy

0.2 0.4 0.6 2.0 1.0 0.0

C o c h r a n e

s y s t e m a t i c

a n a l y s i s o f

s t u d i e s o f E G F R

T K I s i n t h e

f i r s t - l i n e s e t t i n g 4

Dose Reduction in TKI as first line

AE = adverse event; TKIs = tyrosine kinase inhibitors

1. Rosell, et al. Lancet Oncol 2012; 2. Wu, et al. Ann Oncol 2015; 3. Zhou, et al. Lancet Oncol 2011; 4. Sequist, et al. J Clin Oncol 2013; 5.Yang, et al. Ann Oncol 2016; 6. Wu, et al. Lancet Oncol 2014; 7. Gilotrif SmPC; 8. Takeda, et

al. Lung Cancer 2015

10

4

2

0 Gefitinib

8

Patien

ts (

%)

Afatinib Erlotinib

* *

6

Dose Reduct ions

0

10

20

30

40

50

60

Pa

tie

nts

(%

)

0

10

20

30

40

50

60

EURTAC ENSURE OPTIMAL LUX-LUNG

3

LUX-LUNG

6

Dose reductions due to AEs were required by up to 21%

of patients treated with Erlotinib 1–3

Afatinib dose reductions due to AEs were required by up

to 57% of patients7

Erlotinib

phase III studies1–3

Afatinib

phase III studies4–6

T rea t m ent D i s con t inuat ions 8

21.0% 19.1%

6.0%

53.3%

28.0%

*Statistically significant

Acquired drug resistance: persister cells

Oxnard G. Nat Med 2016; Mar:232

Acquired resistance to EGFR inhibition

Activation of other receptor

tyrosine kinases (eg. ERBB2

amplification)

FAS/NFκB activation

Epithelial-mesenchymal

transition? (AXL, Slug

activation?)

Loss or spliced variant of BIM?

Other? (eg/ CRKL or ERK

amplification)

EGFR T790M in NSCLC Indonesia, 2016

Third Generation EGFR TKI targeting

T790M

Osimertinib – (Tagrisso)

Rociletinib

Olmutinib

ASP8273

Nazartinib

PF-06747775

0 3 6 9 12 15 18

5

3

Data cut-off April 15, 2016. Population: intent-to-treat.

Progression-free survival defined as time from randomization until date of objective disease progression or death. Progression included deaths in absence of RECIST progression. Tick marks indicate censored data.

BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; RECIST, Response Evaluation Criteria In Solid Tumors.

1. Mok TS, et al. N Engl J Med. 2017; 376:629-640. 2. Papadimitrakopoulou VA, et al. J Thorac Oncol. 2017; 12(S1), abstract PL03.03.

Analysis of PFS by BICR was consistent with the investigator-based

analysis:

HR 0.28 (95% CI: 0.20, 0.38), P<0.001; median PFS 11.0 vs 4.2 months

279

140

240

93

162

44

88

17

50

7

13

1

0

0

No. at risk

Osimertinib

Platinum-pemetrexed

Months

Osimertinib (n=279)

Platinum-pemetrexed (n=140)

Investigator-based analysis:

HR for disease progression or death,

0.30 (95% Cl: 0.23, 0.41) P<0.001

Median PFS (95% Cl)

10.1 (8.3, 12.3)

4.4 (4.2, 5.6)

Pro

bab

ilit

y o

f P

rog

ress

ion

-fre

e S

urv

iva

l 1.0

0.8

0.6

0.4

0.2

0

AURA3 primary endpoint: PFS by investigator assessment1,2

10.1

N Engl J Med 2017;376:629-40.

4.4

FLAURA double-blind study design

CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; p.o., orally; RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1; qd, once daily; SoC, standard-of-care; TKI, tyrosine kinase inhibitor; WHO, World Health Organization

Stratification by

mutation status

(Exon 19 deletion

/ L858R)

and race

(Asian /

non-Asian)

Patients with locally advanced or

metastatic NSCLC

Key inclusion criteria

• ≥18 years*

• WHO performance status 0 / 1

• Exon 19 deletion / L858R

• No prior systemic anti-cancer /

EGFR-TKI therapy

• Stable CNS metastases allowed

Endpoints

• Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1)

• Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported

outcomes, safety

Randomised 1:1

RECIST 1.1 assessment every

6 weeks¶ until objective

progressive disease

EGFR-TKI SoC§;

Gefitinib (250 mg p.o. qd) or

Erlotinib (150 mg p.o. qd)

(n=277)

Osimertinib

(80 mg p.o. qd)

(n=279)

Ramalingam SS, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA.[ Oral

presentation]. European Society for Medical Oncology Conference, Madrid, Spain, September 8-12, 2017.

Current Osimertinib Approved indication is indicated for the treatment of adult patients with locally advanced or metastatic EGFR T90M mutation positive NSCLC who

progressed on or after EGFR TKI therapy

Primary endpoint: PFS by investigator

assessment

FLAURA data cut-off: 12 June 2017

Tick marks indicate censored data;

CI, confidence interval; DCO, data cut-off; HR, hazard ratio; SoC, standard-of-care; PFS, progression-free survival.

Ramalingam et al. Presented at :ESMO Congress Sep 8-12,, 2017; Madrid, Spain.

Median PFS, months (95% CI)

18.9 (15.2, 21.4)

10.2 (9.6, 11.1)

1.0 P

rob

ab

ilit

y o

f p

rog

res

sio

n-f

ree

su

rviv

al

0.2

0.4

0.6

0.8

0.0

0 3 6 9 12 15 18 21 24 27 Time from randomisation (months)

279

277

262

239

233

197

210

152

178

107

139

78

71

37

26

10

4

2

0

0

No. at risk

Osimertinib

SoC

Osimertinib

SoC

HR 0.46

(95% CI 0.37, 0.57)

p<0.0001

Current Osimertinib Approved indication is indicated for the treatment of adult patients with locally advanced or

metastatic EGFR T790M mutation positive NSCLC who progressed on or after EGFR TKI therapy

Olmutinib

• Irreversible kinase inhibitor binds to cysteine residue near the kinase domain

of mutant EGFR1

• Potent inhibition in T790M and exon 19 deletion, low potency for EGFR wild

type1

Phase Study population NCT No.

I/II NSCLC patients who have EGFR mutations and received prior treatment with EGFR TKI or chemotherapy

NCT01588145

II NSCLC naïve patients who have EGFR mutations including exon 20

NCT02444819

II NSCLC patients who have EGFR mutations incl. T790M and received prior treatment with EGFR TKI

NCT02485652

Ongoing clinical trials2

1. Wang eat al. Journal of Hematology & Oncology (2016) 9:34 2. http://www.clinicaltirals.gov

ASP82731

• Small molecule, irreversible TKI inhibitor that inhibits the kinase activity of EGFR

mutations including T790M, with limited activity against EGFR wild-type (WT)

NSCLC

Phase Study population NCT No.

I NSCLC patients who have EGFR mutations and received

prior treatment with EGFR TKI

NCT02113813

I/II NSCLC with EGFR mutation and had progressive disease after previous treatment with EGFR TKIs

NCT02192697

II NSCLC with EGFR mutation and TKI naïve patients NCT02500927

III Stage IIIB/IV NSCLC with EGFR mutations NCT02588261

Ongoing clinical trials

1. Wang eat al. Journal of Hematology & Oncology (2016) 9:34

Nazartinib1

• Potent inhibitory activity against activating (L858R, del19) and resistant T790M

mutants

Phase Study population NCT No.

I/II Patients with EGFR mutated solid malignancies NCT02108964

Ib/II Patients with EGFR mutated NSCLC NCT02335944

II Patients with EGFR mutated and cMET-positive NSCLC NCT02323126

Ongoing clinical trials

1. Wang eat al. Journal of Hematology & Oncology (2016) 9:34

Brain Metastases

Brain metastasis disease from solid tumor is more frequent than

primary brain tumors.

Dissemination in the central nervous system occurs in up to

44% of patient with NSCLC, especially adenocarcioma.

Poor prognosis, 4-15 months in treated NSCLC-patients

Chemotherapy and targeted therapy have a low capacity to

penetrate into CSF

Cancer Treatment Reviews Cancer Treatment Reviews (2017)

doi: http://dx.doi.org/10.1016/j.ctrv.2017.02.004

The Incidence of Brain Metastasis is higher in EGFR-mutant patients

compared to EGFR-wild type

EGFR mutation status showed a concordance rate of 93.3% (14 of 15

patients) between the primary lung lesions and corresponding brain

metastasis1

1. Li et al, J Thorac Dis 2017;9(8):2510-2520 2. Whitsett et al, Transl Lung Cancer Res 2013:2(4):273-283

The Incidence of Brain Metastasis is higher in EGFR-mutant patients compared to EGFR-wild type1 Incidence of CNS Metastasis from primary lung ca by subtype2

CNS METASTASES ARE ASSOCIATED WITH POOR SURVIVAL

AND REDUCED QUALITY OF LIFE

Survival times for patients with

brain metastases are low1-3

Debilitating symptoms resulting in

anxiety and loss of independence

in brain metastases patients1-3

Behavioural

changes

Headaches

Mental

instability

Seizures

Focal

weakness

Ataxia

Speech

impairment

Without treatment*: 4–11 weeks

With treatment*: 4–15 months

*Treatment encompasses systemic and intrathecal

chemotherapy and radiotherapy

1. Wong, et al. Curr Oncol 2008; 2. Lee, et al. J Thoracic Oncol 2013

3. Tsakonas, et al. Cancer Treatment Review 2017

Symptoms and Clinical Presentation

Brain Mets vs No Brain Mets

J Thoracic Oncol 2015;10:156-63

Leptomeningeal metastases

Incidence

In Patients with NSCLC:3-5%

In patients with EGFRm NSCLC: 9%

Prognosis

Median OS from diagnosis: 4.5-11.0 months

Cause of death:

28% LM progression

31%+systemic progression

41% systemic progression

Author Country EGFR TKI N Study EGFR Status

Intracranial Response

Rate ( icRR )

TTP / PFS OS

Porta (2011)

Spain Erlotinib 17 Retro EGFR

Mutants 82.4% 11.7 m 12.9 m

Park (2012)

Korea Gefitinib/ Erlotinib

28 Pros EGFR

Mutants 83% 6.6 m 15.9 m

Wu

(2013) China Erlotinib 48 Pros

80% NS

93% ade 75% M+ vs

55% uk/wild 10.1 m

(for brain) 18.9 m

Hotta (2004)

Japan Gefitinib 14 Retro EGFR

Mutants 43% 9.1 m NA

Gerber (2014)

USA Erlotinib 63 Retro EGFR

Mutants NR 17 m 24 m

Afatinib 81 Pooled Analysis

EGFR Mutants

21% 8.2 m NA

1. Myung-Ju Ahn, WCLC 2017

Clinical Data of Efficacy of EGFR TKI in EGFR Mut+ Brain Metastasis1,2

2. Curr. Treat. Options in Oncol. (2017) 18:22

CNS Penetration Rate first-/second-generation TKIs

CNS = central nervous system; CSF = cerebrospinal fluid

Publ icat ions TK I

Dose

(mg/day)

Mean CSF Penet ra t ion

( range, %)

Zhao, et al. 2013 Gefitinib 250 0.36–1.3

Togashi, et al. 2012

Zeng, et al. 2015

Togashi, et al. 2012 Erlotinib 75–150 2.7–6.2

Masuda, et al. 2011

Togashi, et al. 2011

Deng, et al. 2014

Hoffknecht, et al. 2015 Afatinib 50 0.6

1. Metro, et al. Expert Opin Pharmacother 2015

SIDE EFFECTS

Asia-Pac J Clin Oncol. 2018;14:23–31.

Asia-Pac J Clin Oncol. 2018;14:23–31.

Re-evaluation of every 2 weeks

Dose

Maintained

Recommended of

dose reduction

and/or discontinue

Topical Therapy

Steroid

Antibiotic

Steroid

Antibiotic

Steroid

Antibiotic

Systemic Therapy

–

Antibiotic

Antibiotic

Corticosteroid Severe

(Stage 3–4)

Moderate

(Stage 2)

Mild

(Stage 1)

1. Lynch, T., Kim, E. & Eaby, B. (2007). Epidermal Growth Factor Receptor Inhibitor–Associated Cutaneous Toxicities: An Evolving

Paradigm in Clinical Management. The Oncologist 12:610-621. Retrieved from www.theoncologist.com (on April 26, 2016)

Maintained

Management of Skin Rash

GUIDELINE

GUIDELINE

Progression after first line TKI

.

RE BIOPSY if possible !!

ctDNA from blood ( t790m mutation)

Acquired resistance to EGFR inhibition

Activation of other receptor

tyrosine kinases (eg. ERBB2

amplification)

FAS/NFκB activation

Epithelial-mesenchymal

transition? (AXL, Slug

activation?)

Loss or spliced variant of BIM?

Other? (eg/ CRKL or ERK

amplification)

ctDNA/ cf DNA

EGFR TKI in Indonesia

2004 Ipass study

2008 Gefitinib and Erlotinib were available in Indonesia

2012 Gefitinib on Askes (special access)

2014 Gefitinib on National Health Insurance (BPJS)

2015 Erlotinib on BPJS

2017 Afatinib on BPJS

NOT COVERED BY National Health Insurance : 3rd Gen TKI

(osimertinib) and ALK inhibitors

The Histology Matters Squamous

Cell

carcinoma

(SCC)

Adeno-

Carcino

ma

Large Cell

Carcinoma

NSCLC not

otherwise

specified

(NOS)

Molecular Testing

Chemotherapy EGFR TKI Crizotinib

Non Squamous Cell Ca

(SCC)

EGFR Sensitizing Mutation Positive

EML4-ALK Trans -location Positive

Molecular testing

negative

Indonesian Association of Thoracic Oncology (IASTho)

Possible strategy for advanced stage

NSCLC EGFRmut

Gefitinib

Erlotinib

Afatinib

Dacomitinib

Osimertinib

Gefitinib + PEM/CAR

Erlotinib + ( Bevacizumab/ramucimumab)

Chemo (platinum based)

Osimertinib Chemo (platinum based)

Chemo (platinum based)

Osimertinib Chemo (platinum based)

Chemo (platinum based)

Chemo (platinum based)

Osimertinib Chemo (platinum based)

Chemo (platinum based)

Osimertinib Chemo (platinum based)

Red box : BPJS possible

Takehome messages

EGFR mutation testing is recomended in NSCLC

For EGFR mut +; Tyrosine kinase inhibitor is recommended

Clinical benefits are similar across firstGeneration and

Second generation of TKI

Side effects, CNS metas, mutation should be considered

Rebiopsy (if possible) is recommended if disease

Progressed after TKI ; ct/cfDNA if possible

Thank You