ROLE OF TKI

IN
ADENOCARSINOMA
NON SMALL CELL
Eko A Pangarsa

LUNG CANCER
 Introduction
Cancer is a genetic disease and this concept is now widely
exploited to design new targeted molecules.
Lung cancer is still the leading cause of death for solid tumors
worldwide.
Mainly diagnosed at locally-advanced/metastatic stages and if
untreated, the median survival after diagnosis is of 4-5 m
whereas the 1-year survival is less than 10%.
Lung cancer is an extremely heterogeneous group of disorders,
and remains a difficult disease to treat and an extremely
diverse genomic alterations has been documented .

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The management of lung cancer patients are
dependent on knowledges of the pathology
of each patient

Lung cancer is not a single disease

And not only NSCLC-SCLC

544-496 BC

know your enemy

Sun Tzu , The Art of War

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Histologic and molecular subtype of NSCLC
Number somatic mutations in human cancers, detecting by genome wide
sequencing studies (SCIENCE 2013;39 :1546-57)
 PREVALENCE OF EGFR MUTATION IN ASIA

Based on PIONEER study

1
published in 2014,
51.4% of patients with
adenocarcinoma are
EGFR mutation
positive

Another study, IGNITE

study 2 (2015) which
involved Indonesia, the
frequency of EGFR
mutation positive
in Asia Pacific is 49%

Ref : 1. Shi Y ,et al. J Thorac Oncol. 2014;9:154-162

2. Han B. et al. Annals of Oncology 26 (suppl.1);2015;i29-i44 PIT PAPDI CAB SEMARANG 2016
 EGFR Mut Adeno Ca ( n 1082 )
EGFR Mut NSCLC ( n > 2000)

Shigematsu et al.
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 EGFR Mutations in Lung Cancer
Found in pts with NSCLC more common in never smokers,
adenocarcinomas, females, Asians.

Associated with good response to first-, second-, and third-

generation TKIs.

The specific EGFR mutation identified is important

Predominantly located in EGFR exons 18-21 85% of EGFR

mutations are either deletions in exon 19 or a single-point mutation
in exon 21 (L858R).

There are : sensitive mutations, primary resistance mutations (often

exon 20), and acquired resistance mutations (T790M).

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 EGFR Mutations in Lung Cancer

T790M < 5% at initial EGFR mutations, however it is the major resistance (50%) after treatment TKI

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 Percent Change in Measurable Tumor at Best Response, by Individual Patient.

Lecia V. Sequist et al. JCO 2008;26:2442-2449

2008 by American Society of Clinical Oncology

 Morpholgical classification (2004)

Small cell lung cancer (15%)

Non Small Cell Ca (85%)

Squamous cell carcinoma
Adenocarcinoma
Bronchoalveolar carcinoma
Large cell carcinoma

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WHO Classification of Lung Cancer 2015

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 Adenocarcinoma
2004 WHO 2015 WHO
Mixed subtype Preinvasive lesions
Acinar Atypical adenomatous
hyperplasia
Papillary Adeno Ca Insitu (AIS)

BAC Minimally invasive ADC (MIA)

Invasive ADC
Solid
G1: Lepidic ( 10%)
Variants G2: Acinar, papillary
G3: Micropapillary, solid
Variants of Invasive

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Source: manual for staging of cancer 3rd edition,
American Joint Committee on Cancer .
JB Lippincott, 1998

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 Chemotherapy or EGFR TKI
for First Line Therapy in
Advanced NSCLC EGFR Mutation ?
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 PFS and ORR with first-line gefitinib versus doublet chemotherapy
in EGFR M+ Asian patients across 3 Phase III studies
HR (95% CI) = 0.48 (0.36, 0.64) HR (95% CI) = 0.30 (0.22, HR (95% CI) = 0.49 (0.34, 0.71)
100 p<0.001 100
0.41) 100 p<0.001
p<0.001
Probability of

80 80 80

60 60 60

40 40 40
PFS

20 20 20

0 0 0
0 4 8 12 16 20 24 0 3 6 9 12 15 18 21 24 27 0 10 20 30 40

Months Months Months

IPASS NEJ002 WJTOG 3405
p<0.001 p<0.001 p<0.001
100 100 100

of
of

80 80 80

Probability
Probability

60 60 60

ORR %
ORR %

40 40 40
73,7% 30,7% 62,1% 32,2%

PFS
71,2% 47,3%
PFS

20 20 20
0 0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24
Gefitinib (n=132) Gefitinib (n=114) Gefitinib (n=86)
C/P (n=129) C/P (n=110) C/D (n=86)
Mok et al. N Engl J Med 2009; Maemondo et al. N Engl J Med 2009; Mitsudomi et al. Lancet Oncol
2010
Effect Chemotheraphy on EGFR status
Effect of First line Ctx on EGFR Mutation Stts Before and
After Treatment
in Plasma Samples (n 264)
Postchemotherapy
Wild Mutated Total
Type
Prechemotherap No. % No. % No. %
y
Wild type 14 56. 24 9.1 173 65.5
9 4
NOTE. P < .001 (McNemar
Mutated 54 test).
20. 37 14. 91 34.5
Abbrevation: NSCLC, non-small-cell
5 lung cancer.
0
Effect of Neoadjuvant Postchemotherapy
Total Ctx
20 on76.
EGFR Mutation
61 23. Stts Before
264 100.and
3Wild
After Treatment in Tissue 9
Samples (n 63) 1
Mutated Total 0
Type
Prechemotherap No. % No. % No. %
y
Wild type 39 61. 2 3.2 41 65.1
9
Mutated
NOTE. 12 test).
P < .001 (McNemar 19. 10 15. 22 34.9
Bai et al
0
Abbrevation: NSCLC, non-small-cell 9
lung cancer. JCO 2012;30: 3077-
Total 51 81. 12 19. 63 84100.
0 0 0
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 EGFR TKI in Advanced NSCLC
EGFR-TKI is recommended as first line treatment in activating EGFR
mutation NSCLC in NCCN guideline. 1

Several clinical practice guidelines recommend EGFR mutation testing before

initiation of first-line therapy for advanced NSCLC. 2

However, for EGFR unknown patients, chemotherapy is the most

common first line treatment. 3

First-line chemotherapy may influence the status of EGFR

mutations, and thus, assessment of EGFR mutations using
specimens collected at the initial diagnosis might be inadequate for
predicting response to EGFR-TKI treatment after chemotherapy. 4

However, it is difficult to obtain tumour biopsies from patients for

whom chemotherapy has failed. 4
1. NCCN guidelines on NSCLC v.3 2014
2. Yunkhai Shi , J Thorac Oncol. 2014;9: 154162)

3.Leight NB. Curr Oncol 2012;19 (suppl 1) : s52-s58

4.Bai H et al. J Clin Oncol 2012; 30:3077-3083
ADJUVANT SETTING
 Adjuvant Gefitinib: NCIC CTG BR. 19
N=503 Gefitinib
250 mg po qd
Stage IB III NSCLC x 2 years
Complete surgical resection R
PS 0-2
Adjuvant chemo and /or XRT Placebo
Unselected Pts PO qd
X 2 years
All patients
EGFR Mutated test
359 (344/15)

Adjuvant trastuzumab improves OS in resected HER2-positive breast cancer

(NEJM. 2011;365(14):12731283) .

Imatinibmesylate significantly improves DFS in patients with resected gastrointestinal stromal

tumor (GIST ) .(Lancet. 2009;373(9669):10971104)
 OS by treatment arm in patients with EGFR wild-type tumors.

Glenwood D. Goss et al. JCO 2013;31:3320-3326

2013 by American Society of Clinical Oncology
 (A) Disease-free survival and (B) overall survival by treatment arm in patients with EGFR exon
19 and 21 mutations.

Glenwood D. Goss et al. JCO 2013;31:3320-3326

2013 by American Society of Clinical Oncology

How to select treatment
for
EGFR+ Patients
 Tolerabilty Profile

This data is taken from a retrospective study at Kyoto University Hospital involving 154 patients and
not based on direct head-to-head study.
Percentage only shows adverse events with grade 2, except for pneumonitis and gastrointestinal
bleeding

Ref : Togashi Y et al. Lung Cancer (74);2011;98-102

 Tolerances and Responses
between Gefitinib and Erlotinib

Ref : Togashi Y et al. Lung Cancer (74);2011;98-102

 Tolerability profile

Gefitinib (Iressa) shows less skin rash incidence than erlotinib

Most of skin rash incidence associated with Gefitinib are grade 1
(mild)
 Similar Efficacy with Erlotinib

1.0 Median PFS (95% Cl)

N : 96 EGFR mut (+)

Survival Probability

0.8
Gefitinib 4.9 months (1.5-8.3)
Erlotinib 3.1 months (0.0-6.4)
0.6

p=0.336
0.4

0.2

0.0
0 3 6 9 12 15 18 21 24

Months

Kim ST et al. Lung Cancer. 2012 Jan; 75(1): 82-88

Gefitinib versus erlotinib as second line treatment
in unselected NSCLC: Phase III trial

Erlotinib
150 mg/day
Stage III-IV
Adenocarcinoma
N: 560
Evaluable disease R
2 line & after
Age >20 years
No interstitial lung disease Gefitinib
250 mg/day

Stratification factor:
Gender, PS, Stage, Smoking history, Mutation status, Institution, Prior regimen
Katakami N, et al. ASCO 2014

Non-Inferiority trial

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Gefitinib versus Erlotinib: PFS according to EGFR status

Treatment mPFS (mos) p value

% 100
Erlotinib 1.09
80
0.532
EGFR mutation 60
(+) 40 Gefitinib 8.90
20
0
0 6 12 18 24 30 36 42 48

% 100 Treatment mPFS (mos) p value

80 Erlotinib 2.10

EGFR mutation 60 0.221

(-) 40 Gefitinib 2.07
20
0
0 6 12 18 24 30 36 42 48

Treatment mPFS (mos) p value

% 100
Erlotinib 2.53
80
0.878
EGFR mutation 60
unknown 40 Gefitinib 2.27
20
0
0 6 12 18 24 30 36 42 48 Katakami N, et al. ASCO 2014

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 MONITORING
(Clinicaly Resistance)
 RECIST
Criteria

1cm 1.3cm
EGFR TKI EGFR TKI

EGFR TKI
Resistance
Defining Resistance by RECIST lead by RECIST
Premature Termination of TKI

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Different clinical presentations of acquired resistance
in EGFR mutant NSCLC

Cancer. 2014 Aug 1; 120(15): 22892298

Options at progression

1. Slow progression how is it defined

and treated?
Asymptomatic
CT evidence of minor progression
No altered PS

Keep TKI until symptoms

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2. Stable in lung but other metastases
(eg bone or brain)

Keep TKI and use local radiation

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3. Rapid progression
Symptoms
Altered PS
Clinical progression
CT scan/radiologic progression

Switch to chemotherapy without

delay
Risk of a Flare effect
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 EGFR TKI failure in NSCLC

Dramatic Local
Gradual progression
progression Disease control > 6 months
progression
Disease control 3months Compared with previous Disease control >3months
Compared with previous Assessment, rapid increment Solitary extracranial
Assessment, rapid increment Of tumour burden progression or intecranial
Of tumour burden Symptom deterioration progressin
Symptom deterioration Symptom benefit

Continuation of
Chemotherapy Continuation of EGFR-TKIs plus local
EGFR-TKIs interventional

Symptom

Switch Chemo

Wu et al. ESMO Lung Cancer

Preceptorship 2015
Switch Chemotheraphy without delay
( Disease flare at TKI discontinuation )
Disease flare definition:
Accelerated disease progression (symptoms, declining PS)
Hospitalization for disease progression
Death
Characteristics associated with disease flare:
Shorter PFS on TKI
Pleural and CNS metastasis
No clear correlation with resistance mechanism
Recommendations to avoid flare
Keep TKI until 2nd line therapy is delivered
The usual wash-out period of 3-4 weeks to be avoided
Disease flare occurs in an median of 8 days after TKI
discontinuation
Chaft J. et al Clin Can Res 2011 17 6298

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How does performance status affect the choice of
2nd-line chemotherapy?
PS 2 may favour 2nd-line choice towards a single-
agent,

PS 0-1 platinum doublet preferred

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 Acquired resistance to EGFR-TKIs
Jackman Criteria
Previously received treatment with a single-agent EGFR TKI.
1. Either of the following:
A. A tumor that harbors an EGFR mutation known to be associated with
drug sensitivity (ie, G719X, exon 19 deletion, L858R, L861Q)
B. Objective clinical benefit from treatment with an EGFR TKI as
defined by either:
A. Documented partial or complete response (RECIST or WHO), or
B. Significant and durable (6 months) clinical benefit (stable disease
as defined by RECIST or WHO)
2. Systemic progression of disease (RECIST or WHO) while on
continuous treatment with TKI within the last 30 days.
3. No intervening systemic therapy between cessation of TKI and
initiation of new therapy.

Jackman D, J Clin Oncol 2010; 28: 357-360

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 Could We Improve Efficacy
EGFR TKI with Combination Chemoterapy ?
Continue with TKI and add chemotherapy ?

IMPRESS Trial
Iressa Mutation Positive Multicenter Treatment Beyond
ProgRESsion Study (IMPRESS; NCT01544179)

Patients Cisplatin Endpoints

+ Primary
Stage IIIB / IV NSCLC Pemetrexed
EGFR mutation (+)
Progression-free
(6 cycles)
Chemotherapy-naive + survival
CR / PR 4 months, Gefitinib 250 mg Secodary
or SD >6 months Overall survival
Objective response rate
With first-line gefitinib Disease control rate
Disease progression Cisplatin
+ Safety and tolerability
<4 weeks prior to QoL
Pemetrexed
study randomisation +
Exploratory
Placebo 250 mg
Biomarkers

Mok Abstract
 IMPRESS trial - primary endpoint

Gefitinib Placebo
(n=133) (n=132)
Median PFS, months 5,4 5,4
Number of events, n (%) 98 (73,7) 107 (81,1)

HR (95% Cl) = 0.86 (0.65, 1.13):

p=0.273

Patients at risk:
Gefitinib 133 110 88 40 25 12 6
Placebo 0 132 100 85 39 17 5 4
0 Esmo.org
26-30 September 2014, Madrid, Spain

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 Take Home Messages
EGFR TKIs improve PFS and QoL and active in pts with poor PS.
First-gen EGFR TKI is PFS superior to chemotherapy in EGFR Mut (+)
metastatic NSCLC.
EGFR TKIs as neo - or adjuvant treatment is not yet established
(The use of EGFR-TKIs outside clinical trial setting is not recommended)
Choice of a s EGFR TKI : consider toxicities and pts preferences.

Gefitinib (IRESSA) has more favorable tolerability profile compares to

chemotherapy and Erlotinib.

Monitoring progression during TKI ( Recist /Jackman Criteria)

Switching to chemotherapy without delay

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Advanced NSCLC:
EGFR Mutation Treatment Strategy

IPASS Study
Impress Study
AE Minimal
First line Treated
Monitoring Chemo
JKN EGFR Resistant
asli ? TKIs

BSC

Death
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NEXT TARGET IN LUNG CANCER

Hammeman PS et al. Cell 2012;150:1107-20

THANK YOU

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