Transcript Maintenance therapy

Advanced NSCLC:
Treatment algorithms 2014
Prof. Christian Manegold
Medical Faculty Mannheim
University of Heidelberg
NSCLC: Incidence of single driver mutations
Mutation found in 54% (280/516) of
tumours completely tested (CI 50-59%)
Kris et al. J Clin Oncol 29 (suppl 15) 477 (abstr 7506); 2011
Advanced NSCLC: Current Treatment algorithm
Mutant tumors
Wild type tumors
Non-Squamous
1st-line
EGFR-TKI
Maintenance
Treatment until
progression
Oligo progression:
2nd-line
Cont. TKI + Local therapy
Diffuse progression
Cont. TKI + Chemo
Chemo  TKI re-expo
2nd generation TKI
Squamous
Platinum-Doublets
(Pem!) plus Bev
Platinum-Doublets
(No Pem, no Bev)
Switch:
Pemetrexed
Erlotinib
Continuous:
Pemetrexed
Switch:
Erlotinib
Single agent
Non-cross resistant
Single agent
Non-cross resistant
ALK-Inhibitor
Advanced NSCLC:
Treatment for non-mutant tumors
First-line – (induction) – therapy
- Selection by histo-type
Maintenance therapy
- Switch / continuation
Second-line / subsequent-line therapy
NSCLC: International 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
Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012
Advanced NSCLC:
Medical management – practical aspects
Feasibility / tolerability: Cis-platin vs carbo-platin
-
Hotta et al. J Clin Oncol 22, 3852-3859, 2004, Rudd et al. J Clin Oncol 23, 142-153, 2005
Artizoni et al. J Natl Cancer Inst 99, 847-857, 2007
Co-morbidity / regimen: Platin based / free
-
D‘Addario et al. J Clin Oncol 23, 2926-2936, 2005
Laack et al. J Clin Oncol 22, 2348-2356, 2004,
Age ≥ 70 years: Single agent / combination
-
Gridelli et al. J Clin Oncol 23, 3125-3137, 2005; Gridelli et al. J Natl Cancer Inst 95, 362-372, 2003
Gridelli et al. J Natl Cancer Inst 91, 66-72, 1999; Sederholm et al. J Clin Oncol 23, 8380-8388, 2005
Performance status ≥ 2: Single agent / combination
-
Gridelli et al. Ann Oncol 15, 419-426, 2004,
Patient’s expectations: Active therapy / BSC
-
Gridelli et al. J Clin Oncol 23, 3125-3137, 2005
Selection by histo-type according to efficacy
(non-squamous vs squamous)
Advanced NSCLC: Treatment by histology
Cisplatin plus Pemetrexed or 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 Time (months)
Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008
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)
Efficacy by Histology in Pemetrexed Studies
NSCLC
Histologic
Group
Non-squamous
Median OS, months
Adjusted HR (95% CI)
P value
Squamous
Median OS, months
Adjusted HR (95% CI)
P value
Second-line
Pem vs. Docetaxel
First-line
Pem/Cis
vs. Gem/Cis
Maintenance
Pem vs. Placebo
Pem
Doc
Cis/Pem
Cis/Gem
Pem
Placebo
n=205
n=194
n=618
n=634
n=325
n=156
9.3
8.0
11.0
10.1
15.5
10.3
0.78 (0.61–1.00)
0.048
0.84 (0.74–0.96)
0.011
0.70 (0.56–0.88)
0.002
n=78
n=94
n=244
n=229
n=116
n=66
6.2
7.4
9.4
10.8
9.9
10.8
1.56 (1.08–2.26)
0.018
1.23 (1.00–1.51)
0.050
1.07 (0.77–1.50)
0.678
Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology
Scagliotti et al. J Thorac Oncol 6, 64-70, 2011
Ifosfamide in NSCLC: MIC Regimen
Mitomycin C
Ifosfamide
6 mg/m²
day 1
i.v. Bolus
3.000 mg/m²
day 1
i.v./3 h
Cisplatin
50 mg/m²
day 1
Cycle repeated q3w
i.v./1 h
MESNA-Uroprotection
20 % (IFO) i.v. fractionated
(0 hours) 4 h + 8 h
100 % (IFO) i.v. continuous
(0 hours) during IFO
+ for additional 12 q 24 h
Cullen et al, Br J Cancer 58, 359-361, 1988
MIC `s Efficacy is not inferior to other Platinum Doublets
n
RR
TTP
MST
NVB / CIS
206
30 %
n.r.
9.5 mo*
VDS / CIS
200
19 %
n.r.
7.6 mo
28 %
(1994)
PAC 135 / CIS
Total
27 %*
4.5 mo*
9.6 mo*
37 %
Bonomi
PAC 250 / CIS
560
32 %*
5.3 mo*
10 mo*
39 %
(1996)
12 %
3.0 mo
7.7 mo
32 %
ETO / CIS
1-y-s
Ref.
37 % Le Chevalier
GEM / CIS
154
40 %
4.8 mo
8.6 mo
33 %
Crino
MIC
152
28 %
5.0 mo
9.5 mo
34 %
(1998)
GEM / CIS
69
41 %*
6.9 mo*
8,7 mo
32 %
Cardenal
ETO / CIS
66
22 %
4.3 mo
7.2 mo
26 %
(1999)
PAC / CARBO
190
23 %*
4.0 mo
7.7 mo
32 %
Belani
ETO / CIS
179
14 %
3.3 mo
8.2 mo
37 %
(1998)
*p<.05
Platinum-free, Ifosfamide based doublets have been
developed
PAC
IFO
Phase II
Stage IIIb/IV
NAV
IFO
A:
B:
RR
MS 1yS
38% 9mo 35%
31% 8mo 38%
250 mg/m² (3h), d 1
1600 mg/m² , d 1-3
q3w x 6
30 mg/m², d 1-3
1600 mg/m², d 1-3
q3w x 6
Arm A
n=48
Arm B
n=45
Perry et al, Lung Cancer 48,63-68, 2000
Platinum-free, Ifosfamide based doublets have been
developed
Phase III
Stage IIIb/IV
PS 0-2
Cis 100 mg/m², d 1
x 6 (n=166)
Gem 1250 mg/m² , d 1, 8
Cis 100 mg/m², d 1 x 6 (n=176)
Gem 1000 mg/m², d 1, 8
Vin
25 mg/m², d 1, 8
Gem 1000 mg/m², d 1, 8 x 3 (n=175)
Vin
30 mg/m², d 1, 8
RR:
MS:
Ntp3/4:
Tbp3/4:
41% 40% 24%
10m 8m 11m
26% 30% 18%
18% 23% 7%0
Ifo
Vin
Alberola et al, J Clin Oncol, 21:3207-3213, 2003
3000 mg/m², d 1
x3
30 mg/m², d 1, 8
Selection by toxicity profile
(non-squamous vs squamous)
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 - Eligibility
Inclusion criteria
Exclusion criteria
 non-squamous NSCLC
 grade 2haemoptysis
 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
Sandler et al N Engl J Med 355, 2542-2550, 2006 Crino et al, LancetOncol 11, 733-740, 2010
Reck et al, J ClinOncol 27, 1227-1235, 2009
Reck et al, Ann Oncol 21, 1227-1234,2010
Sandler et al J Thorac Oncol 5,1416-1423,2010
Soria et al Ann Oncol 24,20-30,2013
Advanced NSCLC:
Basics of medical management
First-line – (induction) – therapy
- Selection by histo-type
Maintenance therapy
- Switch / continuation
Second-line / subsequent-line therapy
Advanced NSCLC:
Medical Treatment in wild type tumors
Traditional (standard) approach
1st-line
Combination
or single agent CT
defined number
of cycles (4-6)
2nd-/subsequent line
Tumor
progression
single agent ,
Non-cross-resistant
until progression
New (maintenance) approach
1st-line
Combination
or single agent CT
defined number
of cycles (4-6)
Maintenance
one of the first line agents until
progression (continuation)
„new“ non-cross-resistant
progression
agent until progression (switch)
Non-
2nd-/
subsequent line
Advanced NSCLC: Switch/continuation maintenance
PARAMOUNT
JMEN
Saturn
Inform
Boston
IFCT
ECOG
5508
Design
2-arms
phase III
2-arms
phase III
2-arms
Phase III
2- arms
phase III
2-arms
phase III
3-arms
phase III
3-arms
phase III
Primary
endpoint
PFS
PFS
PFS
PFS
OS
PFS
OS
Agents
Pemetrexed
Placebo
Pemetrexed
Placebo
Erlotinib
Placebo
Gefitinib
Placebo
Doc
early/late
Erlotinib
Observation
Gem
Bev
Pem
Bev/Pem
No. of
Pts.
539
663
889
296
566
464
1282
Induction
CT
Cis/Pem
Platinum
doublets
Platinum
doublets
Platinum
doublets
Cis/Gem
Cis/Gem
Carbo/
Pac/Bev
Cappuzzo et al. Lancet Oncol 11, 521-529; 2010
Ciuleanu T. et al. Lancet 374, 1432-1440; 2009
Paz-Ares Lancet Oncol 13, 247-255, 2012
Zhang et al. Lancet Oncol 13, 466-475,2012
Fidias et al J Clin Oncol 27, 591-598, 2008
Perol et al J Clin Oncol 30, 3516-3524, 2012
Paz-Ares et al J Clin Oncol 31, 2895-2902, 2013
Advanced NSCLC: Maintenance
Switch type („early second line“)
• Docetaxel
Fidias et al J Clin Oncol 27, 591-598, 2009
Advanced NSCLC - Maintenance:
Docetaxel following Standard Doublet Chemotherapy
Immediate vs delayed (2nd-line) Docetaxel
n=552
• Stage IIIb/IV
• ECOG PS = 0–2
• CNS Mets allowed
Gem, 1000
mg/m2, d1, 8
Carbo AUC 5, d1,
q3w x 4
Off study: n=245
CR, PR
SD
R
A
N
D
O
M
I
Z
E
n=307
Primary endpoint: overall survival
Fidias et al., J Clin Oncol 27, 591-598, 2009
n=142/153
Immediate
Docetaxel
75 mg/m2 d1, q3w x 6
Delayed
Docetaxel
75 mg/m2 d1, q3w x 6
n=91/154
Advanced NSCLC - Maintenance: Extension by Docetaxel
following Standard Doublet Chemotherapy
Immediate vs delayed (2nd-line) Docetaxel
Overall survival time (months)
PFS, mos
(95% CI)
Immediate
Doc
(n=153)
6.5
(4.4–7.2)
Delayed
Doc
(n=154)
2.8
(2.6–3.4)
1-yr-PFS, %
(95% CI)
20%
(13–26)
9%
(5–14)
p-value
<0.0001
MS, mos
(95% CI)
1-yr-S %
(95% CI)
Fidias et al., J Clin Oncol 27, 591-598, 2009
Immediate
Doc
(n=153)
11.9
(10.0–13.7)
48.5%
(39.9–57.1)
Delayed
Doc
p-value
(n=154)
9.1
0.071
(8.0–11.2)
38.3
(30.0–46.5)
Advanced NSCLC: Maintenance
Switch type („early second line“)
• Erlotinib
Cappuzzo et al, Lancet Oncol 11, 521-529, 2010
Advanced NSCLC:
Erlotinib switch maintenance (Saturn)
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 carboplatin/paclitaxel
Advanced NSCLC: Erlotinib switch maintenance
Progression free survival
Progression free Survival
Cappuzzo et al. Lancet Oncol 11, 521-529; 2010
Advanced NSCLC: Erlotinib switch maintenance
Overall survival
Overall Survival
Cappuzzo et al. Lancet Oncol 11, 521-529; 2010
Advanced 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)
Coudert et al. Ann Oncol 23, 388-394, 2012
Measured
from time
randomisation
the maintenance
phase
Cappuzzo
etofal.
Lancet into
Oncol
11, 521-529;
2010
3
6
9 12 15 18 21 24 27 30 33 36
Time (months)
Advanced NSCLC: Maintenance
Switch type („early second line“)
• Pemetrexed
Ciuleanu et al Lancet 374, 1432-1440, 2009
Advanced 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
Advanced NSCLC: Pemetrexed switch maintenance
Progression free survival 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)
Advanced NSCLC: Pemetrexed switch maintenance
Overall survival 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)
Advanced NSCLC: switch maintenance
ASCO recommendations 2011
For patients with SD or response after
4 cycles, immediate treatment with an
alternative, single-agent chemotherapy such
as pemetrexed in patients with non-squamous
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
Fidias et al. J Clin Oncol 27, 591-598, 2009
Coudert et al. Ann Oncol 23, 388-394, 2012
Cappuzzo et al. Lancet Oncol 11, 521-529; 2010
Paz-Ares Lancet Oncol 13, 247-255, 2012
Advanced NSCLC: Maintenance
Continuation type
(„true maintenance“)
• Pemetrexed
Advanced NSCLC: Pemetrexed continuation
maintenance (PARAMOUNT)
Stadium IV
Nonsquamous
SD nach 4-6x
Induktions-CT
Cisplatin/Pem
etrexed
Randomisation 2:1
Non PD
Paz-Ares et al Lancet Oncol 13, 247-255, 2012
Paz-Ares et al J Clin Oncol 31, 2895-2902, 2013
Pemetrexed
3qw bis PD
Placebo
3qw bis PD
Advanced NSCLC: Pemetrexed continuation maintenance
(PARAMOUNT) – Overall survival by response
Paz-Ares et al. J Clin Oncol 31, 2895-2902, 2013
Advanced NSCLC: Pemetrexed registration
Continuation maintenance therapy
......as single agent following platinum based
therapy - predominantly other than squamous cell
histology; non-progression after four cycles of
chemotherapy……
EMA: 2011
Advanced NSCLC - Maintenance
Comparison switch vs continuation
• Erlotinib (switch)
• Gemcitabine (continuation)
Perol et al J Clin Oncol 30, 3516-3524, 2012
Advanced NSCLC: Erlotinib (switch) vs Gemcitabine
(continuation) maintenance (IFCT-GFPC 0502)
•
•
•
Patients stratified by sex, histology, smoking status, treatment center, and
response/stabilization following first-line therapy
Primary endpoint: PFS
Other endpoints: OS, safety, symptom control, effect of EGFR status
Patients without disease
progression randomized 1:1:1
Chemotherapynaive patients with
stage IIIB/IV
NSCLC
Cisplatin/Gemcitabine
for 4 cycles
Gemcitabine
(n = 154)
Pem
74 %
Erlotinib
(n = 155)
Pem
75%
Observation
(n = 155)
Pem
84%
(N = 834)
Perol M et al, J Clin Oncol 30, 3516-3524, 2012
Advanced NSCLC: Erlotinib (switch) vs Gemcitabine
(continuation) maintenance (IFCT-GFPC 0502)
Perol M et al, J Clin Oncol 30, 3516-3524, 2012
Advanced NSCLC:
Basics of medical management
First-line – (induction) – therapy
- Selection by histo-type
Maintenance therapy
- Switch / continuation
Second-line / subsequent-line therapy
Current ASCO Guidelines for NSCLC
Docetaxel, EGFR-TKI’s, and Pemetrexed are
acceptable as second-line therapy for
patients with advanced NSCLC with
adequate performance status when the
disease has progressed during or after firstline platinum-based therapy
Azzoli et al. J Clin Oncol 29, 3825-3831, 2011
Shepherd et al. N Engl J Med 353, 123-132, 2005
Thatcher et al. Lancet 366, 1527-1537, 2005
Hanna et al. J Clin Oncol 22, 1589-1597, 2004
Advanced NSCLC: EGFR-TKIs as second-line therapy
ISEL
Interest
BR21
Titan
Tailor
HORG
Korea
Design
2-arms
phase III
2-arms
phase III
2-arms
phase III
2-arms
phase III
2-arms
phase III
2-arms
phase III
2-arms
phase III
Primary
endpoint
OS
OS
OS
OS
OS
TTP
OS/RR
Agents
Gefitinib
Placebo
Gefitinib
Docetaxel
Erlotinib
Placebo
Erlotinib
Pem or Doc
Erlotinib
Docetaxel
Erlotinib
Pemetrexed
Gefitinib
Erlotinib
No. of
Pts.
1692
1433
731
424
222
357
467
Kim et al. Cancer 116, 3025-3033, 2010
Karampazis et al. Cancer 119, 2754-2764, 2013
Garassino et al. Lancet Oncol 14, 981-988, 2013
Ciuleanu et al. Lancet Oncol 13, 300-308, 2012
Shepherd et al. N Engl J Med 353, 123-132, 2005
Kim et al. Lancet 372, 1809-1818, 2008
Thatcher et al. Lancet 366, 1527-1537, 2005
Meta-analysis in wild-type NSCLC favors CT over
EGFR-TKI therapy: First- / second-line
Lee et al. JAMA 311,1430-1437, 2014
Advanced NSCLC: Systemic therapy in the
absence of driver mutations – Summary (1)
• Chemotherapy remains standard for the majority of patients
- (first-line; platinum doublets; 4 – 6 cycles)
• The selection of the platinum-partner should depend on tumor
histo-type
-
(non-squamous vs squamous; pemetrexed vs gemcitabine etc.)
• Modification of the first-line standard is clinically advisable
according to co-morbidity, performance status, and patient’s age
-
(single agent; platinum-free; BSC only)
• Treatment until progression by the anti-angiogenic bevacizumab as
recommended in selected patients
-
(eligibility criteria; group toxicity)
Advanced NSCLC: Systemic therapy in the
absence of driver mutations – Summary (2)
• Prolongation of induction chemotherapy beyond 4 – 6 cycles for
maintaining “response” until progression has been established
as a new strategy
- (switch/continuation maintenance)
• Second/subsequent – line chemotherapy is recommended in
patients with acceptable performance status
- (single agent; docetaxel; pemetrexed)
• EGFR-TKI’s have also been licensed for wild-type tumors
-
(maintenance; second/third-line therapy)
• A tight cooperation between the pathologist and the clinician is
critical
-
(histology – subtyping; molecular testing; result reporting)
Advanced NSCLC: Current Treatment algorithm
Mutant tumors
Wild type tumors
Non-Squamous
1st-line
EGFR-TKI
Maintenance
Treatment until
progression
Oligo progression:
2nd-line
Cont. TKI + Local therapy
Diffuse progression
Cont. TKI + Chemo
Chemo  TKI re-expo
2nd generation TKI
Squamous
Platinum-Doublets
(Pem!) plus Bev
Platinum-Doublets
(No Pem, no Bev)
Switch:
Pemetrexed
Erlotinib
Continuous:
Pemetrexed
Switch:
Erlotinib
Single agent
Non-cross resistant
Single agent
Non-cross resistant
ALK-Inhibitor
Advanced NSCLC: EGFR-TKIs as first line therapy
Torch
Topical
Optimal
NEJ002
Lux-Lung3
EURTAC
IPASS
Design
2-arms
phase III
2-arms
phase III
2-arm
phase III
2- arms
phase III
2-arms
phase III
2-arms
phase III
2-arms
phase III
Primary
endpoint
OS
PFS
PFS
PFS
PFS
PFS
PFS
Agents
CT-Erlotinib
Erlotinib-CT
Erlotinib
Placebo
Erlotinib
Carbo/Gem
Gefitinib
Carbo/Pac
Afatinib
Pemetrexed
Erlotinib
Platinum
doublets
Gefitinib
Carbo
Pac
No. of
Pts.
760
670
165
230
345
174
1200
Outcome
PE:
not met
PE:
met
PE:
met
PE:
met
PE:
met
PE:
met
PE:
Unselected
population
Poor PFS
Mut.-Tu
Mut-Tu
Mut-Tu
Mut-Tu
Selection
Criteria
Mok et al. N Engl J Med, 361, 947-957, 2009
Rosell et al Lancet Oncol 13;239-246;2012
Lee et al Lancet Oncol 13, 1161-1170, 2012
Zhou et al. Lancet Oncol 12, 735-742, 2011
Mitsudomi et al Lancet Oncol 11, 121-128, 2010
Sequist et al. J Clin Oncol 31, 3327-3334, 2013
Gridelli et al J Clin Oncol 30, 3002-3011, 2012
exceeded
Never
smoker/
Adeno-CA
First-line trials of EGFR tyrosine kinase inhibitors vs.
chemotherapy in pts with EGFR mutations
EGFR
TKI
Comparator
N
(Total)
EGFR
mutpositive
Response
rate
(%)
Progression-free
survival
(months)
Overall survival
(months)
IPASS1,2
Gefitinib
Carboplatin/
paclitaxel
1217
261
71 vs 47
p=0.0001
9.5 vs 6.3
HR 0.48 (0.36‒0.64)
21.6 vs 21.9
HR 1.0 (0.76–1.33)
FirstSIGNAL3
Gefitinib
Gemcitabine/
cisplatin
309
42
85 vs 38
p=0.002
8.0 vs 6.3
HR 0.54 (0.27–1.10)
27.2 vs 25.6
HR 1.04 (0.50–2.18)
NEJ0024
Gefitinib
Carboplatin/
paclitaxel
224
224
74 vs 31
p<0.001
10.8 vs 5.4
HR 0.30 (0.22–0.41)
30.5 vs 23.6
WJTOG34055
Gefitinib
Cisplatin/
docetaxel
172
172
62 vs 32
p<0.0001
9.2 vs 6.3
HR 0.5 (0.34–0.71)
30.9 vs NR
HR 1.64 (0.75–3.6)
OPTIMAL6
Erlotinib
Gemcitabine/
carboplatin
154
154
83 vs 36
p<0.0001
13.1 vs 4.6
HR 0.16 (0.10–0.26)
Not mature
EURTAC7
Erlotinib
Chemotherapy
173
173
58 vs 15
9.7 vs 5.2
HR 0.37 (0.25–0.54)
19.3 vs 19.5
HR 1.04 (0.65–1.68)
LUX-LUNG 38
Afatinib
Pemetrexed/
cisplatin
345
345
56 vs 23
p<0.0001
11.1 vs 6.9
HR 0.58 (0.43–0.78)
Not mature
LUX-LUNG 69
Afatinib
Gemcitabine/
cisplatin
364
364
67 vs 23
p<0.0001
11.0 vs 5.6
HR 0.28 (0.20–0.39)
Not mature
1. Mok T et al., N Engl J Med 2009;361:947–957; 2. Fukuoka M et al., J Clin Oncol 2011; 29:2866‒2874; 3. Han J-Y et al., J Clin Oncol 2012; 30:1122‒128; 4.
Maemondo M et al., N Engl J Med 2010;362:2380–2388; 5. Mitsudomi T et al., Lancet Oncol 2010;:121–128; 6. Zhou C et al., Lancet Oncol 2011;12:735‒742; 7.
Rosell R et al., Lancet Oncol 2012;13:239–246; 8. Yang JC et al., J Clin Oncol 2012;30 (Suppl. 16):LBA 7500, Wu Y et al., Lancet 2014; 15:213. NR = not reported
Advanced NSCLC: First-line EGFR-TKI therapy
ASCO / ESMO-recommendation
… EGFR-TKI therapy should be prescribed for patients
with tumors bearing activated EGFR-mutations …
… Patients with PS 3-4 may also be offered EGFR-TKI
treatment …
Azzoli et al. J Clin Oncol 29, 3825-3831, 2011
Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012
EGFR mutations: whom to test? (1)
EGFR molecular testing should be used to select
patients for EGFR-targeted TKI therapy, and patients
with lung adenocarcinoma should not be excluded
from testing on the basis of clinical characteristics
Lindeman et al., J Thorac Oncol, 823-859, 2013
EGFR mutations: whom to test ? (2)
In the setting of more limited lung cancer specimens
(biopsies, cytology) where an adenocarcinoma
component cannot be completely excluded, EGFR
testing may be performed in cases showing squamous
or small cell histology but clinical criteria (eg, young
age, lack of smoking history) may be useful in selecting
a subset of these samples for testing.
Lindeman et al., J Thorac Oncol, 823-859, 2013
EGFR mutations: laboratory issues
Laboratories should follow similar quality control and
quality assurance policies and procedures for EGFR
testing in lung cancers as for other clinical laboratory
assays. In particular, laboratories performing EGFR
testing for TKI therapy should enroll in proficiency
testing, if available.
Lindeman et al., J Thorac Oncol, 823-859, 2013
Second-line therapy in case of progression
in first-line EGFR-TKI therapy
• Oligo progression:
– Continuous TKI + Local therapy
• Diffuse progression
– Continuous TKI + Chemotherapy
– Chemotherapy  TKI re-exposition
– 2nd generation TKI
Advanced NSCLC:
EMA registration for Erlotinib
• Second / third line:
In patients after failure of at least one prior
chemotherapy
• Maintenance:
In patients with stable disease after 4 cycles of
platinum based first-line chemotherapy
CHMP, 18 March 2010
Advanced NSCLC: Crizotinib for ALK-positive disease
Phase III (PROFILE 1007) – 2nd line
Shaw et al. N Engl J Med 368, 2385-2394, 2013
Advanced NSCLC: Crizotinib for ALK-positive disease
Phase III (PROFILE 1007) – 2nd line
Primary Endpoint: PFS
Randomization
347 patients,
Advanced NSCLC,
Prior platinumbased CT,
all histologies,
EML4-ALK
Translocation
Crizotinib 250
mg bid
Pemetrexed
or
Docetaxel
Shaw et al. N Engl J Med 368, 2385-2394, 2013
PD
Crizotinib 250
mg bid
Advanced NSCLC:
Systemic therapy in existence of driver mutationsRole of TKI’s
• Has changed significantly the treatment algorithm
– (treatment by genotype)
• Is specifically relevant for mutant tumors
– (First-line therapy)
• Has been licensed and recommended in wild type
tumors and tumors with unknown EGFR-status
– (Maintenance, second/third-line therapy)
• Has underlined the importance of the pathologist’s and
its tight cooperation with the clinicians
– (molecular testing)
4th International Thoracic Oncology Congress Dresden
Advances through Molecular Biology in Thoracic Cancer
September 12th – 14th 2014
Maritim Hotel and International Congress Center
Dresden, Germany
Save the date!
Organizers:
Christian Manegold - Mannheim
Giorgio V. Scagliotti - Torino
Nico van Zandwijk - Sydney