Transcript Cancer and Leukemia Group B 9730

FIRST-LINE THERAPY FOR ADVANCED
NSCLC
Rogerio C. Lilenbaum, MD
Clinical Associate Professor of Medicine
University of Miami School of Medicine
Director, Thoracic Oncology Program
The Mount Sinai Comprehensive Cancer Center
Miami Beach, FL
QUESTIONS FOR DISCUSSION
• What are the options for 1st line
therapy?
• What is the optimal management of
the elderly and the PS 2 patients?
• What is the role of the non-platinum
regimens?
• What is the role of the molecular
targeted agents in 1st line therapy?
Survival Probability
Cis/Vin and Cis/Gem vs. Cisplatin :
Overall Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
Cis/Gem vs Cisplatin
Cis/Vin vs Cisplatin
100%
80%
60%
40%
20%
P=.004
5
Gem/Cis
Cis
10
N
260
262
15
20
MS
9.0
7.6
J Clin Oncol 2000, 18:122-30.
25
1YS
39%
28%
0%
0
2YS
15%
8%
12
Vin/Cis
Cis
24
36
48
N MS 1YS 2YS
206 8 36% 12%
209 6 21%
7%
J Clin Oncol 1998, 16:2459-64.
60
Cis-Vinorelbine vs Carbo-Paclitaxel
SWOG 9509
Median
Survival
Survival
N Deaths (Months) 1-Year 2-Year
1CBDCA+Pac 208
159
8
38%
15%
CDDP+Vin 202
156
8
36%
16%
100%
80%
60%
40%
20%
0%
0
6
12
18
Months
24
1J
30
Clin Oncol. 2001;19:3210-3218.
A Phase III Four-Arm Trial in Advanced NSCLC
Stratification
PS 0-2
WT Loss
Stage - IIIB, IV
Brain mets (+/-)
R
A
N
D
O
M
I
Z
E
D
Schiller, NEJM 2002:92-98
Paclitaxel 135 mg/m2 over 24
hours, day 1
Cisplatin 75 mg/m2, day 2
Gemcitabine 1000 mg/m2 days 1,
8, and 15
Cisplatin 100 mg/m2 day 1
Docetaxel 75 mg/m2 day 1
Cisplatin 75 md/m2 day 1
Paclitaxel 225 mg/m2 over 3
hours, day 1
Carboplatin AUC=6 day 1
A Phase III Four-Arm Trial in Advanced NSCLC
Regimen
RR
(%)
MST
(mo.)
TTP
(mo.)
1-yr
Survival
(%)
Cis/Paclitaxel
21.3
7.8
3.5
31
Cis/Gemcitabine
21.0
8.1
4.5*
36
Cis/Docetaxel
17.3
7.4
3.6
31
Carbo/Paclitaxel
15.3
8.2
3.3
35
*P = .002 by log rank test
A Phase III Four-Arm Trial in Advanced NSCLC
CIS-PAC
CIS-GEM CIS-DOC CARBOPAC
N = 282
N = 273
N = 278
N = 272
GR 4 ANC
55
37
49
42
Gr 4 thrombocytopenia
2
26*
1
2
Gr 3 nausea
25
36
23
8*
Gr 3 neuropathy
4
8
5
8
Gr 3-4 febrile neutropenia
16
4*
10
3*
Gr 3-5 renal
3
9*
3
1
Worst Gr 4-5
89
70
86
57*
*P < 0.05 vs. Arm A
Tax 326: Randomized Phase III Trial
for Advanced NSCLC
Stratification Factors:
Stage of Disease
IIIB vs. IV
Region
US/Canada
Latin America
Europe/Lebanon
Israel
South Africa/Australia
New Zealand
R
A
N
D
O
M
I
Z
E
Docetaxel 75mg/m2 IV
Cisplatin 75mg/m2 IV Q 3 wks
Docetaxel 75mg/m2 IV
Carboplatin AUC 6 IV Q 3 wks
vs.
Vinorelbine 25mg/m2 IV D 1, 8, 15 & 22
Cisplatin 100mg/m2 IV D 1Q 4 wks
Response assessment every 2 cycles
Tax 326: Randomized Phase III Trial
for Advanced NSCLC
Docetaxel/
Cisplatin
Navelbine/
Cisplatin
Docetaxel/
Carboplatin
N
406
396
401
Median survival (mo)
10.9
10.0
9.1
1-Yr survival (%)
46
41
38
2-Yr survival (%)
21
14
16
Cis/Tax vs. Cis/Nav
Carbo/Tax vs Cis/Nav
P=.044, Adjusted Log-Rank
P=.66, Adjusted Log-Rank
2y Survival 21 vs 14%, p=.035
2 y Survival 18 vs 14%
Belani et al. 2001
ASCO 2002
Clinical Trials of 2-Drugs vs 1
Study
Therapy
MST
1-Yr Surv
CALGB1
Paclitaxel
P + Carbo
6.7 m
8.8 m
33%
37%
SLUSG2
Gemcitabine
G + Carbo
9.0 m
11.0 m
32%
44%
GCGLC3
Docetaxel
D + Cispl
8.0 m
10.1 m
42%
48%
1Proc ASCO
21:1a (A #2), 2002; 2Proc ASCO 21:291a (A #1162), 2002; 3Proc ASCO 21:291a (A #1163), 2002
CALGB 9730 - DESIGN
IIIB/IV
PS 0-1/2
Age / 70
R
A
N
D
O
M
I
Z
E
Paclitaxel 225 mg/m2
over 3 hours on day 1
Paclitaxel 225 mg/m2
+ Carboplatin to AUC 6
Every 3 weeks for up to 6 cycles
Lilenbaum, ASCO 2002
CALGB 9730 – SURVIVAL
FFS (mo)
(95% CI)
MST (mo)
(95% CI)
1-Y SURV
(95% CI)
P = 277
CP = 284
2.5
4.6
(2.3 , 2.8)
(4.1 , 5.3)
6.7
8.8
(5.8 , 7.9)
(8.8 , 9.9)
33%
37%
(28% , 39%)
(32% , 43%)
Median follow-up was 19.7 months
1.0
CALGB 9730 – OVERALL SURVIVAL
0.6
Log-rank = 0.2022
0.2
0.4
Wilcoxon = 0.0125
0.0
Probability
0.8
Paclitaxel
Paclitaxel and Carboplatin
0
10
20
30
Months
40
Gemcitabine/Carboplatin versus MIC
Gemcitabine 1200
mg/m2d 1, 8
Carboplatin AUC =
5 d 1 q.21 days
Stage IIIb/IV NSCLC
PS 0-3
Mitomycin 6 mg/m2
Ifosfamide 3 g/m2
Cisplatin 50 mg/m2
Day1 q.21 days
Rudd, ASCO 2002:A1164
LLCG: GC vs MIP in Advanced NSCLC
Survival
Proportion Surviving Pts.
1
.8
Med
10.2m
6 .9m
GC
MIP
.6
1-Y
38%
28%
GC
.4
MIP
.2
0
0
3
6
9
12
15 18 21
Months
24
27
30
33
36
What are the options for 1st line therapy?
CISPLATIN
CARBOPLATIN
+
PACLITAXEL
DOCETAXEL
VINORELBINE
GEMCITABINE
• Patients with advanced NSCLC and good PS
should be treated with a platinum-based doublet.
• Platinum-based doublets are better than an old
single agent (Cis) and a new single agent (Paclit)
• All platinum-based doublets have comparable
efficacy, but vary in cost and toxicity
• Three-drug regimens are more toxic and no better
than doublets
• The preferred platinum analog remains
controversial
QUESTIONS FOR DISCUSSION
• What are the options for 1st line
therapy?
• What is the optimal management of
the elderly and the PS 2 patients?
• What is the role of the non-platinum
regimens?
• What is the role of the molecular
targeted agents in 1st line therapy?
Non-Platinum Regimens
• Deliver comparable survival with less
toxicity
better therapeutic index
• Represent alternative regimens to patients
who are not optimal candidates for
platinum-based therapy
Non-Platinum, Taxane-Based Doublets
•
•
•
•
Paclitaxel + gemcitabine
Docetaxel + gemcitabine
Paclitaxel + vinorelbine
Docetaxel + vinorelbine
Non-Platinum, Non-Taxane Doublets
• Vinorelbine + Gemcitabine
• Gemcitabine + Irinotecan
• Vinorelbine + Ifosfamide
A EORTC Randomized Phase III Trial of Three
Chemotherapy Regimens In Advanced Non-Small Cell
Lung Cancer
NSCLC
PS 0-2
Stage
IIIB
or IV
R
A
N
D
O
M
I
Z
E
D
Paclitaxel 175 mg/m2 d 1
Cisplatin 80 mg/m2 d 1
every 21 days
Gemcitabine 1250 mg/m2 d 1, 8
Cisplatin 80 mg/m2 d 1
every 21 days
Gemcitabine 1250 mg/m2 d 1, 8
Paclitaxel 175 mg/m2 d 1
every 21 days
Van Meerbeeck et al, Proc Am Soc Clin Oncol, 20: #1228, 2001
Van Meerbeeck - Efficacy
Response
Rate
PFS
Median
Survival
1-year
Survival
Cis/Pac
Cis/Gem
Pac/Gem
31%
36%
27%
4.4 mo
5.6 mo
3.9 mo
8.1 mo
8.8 mo
6.9 mo
35.5%
32.6%
26.5%
Van Meerbeeck - Toxicity
Toxicity (% of pts)
Cis/Pac
Cis/Gem
Pac/Gem
Gr. 3/4 ANC
33
43
30
Neutropenic Fever
1
3
2
Gr. 3/4 Thrombocytopenia
1
36
6
Gr. 3/4 Bleeding
1
0
1
Gr. 3/4 Anemia
3
11
4
Gr. 3/4 Nausea
8
13
6
Gr. 3/4 Vomiting
8
13
5
Gr. 3/4 Sensory
Neurotoxicity
3
2
1
Gr. 3/4 Motor Neuropathy
3
1
3
Gr. 3/4 Lethargy
9
11
11
Gr. 3/4 Dyspnea
8
10
12
Toxic deaths
3
1
4
GEMVIN – Study design
Cisplatin
Vinorelbine
80 mg/ /m², d 1
30 mg/m², d 1&8
or (at random)
RANDOM
Cisplatin
80 mg/ /m², d 1
Gemcitabine 1200 mg/m², d
1&8
Gemcitabine
Vinorelbine
Gridelli, ASCO 2002
1000 mg/m², d 1&8
25 mg/m², dd 1&8
Every 3 weeks, for a maximum of 6 cycles
GEMVIN – Progression-free survival
CDDP-based
(n=250)
GemVin
(n=251)
212 (85)
222 (88)
23 (18-27)
17 (14-20)
6 – month PFS
probability
0.44
0.26
1 – year PFS probability
0.13
0.09
# events (%)
Median PFS (95% CI)
(wks)
GemVin vs CDDP-based
1.29 (1.10-1.52)* p=0.004
GEMVIN – Overall survival
CDDP-bsed
(n=250)
GemVin
(n=251)
175 (70)
180 (72)
38 (35-45)
32 (30-39)
6 – month OAS probability
0.66
0.62
1 – year OAS probability
0.37
0.31
# events (%)
Median OAS (95% CI)
(wks)
GemVin vs CDDP-based
1.15 (0.96-1.37)*
p=0.08
Phase II Study of Vinorelbine-Gemcitabine
vs Paclitaxel-Carboplatin
Stratification
• Stage IIIB/IV
• PS 0−1/2
Primary endpoint:
QoL analysis (LCSS)
R
A
N
D
O
M
IZ
A
T
I
O
N
Vinorelbine 25 mg/m2 days 1, 8
Gemcitabine 1,000 mg/m2 days 1, 8
Paclitaxel 200 mg/m2 day1
Carboplatin (AUC=6) day 1
Every 3 weeks, for a maximum of 6 Cycles
What is the role of the non-platinum
regimens?
• Taxane-based regimens appear to offer
comparable efficacy to platinum-based
combinations
• Toxicity, however, is not significantly reduced and
ca be substantial, especially in patients with less
than optimal performance status
• The non-platinum, non-taxane based regimens
are less toxic, but questions about equivalent
efficacy remain. They are a viable option for
patients unable to tolerate platinum-based
therapy
QUESTIONS FOR DISCUSSION
• What are the options for 1st line
therapy?
• What is the optimal management of
the elderly and the PS 2 patients?
• What is the role of the non-platinum
regimens?
• What is the role of the molecular
targeted agents in 1st line therapy?
Biological Agents for Solid Tumors
Signal Transduction/Cell-Cycle
Inhibitors
–
–
–
–
Farnesyl transferase
Flavopiridol
Retinoids
UCN-101
Gene Therapy
–
–
–
GM-CSF
Wild-type p53
Antisense
– c-myc
– PKC
Vaccines
–
–
–
–
Angiogenesis Inhibitors
–
–
–
–
–
–
–
–
SU5416/SU6668
Anti-VEGF antibodies
Interferon-a/b
Marimastat
ZD6474
LY317615
TNP-470
Endostatin/angiostatin
Receptor-Targeted Therapy
Tumor cells
Peptides
Dendritic cells
Viral vaccines
–
–
Trastuzumab
Anti-EGFR
– ZD1839
– C225
– OSI-774
ZD1839 Randomized Trials With
Chemotherapy in Advanced NSCLC
Chemotherapy *
x6 cycles
Randomize
Chemotherapy *
+ 500 mg ZD1839
x6 cycles
Chemotherapy *
x6 cycles
Stage III/IV NSCLC
+ 250 mg ZD1839
Continue
ZD1839 or
placebo until
disease
progression
+ Placebo
N=1029/Trial
*Gemcitabine/cisplatin (trial 14)
*Paclitaxel/carboplatin (trial 17)
Primary endpoint: Survival
Bevacizumab (rhuMAb-VEGF) in NSCLC:
ECOG4599 Schema
Eligibility:
• No prior Rx
• Stage IIIB or
IV
• Non-SqCCa
• ECOG PS 0-1
R
A
N
D
O
M
I
Z
E
CBDCA: AUC = 6
Paclitaxel: 200 mg/m2
CBDCA: AUC = 6
Paclitaxel: 200 mg/m2
rhuMAb-VEGF: 15
mg/kg
Upon PD crosssover to Anti-VEGF NOT ALLOWED
The Affinitac Phase III Trial
Eligible patients
randomized to:
ARM A
Day 0: Paclitaxel 175 mg/m2
Carboplatin AUC 6
21-day cycle
Stratified for:
Stage
History of CNS
Disease
ARM B
Days 0-14: ISIS 3521, CIV
Day 3: Paclitaxel 175mg/m2
Carboplatin AUC 6
Days 15-21: Rest
Restaging for response every 2 cycles
Treatment continues up to 6 cycles
(more if patient is benefiting)
Post-Treatment follow-up
• Survival
• Tumor progression
Sample
size = 600
What is the role of the molecular
targeted agents in 1st line therapy?