Transcript Slide 1

1-line Treatment of Advanced-NSCLC WT
Cesare Gridelli
Division of Medical Oncology
“S.G. Moscati” Hospital – Avellino (Italy)
[email protected]
First-Line Treatment of A-NSCLC in EU
EGFR mutation (del 19
or L858R in exon 21)
3
EGFR-mutation
analysis
EGFR wild type
(or not done)
EGFR-TKI
Platinum plus
• Pemetrexed or gemcitabine or taxanes or
vinorelbine
OR
2
Non-squamous
cell carcinoma
Platinum combination plus
• Bevacizumab* (PS 0,1)
Elderly/PS 2
1
Metastatic
NSCLC, PS 0-2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
Platinum plus
2
Squamous
cell carcinoma
• Gemcitabine or taxane or vinorelbine
Elderly/PS 2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
•
•
•
•
Radiotherapy
CNS
Central airways
Bone
Soft tissue
First-Line Treatment of Advanced NSCLC
NCCN Guidelines
PS 0-1
Doublet chemotherapy (category 1)
OR
Bevacizumab + chemotherapy
(if criteria met)
OR
Cisplatin/pemetrexed (category 1)
(if criteria met)
OR
Cetuximab/vinorelbine/cisplatin
(category 2B)
PS 2
Chemotherapy
PS 3-4
Best supportive care only
EGFR mutation and ALK negative
• Adenocarcinoma
• Large cells
• NSCLC NOS
EGFR mutation
positive
Erlotinib
ALK positive
Crizotinib
PS 0-1
Squamous cell
carcinoma
Doublet chemotherapy
(category 1)
OR
Cetuximab/vinorelbine/
cisplatin (category 2B)
PS 2
Chemotherapy
PS 3-4
Best supportive care
First-Line Treatment of Advanced NSCLC
EGFR mutation (del 19
or L858R in exon 21)
EGFR-TKI
Platinum plus
EGFR-mutation
analysis
EGFR wild type
(or not done)
• Pemetrexed or gemcitabine or taxanes or
vinorelbine
OR
Non-squamous
cell carcinoma
Platinum combination plus
• Bevacizumab PS 0,1)
Elderly/PS 2
Metastatic
NSCLC, PS 0-2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
Platinum plus
• Gemcitabine or taxane or vinorelbine
Squamous
cell carcinoma
Elderly/PS 2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
•
•
•
•
Radiotherapy
CNS
Central airways
Bone
Soft tissue
First-Line Treatment of Advanced NSCLC
EGFR mutation (del 19
or L858R in exon 21)
EGFR-TKI
Platinum plus
EGFR-mutation
analysis
EGFR wild type
(or not done)
• Pemetrexed or gemcitabine or taxanes or
vinorelbine
OR
Non-squamous
cell carcinoma
Platinum combination plus
• Bevacizumab PS 0,1)
Elderly/PS 2
Metastatic
NSCLC, PS 0-2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
Platinum plus
• Gemcitabine or taxane or vinorelbine
Squamous
cell carcinoma
Elderly/PS 2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
•
•
•
•
Radiotherapy
CNS
Central airways
Bone
Soft tissue
Overall Survival, %
100
Hazard ratio, 0.79;
P=0.003
80
BPC group
(305 events in 417 patients)
60
40
PC group
(344 events in 433 patients)
20
0
0
6
12
18
24
30
36
Month
BPC, bevacizumab-paclitaxel-carboplatin; PC, paclitaxel-carboplatin.
The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab versus 10.3 months in the
chemotherapy-alone group.
Sandler A, et al. N Engl J Med. 2006;355(24):2542-2550.
42
0.8
• Avastin-based therapy (n=602)
– extends OS to 14.2 months
– 31% reduction in the risk of death (HR=0.69)
0.6
Avastin + CP (n=300)
Probability of OS
0.4
CP (n=302)
0.2
0
10.3
0
6
14.2
12
18
Duration of OS (months)
24
30
36
42
48
First-Line Treatment of Advanced NSCLC
ESMO Guidelines
EGFR mutation (del 19
or L858R in exon 21)
EGFR-mutation
analysis
EGFR wild type
(or not done)
EGFR-TKI
Platinum plus
• Pemetrexed or gemcitabine or taxanes or
vinorelbine
OR
Non-squamous
cell carcinoma
Platinum combination plus
• Bevacizumab PS 0,1)
Elderly/PS 2
Metastatic
NSCLC, PS 0-2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
Platinum plus
Squamous
cell carcinoma
• Gemcitabine or taxane or vinorelbine
Elderly/PS 2
• Platinum combination (preferred in fit elderly) or
• Monotherapy (preferred in unfit elderly)
•
•
•
•
Radiotherapy
CNS
Central airways
Bone
Soft tissue
Cisplatin With Pemetrexed or Gemcitabine
1.0
0.8
0.6
0.4
0.2
0.0
CP
Median; 95% CI
11.8; 10.4, 13.2
CG
10.4; 9.6, 11.2
CP vs CG
0
6
12
18
24
Survival Time (months) in Patients
With Non-squamous Histology
CP
Median; 95% CI
9.4; 8.4, 10.2
CG
10.8; 9.5, 12.1
CP vs CG
0
Adjusted HR; 95% CI
0.81; 0.70, 0.94
6
12
18
30
Adjusted HR; 95% CI
1.23; 1.00, 1.51
24
Survival Time (months) in Patients
With Squamous Cell Carcinoma
PFS Probability
1.0
0.8
0.6
0.4
0.2
0.0
30
PFS Probability
Survival Probability
Survival Probability
JMDB Trial
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
CP
Median; 95% CI
5.3; 4.8, 5.7
CG
4.7; 4.4, 5.4
CP vs CG
0
6
12
18
CP
Median; 95% CI
4.4; 4.1, 4.9
CG
5.5; 4.6, 5.9
6
12
30
Adjusted HR; 95% CI
1.36; 1.12, 1.65
18
24
PFS (months) in Patients
With Squamous Cell Carcinoma
Cisplatin/pemetrexed provides similar efficacy with better tolerability and
more convenient administration than cisplatin/gemcitabine in NSCLC
CP, cisplatin-pemetrexed.
Scagliotti GV, et al. J Clin Oncol. 2008;26(21):3543-3551.
24
PFS (months) in Patients
With Non-squamous Histology
CP vs CG
0
Adjusted HR; 95% CI
0.90; 0.79, 1.02
30
Maintenance Therapy
Continuation vs Switch
Selection of
patients with a
better prognosis
‘Continuation’ maintenance with TT
(eg, bevacizumab)
‘Continuation’ maintenance with the
chemo drug X
P + X ± TT
× 4 cycles
50%
Stabilisation or
objective response
QoL
Symptom control
Toxicities
‘Switch’ maintenance with a new drug
TT (EGFR TKI for SD patients)
‘Switch’ maintenance with a
new chemo drug
Maintenance Therapy in NSCLC
Patient Selection
Histology
• Adenocarcinoma subtypes
• Squamous cell carcinoma
Clinical Features
• Age: Adults 18-70 years (fit, elderly)
• Gender: Any
• ECOG PS 0-1, KPS>80
• ECOG PS 2 (selected cases for TKI)
Genetics
• EGFR Wild type – chemotherapy
• EGFR Mutant – TKI
(TKI responders; Asian, women, never smoker, having adenocarcinoma)
• k-ras mutation – chemotherapy
• EML4-ALK – Crizotinib
Suitable Subset of
Patients
• Clinical benefit; stable disease or regression after induction chemotherapy
• Well-preserved organ function
• No major comorbidity
Study Period
Screening Period
SATURN: Sequential Tarceva in unresectable NSCLC
Stage IIIb/IV NSCLC
Tumour
samples
(mandatory)
4 cycles of a first-line standard
platinum-based doublet
No progression
(n=899)
EGFR protein
expression
(IHC) results
Progression
Randomisation
with stratification
Erlotinib 150mg/day
Placebo
Until PD, death or
unacceptable toxicity
Until PD, death or
unacceptable toxicity
Planned
Recruitment
= 1,700
TITAN
OS from randomization in all patients
1.0
HR=0.81 (0.70–0.95)
Log-rank p=0.0088
OS probability
0.8
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)
24
*OS is measured from time of randomisation into the maintenance phase;
ITT = intent-to-treat population
27
30
33
36
Cappuzzo et al,WCLC 2009
OS according to response to first-line chemo
SD
CR/PR
1.0
1.0
HR=0.94 (0.74–1.20)
HR=0.72 (0.59–0.89)
OS probability
0.8
0.8
Log-rank p=0.0019
0.6
Log-rank p=0.6181
0.6
Erlotinib (n=252)
Placebo (n=235)
0.4
0.2
0
Erlotinib (n=184)
Placebo (n=210)
0.4
0.2
9.6
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)
Multivariate HR for OS in SD population
0.71, p=0.0019
Measured from time of randomisation into the maintenance phase
9 12 15 18 21 24 27 30 33 36
Time (months)
PARAMOUNT: Study Design
Study Treatment Period
Progression
Induction Therapy (4 cycles)
Patients enrolled if:
• Nonsquamous NSCLC
• No prior systemic treatment for
lung cancer
• ECOG PS 0/1
500 mg/m2 Pemetrexed +
75 mg/m2 Cisplatin, d1, q21d
21 to 42 Days
Maintenance Therapy (Until PD)
500 mg/m2 Pemetrexed + BSC, d1, q21d
CR,
PR, SD
2:1 Randomization
Placebo + BSC, d1, q21d
Stratified for:
• PS (0 vs 1)
• Disease stage (IIIB vs IV) prior to induction
• Response to induction (CR/PR vs SD)
PD
PARAMOUNT: Investigator Assessed PFS
(from Maintenance)
1.0
Pem + BSC
Survival Probability
0.9
Placebo + BSC
0.8
0.7
Pemetrexed: median =4.1 mos (3.2-4.6)
Placebo: median =2.8 mos (2.6-3.1)
Log-rank P=0.00006
Unadjusted HR: 0.62 (0.49-0.79)
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
Time (Months)
12
15
Patients at Risk
Pem + BSC
N=359
132
57
21
4
0
Placebo + BSC
N=180
52
15
5
0
0
PARAMOUNT: Final OS from Randomization
Placebo
13.9
(12.8-16.0)
28.7
11.0
(10.0-12.5)
21.7
0.9
OS Median (mo)
(95% CI)
Censoring (%)
0.8
Survival Rate (%) (95% CI)
1.0
Survival Probability
Pem
0.7
1-year
2-year
0.6
58 (53-63)
32 (27-37)
45 (38-53)
21 (15-28)
Log-rank P = 0.0195
Unadjusted HR: 0.78
(95% CI: 0.64–0.96)
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Time from Randomization (Months)
Patients at Risk
Pem + BSC 359
43
Placebo + BSC
23
333
15
180
12
272
2
169
8
235
0
131
3
200
166
138
105
103
0
78
65
49
79
35
PARAMOUNT: Final OS from Induction
Pemetrexed
Median OS =16.9 mos (95% CI: 15.8–19.0)
Placebo
Median OS =14.0 mos (95% CI: 12.9–15.5)
Log-rank P=0.0191
HR=0.78 (95% CI: 0.64–0.96)
1.0
Survival Probability
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
Time from Induction (Months)
Patients at Risk
Pem + BSC 359
42
Placebo + BSC
335
15
2
180
276
0
168
234
200
164
138
106
132
103
78
63
49
77
35
0.8
1.0
Placebo + BSC
Median OS=14.0 months
(95% CI, 12.9–15.5)
0.4
0.6
0.4
0.2
0.0
HR=0.78 (95% CI, 0.64–0.96)
Log-rank P=0.0191
CR/PR
HR=0.81 (0.59–1.11)
0.8
0.6
Survival Probability
Survival Probability
1.0
Pemetrexed + BSC
Median OS=16.9 months
(95% CI, 15.8–19.0)
0.2
0.0
0
3
6
1.0
9 12 15 18 21 24 27 30 33 36
Stable Disease
HR=0.76 (0.57–1.01)
0.8
0.6
0.4
0 3 6 9 12 15 18 21 24 27 30 33 36
0.2
Time From Induction, months
0.0
0
3
6
9 12 15 18 21 24 27 30 33 36
Time From Randomisation, months
Mean value at baseline (Cycle 0)
Top of bar=mean value at that cycle for pemetrexed
∆
EQ-5D UK population-based index score
0.90
0.85
*
∆0.03
∆0.02
∆-0.02
∆-0.01
∆0.01
∆0.04
∆0.00
∆0.01 ∆0.00
∆0.01
0.80
∆0.01
∆0.01
0.75
0.70
0.65
N=265 132
1
241 129 160 83
2
3
149 66
4
108 48
5
Maintenance Cycles
98 36
Mean change from baseline
EQ-5D VAS
Improvement
Mean Rating (Scale 0 to 100)
Improvement
Mean Score (Scale -0.59 to +1.00)
Top of bar=mean value at that cycle for placebo
80
*
*
∆3.01
∆5.99
∆6.15
∆4.90
∆1.55
∆1.42
∆1.82 ∆0.69
∆1.65
∆3.15
75
∆1.24
∆5.76
70
65 126 239 127 162 81
N=266
6
EQ-5D, EuroQol 5-dimensional questionnaire; VAS, visual analog scale.
*P≤0.05, comparing the difference in mean changes from baseline between treatment arms.
Gridelli C, et al. J Thorac Oncol. 2012;7(11):1713-1721.
1
2
3
147 65
4
107 48
5
Maintenance Cycles
98 36
6
Change in ECOG Performance Status from
Baseline to Last Maintenance Treatment
Percent Change from Baseline in
ECOG Performance Status
100
90
16.0%
12.4%
80
70
60
50
76.2%
40
78.6%
30
20
10
0
7.8%
9.0%
Pemetrexed
Placebo
Worse
No Change
Better
PARAMOUNT: Long Term Safety
>10 cycles
Pemetrexed*
n = 84
(%)
≤10 cycles
Pemetrexed
n = 275
(%)
All laboratory
13.1
8.0
0.194
All non-laboratory
8.3
9.1
1.00
Neutropenia†
8.3
2.2
0.015
Infections
1.2
2.9
0.691
CTCAE
Grade 3/4/5 term
P-value
* 10 cycles = 10 total cycles (4 induction cycles + 6 maintenance cycles)
†
Although incidence of G 3-4 neutropenia higher with long-term use; this did not translate into increased G 3-4
infections.
Grade 1-4 Adverse Events
≥70 Yrs Subgroup
Event (%)
Gr 1
<70 Yrs Subgroup
Gr 2
Gr 3/4
Gr 1
Gr 2
Gr 3/4
pem
plc
pem
plc
pem
plc
pem
plc
pem
plc
pem
plc
Fatigue
8
5
15
5
6
5
9
6
9
5
5
0
Anemia
8
5
10
8
12
0
4
0
10
2
6
0.7
Neutropenia
6
0
8
0
17
0
1
0
3
0.7
4
0
Febrile Neutropenia
0
0
0
0
0
0
0
0
0
0
2
0
Leukopenia
2
0
4
0
4
0
1
0
1
0
2
0
Thrombocytopenia
6
0
0
0
2
0
1
0
0.7
0
2
0
Renal*
4
5
6
0
0
0
3
0.7
4
0.7
1
0
Rash
0
3
0
0
0
0
3
2
0.7
0
0
0
Edema
6
3
4
0
0
0
4
4
4
0
0
0
J Thorac Oncol,
in press
Palliative radiation during pemetrexed plus cisplatin
first-line treatment for advanced non-small cell lung
cancer (NSCLC): Patient safety in the JMDB and
PARAMOUNT trials
1Giorgio
V Scagliotti, 2Cesare Gridelli, 3Filippo de Marinis, 4Bonne Biesma, 5Martin
Reck, 6Belen San Antonio, 7Annamaria Hayden Zimmermann, 8Carla Visseren-Grul,
9Nadia Chouaki, 10Luis Paz-Ares
1University
of Torino, San Luigi Hospital, Orbassano (Torino), Italy; 2San Giuseppe Moscati Hospital, Avellino,
Italy;
Camillo - Forlanini Hospital, Rome, Italy; 4Jeroen Bosch Hospital, Hertogenbosch, Netherlands;
5Hospital Grosshansdorf, Grosshansdorf, Germany; 6Eli Lilly and Company, Madrid, Spain; 7Eli Lilly and
Company, Indianapolis, IN, USA; 8Eli Lilly and Company, Houten, Netherlands; 9Eli Lilly and Company, Paris,
France; 10Seville University Hospital, Seville, Spain
3San
Possibly drug-related adverse events during palliative XRT or within 2
weeks after the end of the last fraction in JMDB and PARAMOUNT (N=65)
Patients Receiving Palliative XRT During Pem/Cis
Treatment (N=65)
Patients with adverse events n=12 (18.5%)
CTCAE
Gr 1, n (%)
Gr 2, n (%)
Gr 3-4, n (%)
1 (1.5)
*4 (6.1)
3 (4.6)
Leukocytes
0
2 (3.1)
0
Platelets
0
1 (1.5)
0
Rash/dermatitis
1 (1.5)
1 (1.5)
0
Rash/desquamation
1 (1.5)
1 (1.5)
0
Radiation dermatitis
0
*1 (1.5)
0
Hematologic
Anemia
Nonhematologic
*In JMDB two patients experienced AEs; 1 Grade 2 (Gr 2) anemia and 1 Gr 2 radiation dermatitis.
*In Paramount 10 patients experienced AEs during the induction phase of treatment
Other events commonly associated with the administration of chemotherapy and XRT, such as lung toxicities
(e.g. pneumonitis) and esophagitis, were not reported.
• Dose range for 12 patients with AEs 8-34 Gy
• Half of patients with adverse events received palliative radiation within 7 days of the
last chemotherapy
• Of the patients with brain metastases (n=5) none reported adverse events related to
palliative XRT