PEMETREXED AS FIRST

LINE CHEMOTHERAPY
FOR NSCLC
SURYANTI DWI PRATIWI
LAB/SMF PARU RSSA
MALANG

What is Pemetrexed

PEMETREXED is a novel multi-targeted Anti-folat in the

treatment of Non-Small Cell Lung Cancer that inhibits :
Thymidylate synthase (TS)
Dihydrofolate reductase (DHFR)

Glycinamide ribonucleotide formyltransferase (GARFT)

Pemetrexed has a high binding affinity to folat receptor- ,2
and once in the cell, it rapidly converts to active
polyglutamate derivatives3
Polyglutamation prolongs its intracellular retention and
enhances pemetrexeds interaction with thymidylate synthase
and other folate-dependent target enzymes1,3-5
These multiple mechanisms of action may explain how
pemetrexed, compared with other antimetabolites such as 5fluorouracil, methotrexate, or raltitrexed, has shown greater
1,61998;38:135-152.
1. Shih C, et al. Adv
Enzyme Regul.
potency and a broader spectrum of antitumor
activity

2. Zhao R, et al. Clin Cancer Res. 2000;6:3687-3695.

3. Chattopadhyay S, et al. Mol Cancer Ther. 2007;6:404-41

4.
5.
6.

Mendelsohn et al. Semin Oncol 1999;26(2 Suppl 6):42-7.

Taylor et al. J Med Chem 1992;35(23):4450-4.
Chen et al. Br J Cancer 1998;78(Suppl 3):27-34.

Pemetrexed (Alimta)
Chemical Structure
HO2C
O

CO2H

NH

CO2H

O
N
H
O

H2N

HN

HN
N

N
H

N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1Hpyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]L-glutamic acid

Alimta (Pemetrexed)

H2N

HN

Folic Acid

CO2H

Pemetrexed: Key Intracellular Folate Enzyme

Targets
TS
TS

Pemetrexe
d
10-CHO-THF

dUMP

5,10-CH2-THF

GARF
GARF
TT

PRPP
GAR

5-FU, raltitrexed

dTMP

DHF

DHFR
DHFR
THF

DNA

NADPH
Methotrexate
NADP+

fGAR
AMP, GMP

DNA, RNA

TS: thymidylate synthase, 5-FU: 5-fluorouracil, GARFT: glycinamide ribonucleotide formyl transferase, DHFR: dihydrofolate reductase, DNA: deoxyribonucleic acid, RNA: ribonucleic acid

Kindler. Cancer 2002;95(4 Suppl):928-32.

Alimta Mechanism of Action

Membrane

AMP

GARFT IMP

PRPP + Gln

GMP
10-CHO-FH4
Alimta

5, 10-CH2FH4

FPGS
Alimta-Glun

Cell

Alimta

Folate
Carriers
(mainly
RFC)

FH4

dUMP

DHFR

TS
FH2
dTMP
DNA Synthesis

RNA &
DNA
Synthesis

Indication of Alimta
1st line Advanced NSCLC, non squamous type

Combination Alimta + Cisplatin

2nd line Advanced NSCLC, non squamous type
Monotherapy Alimta
Switch Maintenance NSCLC
Monotherapy Alimta

1st line Malignant Pleural Mesothelioma ( MPM )

Combination Alimta + Cisplatin
6

Proposed Treatment Algorithm for

Advanced NSCLC: First-line Therapy
2012
Advanced-Stage NSCLC and PS 0-1
EGFR
mutation
positive

ELM4-ALK
positive

EFGR mutation and ALK

negative and
nonsquamous histology

Bevacizumab
appropriate
Erlotinib or
gefitinib
first line

Consider
crizotinib
first or second
line

Consider
carboplatin/paclitax
el + bevacizumab
Or
cisplatin/pemetrex
ed
Bevacizumab

EFGR mutation and

ALK negative and
squamous histology

Bevacizumab
inappropriate
Consider
cisplatin or
carboplatin
combined with
pemetrexed,
docetaxel or
gemcitabine or
paclitaxel
or
cisplatin/vinorelbine
cetuximab

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394 .

Consider
cisplatin or
carboplatin
combined with
docetaxel or
gemcitabine or
paclitaxel
or
cisplatin/vinorelbi
ne
cetuximab

Proposed Treatment Algorithm for

Advanced NSCLC: First-line
Therapy 2012
Advanced-Stage NSCLC & PS 0-1
EGFR
mutation
positive

ELM4-ALK
positive

Molecular
Erlotinib or
gefitinib
first line

Consider
crizotinib
first or second
line

EFGR mutation and ALK

negative and
nonsquamous histology

EFGR mutation and

ALK negative and
squamous histology

Bevacizumab
appropriate

Bevacizumab
Histology:
Clinical
inappropriate

Consider
carboplatin/paclitax
el + bevacizumab
or
cisplatin/pemetrexe
d
bevacizumab

Consider
cisplatin or
carboplatin
combined with
pemetrexed,
docetaxel or
gemcitabine or
paclitaxel
or
cisplatin/vinorelbine
cetuximab

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Consider
cisplatin or
carboplatin
combined with
docetaxel or
gemcitabine or
paclitaxel
or
cisplatin/vinorelbi
ne
cetuximab

The Development of
Pemetrexed

Pemetrexed has shown activity in NSCLC

Single agent 1st and 2nd-line

Combination with platinum agents in 1st-line

Safety of Alimta has been well characterized

Toxicity significantly reduced after Folic Acid / B12

Very low incidence of neutropenia, febrile neutropenia,
and other non-hematologic toxicities

A pivotal Phase III study in the treatment of 2nd-line

NSCLC was indicated

Pemetrexed Safety Profile

As with most antifolates, the primary toxicity is

hematologic

Early data showed that high serum

homocysteine
levels a surrogate for functional folate and/or
B12

deficiency correlated with higher levels of

toxicity
A decision was made to supplement all patients
with
folic acid and vitamin B12

This resulted in decreased toxicity with no

Vitamin Supplementation and Premedication

for Pemetrexed Administration

Folic acid (Once daily): 0.35-1mg taken 1 week before treatment and continued until 21 days of last dose
Dexamethasone (twice daily): 4mg taken twice daily the day before, day of and day after treatment
Vitamin B12 (IM): 1mg taken 1 week before treatment and repeated every 9 weeks. Subsequent injections may be given
on the same day as pemetrexed

Company Confidential
14
Copyright 2006 Eli Lilly and Company

JMDB: Largest ever clinical trial conducted

in 1st line NSCLC (N=1,725)

21

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

JMDB: Histology is
predictive factor for Alimta*

22

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

JMDB: Alimta/Cisplatin shows superior

survival in adenocarcinoma

histology (N=847)

23

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

JMDB: Alimta/Cisplatin shows superior survival

in large cell carcinoma histology (N=153)

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

24

Efficacy by Histology
Median PFS, mos

Median OS, mos

Pemetrexed plus Cisplatin versus Gemcitabine plus Cisplatin

Pem/Cis

Gem/Cis

p-value

Pem/Cis

Gem/Cis

p-value

Nonsquamous
N=1252

5.3

5.0

0.349

11.0

10.1

0.011

Squamous
N=473

4.4

5.5

0.002

9.4

10.8

0.050

Pemetrexed vs Placebo*
Pem

Placebo

p-value

Pem

Placebo

p-value

Nonsquamous
N=482

4.4

1.8

<0.00001

14.4

9.4

0.005

Squamous
N=181

2.4

2.5

0.896

9.6

11.9

0.231

* PFS data independently reviewed (N=430 nonsquamous;

N=151 squamous); OS data is preliminary

JMDB: East Asian patients with non-squamous

histology survive longer with Alimta/Cisplatin

Orlando M. et al. J Clin Oncol 27:15s, 2009 (suppl; abstr

8045).

26

JMDB: Alimta/Cisplatin offers significant

safety advantages in 1st line NSCLC

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

27

JMDB: Alimta/Cisplatin offers significant

safety advantages in 1st line NSCLC

28

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

JMDB: Alimta/Cisplatin needs

less transfusion/supportive care

29

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

Lung Cancer Therapy: 2012

Looking Forward to 2015

We are making progress

Reality: the transition to

rationally selected and
personalized therapy is
challenging

Histology
Maintenance therapy
Predictive biomarkers

Progress requires
continuing change

Culture change
Requirement for more
tumor tissue (molecular
profiling)
Ungroup NSCLC into
individual patients
(personalized therapy)

In every challenge, there

are opportunities
We must take advantage of
each of these opportunities
if we are to advance the
care and cure of patients
with lung cancer

Evolution From Empiric to

Personalized Therapy in
Factors
Agent Affected
NSCLC
Asian, never-smoker, female
Erlotinib, gefitinib
Clinical

Untreated CNS metastases, no

hemoptysis, uncontrolled
hypertension

Bevacizumab

Adenocarcinoma

Erlotinib, gefitinib

Histologic

Nonsquamous

Bevacizumab,

pemetrexed

Thymidylate synthase

Pemetrexed

EGFR mutation

Erlotinib, gefitinib

ERCC1/RRM1

Platinum

RRM1

Gemcitabine

KRAS mutation

Erlotinib, gefitinib

EGFR by FISH

Erlotinib? Gefitinib?

EGFR by IHC

Cetuximab?

EML4-ALK fusion

Crizotinib

Molecular
Adapted from Gandara DR,
32
et al. Clin Lung Cancer.
2009;10:148-150.

THANK YOU