Advanced NSCLC:
treatment options for non-squamous,
EGFR wildtype tumors
Prof. Christian Manegold
Interdisciplinary Thoracic Oncology
Department of surgery
Medical Center Mannheim – University Heidelberg
Disclosures
• Consultancy: Hoffmann-La Roche, Pfizer,
Eli Lilly, Merck-Serono, Novartis, Amgen, Boehringer
Ingelheim, AstraZeneca
• Speaking: Hoffmann-La Roche, Eli Lilly, MerckSerono, AstraZeneca
• Grant support: Merck-Serono, Sanofi-Aventis,
Eli Lilly
• Travel Support: Hoffmann-La Roche, Merck-Serono,
Eli Lilly, AstraZeneca
NSCLC: Incidence of single driver mutations
No mutation detected
KRAS
22%
AKT1
NRAS
EML4-ALK
7%
MEK1
MET AMP
EGFR
17%
HER2
PIK3CA
BRAF
Double
mutants 3%
Mutation found in 54% (280/516) of
tumours completely tested (CI 5059%)
Kris et al. J Clin Oncol 29: 2011 (suppl; abstr 7506)
Treatment Strategies for NSCLC
Stage IIIB-IV
Chemotherapy
PS 0-1 / 2
Elderly
First –line
Maintenance
Second / Third –
line
Stage I-III
operable
Stage I-III
inoperable
Chemotherapy
adjuvant / postoperative
ChemoRadiotherapy
sequential
Chemotherapy
neoadjuvant /
preoperative
ChemoRadiotherapy
concomitant
Advanced NSCLC: Treatment algorithm in 2012
Mutated tumours
1st-line
EGFR-TKI;
ALK-Inhibitor
Maintenance in
case of non-PD/SD
Non-Squamous
Squamous
Platinum-Doublets
(Pem!) plus Bev or
Cet
Platinum-Doublets
(No Pem, no Bev)
plus Cet
Switch:
Pemetrexed
Erlotinib
Continuous:
Pemetrexed
Switch:
Erlotinib
Single agent
Non-cross resistant
2nd-line
Dealer’s choice
Single agent
Non-cross resistant
3rd-line
Dealer’s choice
Dealer’s choice
Dealer’s choice
NSCLC: ASCO treatment
recommendations for advanced disease
• Chemotherapy prolongs survival and is most appropriate for
individuals with good performance status (PS 0 or 1, and possibly 2).
• Chemotherapy should be a platinum-based two-drug combination
regimen.
• Non-platinum containing regimens may be used as alternatives to
platinum-based regimens. For elderly patients, or patients with PS 2,
available data support the use of single-agent chemotherapy.
• Chemotherapy should be stopped at 4 cycles in patients who are not
responding to treatment, and should be administered for no more
than six cycles .
• If chemotherapy is to be given it should be initiated while the patient
still has good PS.
Azzoli et al. J Clin Oncol 29, 3825-3831, 2011
First line Gemcitabine/Cisplatin combination therapy
for advanced NSCLC: outcome plateau
Study
Schedule
Gem mg/m² / DDP mg/m²
ORR
%
TTP
mos
MS
mos
1-YS
%
Sandler 2000
1000 d1, 8, 15 /100 d1 q4w
34
5.6
9.1
39
Schiller 2002
1000 d1, 8, 15 /100 d1 q4w
21
4.2
8.1
36
Crinò 1999
1000 d1, 8, 15 /100 d2 q4w
38
5.0
8.6
33
Melo 2002
1000 d1, 8, 15 /100 d15 q4w
48.4
n.r.
9.6
n.r.
Cardenal 1999
1250 d1, 8 /100 d1 q3w
40.6
6.9
8.7
32
Smit 2003
1250 d1, 8 / 80 d1 q3w
31.8
5.1
8.9
33
Giaccone 2002
1250 d1, 8 / 75 d1 q3w
35
6.0
11.1
34
Scagliotti 2002
1250 d1, 8 / 70 d2 q3w
30
5.3
9.8
37
Alberola 2003
1250 d1, 8 / 100 d1 q3w
42
6.3
9.3
38
NSCLC: Pivotal phase III trails in stage IIIB/IV disease
relevant for the treatment of non-mutated,
non-squamous tumours
PARAMOUNT
JMEN
Saturn
JMDB
AVAiL
FLEX
Design
2-arms
maint.
2-arms
maint.
2-arms
maint.
2- arms
1st-line
4-arms
1st-line
2-arms
1st-line
Primary
endpoint
PFS
PFS
PFS
OS
PFS
OS
Agents
Pemetrexed
Placebo
Pemetrexed
Placebo
Erlotinib
Placebo
Pemetrexed
Gem
Cis
Bevacizumab
Gem
Cis
Cetuximab
Vin
Cis
No. of Pts.
539
663
889
1700
1043
1100
Outcome
PE:
met
PE:
met
PE:
met
PE:
met
PE:
met
PE:
met
Advanced NSCLC: Bevacizumab plus Standard CT
ECOG 4599: Carbo/Taxol
PD
CP
Previously
untreated stage
IIIB/IV
non-squamous
NSCLC
Bev (15mg/kg)
every 3 weeks +
CP
2
Previously
untreated, stage
IIIB/IV
non-squamous
NSCLC
AVAiL: Cis/Gem
R
A
N
D
O
M
IS
E
1
1
2
Bev every
3 weeks until
progression
Bev
7.5mg/kg + CG
Bevacizumab
PD
PD
Placebo + CG
PD
Placebo + CG
Bev
15mg/kg + CG
Bevacizumab
PD
Advanced NSCLC: Bevacizumab plus Standard CT
Results by primary endpoints
ECOG 4599: Carbo/Taxol
AVAiL: Cis/Gem
6.7 m
6.1 m
12.3 m
10.3 m
6.5 m
6.1 m
Sandler et al N Engl J Med 355, 2542-2550, 2006
Reck et al, Ann Oncol 21, 1804-1809, 2010
Reck et al, J Clin Oncol 27, 1227-1235, 2009
Time Months
NSCLC: Bevacizumab - EMA Registration
• BEV at a dose of 7.5mg/kg or 15mg/kg, in
combination with platinum-based chemotherapy, for
the first-line treatment of patients with unresectable
advanced, metastatic or recurrent NSCLC other than
predominantly squamous cell histology
• Removal of Bev- contraindication in patients with
untreated CNS metastases (2008)
NSCLC: Bevacizumab - Key eligibility criteria
Inclusion criteria
Exclusion criteria
 non-squamous NSCLC
 grade 2 haemoptysis
 chemo-naïve
 radiological evidence of
tumour invasion of major
blood vessels
 ECOG PS of 0–1
 spinal cord compression
 uncontrolled hypertension
 history of thrombotic or
haemorrhagic disorders
 therapeutic anticoagulation
within 10 days of first dose
JMDB: Pemetrexed vs Gemcitabine
Randomization
Factors
• Stage
• PS
• Gender
• Histo vs cyto
• Brain mets
Cisplatin 75 mg/m2 day 1 plus
Pemetrexed 500 mg/m2 day 1
R
Each cycle repeated
q3 weeks up to 6 cycles
Cisplatin 75 mg/m2 day 1 plus
Gemcitabine 1250 mg/m2 days 1 & 8
Vitamin B12, folate, and dexamethasone given in both arms
Primary endpoint: survival; non-inferiority design
Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008
JMDB: Pemetrexed vs Gemcitabine
Squamous (n=473)
Nonsquamous* (n=1252)
HR=1.229
(95% CI: 1.00–1.51)
p=0.051
Pemetrexed+Cisplatin
Median OS: 11.0 mos
Gemcitabine+Cisplatin
Median OS: 10.1 mos
Survival Probability
Survival Probability
HR=0.844
(95% CI: 0.74–0.96)
p=0.011
Gemcitabine+Cisplatin
Median OS: 10.8 mos
Pemetrexed+Cisplatin
Median OS: 9.4 mos
Survival Time (months)
Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008
Survival Time (months)
Treatment-by-Histology Interaction Analyses in Three Phase III
Trials Show Superiority of Pemetrexed in Nonsquamous
NSCLC
Scagliotti J Thorac Oncol 6, 64–70, 2011
FLEX: First-Line ErbituX in lung cancer
Pirker et al. Lancet 373, 1525-1531, 2009
Flex: Kaplan-Meier estimates of overall survival
time in the intention-to-treat population
Pirker et al. Lancet 373, 1525-1531, 2009
FLEX: Stained tumour sections from study patients
Pirker et al. Lancet Oncol 13: 33–42, 2012
FLEX: Objective response rate by IHC score
Pirker et al. Lancet Oncol 13: 33–42, 2012
FLEX: Response rate by EGFR-IHC expression
High EGFR expression (≥200)
n=345 (31%)
Response rate (%)
Low EGFR expression (<200)
n=776 (69%)
50
50
40
40
30
29.6
44.4
30
32.6
28.1
20
20
10
10
0
0
p=0.36
CT + cetuximab
CT
Treatment interaction test p=0.040
Pirker et al. Lancet Oncol 13: 33–42, 2012
p=0.002
FLEX: Overall survival for patients according to
treatment group and EGFR expression group
Low EGFR
Pirker et al. Lancet Oncol 13: 33–42, 2012
High EGFR
Advanced NSCLC: Treatment algorithm in 2012
Mutated tumours
1st-line
EGFR-TKI;
ALK-Inhibitor
Maintenance in
case of non-PD/SD
Non-Squamous
Squamous
Platinum-Doublets
(Pem!) plus Bev or
Cet
Platinum-Doublets
(No Pem, no Bev)
plus Cet
Switch:
Pemetrexed
Erlotinib
Continuous:
Pemetrexed
Switch:
Erlotinib
Single agent
Non-cross resistant
2nd-line
Dealer’s choice
Single agent
Non-cross resistant
3rd-line
Dealer’s choice
Dealer’s choice
Dealer’s choice
NSCLC – Erlotinib switch maintenance
Chemonaïve
advanced
NSCLC
n=1,949
Mandatory tumour
sampling
4 cycles of
first-line
platinum
doublet
chemotherapy
*
Stratification factors:
•
•
•
•
•
•
EGFR IHC (positive vs negative vs indeterminate)
Stage (IIIB vs IV)
ECOG PS (0 vs 1)
CT regimen (cis/gem vs carbo/doc vs others)
Smoking history (current vs former vs never)
Region
Erlotinib
150mg/day
Non-PD
n=889
PD
1:1
Placebo
PD
Co-primary endpoints:
• PFS in all patients
• PFS in patients with EGFR IHC+ tumours
Secondary endpoints:
• OS in all patients and those with EGFR IHC+
tumours, OS and PFS in EGFR IHC– tumours;
biomarker analyses; safety; time to symptom
progression; QoL
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel
cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel
NSCLC – Erlotinib switch maintenance
Progression free survival
Progression free Survival
Cappuzzo et al. Lancet Oncol 11, 521-529; 2010
NSCLC – Erlotinib switch maintenance
Overall survival
Overall Survival
Cappuzzo et al. Lancet Oncol 11, 521-529; 2010
NSCLC: Erlotinib switch maintenance
Overall survival by response
CR/PR
Stable disease
Overall Survival
1.0
1.0
HR=0.72 (0.59–0.89)
0.8
0.8
HR=0.94 (0.74–1.20)
0.6
Log-rank p=0.6181
Erlotinib
(n=184)
0.4
Placebo
(n=210)
Log-rank p=0.0019
0.6
Erlotinib
(n=252)
0.4
Placebo
(n=235)
0.2
0.2
9.6
0
0
3
6
11.9
9 12 15 18 21 24 27 30 33 36
12.0 12.5
0
0
Time (months)
Measured from
into the
maintenance
phase 2012
Coudert
ettimeal.of randomisation
Ann Oncol
23,
388-394,
3
6
9 12 15 18 21 24 27 30 33 36
Time (months)
NSCLC: Erlotinib switch maintenance
Overall survival by response (subgroups)
Coudert et al. Ann Oncol 23, 388-394, 2012
NSCLC: Erlotinib switch maintenance
Survival for SD in wild-type tumours
Coudert et al. Ann Oncol 23, 388-394, 2012
NSCLC – Erlotinib switch maintenance
(registration)
Erlotinib Maintenance :
as single agent in patients with stable disease after
4 cycles of platinum based first-line chemotherapy
EMA: 2010
NSCLC – Pemetrexed switch maintenance
• Stage IIIB/IV NSCLC
• PS 0-1
Pemetrexed 500 mg/m2 (d1,q21d)
+ BSC (N=441)*
• 4 prior cycles of gem,
doc, or tax + cis or
carb, with CR, PR, or
SD
• Randomization
•
•
•
•
•
•
factors:
gender
PS
stage
best tumor response
to induction
non-platinum
induction drug
brain mets
2:1
Randomization
Primary Endpoint = PFS
Placebo (d1, q21d) + BSC (N=222)*
*B12, FOLATE, AND DEXAMETHASONE GIVEN IN
BOTH ARMS
Ciuleanu T. et al. Lancet 374, 1432-1440; 2009
Progression-free Probability
NSCLC – Pemetrexed switch maintenance
PFS by histology
Non-squamous
Squamous
HR=0.47
(95% CI: 0.37-0.6)
p <0.00001
HR=1.03
(95% CI: 0.77-1.5)
p=0.896
Pemetrexed: 4.4 mos
Placebo:
1.8 mos
Placebo: 2.5 mos
Pemetrexed:
2.4 mos
Time (months)
Ciuleanu T. et al. Lancet 374, 1432-1440; 2009
Time (months)
NSCLC – Pemetrexed switch maintenance
OS by histology
Overall Survival
Non-squamous
Squamous
HR=0.70
(95% CI: 0.56-0.88)
p=0.002
HR=1.07
(95% CI: 0.49-0.73)
p=0.678
Pemetrexed: 15.5 mos
Placebo: 10.3 mos
Placebo: 10.8 mos
Pemetrexed: 9.9 mos
Time (months)
Ciuleanu T. et al. Lancet 374, 1432-1440; 2009
Time (months)
NSCLC – Pemetrexed continuation maintenance
PARAMOUNT
Stadium IV
Nonsquamous
SD nach 4-6x
Induktions-CT
Cisplatin/Pem
etrexed
Randomisation 2:1
Non PD
Pemetrexed
3qw bis PD
Placebo
3qw bis PD
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC – Pemetrexed continuation maintenance
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
Progression free Survival
NSCLC – Pemetrexed continuation maintenance
Progression free survival
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC – Pemetrexed continuation maintenance
Progression free survival (subgroups)
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC – Pemetrexed continuation maintenance
Adverse events
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC-maintenance: ASCO 2011
For patients with SD or response after
4 cycles, immediate treatment with an
alternative, single-agent chemotherapy
such as pemetrexed in patients with nonsquamous histology, docetaxel in
unselected patients, or erlotinib in
unselected patients may be considered
(alternative to second-line therapy!)
Azzoli et al. J Clin Oncol 29, 3825-3831, 2011
NSCLC – Pemetrexed switch and
continuation maintenance (registration)
Pemetrexed Maintenance :
as single agent following platinum based
therapy (predominantly other than
squamous cell histology; non-progression
after four cycles of chemotherapy)
EMA: 2009 / 2011
Advanced NSCLC: Treatment algorithm in 2012
Mutated tumours
1st-line
EGFR-TKI;
ALK-Inhibitor
Maintenance in
case of non-PD/SD
Non-Squamous
Squamous
Platinum-Doublets
(Pem!) plus Bev or
Cet
Platinum-Doublets
(No Pem, no Bev)
plus Cet
Switch:
Pemetrexed
Erlotinib
Continuous:
Pemetrexed
Switch:
Erlotinib
Single agent
Non-cross resistant
2nd-line
Dealer’s choice
Single agent
Non-cross resistant
3rd-line
Dealer’s choice
Dealer’s choice
Dealer’s choice
Advanced NSCLC - Medical Treatment
Standard Approach
In case of PD
1st-line
Combination CT
or single agent
defined number
of cycles (4-6)
In case of PD
2nd-line
single agent ,
Non-cross-resistant
until progression
Docetaxel
Pemetrexed
Erlotinib
Gefitinib
3rd-line
single agent,
Non-cross-resistant
until progression
Erlotinib
Gefitinib