1. Maintenance therapy for NSCLC
Istituto Toscano Tumori-Livorno-Italy
Federico Cappuzzo
Istituto Toscano Tumori
Ospedale Civile
Livorno-Italy

2. 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
Istituto Toscano Tumori-Livorno-Italy
CR/PR SD
Continuation maintenance
SCC: Switch
maintenance
Non-SCC: cont/switch
maintenance
SCC
Gemcitabine
Non-SCC
Pemetrexed or beva
Erlotinib or Docetaxel
Pem or beva
Erlot or Docetax

3. Immediate vs. delayed docetaxel as 2nd line NSCLC treatmentMI Z E
CR, PR SD
Immediate
Docetaxel
Carboplatin
Plus
Gemcitabine X 4
Istituto Toscano Tumori-Livorno-Italy
Delayed
Docetaxel at time of PD

4. Docetaxel study results Istituto Toscano Tumori-Livorno-Italy
Immediate (n=153)
Delayed (n=154) LR
p-Value
Median PFS months
(95% CI)
6.5
(4.4, 7.2)
2.8
(2.6, 3.4)
<0.0001
12-month PFS, %
20% (13, 26)
9% (5, 14)
PFS
Istituto Toscano Tumori-Livorno-Italy
Immediate (n=153)
Delayed (n=154) LR
p-Value
Median OS, months
(95% CI)
11.9
(10.0, 13.7)
9.1
(8.0, 11.2)
0.071
12-mo survival
48.5% (39.9, 57.1)
38.3%
(30.0, 46.5) OS

5. Istituto Toscano Tumori-Livorno-Italy
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 q 3wk
Up to six cycles
BSC
IIIB/IV
Chemo-Naïve
NSCLC
N=382 R1 CR PR SD R2
Docetaxel 75 mg/m2 IV Cisplatin 75 mg/m2 IV q
Istituto Toscano Tumori-Livorno-Italy
a 50% improvement of PFS
Zhang et al. ASCO 2013, Abstract # 8015

6. TFINE study, C-TONG 0904 PFS results
Istituto Toscano Tumori-Livorno-Italy
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

7. 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)*
Placebo (d1, q21d) + BSC (N=222)*
2:1
Randomization
Istituto Toscano Tumori-Livorno-Italy
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
Stratified for:
PS (0 vs 1)
Disease stage (IIIb vs IV) prior to induction
Response to induction (CR/PR vs SD) PD 7

8. Progression-free Survival
Continuation maintenance:
PARAMOUNT
Switch maintenance:
JMEN
Istituto Toscano Tumori-Livorno-Italy 8

9. Overall Survival: pemetrexed maintenance data
Continuation maintenance:
PARAMOUNT
Switch maintenance:
JMEN
Istituto Toscano Tumori-Livorno-Italy

10. JMEN & PARAMOUNT: OS according to response to first-line chemotherapyHR
Induction response CR/PR*
0.81
Induction response SD*
0.61
Istituto Toscano Tumori-Livorno-Italy
Induction response CR/PR
0.81
Induction response SD
0.76
0.4
0.6
0.8
1.0
1.2
Favours pemetrexed HR
Favours placebo
*Non-squamous group
Ciuleanu et al. Lancet 2009; Paz Ares et al. ASCO 2012

11. Maintenance trials with EGFR-TKIs
Erlotinib maintenance: SATURN
Erlotinib
150mg/day PD
Chemonaïve advanced NSCLC
n=1,949
4 cycles of 1st-line platinum-based doublet*
Non-PD
n=889
1:1
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
Placebo PD
Istituto Toscano Tumori-Livorno-Italy
Mandatory tumor sampling
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)

12. Progression-free Survival Istituto Toscano Tumori-Livorno-Italy
in ITT population
Erlotinib maintenance: SATURN
Gefitinib maintenance: INFORM
HR=0.71 (0.62–0.82)
p<0.0001
HR=0.42 (0.32–0.54)
Istituto Toscano Tumori-Livorno-Italy

13. Istituto Toscano Tumori-Livorno-Italy
Overall Survival
in ITT population
Erlotinib maintenance: SATURN
Gefitinib maintenance: INFORM
HR=0.81 (0.70–0.95)
p=0.0088
HR = 0.83 (0.61, 1.12)
p=0.2109
Istituto Toscano Tumori-Livorno-Italy

14. Istituto Toscano Tumori-Livorno-Italy
Effect of erlotinib and gefitinib in EGFR wild-type patients: PFS and OS data
PFS and OS in SATURN
PFS in INFORM
Istituto Toscano Tumori-Livorno-Italy

15. OS according to response to first-line chemotherapy*SD
CR/PR
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR=0.72 (0.59–0.89)
HR=0.94 (0.74–1.20)
Istituto Toscano Tumori-Livorno-Italy
Log-rank p=0.0019
Log-rank p=0.6181
OS probability
Erlotinib (n=252)
Placebo (n=235)
Erlotinib (n=184)
Placebo (n=210)
9.6
11.9
12.0
12.5
Time (months)
Time (months)
*OS is measured from time of randomisation into the maintenance phase

16. IFCT-GFPC 0502 study design
PD: off
Maintenance
treatment
Progression:
2nd line A
Observation PD
Pemetrexed
N=155
Cisplatin
gemcitabine
x 4 cycles
N=834
Objective
response or
stable disease B
R* N=464
Gemcitabine PD
Pemetrexed
N=154
Istituto Toscano Tumori-Livorno-Italy C
Erlotinib PD
Pemetrexed
NSCLC
Stage IIIB wet – IV
PS 0-1, years
Asymptomatic brain
mets allowed
Tumor tissue
EGFR IHC
EGFR mutation
N=155
Primary endpoint: PFS
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
*Stratification factors:
gender
histology: adenocarcinoma vs other histology
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

17. PFS and OS results with continuation gemcitabine
Istituto Toscano Tumori-Livorno-Italy
Perol et al. JCO 2012

18. PFS and OS results with switch erlotinib
Istituto Toscano Tumori-Livorno-Italy
Perol et al. JCO 2012

19. 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
Istituto Toscano Tumori-Livorno-Italy
Avastin n=125
CR/PR/SD
per RECIST§ 1
Previously
untreated
stage IIIB-IV
NSCLC
N=376
Avastin‡
+ pemetrexed‡
+ cisplatin‡
n=253 R
67%
Avastin + pemetrexed n=128 1 PD
Stratification factors
Gender
Smoking status
Response at randomisation
Follow-up

20. AVAPERL: PFS from randomisation
1.0
0.8
0.6
0.4
0.2
Avastin + Pem 7.4m
Avastin 3.7m
HR: 0.48; p<0.001
PFS estimate
Istituto Toscano Tumori-Livorno-Italy
Time (months)
OS for Pem/Bev was better than for Bev (17.1 vs 13.2 months), p=0.29, HR 0.87 (CI )
EMCC 2011, ASCO 2013

21. PointBreak: Study Design
Pemetrexed
+ Carboplatin
+ Bevacizumab
Paclitaxel
Bevacizumab
Istituto Toscano Tumori-Livorno-Italy
Last year Dr. Patel reported the results of this trial where carbo/pem bev followed by maintenance peme/bev was compared to carbotaxol bev followed by maintenance bev
Patel et al., 2012 Chicago Multidisciplinary symposium in Thoracic Oncology 21

22. PointBreak: KM Plot for OS (Intent-to-treat)
HR=1.0 (95% CI: 0.86–1.16)
Log-rank P=0.949
100
Pem Arm Median OS = mo (95% CI: 11.30–14.03)
Pac Arm Median OS = 13.4 mo (95% CI: 11.86–14.91) 80 60
Istituto Toscano Tumori-Livorno-Italy 40
20% off people are alive at 2 years, maybe the never smokers 20 3 6 9 12 15 18 21 24 27 30 33 36 39

23. 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
Bev-Eligible Population
Inclusion:
- Chemo-naïve patients
- PS 0/1
- Stage IV, nonsquam
- Stable treated CNS mets
Exclusion:
- Uncontrolled effusions
Pemetrexed
(folic acid & vitamin B12)
+ Carboplatin
Pemetrexed
(folic acid & vitamin B12)
Istituto Toscano Tumori-Livorno-Italy
R 1:1
Lo studio è stato disegnato per dimostrare una superiorità per carbo-pme in termini di PFS libera da eventi di grado 4
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 23

24. Primary Endpoint: G4PFS (ITT)
100
Pem+Cb: median G4PFS = 3.9 (mo)
Pac+Cb+Bev: median G4PFS = 2.9 (mo)
Log-rank p-value = 0.176
HR (90% CI) = 0.85 (0.70, 1.04) 80 60
Istituto Toscano Tumori-Livorno-Italy 40 20 3 6 9 12 15 18 21 24 27
Number of G4PFS events
Pem+Cb
n = 152 %
Pac+Cb+Bev
n = 144
G4 AE
24.3
44.4 PD
62.5
47.2
Death
13.2
8.3
Patients at Risk PC
182 87 44 26 14 7 5 3 1
PC+Bev
179 75 33 17 9
Zinner ASCO 2013

25. Istituto Toscano Tumori-Livorno-Italy
Secondary end-points
Istituto Toscano Tumori-Livorno-Italy
Zinner ASCO 2013

26. There is any patient unsuitable for maintenance therapy?
Randomization factors:
PS status
Stage
Best tumour repsonse
Primary Endpoint OS
~60% of PS2 Patients R A N D O MI Z E
Istituto Toscano Tumori-Livorno-Italy
Gemcitabine q 21 days + BSC
N= 128
CR, PR SD
Gemcitabine +
Carboplatin X
4 cycles
Key Eligibility Criteria
Stage IIB (wuth pleural effusion and or positive spravclavicular nodes or stage IV
Age greater than or equal to 18
ECOG PS 0-2
Adequate renal, hepatic and bone marrow function
Asymptomatic or treated and controlled brain mets were allowed
Presence of measurable disease
No prior chemotherapy
BSC
N= 127 PD
Off study
Belani et al, ASCO 2010

27. No benefit with maintenance therapy in
PS2 patients
Survival Probability
Overall Survival (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Gemcitabine 8.0 mos.
BSC 9.3 mos.
HR=0.97 (95% CI:0.72, 1.30)
P =0.838
Istituto Toscano Tumori-Livorno-Italy

28. The maintenance therapy paradigm
No progression after 4 cycles of platinum-based CT, PS irrelevant
EGFR
mutated
Istituto Toscano Tumori-Livorno-Italy
EGFR-TKI

29. Progression-free Survival Istituto Toscano Tumori-Livorno-Italy
in mutated patients
Erlotinib maintenance: SATURN
Gefitinib maintenance: INFORM
HR=0.10 (0.04–0.25)
P<0.0001
HR=0.17 (0.07–0.42)
100
Erlotinib (n=22)
Placebo (n=27)
Gefitinib (n=15)
Placebo (n=15)
100
Istituto Toscano Tumori-Livorno-Italy 80 80 60 60
PFS (%)
PFS (%) 40 40 20 20
Time (weeks) 8 16 24 32 40 48 56 64 72 80 88 96
104
112
Time (weeks)

30. The maintenance therapy paradigm
No progression after 4 cycles of platinum-based CT, PS irrelevant ?
ALK+
Istituto Toscano Tumori-Livorno-Italy
Pemetrexed
Crizotinib

31. TTP on EGFR-TKI monotherapy Istituto Toscano Tumori-Livorno-Italy
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
TTP on platinum-based chemotherapy
TTP on EGFR-TKI monotherapy
Istituto Toscano Tumori-Livorno-Italy
100
100 80 80
ALK-positive
EGFR mut-positive
WT/WT
ALK-positive
EGFR mut-positive
WT/WT 60 60
Progression-free (%)
Progression-free (%) 40 40
p=0.004
(ALK vs EGFR) 20 20
Months
Months
Shaw AT, et al. J Clin Oncol 2009;27:4247‒53

32. ALK fusion predictive for pemetrexed sensitivity
Istituto Toscano Tumori-Livorno-Italy
Low TS levels in ALK+
Takeda M, Clin Lung Cancer 2012; Camidge JTO 2011

33. 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
Istituto Toscano Tumori-Livorno-Italy
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

34. Istituto Toscano Tumori-Livorno-Italy
Overall Survival
Treatment
mOS (mos)
HR/p value
Crizotinib
20.3
0.54/P=0.54
Chemotherapy
22.8
Istituto Toscano Tumori-Livorno-Italy
* 112 patients crossed over to crizotinib
Shaw AT., Lancet Oncol 2013

35. 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
Istituto Toscano Tumori-Livorno-Italy