1. No category

Maintenance in Lung cancer –
Yes ?
Dr. Ryvo Larisa
TASMC
Maintenance of early second line
Maintenance therapy :
continuing the treatment or part of the
it until PD
Early second line:
introducing a new agent without PD
Definitions
Maintenance therapy
Defined tumor response
Defined no. of cycles
Defined time
or
until PD
•
Extension of treatment duration by administration of ≥1 agents after
a defined no. of treatment cycles
•
Patients must demonstrate a defined tumor response to be eligible
Sequential therapy
Defined no. of cycles
Defined no. of cycles
•
Therapy for a defined no. of cycles, followed by a different therapy for a defined no. of cycles
•
Switch between therapies does not require documented disease progression vs.
regular switch from 1st- to 2nd-line treatment
Grossi et al. Oncologist 2007;12:451–464
In recent studies, approximately 50%
of patients did not receive second-line
therapy
Socinski et al. 20021
Belani et al. 20032
Brodowicz et al. 20063
von Plessen et al. 20064
Barata et al. 20075
Park et al. 20076
Ciuleanu et al. 20097
Pirker et al. 20088
Scagliotti et al. 20089
Fidias et al. 200910
0
25
50
75
Patients receiving 2nd-line therapy (%)
1. J Clin Oncol 2002;20:1335–43; 2. J Clin Oncol 2003;21:2933–39; 3. Lung Cancer 2006;52:155–63;
4. Br J Cancer 2006;95:966–73; 5. J Thorac Oncol 2007;2(Suppl. 4):S666 (Abs. P2-235);
6. J Clin Oncol 2007;25:5233–39; 7. Lancet 2009;374:1432–40;
8. J Clin Oncol 2008;26(Suppl. 15):6s (Abs. 3); 9. J Clin Oncol 2008;26:3543–51;
10. J Clin Oncol 2009;27:591–98
100
Delaying further therapy is not a viable
option for a large group of patients
100
46% do not
receive 2L
therapy
80
17% die before decision
is made
60
29% only receive BSC
100%
40
Main reasons
54%
Poor PS (58%)
Poor response to 1L (24%)
Co-morbidities (24%)
Extent of disease (22%)
20
0
Pts receiving 1L
therapy
Pts receiving 2L
therapy
TNS Healthcare, Brand Tracking Study, December 2007
Data from study involving
306 EU physicians
Maintenance chemotherapy
1. Cytotoxics
• Gemcitabine
• Docetaxel
• Pemetrexed
2. Small Molecule
• Erlotinib
3.
Antibody
Erbitux
Bevacizumab
Immediate vs delayed docetaxel
Fidias, et al. ASCO 2007; Abstract No. LBA7516
Immediate vs delayed docetaxel
Immediate
(n=153)
Delayed P-value
(n=154)
TTP (mo)
6.5
2.8
<0.001
OS (mo)
11.9
9.1
0.071
20/46/17
0.34
QoL I/S/W 17/57/14
I, improved; S, stable; W, worsened
Fidias, et al. ASCO 2007; Abstract No. LBA7516
Pem/BSC vs placebo/BSC in NSCLC:
Sequential study design
 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
(NO PEMETREXED)
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, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 2008; Chicago, IL.
Objectives
Primary Objective
Progression-free survival
Secondary Objectives
Overall survival
Objective response rate (CR+PR)
Disease control rate (CR+PR+SD)
Safety and toxicity profile
Pem/BSC vs placebo/BSC in NSCLC: PFS
Progression-free Probability
1.0
N=581
HR=0.599
(95% CI: 0.49–0.73)
p <0.00001
Pemetrexed: 4.04 mos
(95% CI: 3.06–4.44)
Placebo: 1.97 mos
(95% CI: 1.54–2.76)
Time (months)
24% censored
Ciuleanu, et al. Presented at: Annual Meeting of the American Society of Clinical Oncology, June 2, 2008; Chicago, IL.
Overall Survival (ITT)
HR=0.79 (95% CI: 0.65–0.95)
P =0.012
1.0
Survival Probability
0.9
0.8
0.7
0.6
0.5
Pemetrexed 13.4 mos
0.4
Placebo 10.6 mos
0.3
0.2
0.1
0.0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
Progression-free Survival by
Histology
Progression-free Probability
Nonsquamous
Squamous
HR=0.47 (95% CI: 0.370.6)
P <0.00001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Pemetrexed 4.4 mos
Placebo
1.8 mos
0
3
6
9
12
15
Time (months)
HR=1.03 (95% CI: 0.771.5)
P =0.896
18
21
24
Pemetrexed 2.4 mos
Placebo
2.5 mos
0
3
6
9
12
15
Time (months)
18
21
24
SATURN – a prospective phase III study of
Tarceva as maintenance
Tarceva
150mg/day
Chemonaïve
advanced NSCLC
n=1,949
4 cycles of firstline platinum
doublet
chemotherapy
Non-PD
n=889
PD
1:1
Placebo
PD
Mandatory tumour
sampling
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
Cappuzzo, ASCO 2009
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
Tarceva significantly prolongs OS in all
patients (ITT)
1.0
HR=0.81 (0.70–0.95)
OS probability
0.8
Log-rank p=0.0088
0.6
Erlotinib (n=438)
Placebo (n=451)
0.4
0.2
11.0
0
0
3
6
9
12.0
12
15
18
21
Time (months)
*OS is measured from time of randomisation into the maintenance phase;
ITT = intent-to-treat population
Cappuzzo, WCLC 2009
24
27
30
33
36
OS in patients with SD on first-line
chemotherapy according to histology
1.0
Squamous-cell
HR=0.67 (0.48–0.92)
OS probability
0.8
Log-rank p=0.0116
0.6
Erlotinib (n=97)
Placebo (n=93)
0.2
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
Measured from time of randomisation into the maintenance phase
Log-rank p=0.0457
Erlotinib (n=155)
Placebo (n=142)
0.6
0.4
11.3
HR=0.76 (0.59–1.00)
0.8
0.4
8.3
Non-squamous
1.0
0
10.6
13.7
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
OS* according to response to first-line
chemotherapy
SD
CR/PR
1.0
1.0
HR=0.72 (0.59–0.89)
OS probability
0.8
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=184)
Erlotinib (n=252)
0.4
Placebo (n=235)
0.2
0
Placebo (n=210)
0.4
0.2
9.6
0
3
6
11.9
9 12 15 18 21 24 27 30 33 36
0
12.0 12.5
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)
SATURN: All patient subgroups obtains
significant PFS benefit from Tarceva
All
HR (95% CI)
0.71 (0.62–0.82)
n
884
Male
0.78 (0.66–0.92)
654
Female
0.56 (0.42–0.76)
230
Caucasian
0.75 (0.64–0.88)
744
Asian
0.58 (0.38–0.87)
128
Adenocarcinoma
0.60 (0.48–0.75)
401
Squamous-cell
0.76 (0.60–0.95)
359
Never smoker
0.56 (0.38–0.81)
152
Former smoker
0.66 (0.50–0.88)
242
Current smoker
0.80 (0.67–0.97)
490
0.4
Cappuzzo, ASCO 2009
0.6
0.8
1.0
1.2
Favours
Tarceva
HR
Favours
placebo
Symptom benefits and no impairment
of QoL with maintenance Tarceva
Time to . . .
HR (95% CI)
p value
Deterioration in QoL*
0.96 (0.79–1.16)
0.65
Pain‡
0.61 (0.42–0.88)
0.01
Opioid or analgesic§
0.66 (0.46–0.94)
0.02
Dyspnoea‡
0.75 (0.48–1.17)
0.21
Cough‡
0.77 (0.49–1.21)
0.25
*Assessed using Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire
‡Data from AE records
§Data from concomitant medication records
Cappuzzo F, et al. J Thorac Oncol 2009;4(9 Suppl. 1):S289 (Abs. A2.1)
Conclusions
• Maintenance (chemo) therapy
– Improves PFS
– Improves OS
– Toxicity issues
– QoL?
• Choice of maintenance (chemo)therapy?
• TKI
Which patients have the greatest
clinical need for maintenance therapy?
• Patients with the greatest need for maintenance
therapy are those with
– sub-optimal response to first-line chemotherapy
– remaining disease symptoms
– less chance to receive subsequent therapy
– worse overall prognosis
 patients with SD following first-line chemotherapy
PARAMOUNT (S124): Study Design
A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed Plus Best Supportive Care Versus
Best Supportive Care Immediately Following Induction Treatment With Pemetrexed + Cisplatin for Advanced
Nonsquamous NSCLC
MaintenanceTherapy
Induction Therapy
Pemetrexed 500 mg/m2, day 1
Cisplatin 75 mg/m2, day 1
every 21 days x 4 cycles
Primary Objective:
Secondary Objective:
PFS
OS
Patient-Reported Outcomes
Resource Utilization
Adverse Events
Serious Adverse Events
Objective Tumor Response Rate
(whole treatment, maintenance)
R
A
N
D
O
M
I
Z
E
If CR,
PR, SD
Pemetrexed 500 mg/m2, day 1
every 21 days
+
Best Supportive Care
Placebo, day 1
every 21 days
+
Best Supportive Care
Maintenance in Lung cancer –
Yes !