Transcript ADVANCED NSCLC

ADVANCED NSCLC
Special Populations
 PS 2
 Elderly
Corey J. Langer, M.D.
Co-Director, Thoracic Oncology
Fox Chase Cancer Center
Philadelphia, PA 19111
PS 2 and Elderly
NSCLC
• NEGLECTED SUBSETS
• BASIC UNADDRESSED QUESTIONS
• CONSTITUTE > 2/3 OF NEWLY DX’D
ADVANCED NSCLC
IS THERE OPTIMAL TX
FOR THE ELDERLY WITH
ADVANCED NSCLC?
Objectives
• Public Health Perspective
• Cooperative Group Elderly NSCLC
Subanalyses
• Isolating role of Platinum (Carbo)
• Evidence-based literature: ELVIS, SICOG,
MILES, etc.
• Future Directions
The U.S. Population Is Aging
350
300
65 years
65 years
250
200
150
100
20.0%
50
12.7%
8.1%
0
1950
1990
Yancik R, et al. Hematol Oncol Clin North Am. 2000;14:17–23.
2030
Cancer Risk Increases With Age
50
40
Male
Female
33.7
Risk
(%)
30
22.2
20
8.2
10
1.6
9.2
1.9
0
0–39
40–59
Age
American Cancer Society. Cancer Facts & Figures 2000. Atlanta, GA; 2000.
60–79
Incidence of Lung Cancer
Increases With Age
U.S. incidence of lung cancer by age
600
Men
Women
500
Incidence
(per 100,000)
400
300
200
100
0
35
40 45
50 55
60 65
70
Age
Yancik R, et al. Comprehensive Geriatric Oncology. 1998:95–104.
75
80
85+
Elderly Lung Cancer Patients are
Under-Represented on Clinical Trials
• 60% of lung cancer patients are 60
• 35% - 40% of lung cancer patients are 70
• Elderly representation on N.A. Trials
Study
% 70
E5592
15%
S9509/9305
19%
E5594
20%
CALGB 9730
27%
UNC
29%
Explanations for
Under-Representation on Clinical Trials
•
•
•
•
Therapeutic nihilism
Misperception
Societal pressure (UK > EUR > NA)
Increased co-morbidity or “unfitness” (??)
ECOG 5592: Elderly Data
• RANDOMIZATION cDDP 75 mg/m2 &
– Etoposide 100 mg/m2 d 1-3
– Paclitaxel 135 mg/m2/24o d 2
– Paclitaxel 250 mg/m2/24o d 2 + G-CSF
• BREAKDOWN by Elderly ( 70) v “Young” (<70)
– Elderly:  cardiovascular (p=0.0089) + resp (p=0.0441) co-morbidities
Age
N RR(%)
<70
488 21.5
70
86
23.3
P value
0.666
TTP (mo)
4.37
4.30
0.294
MS (mo) 1 YS (%) 2YS (%)
9.05
38
14
8.53
28
12
Log rank 0.2857
–  leukopenia (p=0.0001) and neuropsych tox (0.0025) in  70 yrs
– No difference baseline QoL, TOI, or  over time
• CONCLUSION: PS trumps age; Fit elderly merit/benefit from Tx
...Langer et al., J Natl Cancer Inst. 94(3): 173-181, 2002
Should Older Patients Receive
Combination Chemotherapy For
Advanced Stage Non-Small Cell Lung
Cancer (NSCLC)? An Analysis of
Southwest Oncology Trials 9509 and 9308
Karen Kelly, Sheryl Giarritta, Stephen Hayes,
Wallace Akerley, Paul Hesketh, Antoinette
Wozniak, Kathy Albain, John Crowley,
David R. Gandara
OBJECTIVES
To determine the effect of age > 70 on
survival, toxicity, and drug delivery in
patients with a good performance status
(PS) 0 - 1 receiving combination
chemotherapy for advanced stage NSCLC.
RATIONALE
1.
Adults of advanced age constitute a
growing proportion of patients with
metastatic NSCLC.
2.
Older lung cancer patients often
present with a decreased PS and/or
co-morbidities.
3.
Appropriate treatment options must be
identified for this group of patients.
METHODS
A retrospective analysis was conducted on two
recent SWOG trials in advanced NSCLC:
SWOG 9509
Paclitaxel + Carboplatin
versus
Vinorelbine + Cisplatin
SWOG 9308
Vinorelbine + Cisplatin
versus
Cisplatin
METHODS
1.
The analysis identified two age groups:
patients < 70 years of age and patients
> 70 years of age.
2.
The cohorts were compared for:
a) baseline characteristics
b) efficacy of treatment
c) toxicity
d) drug delivery
RESULTS
Number of Evaluable Patients
by Age and Treatment
Paclitaxel/Carbo
(N = 202)
Vinorelbine/Cis*
(N = 406)
Total
(N = 608)
Age < 70
164 (82%)
327 (81%)
491 (71%)
Age > 70
38 (18%)
79 (19%)
117 (19%)
* Total number of patients from SWOG 9509 and 9308
RESULTS
Patient Characteristics
Variable
Stage IIIB
IV
PS 0
1
Weight loss <5%
5%
Age <70
Age 70
Total
p-value
45 (9%)
446 (91%)
178 (37%)
309 (63%)
261 (55%)
216 (45%)
17 (15%)
100 (85%)
37 (33%)
76 (67%)
63 (56%)
50 (44%)
62 (10%)
542 (90%)
215 (36%)
385 (64%)
324 (55%)
266 (45%)
.08
.45
.84
Patient characteristics were similar between the two
groups except for stage of disease in which there was a
trend toward higher stage in younger patients
RESULTS
Toxicity
Hem Gr 0-2
< 70
(n=490)
119 (24%)
> 70
(n=115)
20 (17%)
Hem Gr 3-5
371 (76%)
95 (83%)
Non-Hem Gr 0-2
225 (46%)
50 (44%)
Non-Hem Gr 3-5
265 (54%)
65 (56%)
Max Tox Gr 0-2
60 (12%)
7 (6%)
Max Tox Gr 3-5
430 (88%)
108 (94%)
* p-value for all grades of toxicities
P-value
.11*
.63*
.06*
RESULTS
Drug Delivery: SWOG 9509, 9305
< 70 (n=475)
> 70 (n=112)
% Planned Dose
57%
54%
P-value
.32
Completed PCb
49/153 (32%)
12/34 (35%)
.35*
Completed VC
32/322 (10%)
3/78 (4%)
Off for toxicity:
PCb
VC
418/165 (11%)
93/325 (29%)
PCb - Paclitaxel + Carboplatin
VC - Vinorelbine + Cisplatin
* p-value for comparison by age
6/37 (16%)
36/78 (46%)
.37
.003
RESULTS: Elderly S9305, 9509
Efficacy
<70
(n=491)
70
(n=117)
p-value
TTP (mo)
4.2
3.9
.62
Median Survival (mo)
8.6
6.9
.06
1 Yr OS
40%
30%
----
2 Yr OS
16%
10%
----
In a multivariate analysis including age, treatment arm, stage, PS and weight
loss, there was no effect of age on PFS (p=.74) or survival (p=.10)
…Kelly et al., ASCO 2001, A-1313
CONCLUSIONS
1.
Relatively few older patients (19%)
entered these cooperative group trials.
2.
There was a trend toward shorter
survival in older patients (p=.06).
3.
Grade 3-5 toxicities occurred more
frequently in older patients (p=.06).
CONCLUSIONS
4.
Fewer patients of any age were able to
complete VC compared to PCb.
5.
A significantly larger number of older
patients discontinued VC due to toxicity
as compared to PCb.
6.
Trials should be specifically designed for
this population.
FUTURE PLANS
SWOG 0027
A phase II trial of vinorelbine followed by
docetaxel in advanced NSCLC patients with a
PS of 2 or Age > 70 years old
Vinorelbine
25 mg/m2, d 1 & 8
every 3 weeks x 3
Docetaxel
35 mg/m2 weekly
3/4 weeks x 3
TAX326: Study Design
: Stratification by
• Stage (IIIB or IV)
• Geographic region
R
A
N
D
O
M
IZ
E
Docetaxel 75 mg/m2 IV +
Cisplatin 75 mg/m2 IV q 3 wk
Docetaxel 75 mg/m2 IV +
Carboplatin AUC 6 IV q 3 wk
Vinorelbine 25 mg/m2 IV d
1, 8, 15, 22 + Cisplatin
100 mg/m2 IV d 1 q 4 wk
Premed: Dexamethasone 8 mg PO bid  6 doses (first dose 12 hours prior to Docetaxel infusion) for
the Docetaxel groups.
Fossella FV. Eur J Cancer 2001;37(suppl 6):S154. (abstr & oral presentation 562)
TAX326
SURVIVAL
All patients
D+CIS VS. V+CIS: Non-inferiority vs improved survival
Cumulative Probability
1.0
0.9
Docetaxel
Cisplatin
0.8
Vinorelbine
Cisplatin
0.7
0.6
P = 0.044
(adjusted log-rank)
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
Survival Time (Mos.)
27
30
33
Tax 326 Elderly Subanalysis
Docetaxel-Cisplatin
All
65
N
408
148
OR%
32
NA
MS (mo)
10.9
12.6
1 yr OS%
38
52
2 yr OS%
21
24
Tax 326 Elderly Subanalysis
Docetaxel-Carboplatin
All
65
N
406
114
OR%
24
NA
MS (mo)
9.1
9.0
1 yr OS%
38
52
2 yr OS%
16
17
Tax 326 Elderly Subanalysis
Vinorelbine-Cisplatin
All
65
N
404
126
OR%
25
NA
MS (mo)
10
10.3
1 yr OS%
42
41
2 yr OS%
14
17
% Grade 3/4 Nonhematologic
Toxicity: Docetaxel/Cisplatin
Age <65
Age 65
No.
287
114
N/V
13
12
Asthenia
11
14
Infection
7
12
Diarrhea
6
8
Neurotoxicity
9
16
% Grade 3/4 Nonhematologic
Toxicity: Docetaxel/Carboplatin
Age <65
Age 65
No.
288
114
N/V
9
3
Asthenia
10
13
Infection
8
18
Diarrhea
6
4
Neurotoxicity
7
11
% Grade 3/4 Nonhematologic
Toxicity: Vinorelbine/Cisplatin
Age <65
Age 65
No.
268
128
N/V
18
26
Asthenia
13
17
Infection
7
10
Diarrhea
3
3
Neurotoxicity
14
16
TAX 326 Elderly Conclusions
• Survival benefit is independent of age
• Modest increase in toxicity in elderly
• Docetaxel/Carboplatin is well tolerated
in elderly NSCLC patients
E1594 Schema
Stratification
Performance status
0-1 vs. 2
Weight loss in
previous 6 months
<5% vs. 5%
Disease stage IIIB
or IV
Presence or absence
of brain metastases
R
A
N
D
O
M
I
Z
E
Arm A: Cisplatin + Paclitaxel
Paclitaxel: 135 mg/m2 over 24 hours, day 1
Cisplatin: 75 mg/m2 day 2
3-week cycle
Arm B: Cisplatin + Gemcitabine
Gemcitabine: 1,000 mg/m2 days 1,8,15
Cisplatin: 100 mg/m2 day 1
4-week cycle
Arm C: Cisplatin + Docetaxel
Docetaxel: 75 mg/m2 day 1
Cisplatin: 75 mg/m2 day 1
3-week cycle
Arm D: Carboplatin + Paclitaxel
Paclitaxel: 225 mg/m2 over 3 hours, day 1
Carboplatin: AUC 6.0 day 1
3-week cycle
0.8
1.0
Survival by Treatment Group
Stage IV
0.0
0.2
0.4
0.6
Cis/Paclitaxel
Cis/Gemcitabine
Cis/Docetaxel
Carbo/Paclitaxel
0
5
10
15
Months
20
25
30
ECOG 1594
• 1207 pts enrolled
• 227 (20%) 70 years; 9 (1%)  80 yrs
• Demographics similar for pts 70 yrs and
<70 yrs
• Septuagenarians: signif more cardiac
(p<0.0001) & other non-cardiorespiratory
co-morbidities (p=0.008, Fisher’s exact
test)
ECOG 1594: Outcome Based on Age
Age Cohort
No.
Completion of 6 cycles
Gr 4 toxicity
Median no. of cycles
OR(%)
PFS (mo) PS 0-1
PFS 1yr (%)
PFS 2yr (%)
MS (mo)
1yr OS(%)
2yr OS(%)
<70 yrs
912
34%
66%
4
22.1
3.71
6.5
0.5
8.15
32.8
10.6
70 yrs
227
30%
71.2%
3
24.5
3.75
8.6
2.2
8.25
35.2
13.7
p value
0.36
0.04
0.24
0.76
0.37
0.04
0.53
0.24
Outcome in Patients
 80 Years of Age: E1594
Age range
No.
Tx completion (6 cycles)
OR (%)
PFS (mo)
MS (mo)
CONCLUSION: Low numbers
preclude broad inferences, but
octogenarians with advanced
NSCLC, even though fit, fared
no better than PS 2 patients.
70-79
215
32.5
21.5
3.7
8.2
80
9
0*
0
2.2
4.2
*Tx completion
1 cycle
2 cycles
3 cycles
4 cycles
p value
0.16
0.16
0.09
No.
2
3
3
1
Elderly Subanalysis:
PCb X 4 vs PCb (indef)
AGE
Gr 2 Toxicity (%)
Neutropenia
Anemia
Thrombocytopenia
Peripheral Neuropathy
Nausea/Vomiting
Myalgia
Fatigue
Outcome
Median Survival (mos)
1-Year Survival (%)
2-Year Survival (%)
<70 (n=163)
 70 (n=67)
38
9
7
13
14
15
8
35
13
9
16
15
9
15
7.8
30
15
7.1
34
9
…Hensing, Socinski et al., Proc ASCO 2001, A-1382
CALGB 9730: CbT v T
R
A
N
D
Carboplatin AUC 6 Q 3 wk
Paclitaxel 225 mg/m2 Q 3 wk
Paclitaxel 225 mg/m2 Q 3 wk
N=584 Tx-naïve advanced NSCLC; accrued 10/97 - 1/01
Well balanced with respect to stage (III vs IV), gender (M v F),
PS (0/1 vs 2)
Demographics: 156 (27%) >70 yrs; 399 M; 100 PS 2
…A-2 ASCO 2002, Lilenbaum
CALGB: Results
• Response rates significantly better for
carboplatin/paclitaxel vs paclitaxel (30% vs 16%,
P<.0001)
• Median survival after 12.5 m follow-up
significantly better for carboplatin/paclitaxel vs
paclitaxel (8.8 m vs 6.7 m, P<.023)
• 1-year survival not significantly different for
carboplatin/paclitaxel (37% vs 33%)
Lilenbaum et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 2
CALGB 9730
Elderly
Overall
N
OR%
FFP (m)
MST (m)*
1 yr OS%
*p=0.1014
P
287
17
2.5
6.7
33
PCb
284
29
4.6
8.8
37
P
98
21
NA
5.8
31
Cb
77
36
NA
8.01
35
Role of Schedule
Paclitaxel-Carbo (RP2)
R
A
N
D
Arm 1) PACLITAXEL 100 mg/m2 Q wk X 3 Q 4 wk
CARBOPLATIN AUC 6 Q 4 wk
Arm 2) PACLITAXEL 100 mg/m2 Q wk X 3 Q 4 wk
CARBOPLATIN AUC 2 Q wk X 3 Q 4 wk
Arm 3) PACLITAXEL 150 mg/m2 Q wk X 6 Q 8 wk
Arm 2
CARBOPLATIN AUC 2 Q wk X 6 Q 8 wk
…Belani, ASCO 2001, A1287
Response Rates at 8 Week Follow-up
Arm 1
Arm 2
Arm 3
Week 8 CR-PR (%)
35
38
31
Week 16 CR-PR (%)
32
24
18
Median survival (wks)
49
30
40
Conclusion
• Arm 1: best Tx index
• Best survival with lowest inc. of FN; gr 3
neuropathy; N/V; fewest dose reductions
Phase III Scheduling Trial
R
A
N
D
Carbo AUC 6 Q 4 wk
Paclitaxel 100 mg/m2 d1, 8, 15 Q 4 wk
Carbo AUC 6 Q 3 wk
Paclitaxel 225 mg/m2 Q 3 wk
PI:
C. Belani
NON-PLATINUM TX
IN ELDERLY WITH NSCLC
Randomized Trials in Elderly NSCLC
Trial
Group
Comment
V vs BSC
ELVIS
Completed
GV vs V
SICOG
Completed
G vs V vs GV
ITA-MILES
Completed
ELVIS Trial
• E.L.V.I.S.: Elderly Lung Vinorelbine Italian Study
• Eligibility: St IIIB/IV NSCLC: PS 0-2
• Outcome clearly favored vinorelbine
Arm
N OR(%) MS(mo) 1y OS%
VNR
78
20
6.5
32%
BSC
76
4.9
14%
• Statistically significant QoL benefit for patients
receiving VNR
…Gridelli, JCNI 1999; 85: 365-376
Navelbine in the Elderly: Summary
• E.L.V.I.S.: first Phase III trial demonstrating a
survival advantage for single-agent
chemotherapy vs BSC
• Navelbine is generally well tolerated in the
elderly patient
– Age does not appear to change or increase
toxicity
– Greater sensitivity of some older individuals
cannot be ruled out
Gemcitabine in Advanced NSCLC
• Phase II trials
– RR 21% - 26%
– Median survival 7 - 12.3 months
– One-year survival of 30% - 50%
• Phase III trials
– Gemcitabine 1000 mg/m2 weekly in symptomatic
patients vs BSC
– Improvement in symptom control 93% vs 67%
• Toxicities are mainly myelosuppression and
fatigue
Rationale for Combining
Gemcitabine and Vinorelbine in NSCLC
• Both drugs have activity in NSCLC
• Nonoverlapping toxicities except
myelosuppression
• Outpatient schedule
• Both drugs well tolerated by elderly
Gemcitabine Plus Vinorelbine vs Vinorelbine
Alone in Patients with NSCLC: SICOG Study
• Patients with Stage IIIB/IV NSCLC
• Age  70 years at diagnosis
• Randomized to:
– Vinorelbine 30 mg/m2 d1, 8 q 3 weeks
vs.
– Vinorelbine 30 mg/m2 d 1, 8
– Gemcitabine 1250 mg/m2 d 1, d 8
administered q 3 weeks
Gemcitabine Plus Vinorelbine vs Vinorelbine
Alone in Patients with NSCLC: SICOG Study
GV
V
76
76
Stage IV
60%
60%
PS 0-1
73%
78%
OR
22%
15%
SD
27%
12%
29 wks
18 wks
30%
13%*
N
MST
1-yr survival
*P<.01
Chemotherapy in Elderly Patients with
Advanced NSCLC
Author
Regimen
N
Response
MS (mo)
1 YR
Vinorelbine
78
20%
6.5
32%*
BSC
76
---
4.9
14%
76
22%
7
30%*
76
15%
4.5
13%
Gridelli*
Frasci‡
Gemcitabine +
Vinorelbine
Vinorelbine
*
p<0.05
*Gridelli, J Natl Cancer Inst 1999; 85:365-376.
‡Frasci et al, Proc ASCO 2001, 19:A1895
The MILES Phase III Trial: Gemcitabine + Vinorelbine
vs Vinorelbine and vs Gemcitabine in Elderly
Advanced NSCLC Patients
Gridelli et al Multicenter Italian Lung Cancer in the Elderly Study
NSCLC
70+ years old
Chemotherapy naïve
Stage IIIB
(N3 or pleural effusion)
or IV
PS 0-2
R
A
N
D
O
M
IZ
E
Vinorelbine 30 mg/m2 d1,8
Q 3 weeks
Gemcitabine 1200 mg/m2 d1,8
Q 3 weeks
Gemcitabine 1000 mg/m2 d1,8
Vinorelbine 25 mg/m2 d1,8
Q 3 weeks
ASCO 2001 Abstract 1230
MILES STUDY: ELDERLY NSCLC
VNR
GEM
VNR/GEM
# Patients (n)
233
233
232
Stage IIIB (%)
29
30
31
18.5
17.3
20
TTP (wk)
18
18
19
Median Survival
(mo)
8.8
6.6
7.6
1 year Survival (%)
41%
26%
31%
Response Rate (%)
…Gridelli et al., ASCO 2001, A-1230
Baseline Quality of Life and Survival
Prediction in NSCLC Elderly
• Patients enrolled in MILES study
• Assessment at baseline
– Activities of daily living (ADL)
– Instrumental ADL
– EORTC C30 global (items 29-30)
• Analysis using multivariate Cox model
• Data on 81% (566/698) of patients
Perrone et al. Proc Am Soc Clin Oncol 2002;21. Abstract 1346
Baseline Quality of Life and IADL Predicted
Survival in NSCLC Elderly: Results
Score
IADL
100%
51-99%
50%
QOL
>67%
42-67%
<42%
Median Survival, weeks (95% CI)
43 (34-49)
32 (26-43)
21 (17-27)
53 (46-76)
30 (26-34)
20 (16-28)
Perrone et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346
Baseline Quality of Life and Survival
Prediction in NSCLC Elderly: Results
• ADL has no prognostic value
• IADL and QoL have prognostic value
– Independently: IADL P=.0006, QoL P<.0001
– Together IADL P=.051, QoL P<.0006
Perrone et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346
MILES Trial - Conclusions
• Polychemotherapy with gemcitabine +
vinorelbine does not improve outcomes
compared to single-agent vinorelbine or
gemcitabine
• Single-agent chemotherapy should remain
a standard for advanced NSCLC elderly
patients
• Baseline QoL predictive of outcome,
though no difference observed in Qol or
IADL between each arm
ASCO 2001 Abstract 1230 ORAL PRESENTATION
Chemotherapy in
Elderly Patients with Advanced NSCLC
Author
Regimen
Vinorelbine
BSC
N
78
76
Response
20%
--
MS (mo)
6.5
4.9
1 YR
32%*
14%
Frasci‡
Gemcitabine +
Vinorelbine
Vinorelbine
76
76
22%
15%
7
4.5
30%*
13%
Gridelli
Vinorelbine
233
Gemcitabine
233
Gemcitabine +
Vinorelbine 237
18.4%
17.3%
8.8
6.6
41%
26%
20%
7.6
31%
Gridelli*
*
p<0.05
*Gridelli, J Natl Cancer Inst 1999; 85:365-376.
‡Frasci et al, Proc ASCO 2000, 19:A1895
 Gridelli, Proc ASCO 2001, 20: A-1230
Phase II/III Trials in the Elderly
Trial
Group
Comment
Oral Vinorelbine (V)
NCCTG
Open
VX3  DX3
SWOG
Closed (?)
DG v D
SCCC
Open
V - vinorelbine, D - docetaxel, G - gemcitabine
Elderly: Adv NSCLC
Outstanding Issues
• No elderly-specific phase III trial (yet)
comparing single agent(s) +/- platinum
• Comprehensive analysis of co-morbidities
and their influence on toxicity, Tx tolerance,
QoL and survival (CRASH score)
• Sparse data for pts  80 yrs
Main Domains of Multidimensional
Assessment in Elderly Cancer Patients
Domains
Measuring Tool
Comorbidity
Charlson comorbidity scale
CIRS-G
Functional Status
ADL
IADL
Depressive symptoms
Mental Status
Nutritional State
GDS
MMSE
Mini nutritional assessment
CIRS-G, cumulative illness rating scale-geriatric; ADL, activities of Daily living; IADL,
instrumental activities of daily living; GDS, geriatric Depression scale; MMSE, mini
mental state examination
Study Concepts: Elderly NSCLC
• MONOTHERAPY VS PLATINUM
COMBINATIONS: e.g.,
– gemcitabine +/- cisplatin or carboplatin
– vinorelbine or gemcitabine +/- oxaliplatin
• COMBINATION CHEMO & TARGETED TX: e.g.,
vinorelbine +/- OSI-774 or other EGFr inhibitor
• MONOTHERAPY COMPARISONS: e.g., weekly
vinorelbine vs weekly paclitaxel or docetaxel
• NESTED PHARMACOKINETIC ANALYSES
Randomized Trials with
CT+/- Targeted Therapies
TRIAL
ZD1839
TARGET
EGFR
CT
GC
GROUP
AstraZeneca
COMMENT
Closed, no benefit
ZD1839
OSI 774
EGFR
EGFR
TCb
TCb
AstraZeneca
Genentech/OSI
Closed, no benefit
Closed
ABXEGFR
EGFR
TCb
Immunex
Proposed
Herceptin
Her-2/neu
TCb
ECOG
Proposed
AG3340
AG3340
MMP
MMP
TCb
GC
Agouron
Agouron
Closed no benefit
Closed no benefit
BMS275291
TNP-470
MMP
Angiogenesis
TCb
TCb
BMSO
MDACC
Closed
Proposed (or ditched)
rhuMabVEGF
ISIS3521
Angiogenesis
PKC
TCb
TCb
ECOG
ISIS
Open
Closed, no benefit
Deltaparin
Metastases
Std
NCCTG
Open
PS 2 NSCLC
What are the data?
Impact of PS on Outcome
ECOG 1581
Performance
Status
Objective
Median
Response (%) Survival (wks)
Toxic
Deaths (%)
0
26
36
3
1
25
26
2
2
-
10
10
ECOG
Recursive Partitioning Analysis Terminal Nodes
Median Survival Months
Appetite
Intact (N)
Diminished (N)
Jiroutek et al.
PS-0
Female
Male
12.58 (111)
9.86 (219)
8.54 (15)
6.74 (50)
PS-1
Female
Male
7.77 (214)
6.70 (421)
6.95 (102)
5.08 (224)
PS-2
Female
Male
5.31 (24)
4.30 (64)
2.30 (27)
3.43 (100)
GEPC/98-02: Outcomes
Arm
CG
CGV
OR(%)
43
38
26*
PS 0-1
9.11
TTP (wk)
25
21
22
PS 2
4.79
MST (m)
8.7
7.9
8.1
ST IIIB
9.4
1y OS (%)
35
31
35
ST IV
8.1
*CG
GVIV Subgroups (MST)
v GVIV (p=0.0003); CGV v GVIV (p=0.01)
…Alberola, ASCO 2001, A-1229
EORTC: TP v GP v TG
Outcome Measures
T+P
G+P
T+G
OR%
31
36
27
PFS (m)
4.4
5.6
3.9
MST (m)
8.1
8.8
6.9
1 yr OS (%)
36
33
27
(0.08)
(.09)
…Van Meerbeeck et al. (EORTC), ASCO 20001, A-1228
EORTC: TP v GP v TG
Subgroups: Median Survival
STAGE
MST (m)
IIIB
9.5
IV
7.5
0-1
8.6
2
3.3
PS
p <0.0001
HeCOG Trials: Outcome based on PS
Tax (175 vs 225)
TTP (mo)
MS (mo)
1 y OS %
PS 0-1
6.3
11.25
N/A
PS 2
2.4
3.8
N /A
PCb vs PG
TTP (mo)
MS (mo)
1 y OS %
PS 0-1
6.6
11.1
44.4
PS 2
3.8
5.9
20
Impact of PS on Toxicity in Elderly pts
ELVIS Trial
Performance
Status
Patients
Grade 4
Neutropenia (%)
Grade 3/4
Constipation (%)
0-1
53
3 (5.7)
4 (7.5)
2
18
0
0
Perrone F. Personal Communication to P. Hesketh
Impact of PS on Outcome
ELVIS Trial
Patients
Response (%)
MS (wks)*
BSC
78
-
21
V
76
19.7
28
BSC
19
-
8
V
18
0.0
26
Group
Overall
PS 2
*P=0.03
Perrone F. Personal Communication to P. Hesketh
E1594 Schema
Stratification
Performance status
0-1 vs. 2
Weight loss in
previous 6 months
<5% vs. 5%
Disease stage IIIB
or IV
Presence or absence
of brain metastases
R
A
N
D
O
M
I
Z
E
Arm A: Cisplatin + Paclitaxel
Paclitaxel: 135 mg/m2 over 24 hours, day 1
Cisplatin: 75 mg/m2 day 2
3-week cycle
Arm B: Cisplatin + Gemcitabine
Gemcitabine: 1,000 mg/m2 days 1,8,15
Cisplatin: 100 mg/m2 day 1
4-week cycle
Arm C: Cisplatin + Docetaxel
Docetaxel: 75 mg/m2 day 1
Cisplatin: 75 mg/m2 day 1
3-week cycle
Arm D: Carboplatin + Paclitaxel
Paclitaxel: 225 mg/m2 over 3 hours, day 1
Carboplatin: AUC 6.0 day 1
3-week cycle
0.8
1.0
Survival by Treatment Group
Stage IV
0.0
0.2
0.4
0.6
Cis/Paclitaxel
Cis/Gemcitabine
Cis/Docetaxel
Carbo/Paclitaxel
0
5
10
15
Months
20
25
30
0.8
1.0
Survival by Treatment Group
Stage IIIB
0.0
0.2
0.4
0.6
Cis/Paclitaxel
Cis/Gemcitabine
Cis/Docetaxel
Carbo/Paclitaxel
0
5
10
15
Months
20
25
30
ECOG 1594: PS 2 Subanalysis
CONCLUSIONS
• 68 of 1207 pts enrolled had PS 2
• Accrual suspended b/o untoward inc. of Gr 4/5 AEs
• Overall toxicity rate, however, did not differ
significantly from that observed in PS 0-1 pts
• 5 deaths (7.35% Grade 5 AE), but only two were
directly attributable to Tx
• Med survival of 4.1 mo and 1-yr survival rate 19.1%
likely 2o to disease process rather than toxicity
….Sweeney et al Cancer 2001, 92:2639-47
ECOG 1594: PS 2 Subanalysis
% G3 Heme Tox (n=64)
PC
GC
DC
PCb
N
18
13
18
15
ANC
60
58
59
47
PLT
0
50
0
7
H/H
25
33
6
20
NF
5
0
12*
0
*1
gr 5
….Sweeney et al cancer 2001, 92:2639-47
ECOG 1594: PS 2 Subanalysis
% Gr3 Non-Heme Tox (n=64)
PC
GC
DC
PCb
Renal
6
24*
0
0
N/V
40
42
41
0
Diarrhea
5
8
18
0
Neuropathy
15
13
18
20
Allergy
6
0
12
0
Grade 5
0
8
6
0
*One Gr
5 toxicity
….Sweeney et al Cancer 2001, 92:2639-47
ECOG 1594: PS 2 Subanalysis
OUTCOME
PC
GC
DC
PCb
Overall
Total
21
13
19
15
68
Evaluable
18
13
18
15
64
OR(%)
17
23
6
13
14
TTP (mo)
1.4
4.6
1.4
1.5
1.7
MST (mo)
7.0
7.9
2.3
4.6
4.1
1yr OS(%)
19
38.5
10.5
13.3
19.1
….Sweeney et al Cancer 2001, 92:2639-47
ECOG 1599
RP2: CbT or GC in PS 2 Adv NSCLC
R
A
CARBOPLATIN AUC 6 Q 3 wk
PACLITAXEL
200 mg/m2 Q 3 wk
N
D
GEMCITABINE
CISPLATIN
1gm/m2 d1, 8 Q 3 wk
60 mg/m2 Q 3 wk
E1599: RP2 Adv NSCLC:
Status Update 8/18/01
• Activated 5/31/00
• Suspended 5/8/01 for interim toxicity analysis (n=47)
CbT
GC
No. Evaluable (to date)
32
30
% Gr  3(4) Toxicity
ANC
44(28)
40(13)
Plt
9(0)
37(7)
H/H
9
13
N/V
6(0)
23(0)
PNS
13
0
Worst
75(29)
80(28)
• Reopened 1/02; 103 accrued as of 11/15/02
• 2 grade 5 toxicities to date (CbT)
Randomized HeCOG Phase II Trial PS 2 NSCLC
R
A
N
D
O
M
I
Z
E
Gemcitabine 1250 mg/m2 d 1 +15
Carboplatin AUC 3 d 1+ 15
Gemcitabine 1250 mg/ms2 d 1+ 15
100 pts targeted; 4 cycles of Tx projected
Endpoint: clinical benefit
CALGB 9730
• Single agent Paclitaxel vs. combination
chemotherapy Paclitaxel/Carboplatin in
advanced NSCLC
• Select eligibility criteria:
–
–
–
–
–
Stage IIIB/IV NSCLC
Chemotherapy naïve
Performance status 0-2
No CNS disease
Measurable or evaluable disease
CALGB: Subanalysis
Elderly
PS 2
P
CbP
P
CbP
All
N
78
77
50
49
99
OR (%)
21
36
10
24
17
MST (mo)
5.8
8.0
2.4
4.7
3.1
1yr OS%*
31
35*
10
18
14
2y OS%
NA
NA
0
9
5
*Wilcoxon=0.1014
log rank p=0.0123
ss (<0.0001) vs PS 0-1
Conclusion: PS 2 may benefit from combination, carboplatin-based tx
… Lillenbaum et al ASCO 2002, A-2;21
PS 2 NSCLC: Treatment Efficacy
Trial
 ECOG
 HeCOG
 HeCOG
 CALGB
PCb
P
RR (%)
14
-11
24
10
TTP (mo)
1.7
2.4
3.8
---
MS (m)
4.1
3.8
5.9
4.7
2.4
1y OS%
19.1
-20.9
18
10
Alternative Approach for
PS 2 Patients with Advanced NSCLC
• Use “new” active single agents
• Use schedules with demonstrated favorable
toxicity profiles
• Use agents sequentially
• Avoid cisplatin (off study) although carboplatin
combinations appear reasonable
• Consider formal phase III study evaluating new
agent +/- carbo or new agent +/- targeted Tx
• Integrate quality of life into any future efforts
Elderly vs “Poor Risk”
Patients with Advanced NSCLC
• “Healthy” elderly fare as well as younger
patients with standard chemotherapy
approaches
• “Poor risk” patients (PS2 ± low albumin ±
weight loss) fare poorly
• Tolerability and potential benefits of
chemotherapy in “poor risk” patients remain to
be determined