Istituto Toscano Tumori-Livorno-Italy
Aprile
Maintenance therapy for NSCLC
Piano Generale di Emergenza
Federico Cappuzzo
PresidioIstituto
Ospedaliero
di Livorno
Toscano Tumori
Viale AlfieriOspedale
36 Civile
Livorno-Italy
Istituto Toscano Tumori-Livorno-Italy
The maintenance therapy paradigm
No progression after 4 cycles of platinum-based CT, PS=0-1
Stratification for EGFR, ALK, histology, response to CT
EGFR WT/ALK-:
Response to CT /Histology
CR/PR
Continuation
maintenance
SCC
Gemcitabine
Non-SCC
Pemetrexed or beva
SD
SCC: Switch
maintenance
Erlotinib or
Docetaxel
Non-SCC:
cont/switch
maintenance
Pem or beva
Erlot or Docetax
Istituto Toscano Tumori-Livorno-Italy
Immediate vs. delayed docetaxel
as 2nd line NSCLC treatment
Carboplatin
Plus
Gemcitabine X 4
CR, PR
SD
R
A
N
D
O
M
I
Z
E
Immediate
Docetaxel
Delayed
Docetaxel at
time of PD
Istituto Toscano Tumori-Livorno-Italy
Docetaxel study results
LR
Immediate Delayed
(n=153)
(n=154) p-Value
PFS
OS
Median PFS
months
(95% CI)
6.5
(4.4, 7.2)
12-month PFS, %
(95% CI)
20%
(13, 26)
9%
(5, 14)
Immediate
(n=153)
Delayed
(n=154)
Median OS,
months
(95% CI)
12-mo survival
(95% CI)
2.8
<0.0001
(2.6, 3.4)
11.9
9.1
(10.0, 13.7) (8.0, 11.2)
48.5%
(39.9, 57.1)
38.3%
(30.0,
46.5)
LR
p-Value
0.071
Istituto Toscano Tumori-Livorno-Italy
TFINE study: multicenter, randomized phase III
study of continuation docetaxel
Docetaxel 75 mg/m2 IV
Cisplatin 75 mg/m2 IV q
Docetaxel 60
mg/m2 IV q 3wk
Up to six cycles
IIIB/IV
ChemoNaïve
NSCLC
N=382
CR
PR
SD
R1
Docetaxel 60 mg/m2 IV
Cisplatin 75 mg/m2 IV
R2
BSC
Zhang et al. ASCO 2013, Abstract # 8015
Istituto Toscano Tumori-Livorno-Italy
TFINE study, C-TONG 0904
PFS results
Trial
Strategy
Induction regimen
mPFS
(months)
Docetaxel dose
Fidias et al.
Switch
Carbo+Gem
5.7 vs 2.7
(early vs.
delayed)
75mg/m2
Zhang et al.
Continuation
Cis+Doc
5.4 vs 2.7
(Doc vs. BSC)
60mg/m2
Istituto Toscano Tumori-Livorno-Italy
Maintenance trials with pemetrexed
Switch maintenance: JMEN



Stage IIIB/IV NSCLC
ECOG PS 0-1
4 prior cycles of gem, doc, or tax +
cis or carb, with CR, PR, or SD

Randomization factors:
•
gender
•
PS
•
stage
•
best tumor response
•
non-platinum drug
•
brain mets
Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*
2:1
Randomization
Placebo (d1, q21d) + BSC (N=222)*
Continuation maintenance: PARAMOUNT



Nonsquamous NSCLC
No prior systemic treatment for lung
cancer
ECOG PS 0-1
500 mg/m2 Pemetrexed + BSC, d1, q21d
CR, CP,
SD
2:1 randomization
Placebo + BSC, d1, q21d
500 mg/m2 Pemetrexed +
75 mg/m2 Cisplatin, d1, q21d
PD
Stratified for:
-PS (0 vs 1)
-Disease stage (IIIb vs IV) prior to induction
-Response to induction (CR/PR vs SD)
Istituto Toscano Tumori-Livorno-Italy
Progression-free Survival
Continuation maintenance:
PARAMOUNT
Switch maintenance:
JMEN
Istituto Toscano Tumori-Livorno-Italy
Overall Survival: pemetrexed
maintenance data
Continuation maintenance:
PARAMOUNT
Switch maintenance:
JMEN
Istituto Toscano Tumori-Livorno-Italy
JMEN & PARAMOUNT: OS according to
response to first-line chemotherapy
HR
Induction response CR/PR*
0.81
Induction response SD*
0.61
Induction response CR/PR
0.81
0.76
Induction response SD
0.4
0.6
0.8
Favours pemetrexed
*Non-squamous group
1.0
HR
1.2
Favours placebo
Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012
Istituto Toscano Tumori-Livorno-Italy
Maintenance trials with EGFR-TKIs
Erlotinib maintenance: SATURN
Chemonaïve
advanced NSCLC
n=1,949
Mandatory tumor
sampling
Erlotinib
150mg/day
4 cycles of
1st-line platinumbased doublet*
Non-PD
n=889
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
Gefitinib maintenance: INFORM
Patients
• Age ≥18 years
• Completed 4 cycles of
first-line platinum-based
chemotherapy without
PD or unacceptable
toxicity
• Life expectancy
≥12 weeks
• WHO PS 0-2
• Measurable
Stage IIIB/IV disease
Gefitinib
(250 mg/day)
1:1 randomization
Placebo
(once daily)
PD
1:1
Placebo
PD
Istituto Toscano Tumori-Livorno-Italy
Progression-free Survival
in ITT population
Erlotinib maintenance: SATURN
HR=0.71 (0.62–0.82)
p<0.0001
Gefitinib maintenance: INFORM
HR=0.42 (0.32–0.54)
Istituto Toscano Tumori-Livorno-Italy
Overall Survival
in ITT population
Erlotinib maintenance: SATURN
HR=0.81 (0.70–0.95)
p=0.0088
Gefitinib maintenance: INFORM
HR = 0.83 (0.61, 1.12)
p=0.2109
Istituto Toscano Tumori-Livorno-Italy
Effect of erlotinib and gefitinib in EGFR wildtype patients: PFS and OS data
PFS and OS in SATURN
PFS in INFORM
SD
CR/PR
1.0
1.0
HR=0.72 (0.59–0.89)
0.8
OS probability
Istituto Toscano Tumori-Livorno-Italy
OS according to response to first-line
chemotherapy*
HR=0.94 (0.74–1.20)
0.8
Log-rank p=0.0019
0.6
Log-rank p=0.6181
0.6
Erlotinib (n=252)
0.4
Placebo (n=235)
0.2
Erlotinib (n=184)
0.4
Placebo (n=210)
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
3
6
Time (months)
*OS is measured from time of randomisation into the maintenance phase
9 12 15 18 21 24 27 30 33 36
Time (months)
Istituto Toscano Tumori-Livorno-Italy
IFCT-GFPC 0502 study design
Maintenance
treatment
PD: off
A
PD
Pemetrexed
PD
Pemetrexed
PD
Pemetrexed
N=155
Cisplatin
gemcitabine
x 4 cycles
N=834
Objective
response or
stable disease
R*
N=464
B
Tumor tissue
EGFR IHC
EGFR mutation
Induction chemo: cisplatin 80mg/m2 d1
Gemcitabine
N=154
C
NSCLC
Stage IIIB wet – IV
PS 0-1, 18-70 years
Asymptomatic brain
mets allowed
Observation
Progression:
2nd line
Erlotinib
N=155
Primary endpoint: PFS
*Stratification factors:
+ gemcitabine 1,250mg/m2 d1, d8
– gender
Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks
– histology: adenocarcinoma vs other histology
Arm C: erlotinib 150mg daily
– smoking status: non-smokers vs current/former smokers
– center
– response vs stabilization to induction chemotherapy
EGFR = epidermal growth factor receptor
IHC = immunohistochemistry; PD = progressive disease
Istituto Toscano Tumori-Livorno-Italy
PFS and OS results with continuation gemcitabine
Perol et al. JCO 2012
Istituto Toscano Tumori-Livorno-Italy
PFS and OS results with switch erlotinib
Perol et al. JCO 2012
Istituto Toscano Tumori-Livorno-Italy
Is continuation maintenance with pemetrexed
plus bevacizumab better than beva or pem alone?
AVAPERL
First-line induction
4 cycles, q3w
Continuation maintenance
q3w until PD
CR/PR/SD
per RECIST§
Previously
untreated
stage IIIB-IV
NSCLC
N=376
Stratification factors
•Gender
•Smoking status
•Response at randomisation
Avastin‡
+ pemetrexed‡
+ cisplatin‡
n=253
1
R
67%
1
PD
Follow-up
Avastin
n=125
Avastin +
pemetrexed
n=128
1.0
Avastin + Pem 7.4m
Avastin
3.7m
HR: 0.48; p<0.001
0.8
PFS estimate
Istituto Toscano Tumori-Livorno-Italy
AVAPERL: PFS from randomisation
0.6
0.4
0.2
0
0
3
6
9
Time (months)
12
15
OS for Pem/Bev was better than for Bev (17.1 vs 13.2
months), p=0.29, HR 0.87 (CI 0.63-1.21)
EMCC 2011, ASCO 2013
Istituto Toscano Tumori-Livorno-Italy
PointBreak: Study Design
Pemetrexed
+ Carboplatin
+ Bevacizumab
Pemetrexed
+ Bevacizumab
Paclitaxel
+ Carboplatin
+ Bevacizumab
Bevacizumab
Patel et al., 2012 Chicago Multidisciplinary symposium in Thoracic Oncology
HR=1.0 (95% CI: 0.86–1.16)
Log-rank P=0.949
1.0
100
Pem Arm
Median OS = 12.55 mo (95% CI: 11.30–14.03)
Pac Arm
Median OS = 13.4 mo (95% CI: 11.86–14.91)
0.9
0.8
Survival Probability
Istituto Toscano Tumori-Livorno-Italy
PointBreak: KM Plot for OS (Intent-to-treat)
80
0.7
0.6
60
0.5
0.4
0.3
40
0.2
0.1
20
0.0
0
0
0
3
3
6
6
9
9
12
12
15
15
18
21
24
27
Time from Induction (Months)
18
21
24
27
30
30
33
33
36
36
39
39
Istituto Toscano Tumori-Livorno-Italy
PRONOUNCE: Study Design
 Randomized, open-label, phase III superiority study conducted in US
 Pemetrexed 500 mg/m2, Carboplatin AUC 6 (Pem+Cb)
 Paclitaxel 200 mg/m2, Carboplatin AUC 6, Bevacizumab 15 mg/kg (Pac+Cb+Bev)
Induction Phase
q21d, 4 cycles
Maintenance Phase
q21d until PD
Pemetrexed
Pemetrexed
Bev-Eligible Population
Inclusion:
- Chemo-naïve patients
- PS 0/1
- Stage IV, nonsquam
- Stable treated CNS mets
(folic acid & vitamin B12)
+ Carboplatin
R
1:1
Exclusion:
- Uncontrolled effusions
(folic acid & vitamin B12)
180 patients each
Paclitaxel
+ Carboplatin
+ Bevacizumab
Bevacizumab
Stratified for:
PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b)
Zinner ASCO 2013
100
100
Pem+Cb:
median G4PFS = 3.9 (mo)
-------- Pac+Cb+Bev: median G4PFS = 2.9 (mo)
80
80
Proportion
Istituto Toscano Tumori-Livorno-Italy
Primary Endpoint: G4PFS (ITT)
Log-rank p-value
HR (90% CI)
60
= 0.176
= 0.85 (0.70, 1.04)
60
40
40
20
20
0 0
0 0
33
66
99
1212
1515
18
18
2121
24
24
27
27
Months
Patients at Risk
PC
182
87
44
26
14
7
5
3
1
0
PC+Bev
179
75
33
17
9
3
0
0
0
0
Zinner ASCO 2013
Istituto Toscano Tumori-Livorno-Italy
Secondary end-points
Zinner ASCO 2013
Istituto Toscano Tumori-Livorno-Italy
There is any patient unsuitable for maintenance
therapy?
Randomization factors:
•
•
•
PS status
Stage
Best tumour repsonse
~60% of PS2 Patients
Primary Endpoint OS
Gemcitabine +
Carboplatin X
4 cycles
PD
CR, PR
SD
R
A
N
D
O
M
I
Z
E
Gemcitabine q 21 days
+ BSC
N= 128
BSC
N= 127
Off study
Belani et al, ASCO 2010
Istituto Toscano Tumori-Livorno-Italy
No benefit with maintenance therapy in
PS2 patients
1.0
HR=0.97 (95% CI:0.72, 1.30)
P =0.838
0.9
0.8
0.7
0.6
BSC 9.3 mos.
0.5
0.4
0.3
0.2
0.1
Gemcitabine 8.0 mos.
0.0
0
6
12
18
24
30
36
42
48
54
60
Overall Survival (months)
Istituto Toscano Tumori-Livorno-Italy
The maintenance therapy paradigm
No progression after 4 cycles of platinum-based CT, PS
EGFR
mutated
EGFR-TKI
irrelevant
Erlotinib maintenance: SATURN
Gefitinib maintenance: INFORM
HR=0.10 (0.04–0.25)
P<0.0001
100
HR=0.17 (0.07–0.42)
Erlotinib (n=22)
Gefitinib (n=15)
100
Placebo (n=27)
80
Placebo (n=15)
80
60
60
PFS (%)
PFS (%)
Istituto Toscano Tumori-Livorno-Italy
Progression-free Survival
in mutated patients
40
40
20
20
0
8
16
24
32
40
48 56 64
Time (weeks)
72
80
88
96
0
8
16 24 32 40 48 56 64 72 80 88 96 104 112
Time (weeks)
Istituto Toscano Tumori-Livorno-Italy
The maintenance therapy paradigm
No progression after 4 cycles of platinum-based CT, PS
irrelevant ?
ALK+
Pemetrexed
Crizotinib
• ALK-positive patients display similar sensitivity to platinum-based
chemotherapy compared with ALK-negative patients
• Patients with the ALK fusion gene may not benefit from EGFR TKIs
TTP on platinum-based chemotherapy
TTP on EGFR-TKI monotherapy
100
80
ALK-positive
EGFR mut-positive
WT/WT
60
40
20
0
12
24
Months
36
48
Progression-free (%)
100
Progression-free (%)
Istituto Toscano Tumori-Livorno-Italy
ALK Fusion not Associated with Sensitivity to
Platinum-based Chemotherapy and EGFR –TKIs
80
ALK-positive
EGFR mut-positive
WT/WT
60
p=0.004
(ALK vs EGFR)
40
20
0
12
24
36
48
60
Months
Shaw AT, et al. J Clin Oncol 2009;27:4247‒53
Istituto Toscano Tumori-Livorno-Italy
ALK fusion predictive for pemetrexed
sensitivity
Low TS levels in ALK+
Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011
Profile 1007: PFS by Independent Radiologic Review
Istituto Toscano Tumori-Livorno-Italy
(in overall population and according to chemotherapy)
Treatment
mPFS (mos)
Crizotinib
7.7
Pemetrexed
4.2
0.59/P<0.001
Docetaxel
2.6
0.30/P<0.001
Treatment
mPFS (mos)
Crizotinib
7.7
Chemotherapy
3.0
HR/p value
0.49/P<0.001
HR/p value
Shaw AT., Lancet Oncol 2013
Istituto Toscano Tumori-Livorno-Italy
Overall Survival
Treatment
mOS (mos)
Crizotinib
20.3
Chemotherapy 22.8
HR/p value
0.54/P=0.54
* 112 patients crossed over to crizotinib
Shaw AT., Lancet Oncol 2013
Istituto Toscano Tumori-Livorno-Italy
Conclusions
• Maintenance therapy is a relevant option to discuss with patients
• Treatment choice should be based on EGFR, ALK, histology,
response to front-line therapy and patient preferences
• In EGFR/ALK wild-type maintenance is not recommended for
patients with low performance status
• In EGFR mutated patients EGFR-TKIs are the best option
• In ALK+ any effort should be done for reducing the risk to
preclude crizotinib therapy