maintenance therapy for nsclc federico cappuzzo istituto toscano tumori ospedale civile...
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Maintenance therapy for NSCLC
Federico CappuzzoIstituto Toscano Tumori
Ospedale CivileLivorno-Italy
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The maintenance therapy paradigm
Stratification for EGFR, ALK, histology, response to CT
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No progression after 4 cycles of platinum-based CT, PS=0-1
SD
Continuation maintenance
SCC: Switch maintenance
SCCGemcitabine
EGFR WT/ALK-:Response to CT
/Histology
CR/PR
Non-SCCPemetrexed or beva
Erlotinib or Docetaxel
Non-SCC: cont/switch
maintenance
Pem or beva Erlot or Docetax
Immediate vs. delayed docetaxelas 2nd line NSCLC treatment
CarboplatinPlus
Gemcitabine X 4
RANDOMIZE
ImmediateDocetaxel
DelayedDocetaxel at time of PD
CR, PRSD
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Docetaxel study results
Immediate (n=153)
Delayed (n=154)
LRp-Value
Median PFS months (95% CI)
6.5(4.4, 7.2)
2.8(2.6, 3.4)
<0.0001
12-month PFS, % (95% CI)
20%(13, 26)
9%(5, 14)
PFS
OS
Immediate (n=153)
Delayed (n=154)
LRp-Value
Median OS, months (95% CI)
11.9(10.0, 13.7)
9.1(8.0, 11.2)
0.071
12-mo survival (95% CI)
48.5%(39.9, 57.1)
38.3%(30.0, 46.5)
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TFINE study: multicenter, randomized phase III study of continuation docetaxel
Docetaxel 60 mg/m2 IV Cisplatin 75 mg/m2 IV Docetaxel 60 mg/m2 IV Cisplatin 75 mg/m2 IV
Docetaxel 60 mg/m2 IV q 3wkUp to six cycles
Docetaxel 60 mg/m2 IV q 3wkUp to six cycles
BSCBSC
IIIB/IVChemo-NaïveNSCLC
N=382
R1
CRPRSD
R2
Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV q
Zhang et al. ASCO 2013, Abstract # 8015
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TFINE study, C-TONG 0904PFS 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
Maintenance trials with pemetrexed
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
2:1 Randomization
Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*
Placebo (d1, q21d) + BSC (N=222)*
Switch maintenance: JMEN
Continuation maintenance: PARAMOUNT Nonsquamous NSCLC No prior systemic treatment for lung
cancer ECOG PS 0-1
500 mg/m2 Pemetrexed +75 mg/m2 Cisplatin, d1, q21d
CR, CP, SD
PD
500 mg/m2 Pemetrexed + BSC, d1, q21d
Placebo + BSC, d1, q21d
2:1 randomization
Stratified for:-PS (0 vs 1)-Disease stage (IIIb vs IV) prior to induction-Response to induction (CR/PR vs SD)
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Progression-free Survival
Switch maintenance: JMEN
Continuation maintenance: PARAMOUNT
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Overall Survival: pemetrexed maintenance data
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Switch maintenance: JMEN
Continuation maintenance: PARAMOUNT
JMEN & PARAMOUNT: OS according to response to first-line chemotherapy
1.2
Favours pemetrexed Favours placeboHR
1.00.80.60.4
*Non-squamous group
HR
Induction response SD* 0.61
Induction response CR/PR* 0.81
Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012
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Induction response SD 0.76
Induction response CR/PR 0.81
Maintenance trials with EGFR-TKIs Erlotinib maintenance: SATURN
Gefitinib maintenance: INFORM
1:1
Chemonaïve advanced NSCLC
n=1,949Non-PDn=889
4 cycles of 1st-line platinum-
based doublet*
Placebo PD
PD
Mandatory tumor sampling
Erlotinib150mg/day
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(250 mg/day)
Placebo(once daily)
1:1 randomization
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
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Progression-free Survival in ITT population
Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM
HR=0.42 (0.32–0.54)HR=0.71 (0.62–0.82)p<0.0001
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HR=0.81 (0.70–0.95)p=0.0088
Overall Survival in ITT population
Erlotinib maintenance: SATURN
HR = 0.83 (0.61, 1.12) p=0.2109
Gefitinib maintenance: INFORM
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Effect of erlotinib and gefitinib in EGFR wild-type patients: PFS and OS data
PFS and OS in SATURN PFS in INFORM
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OS according to response to first-line chemotherapy*
OS
prob
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ty
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
9.6 11.9
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
12.0 12.5
Log-rank p=0.0019
HR=0.72 (0.59–0.89)
Erlotinib (n=252)
Placebo (n=235)
Log-rank p=0.6181
HR=0.94 (0.74–1.20)
Erlotinib (n=184)
Placebo (n=210)
SD CR/PR
*OS is measured from time of randomisation into the maintenance phase
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Observation
IFCT-GFPC 0502 study design
Progression:2nd line
Primary endpoint: PFS
A
C
Maintenancetreatment
PD
*Stratification factors:– gender– histology: adenocarcinoma vs other histology– smoking status: non-smokers vs current/former smokers– center– response vs stabilization to induction chemotherapy
Induction chemo: cisplatin 80mg/m2 d1
+ gemcitabine 1,250mg/m2 d1, d8
Arm B: gemcitabine 1,250mg/m2 d1, d8 /3 wks
Arm C: erlotinib 150mg daily
N=155
N=154
N=155
EGFR = epidermal growth factor receptorIHC = immunohistochemistry; PD = progressive disease
PD: off
Objectiveresponse or
stable disease
Cisplatingemcitabine
x 4 cyclesN=834
NSCLCStage IIIB wet – IVPS 0-1, 18-70 years
Asymptomatic brainmets allowed
Tumor tissueEGFR IHC
EGFR mutation
R*N=464
BGemcitabine
Erlotinib
PD
PD
Pemetrexed
Pemetrexed
Pemetrexed
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PFS and OS results with continuation gemcitabineIs
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Perol et al. JCO 2012
PFS and OS results with switch erlotinibIs
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Perol et al. JCO 2012
Is continuation maintenance with pemetrexed plus bevacizumab better than beva or pem alone?
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Stratification factors •Gender•Smoking status•Response at randomisation
Avastinn=125
Avastin + pemetrexed
n=128
Avastin‡
+ pemetrexed‡ + cisplatin‡
n=253
CR/PR/SDper RECIST§
First-line induction4 cycles, q3w
PD
Continuation maintenanceq3w until PD
Follow-up
R67%
11
11
Previously untreated
stage IIIB-IVNSCLCN=376
AVAPERL
AVAPERL: PFS from randomisation
0 3 6 9 12 15
1.0
0.8
0.6
0.4
0.2
0
EMCC 2011, ASCO 2013
PFS
estim
ate
Time (months)
Avastin + Pem 7.4mAvastin 3.7mHR: 0.48; p<0.001
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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)
PointBreak: Study Design
Pemetrexed + Carboplatin
+ Bevacizumab
Pemetrexed + Bevacizumab
Paclitaxel+ Carboplatin
+ BevacizumabBevacizumab
Patel et al., 2012 Chicago Multidisciplinary symposium in Thoracic Oncology
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PointBreak: KM Plot for OS (Intent-to-treat)
0 3 6 9 12 15 18 21 24 27 30 33 36 39
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time from Induction (Months)
Su
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Pro
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bil
ity
HR=1.0 (95% CI: 0.86–1.16)Log-rank P=0.949
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20
40
60
80
100
00
3 6 9 12 15 18 21 24 27 30 33 36 39
PRONOUNCE: Study Design
Stratified for:
PS (0 vs 1); gender (M vs F); disease stage (M1a vs M1b)
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)
Bev-Eligible Population
Inclusion:- Chemo-naïve patients- PS 0/1- Stage IV, nonsquam- Stable treated CNS mets
Exclusion:- Uncontrolled effusions
Induction Phaseq21d, 4 cycles
Maintenance Phase q21d until PD
Pemetrexed (folic acid & vitamin B12)
+ Carboplatin
Paclitaxel + Carboplatin + Bevacizumab
R1:1
Pemetrexed (folic acid & vitamin B12)
Bevacizumab
180 patients each
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Zinner ASCO 2013
0 3 6 9 12 15 18 21 24 27
0
20
40
60
80
100
Months
Pro
po
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n
Pem+Cb: median G4PFS = 3.9 (mo)-------- Pac+Cb+Bev: median G4PFS = 2.9 (mo)
Log-rank p-value = 0.176HR (90% CI) = 0.85 (0.70, 1.04)
PC 182 87 44 26 14 7 5 3 1 0PC+Bev 179 75 33 17 9 3 0 0 0 0
Patients at Risk
Primary Endpoint: G4PFS (ITT)Is
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Zinner ASCO 2013
100
00
20
3 6 9 12 15 18 21 24
40
27
60
80
Secondary end-points
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Zinner ASCO 2013
There is any patient unsuitable for maintenance therapy?
Gemcitabine + Carboplatin X 4 cycles
RANDOMIZE
Gemcitabine q 21 days + BSC
N= 128
BSCN= 127
CR, PRSD
Off study
PD
Randomization factors:• PS status• Stage• Best tumour repsonse
Primary Endpoint OS
Belani et al, ASCO 2010
~60% of PS2 Patients
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Overall Survival (months)0 6 12 18 24 30 36 42 48 54 60
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0Gemcitabine 8.0 mos.
BSC 9.3 mos.
HR=0.97 (95% CI:0.72, 1.30)P =0.838
No benefit with maintenance therapy in PS2 patients
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The maintenance therapy paradigm
EGFR mutated
EGFR-TKI
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No progression after 4 cycles of platinum-based CT, PS irrelevant
HR=0.10 (0.04–0.25)P<0.0001
Time (weeks)
Erlotinib (n=22)
Placebo (n=27)
0 8 16 24 32 40 48 56 64 72 80 88 96
20
40
60
80
100
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112
PFS
(%)
Time (weeks)
HR=0.17 (0.07–0.42)
20
40
60
80
100
PFS
(%)
Gefitinib (n=15)
Placebo (n=15)
Progression-free Survival in mutated patients
Erlotinib maintenance: SATURN Gefitinib maintenance: INFORM
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The maintenance therapy paradigmIs
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No progression after 4 cycles of platinum-based CT, PS irrelevant ?
ALK+
Pemetrexed Crizotinib
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ALK Fusion not Associated with Sensitivity to Platinum-based Chemotherapy and EGFR –TKIs
• 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
Shaw AT, et al. J Clin Oncol 2009;27:4247‒53
TTP on EGFR-TKI monotherapy
Months
0 12 24 36 48
Prog
ress
ion-
free
(%)
Prog
ress
ion-
free
(%)
p=0.004(ALK vs EGFR)
Months
100
80
60
40
20
0 12 24 36 48 60
TTP on platinum-based chemotherapyTTP on platinum-based chemotherapy
ALK-positiveEGFR mut-positiveWT/WT
ALK-positiveEGFR mut-positiveWT/WT
100
80
60
40
20
ALK fusion predictive for pemetrexed sensitivity
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Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011
Low TS levels in ALK+
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Profile 1007: PFS by Independent Radiologic Review(in overall population and according to chemotherapy)
Treatment mPFS (mos) HR/p value
Crizotinib 7.7 0.49/P<0.001
Chemotherapy 3.0
Treatment mPFS (mos) HR/p value
Crizotinib 7.7
Pemetrexed 4.2 0.59/P<0.001
Docetaxel 2.6 0.30/P<0.001
Shaw AT., Lancet Oncol 2013
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Overall Survival
* 112 patients crossed over to crizotinib
Treatment mOS (mos) HR/p value
Crizotinib 20.3 0.54/P=0.54
Chemotherapy 22.8
Shaw AT., Lancet Oncol 2013
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
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