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Management of Special Populations with
Advanced NSCLC:
Women
The Elderly (age > 70) and
PS 2 Patients
Corey J Langer MD, FACP Professor of Medicine
Director of Thoracic Oncology University of Pennsylvania
Management of Special Populations with
Advanced NSCLC:
Women [with apologies]
The Elderly (age > 70) and
PS 2 Patients
Corey J Langer MD, FACP Professor of Medicine
Director of Thoracic Oncology University of Pennsylvania
Incidence of NSCLC in the US
by age at diagnosis
0
5000
10,000
15,000
20,000
25,000
30,000
35,000
<50 50-54 55-59 60-64 65-69 70-74 75-79 80-84 >84
Median age
at diagnosis: 71
Age at diagnosis (y)
No
. o
f p
atie
nts
Data from SEER Cancer Statistics Review, 1975-2001.
Demographics of Lung Cancer in
the Older Patient
Individuals > age 65: fastest growing segment of U.S. population
More than 2/3 of patients with adv. lung cancer older than 65*
Median age of diagnosis for lung cancer in the U.S. is 70*
35% of lung cancer patients > 75*
Likelihood of receiving treatment decreases with advancing age
Clinical trial participation also decreases with advancing age – Analysis of SWOG trials 1993 – 1996 (Hutchins NEJM 341:2061,1999)
39% of patients on lung trials > 65 vs. 66% of general population > 65
– NCI analysis 1997 – 2000 (Lewis J Clin Oncol 21:1383, 2003) 42% of patients on lung trials > 65 vs. 70% of general population > 65
*SEER Data 2000 - 2003
Elderly Patients - Representation
in Clinical Trials
65% of lung cancer patients are 65
50% of lung cancer patients are 70
Elderly representation on US NSCLC Trials
Study % 70 E5592 15%
S9509/9305 19%
E1594 20%
E4599 25%
CALGB 9730 27%
Unique Issues in the Elderly
Physiologic Compromise
– Declining renal and marrow function
– Cardiac risk
Co-Morbidities and (I)ADL
Polypharmacy: potentially increasing risk of
adverse reactions
Exaggerated Influence of PS and advancing age
Impaired social, emotional and financial resources
Prospective Phase III Chemotherapy
Trials in Elderly Patients with
Advanced NSCLC ELVIS (1999) (154 pts) – vinorelbine vs. BSC: improved survival and QOL with vinorelbine
SIOG (2000) (120 pts) – vinorelbine vs. vinorelbine + gemcitabine: improved survival and
enhanced toxicity with the combination
MILES (2003) (698 pts) – vinorelbine vs. gemcitabine vs. vinorelbine + gemcitabine:
overall survival similar among arms; combination regimen more toxic
WJTOG (2006) (182 pts) – vinorelbine vs. docetaxel: improved response, PFS and survival
with docetaxel
Single Agent Chemotherapy in Elderly Patients with Advanced NSCLC
*Gridelli, J Natl Cancer Inst 1999; 85:365-376.
‡Frasci et al, JCO 2000; 18(13): 2529-2536 Gridelli, J Natl Cancer Inst 2003; 95: No5
* p<0.05
Author Regimen N Response MS (mo) 1 YR
Vinorelbine 78 20% 6.5 32%*
BSC 76 -- 4.9 14%
Gemcitabine +
Vinorelbine 76 22% 7 30%*
Vinorelbine 76 15% 4.5 13%
Vinorelbine 233 18.4% 8.8 41%
Gemcitabine 233 17.3% 6.6 26%
Gemcitabine +
Vinorelbine 237 20% 7.6 31%
Gridelli*
Frasci‡
Gridelli
TREATMENT SCHEMA – WJTOG
2005
Stratification
Institution
Stage IV/IIIB
PS 0-1/2
R
A
N
D
O
M
I
Z
E
Docetaxel (D)
Docetaxel
60 mg/m2
Day 1 8 15 22 29
Day 1 8 15 22 29
Vinorelbine (V)
Vinorelbine
25 mg/m2
Both treatments were repeated over 4 cycles to disease progression.
Takeda ASCO 2005, A-7009
Docetaxel vs Vinorelbine for Elderly
Patients with Advanced NSCLC
182 pts accrued
Toxicities consistent with known profile of each agent
Global QoL similar but overall symptom improvement
better with D than V
Higher ORR with D (23% vs. 10%; p=0.019)
Longer PFS with D (5.4 vs. 3.1 mo; p<0.001)
Survival: MST 1-y Surv
– D 14.3mo 59%
– V 9.9 mo 37% HR=0.780 (0.561-1.085)
p=0.138
WJTOG – ASCO 2005
Retrospective Data
Assessing Role of
Platinum
Retrospective Analyses of Platinum-
based Doublets in Elderly(> 70) Patients
with Advanced NSCLC
Several subset analyses conducted assessing outcome in patients > age 70
– SWOG 9509/9308 - carbo/paclitaxel vs. cis/vinorelbine (Kelly 2001)
– ECOG 5592 – carbo/etoposide vs. carbo/paclitaxel (Langer 2002)
– CALGB 9730 – carbo/paclitaxel (Lilenbaum 2002)
– ECOG 1594 – four platinum doublets (Langer 2003)
– TAX 326 – cis/docetaxel vs. cis/vinorebine vs. carbo/docetaxel (Fossella 2003)
No differences in survival
Trend for greater toxicity in some studies, particularly myelosuppression
Trend for improved tolerance of carboplatin vs. cisplatin
Major potential limitation – these elderly subsets may not be representative of the general elderly population
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=0.009) + resp (p=0.044) co-morbidities
Age N RR(%) TTP (mo) MS (mo) 1 YS (%) 2YS (%)
<70 488 21.5 4.37 9.05 38 14
70 86 23.3 4.30 8.53 28 12
P value 0.666 0.294 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
JCOG phase III randomized trial in
advanced NSCLC elderly patients
Age > 70 yrs IIIB-IV NSCLC PS 0- 1
R a n d o m i z a t i o n
Weekly Docetaxel
Weekly CDDP+ Docetaxel
DOC 25 mg/m2 day 1, 8, 15 every 4 weeks
CDDP 25 mg/m2 DOC 20 mg/m2 day 1, 8, 15 every 4 weeks
Tsukada et al, ASCO ’07, A-7629
Phase II Trial of Cisplatin
+ Docetaxel in the Elderly
Results: N= 33
Median age: 77
Median cycles: 3
ORR: 52%
MS: 15.8 mos
1 YR OS: 64%
2 YR OS: 26%
Ohe Y et al: Ann Onc 15:45-50, 2004
Schema: CDDP 25 mg/m2
DOC 20 mg/m2
Days 1, 8, 15
Q 4 wks
Background (4) JCOG0207
Tsukada et al: J Clin Oncol 25:18s, 2007(suppl; abstr 7629)
<75yrs
≥75yrs
Unexpected large difference in
the subgroup of 70-74 years,
↓
Early termination of the study
due to DSMC recommendation
Tsukada et al, ASCO ’07, A-7629
70-74
Weekly paclitaxel combined with monthly
carboplatin versus single agent therapy in
patients aged 70 to 89 : IFCT-0501
randomized phase III study in advanced non-
small cell lung cancer
Elisabeth Quoix, JP Oster, V Westeel,
E Pichon, G Zalcman, L Baudrin, A Lavolé,
J Dauba, MP Lebitasy & B Milleron
on behalf of the French Intergroup (IFCT)
Study scheme
*Choice of the center at the beginning of the study
** In case of PD or excessive toxicity
NSCLC
Stage III-IV
Age 70-89 years
PS 0-2
n = 451
Vinorelbine
or
Gemcitabine*
Carboplatin +
paclitaxel
Erlotinib**
150 mg/d
R
A
N
D
O
M
Stratification by centre, PS 0-1 vs. 2, age ≤80 vs. >80 and stage III vs. IV
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
First-line Treatment
ARM A
V V V V V V V V V V
G G G G G G G G G G
WEEKS 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
ARM B C
P P P
C
P P P
C
P P P
C
P P P
EVALUATION
V : Vinorelbine : 30 mg/m2
G : Gemcitabine : 1150 mg/m2
C : Carboplatin : AUC 6
P : Paclitaxel : 90 mg/m2
Choice of
the center
Inclusion criteria
Age 70-89
With Stage III (not amenable to RT) or Stage IV NSCLC
PS 0-2
No prior treatment except surgery or palliative radiation
therapy
At least 3 weeks after must have elapsed after radiation
therapy or major surgery.
Adequate hematological, renal and hepatic function
Life expectancy of at least 12 weeks
Signed informed consent
Geographically near enough for follow-up
Patients characteristics (1)
Single agent (n= 226) G (n = 164) V (n = 62) All
Doublet
(n= 225)
p
Gender
Male
129 (78.7%)
43 (69.4%)
172 (76.1%)
161 (71.6%)
0.27
Median age
Range
76.9
70.1 - 88.8
76.3
70.1- 88.0
76.9
70.0 - 88.8
77.1
70.0 - 88.8
0.59
PS
0-1
2
115 (70.1%)
49 (29.9%)
50 (80.6%)
12 (19.4%)
165 (73%)
61 (27%)
164 (72.9%)
61 (27.1%)
0.98
Stage
IIIA-B
IV
35 (21.3%)
129 (78.7%)
7 (11.3%)
55 (88.7%)
42 (18.6%)
184 (81.4%)
46 (20.4%)
179 (79.6%)
0.62
Histology
Squamous
Adeno
Other
54 (32.9%)
85 (51.8%)
25 (15.2%)
20 (32.3%)
30 (48.4%)
12 (19.4%)
74 (32.7%)
115 (50.9%)
37 (16.4%)
77 (34.2%)
114 (50.7%)
34 (15.1%)
0.91
Never smokers 33 (20.2%) 17 (27.4%) 50 (22.2%) 44 (19.6%) 0.49
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
Patients characteristics (2) Single agent (n= 226)
G (n = 164) V (n = 62) All
Doublet
(n= 225)
p
Mini Mental S
<=23
> 23
MD
25 (15.8%)
133 (84.2%)
6
9 (14.5%)
53 (85.5%)
0
34 (15.5%)
186 (84.5%)
6
36 (16.2%)
186 (83.8%)
3
0.83
ADL score
6
<6
MD
124 (80%)
31 (20%)
9
51 (83.6%)
10 (16.4%)
1
175 (81%)
41 (19%)
10
176 (79.3%)
46 (20.7%)
3
0.65
Charlson‟s Ind.
≤ 2
> 2
MD
120 (79.5%)
31 (20.5%)
13
43 (71.7%)
17 (28.3%)
2
163 (77.3%)
48 (22.7%)
15
161 (74.9%)
54 (25.1%)
10
0.57
Weight loss
< 5%
[5-10%]
> 10%
MD
58 (36.5%)
57 (35.8%)
44 (27.7%)
5
25 (41%)
15 (24.6%)
21 (34.4%
1
83 (37.7%)
72 (32.7%)
65 (29.5%)
6
115 (51.3%)
55 (24.6%)
54 (24.1%)
1
0.048
BMI
≤20
]20 - 25]
[26 – 30]
>30
25 (15.2%)
87 (53.0%)
31 (18.9%)
21 (12.8%)
11 (17.7%)
35 (56.5%)
12 (19.4%)
4 (6.45%)
36 (15.9%)
122 (54.0%)
43 (19.0%)
25 (11.1%)
16 (7.11%)
127 (56.4%)
56 (24.9%)
26 (11.6%)
0.023
Response rate at 6 weeks (ITT)
Single Agent
Arm A (n = 211)
Doublet
Arm B (n = 210)
p
PR 23 (10.9%) 61 (29.05%) <10-5
ST 96 (45.5%) 81 (38.57%) 0.18
DCR (PR + ST) 119 (56.4%) 142 (67.62%) 0.02
PD 46 (21.8%) 15 (7.14%) <10-4
Not reported 15 (7.11%) 20 (9.53%) 0.47
Withdrawal before
1st evaluation*
31 (14.7%) 33 (15.7%) 0.88
*Main causes : deaths (20 in arm A and 23 in arm B),
reduced general condition (respectively 7 and 4), toxicity
0 and 4 cases respectively and withdrawal of consent (6 cases)
Hematological toxicity
(418* evaluable pts)
Grade 3-4 Arm A Single agent
Gem VNR All
n=149 n=61 n=210
Arm B
Doublet
n=208
p
Neutropenia 7 (4.7%) 23
(37.7%)
30
(14.3%)
113
(54.3%)
< 10-5
Febrile neutropenia 0
(0%)
6
(9.84%)
6
(2.9%)
20
(9.6%)
0.004
Anemia 3
(2.01%)
6
(9.84%)
9
(4.3%)
16
(7.7%)
0.14
Thrombocytopenia 2
(1.34%)
0
(0%)
2
(1%)
13
(6.3%)
0.004
*3 patients did not receive any dose of CT
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
Non hematological toxicity
(418 evaluable patients) Grade 3-4 Arm A Single agent
Gem VNR All
n =149 n=61 n=210
Arm B
Doublet
n=208
p
Neuropathy 0 (0%) 0 (0%) 0 (0%) 6 (2.9%) 0.015
Asthenia 9 (6.04%) 4 (6.56%) 13 (6.2%) 20 (9.6%) 0.19
Anorexia 2 (1.34%) 0 (0%) 2 (1%) 8 (3.8%) 0.061
Nausea/vomiting 1 (0.67%) 1 (1.64%) 2 (1%) 6 (2.9%) 0.17
Diarrhea 1 (0.67%) 0 (0%) 1 (0.5%) 6 (2.9%) 0.067
Pneumonia 3 (2.01%) 1 (1.64%) 4 (2%) 3 (1.4%) 1.0
Reduced general
condition
1 (0.67%) 2 (3.28%) 3 (1.5%) 3 (1.4%) 1.0
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
Doublet
Single
Doublet
Single
Months 0 6 12 18 24 30 36 42
Single 226 50 4 1 1 1 0
Doublet 225 107 27 12 7 4 3
PFS probabi l I t y
Median : 6.1 months (95% CI 5.5-6.9)
1-year PFS : 15.4% (95% CI 10.8-20.8)
Median : 2.8 months (95% CI 2.6-3.9)
1-year PFS : 2.3% (95% CI 0.8-5.3)
p <10-6 HR: 0.51 (95% CI: 0.42-0.62)
PFS (ITT)
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
Doublet
Single agent
Months 0 6 12 18 24 30 36 42
Single 226 112 45 24 11 4 1
Doublet 225 150 78 46 30 14 7
Doublet
Single
S U R V I V A L
MST = 10.3 months (95% CI 8.3-13.3
1-year survival 44.5% (95% CI 38.2-51.8)
MST = 6.2 months (95% CI 5.3-7.4)
1-year survival 25.4% (95% CI 21-33.1)
p= 0.00004 HR: 0.64 (95% CI: 0.52-0.78)
Overall survival (ITT)
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
Exploratory Sub-group analysis N HR 95%
LCL
95%
UCL p
All (B:A) 451 0.639 0.515 0.792 0.000046
PS 0/1 329 0.622 0.479 0.806 0.0003
PS 2 122 0.646 0.439 0.951 0.0268
Age ≤ 80 yr 337 0.668 0.519 0.859 0.0016
Age > 80 yr 114 0.559 0.368 0.851 0.0067
Adenocarcinoma 229 0.712 0.518 0.979 0.0365
Other histology 222 0.539 0.399 0.727 0.000053
Smokers 356 0.631 0.498 0.800 0.0001
Never smokers 94 0.625 0.368 1.060 0.0810
Weight loss < 5 % 198 0.610 0.431 0.864 0.0053
Weight loss ≥ 5 % 246 0.732 0.553 0.968 0.0287
ADL = 6 351 0.593 0.462 0.761 0.000042
ADL < 6 87 0.655 0.417 1.029 0.0665
MMS ≥ 24 372 0.601 0.473 0.764 0.000032
MMS < 24 70 0.909 0.540 1.530 0.7188
OS – The univariate hazard ratio was
derived from a Cox model with a single
treatment covariate
Favors
doublet
Quoix E, et al "Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with
advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial" Lancet 2011; DOI: 10.1016/S0140-6736(11)60780-0.
Multivariate analysis of survival (Cox model)
N=407 (patients without any missing data)
Variables Hazard ratio [95% CI] p
Arm B
A
0.639 [0.51-0.801]
1
0.0001
PS 0-1
2
0.580 [0.45-0.747]
1
0.00026
Smoking history
No
Yes
0.664 [0.488-0.90]
1
0.0092
Histology
ADC
Squamous
Other
0.679 [0.497-0.929]
0.843 [0.507-1.17]
1
0.0155
0.3072
ADL 6
<6
0.653 [0.495-0.861]
1
0.0025
Weight loss
≤ 5%
> 5%
0.669 [0.527-0.85]
1
0.001
Stepwise variable selection procedure, entry level=0.20, stay level=0.05
Conclusions:
First fully accrued study entirely devoted to elderly patients
showing the superiority of a platinum-based doublet over single
agent therapy in advanced NSCLC
– Carboplatin-based doublet resulted in a doubling of median
PFS from 3 to 6.1 months, an improvement of median OS
from 6.2 months to 10.3 and of 1-year survival rate from 27%
to 45%.
– Carbo-based doublet had a beneficial effect on survival in
most of the subgroups tested even those with lower
prognosis
– Manageable (acceptable) toxicity
New paradigm for elderly patients with advanced
NSCLC: monthly carboplatin + weekly paclitaxel
Abstract 7511 Phase III Trial nab-
paclitaxel-carbo vs carbo-paclitaxel
Chemo-naïve NSCLC
IIIB/IV
ECOG PS 0-1
Baseline
peripheral neuropathy >
grade 2
N=1050
Nab-paclitaxel 100 mg/m2 d1, 8, 15
Carbo AUC 6 d1 No premeds
Paclitaxel 200 mg/m2 d1
Carbo AUC 6 d1 Premeds: dex, antihistamines
R
A
N
D
O
M
I
Z
E
D
Stratification factors: stage IIIb vs IV, age <70 or > 70, gender, histology
(SCC vs non-SCC), geography
Primary endpoint: ORR
Secondary endpoint: PFS, OS, DCR, safety (NCI CTCAE v3)
Socinski et al. ASCO 2011 Abstract 7551
Patient Characteristics ab-P/C
(n=521)
P/C
(n=531)
All Patients
(N=1052)
Age, median (range) years
<65 years, n (%)
≥65 years, n (%)
60 (28, 81)
360 (69)
161 (31)
60 (24, 84)
348 (66)
183 (34)
60 (24, 84)
708 (67)
344 (33)
Female, n (%) 129 (25) 134 (25) 263 (25)
ECOG Performance Status
0
1
2
133 (26)
385 (74)
3 (<1)
113 (21)
416 (78)
2 (<1)
246 (23)
801 (76)
5 (<1)
Histology, n (%)
Adenocarcinoma
Squamous Cell Carcinoma
Large Cell Carcinoma
Other
254 (49)
228 (44)
9 (2)
29 (6)
264 (50)
221 (42)
13 (2)
33 (6)
518 (49)
450 (43)
22 (2)
62 (6)
Stage at Current Diagnosis, n (%)
Stage IIIB
Stage IV
108 (21)
413 (79)
110 (21)
421 (79)
218 (21)
834 (79)
Prior Chemotherapy, n (%) 12 (2) 8 (2) 20 (2)
Smoking Status, n (%)
Never Smoked
Smoked and Quit
Smoked and Still Smokes
519
137 (26)
168 (32)
214 (41)
526
144 (27)
148 (28)
234 (44)
1045
281 (27)
316 (30)
448 (43)
Primary Endpoint Results
Objective Responses – ITT
Response Ratio = 1.31
(1.082 – 1.593)
P = 0.005
Pe
rce
nt R
esp
on
se
s
33%
25%
0%
10%
20%
30%
40%
Independent
Radiologic Review
Ab-P/C
P/C
Re
spon
se R
ate
(%
) Objective Responses by Histology*
P < 0.001
RR =1.680
P = 0.808
RR=1.034
n = 228 n = 221 n = 292 n = 310
* Not a pre-specified subgroup analysis
41%
26% 24% 25%
0%
10%
20%
30%
40%
50% Ab-P/C
P/C
Interaction p-
Value for
Histology: 0.036
Squamous
Histology
Non-
Squamous
Histology
PFS – ITT Population P
rop
ort
ion
No
t P
rog
res
se
d
Months
Pt at risk
Ab-P
P
521
531
330
321
167
162
86
75
38
48
23
19
10
10 4
4
0
2
0
1
0
0
Ab-P/carboplatin (N=521)
paclitaxel/carboplatin (N=531)
0 3 6 9 12 15 18 21 24 27 30 33
0.00
0.25
0.50
0.75
1.00 Ab-P/
Carbo
Paclitaxel/
Carbo HR P-Value
N/Events 521/297 531/312
Median PFS
(mo)* 6.3 5.8 0.902 0.214
95% CI 5.6-7.0 5.6-6.7 0.767-1.060
* PFS based on Independent assessment
Overall Survival – ITT
Population P
rob
ab
ilit
y o
f S
urv
iva
l
Months
Pt at risk
Ab-P
Pac
521
531
469
470
381
389
313
308
246
243
200
191
163
148 98
89
23
24
0
5
0
1
Ab-P/carboplatin (N=521)
Paclitaxel/carboplatin (N=531)
0 3 6 9 12 15 18 21 24 27 30 33
0.00
0.25
0.50
0.75
1.00
0
0
Ab-P/Carbo Paclitaxel/
Carbo HR P-Value
N/Events 521/360 531/384
Median OS
(mos) 12.1 11.2 0.922 0.271
95% CI 10.8-12.9 10.3-12.6 0.797-1.066
Secondary Endpoint: OS
0.0 0.5 1.0 1.5 2.0
Stage IV
Stage IIIB
Nonsquamous
Squamous
70 yrs
<70 yrs
Female
Male
North America
Russia/Ukraine
Japan
All patients
Median OS (mo)
Events / N HR ab-P/C P/C
744 / 1052
86 / 149
521 / 724
127 / 165
589 / 789
155 / 263
639 / 896
105 / 156
343 / 450
401 / 602
142 / 218
602 / 834
0.922
0.950
1.019
0.622
0.894
0.995
0.999
0.583
0.890
0.950
0.896
0.917
12.1
16.7
11.0
12.7
11.4
16.8
11.4
19.9
10.7
13.1
12.4
12.0
11.2
17.2
11.1
9.8
10.0
16.0
11.3
10.4
9.5
13.0
13.6
11.0
Favors ab-P/C
Secondary Endpoint: OS
0.0 0.5 1.0 1.5 2.0
Stage IV
Stage IIIB
Nonsquamous
Squamous
70 yrs
<70 yrs
Female
Male
North America
Russia/Ukraine
Japan
All patients
Median PFS (mo)
Events / N HR ab-P/C P/C
744 / 1052
86 / 149
521 / 724
127 / 165
589 / 789
155 / 263
639 / 896
105 / 156
343 / 450
401 / 602
142 / 218
602 / 834
0.922
0.950
1.019
0.622
0.894
0.995
0.999
0.583
0.890
0.950
0.896
0.917
12.1
16.7
11.0
12.7
11.4
16.8
11.4
19.9
10.7
13.1
12.4
12.0
11.2
17.2
11.1
9.8
10.0
16.0
11.3
10.4
9.5
13.0
13.6
11.0
Favors ab-P/C
Summary Abstract 7511
Nab-paclitaxel-carboplatin had a higher response rate
than carbo-paclitaxel (33% vs 25%, p<0.001); especially
in the SCC population (41% vs 24%, p<0.001)
Nab-paclitaxel –carboplatin yielded more anemia and
thrombocytopenia, but less sensory neuropathy,
myalgia and neutropenia when compared to carbo-
paclitaxel.
No significant improvement in PFS or OS was seen.
– But non-inferiority was demonstrated
Subgroup analysis suggests benefit in SCC and in the
elderly
Socinski et al. ASCO 2011 Abstract 7551
Study Design
R
A
N
D
O
M
I
Z
E
Docetaxel alone (D)
Docetaxel
60 mg/m2
Day 1 8 15 22 29
Day 1 8 15 22 29
Weekly Docetaxel + Cisplatin (DP)
Docetaxel
20 mg/m2 Cisplatin
25 mg/m2
≥ 70yrs
PS 0,1
Advanced
NSCLC Stratification Institution
Stage
III / IV or relapse
Age
<75 / ≥ 75
JCOG0803/WJOG4307L
Both treatments were repeated until disease progression
or unacceptable toxicity. Primary endpoint: OS
Secondary endpoints: Toxicity, OR%, PFS, QoL
Abe et al ASCO 2011
Eligibility Criteria
Cytologically and/or histologically proven NSCLC
Stage* IIIA/ IIIB ( ineligible for definitive radiotherapy ), IV or postoperative recurrence
Age ≥70 yrs old
ECOG PS of 0 - 1
No prior chemotherapy
No prior radiotherapy for primary lesion
Unfit for bolus CDDP administration
Adequate organ function
Signed informed consent
JCOG0803/WJOG4307L
*: based on UICC ver.5
Results of 1st Interim Analysis Study opened Oct 2008
1st planned interim analysis Performed on 221 assessable patients on Sep 2010
D/DP: 108/113, <75/≥75: 22/78%, PS0/1: 35/65%, III/IV: 32/68%
Information time: 24% (observed events 73/ planned events 304)
Arm MST(months)
D 17.3
DP 13.3
HR 1.557 [99.99%CI 0.624-3.884], p=0.969*
The predictive probability that DP would be superior to D
at the time of the final analysis was 0.996%.
→Recommendation for early termination of the study
JCOG0803/WJOG4307L
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
Months after randomization
Pro
po
rtio
n
*by stratified log-rank with age, one-sided
Abe et al ASCO 2011
Hematological Toxicity(CTCAE v3.0)
D
(N=134)
DP
(N=129)
Grade 3-4 4 3-4 4
Leukopenia 63% 8% 5% 0%
Neutropenia 89% 68% 10% 1%
Anemia 4% 1% 16% 1%
Thrombocytopenia 0% 0% 1% 0%
JCOG0803/WJOG4307L
3 pts‟ data in D arm and 10pts‟ data in DP arm were missing.
Abe et al ASCO 2011
Non-Hematological Toxicity
JCOG0803/WJOG4307L
3 treatment related deaths were observed in DP arm (2.2%).
D(N=133) DP(N=131)
Grade Any 3-4 Any 3-4
Nausea 48% 1% 64% 4%
Anorexia 69% 2% 82% 11%
Diarrhea 28% 4% 27% 1%
Fatigue 75% 3% 72% 5%
Hypoalbuminemia 96% 2% 94% 5%
Hyponatremia 55% 5% 72% 15%
Infection 11% 8% 11% 8%
Febrile neutropenia 15% 15% 0% 0%
Alopecia 72% - 53% -
Pneumonitis 6% 5% 6% 2%
4 pts‟ data in D arm and 8pts‟ data in DP arm were missing. Abe et al ASCO 2011
Response (RECIST 1.0) D
(N=126)
DP
(N=131)
CR 0 0
PR 31 45
SD 66 48
PD 16 15
NE 3 9
ORR
[95% C.I.]
24.6%
[17.4-33.1]
34.4%
[26.3-43.2]
(two-sided p=0.1013, Fisher‟s exact test)
( 10 pts‟ data in D arm and 14 pts‟ data in DP arm were missing. )
JCOG0803/WJOG4307L
Abe et al ASCO 2011
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
Progression-Free Survival
JCOG0803/WJOG4307L
Arm N Events Median(m) [95% C.I.]
6M-PFS(%) [95% C.I.]
D 134 116 4.4 [3.4-5.1]
32.0 [24.0-40.2]
DP 138 117 4.7 [4.1-5.8]
40.7 [32.1-49.1]
HR: 0.924 [95%C.I. 0.714-1.197], p = 0.3036*
Months after randomization
Pro
po
rtio
n
Data cut-off: Nov/2010 * log-rank test, one-sided
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
Overall Survival
Median follow-up time for censored case:
13.1 months
Arm N Events Median(m) [95% C.I.]
1y-survival (%) [95% C.I.]
D 134 59 14.8 [11.9-24.1]
58.2 [48.3-66.9]
DP 138 65 13.3 [10.8-19.4]
54.5 [44.8-63.3]
HR: 1.183 [95%C.I. 0.830-1.687], p = 0.824*
JCOG0803/WJOG4307L P
rop
ort
ion
Months after randomization *stratified log-rank by age, one-sided
Data cut-off: Nov/2010
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
Months after randomization
Pro
po
rtio
n
Subset Analysis (Age <75 vs. ≥75)
Events MST(m)
D (n=104) 49 14.5
DP (n=106) 53 13.3
HR:1.131 [95%CI 0.767-1.669]
Events MST(m)
D (n=30) 10 24.1
DP (n=32) 12 17.3
HR:1.474 [95%CI 0.621-3.501]
<75 ≥75
JCOG0803/WJOG4307L
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
Months after randomization
Pro
po
rtio
n
Subgroup Analysis of Survival
JCOG0803/WJOG4307L
Favors D Favors DP *: 3 pts‟ data were missing
*
*
Conclusions
This study failed to demonstrate any
advantage of the addition of weekly
CDDP to single-agent DOC in first line
chemotherapy for elderly advanced
NSCLC patients.
JCOG0803/WJOG4307L
Conclusions This study failed to demonstrate any advantage of the
addition of weekly CDDP to single-agent DOC in first
line chemotherapy for elderly advanced NSCLC
patients.
Langer‟s comments Bolus platinum (not weekly) is standard
Study was terminated after fewer than 25%
expected events
Higher proportion of EGFR mutations may have
favored the Doc arm
Docetaxel may be superior to VNR/GEM
JCOG0803/WJOG4307L
INVITE trial in advanced NSCLC elderly
(>70 yrs) pts with PS < 2
Vinorelbine 30
mg/m2 days 1 + 8
Gefitinib
(250 mg/d)
Prim. Obj.= time to progression
Crino et al IASLC ‟07
Crino L, Cappuzzo F, Zatloukal R et al J Clin Oncol. 2008 Sep 10;26(26):4253-60
RP2
INVITE: Outcome
Crino et al, J Clin Oncol, 2008.
INVITE: Results by EGFR FISH Status
FISH [+] FISH [-]
Crino et al, J Clin Oncol, 2008.
INVITE trial in Tx-naive, advanced
NSCLC elderly (>70 yrs) pts with PS < 2
Conclusions
Crino et al IASLC ‟07
Crino L, Cappuzzo F, Zatloukal R et al J Clin Oncol. 2008 Sep 10;26(26):4253-60
Gefitinib and vinorelbine similar efficacy
Gefitinib better tolerated with better QOL
Paradoxical benefit for VNR in FISH (+) pts
Outcomes for Elderly Advanced Stage Non-small Cell Lung Cancer Patients
Treated With Bevacizumab in Combination with Carboplatin and
Paclitaxel: Analysis of ECOG 4599 Study Abstract # 7535, ASCO ‘07
S. Ramalingam1, S. E. Dahlberg2, C. J. Langer3, R. Gray2, C. P. Belani1, J. R. Brahmer4, A. Sandler5, J.
H. Schiller6, D. H. Johnson5
1University of Pittsburgh Cancer Institute, Pittsburgh, PA,
2 Dana Farber Cancer Institute, Boston, MA.
3 Fox Chase Cancer Center, Philadelphia, PA. 4 The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
5 Vanderbilt-Ingram Cancer Center, Nashville, TN. 6 University of Texas Southwestern Medical Center, Dallas, TX.
Elderly analysis of ECOG 4599
224 patients aged ≥ 70 years in E4599
No improvement in survival with PCB vs PC:
– PFS: 5.9m vs. 4.9m; P = .063
– OS: 11.3m vs. 12.1m; P = .4
More Grade 3/4 toxicity in elderly patients on PCB arm:
Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology
Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and
paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599.J Clin Oncol. 2008 Jan 1;26(1):13-5.
≥ 70 y < 70 y P Value
Neutropenia (G4) 34% 22% .02
Melena/GI bleed 3.5% 1% .005
Muscle weakness 8% 2% .02
Motor neuropathy 3.5% < 1% .05
Tx-related deaths 6% 3% .08
PFS in Elderly: PCB vs. PC
Hazard ratio: 0.76 (0.57,1.01) Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology
Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and
paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599.J Clin Oncol. 2008 Jan 1;26(1):13-5.
Overall Survival in Elderly: PCB vs. PC
Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology
Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and
paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599.J Clin Oncol. 2008 Jan 1;26(1):13-5.
Median Survival (mos) by Sex and Age -/+ BEV
on E4599: 3 age cut-points
Age in Years
Age Cohort < 45 45-59 60
Women Control 5.8 12.5 13.8
Women + BEV 16.8 15.5 12.8
Men Control 3.4 9.5 8.5
Men + BEV 12.6 12.3 11.0
Wakelee, H et al IASLC/ASTRO 2008
Conclusion: Only group that failed to have a
conclusive benefit were women over 60.
ECOG 4599: Outcome by Gender and Age
Protoplasmic Issues Co-morbidities may have a deleterious influence
on survival
Normal physiologic changes with aging will often
restrict our therapeutic options
– Renal function:
Carboplatin likely preferable to cisplatin in a significant
percentage of patients
Pemetrexed may not be “safe” in pts with Cr Cl < 45
– Myelosuppression: worse with aging
Strong consideration of growth factor support
Weekly dosing of taxanes to mitigate inc. of NF
– Increasing fat mass and decreasing water content can
increase the Vol of Distribution, leading to higher AUCs
for lipophilic compounds
Advantage of the PK Dosing
Use of Carboplatin
Calvert + Cockroft Gault Formulae
(140 – age) (Wt in lbs)*
(72)(2.2)(serum Cr)
Accounts for age-related changes in
renal function
+ 25 X AUC
* Multiply by Factor of 0.85 in women
NSCLC in the Elderly Analysis of E5592 Data
Parameter: <70 Yrs: 70 Yrs: P value:
Cardiac Dz: 21.5% 35% 0.009
Resp Dz: 16% 26% 0.04
Other Dz: 25% 35% 0.08
Analgesics: 42% 31% 0.14
Other Meds: 51% 66% 0.02
0%
20%
40%
60%
80%
100%
0 6 12 18 24 30 Months After Registration
None One Two or More
N 18 31 25
Deaths 11 23 20
Median in Months
15 9 8
P = .22
SWOG 0027: Survival by Co-morbidities
in pts receiving VNR DOC
Influence of PS & Co-Morbidity on
Tx Tolerance & Outcome
Performance Status MedS Early Tx Discontinuation
0-1 6 31%
2 4.4 59%
Charlson Score
0 6.5
1-2 4.8
>2 3.7 82%
30%
‡Frasci et al, Proc ASCO 2001, 19:A1895, JCO 18: 2529-2536, 2000
QoL AND FUNCTIONAL STATUS IN
ELDERLY PATIENTS - MILES
Overall survival
A: QoL
B: IADL
Charlson score was not
associated with prognosis
Maione et al. JCO 2005
AGE
PS COI
ASSESMENT OF CHEMOTHERAPY
IN ELDERLY PATIENTS
Precepts: NSCLC Elderly (1)
Median age at diagnosis based on SEER data is ~ 70, but the elderly are under-represented on clinical trials
Elderly are more likely to be frail and/or vulnerable compared to younger pts
Functional reserve is compromised, even in fit elderly
CGA which assesses co-morbidities, functional status (ADL, IADL), ECOG PS, mental status, poly-pharmacy, social support, and nutrition and other similar instruments (VES-13, etc) may fine tune our predictions of vulnerability and prognosis
Precepts: NSCLC Elderly (2)
Level 1, evidence based data show clear benefit for non-platinum mono-therapy vs BSC in PS 0-2 NSCLC, – no consistent superiority for non-platinum doublets;
– co-morbidity indices predictive of outcome
Retrospective analyses of platinum-based combinations demonstrate similar outcome for fit elderly and younger cohorts with respect to RR, TTP, MS, and 1-2 yr OS, although these benefits are vitiated by increased toxicity in the elderly
Precepts: NSCLC Elderly
There is now a single phase III, elderly-specific trial proving
therapeutic superiority for platinum based combinations vs
single agent
Decisions regarding Tx hinge on multiple factors:
– Toxicity profile of the agent(s)
– Performance status
– Pharmacokinetics
– Co-morbidities
– Organ function
– Social support
70 to 80 and > 80 functionally may be two different groups
Individualize, but do not ignore the data
Treatment of PS 2 Patients
with Advanced NSCLC:
Current State of the Art
Corey J Langer MD, FACP
Director, Thoracic Oncology
Abramson Cancer Center
Professor of Medicine
University of Pennsylvania
Philadelpia, PA 19104
PS2 Patients with NSCLC:
What We Know
1. Heterogeneous group of patients
2. A large proportion of the NSCLC population (30%–40%)
3. Frequently excluded from clinical trials
– When included, frequently combined with the elderly, although each represents different populations
4. Generally tolerate therapy poorly
5. PS 2: associated with poorer survival
PS2 Patients with NSCLC:
What We Don‟t Know
1. How to accurately assess PS2 patients
2. The influence of co-morbidities vs disease burden on PS and treatment outcome
3. Best therapy – Chemo vs BSC
– Doublets versus monotherapy
– Targeted agents
Assessment of PS
Significant discordance between assessment of performance status by physician versus patient
– Agreement between patients and physicians occurred in only 43% of the 3272 patients studied
– Physicians overestimated PS by 38%
Cella et al, BIOQOL/Q-SCORE Database, 2004
ECOG Recursive Partitioning
Analysis Terminal Nodes
Jiroutek M, et al. Proc Am Soc Clin Oncol. 1998;17:1774.
Median Survival (mos) Intact Appetite (n) Diminished Appetite (n)
PS0
Female 12.58 (111) 8.54 (15)
Male 9.86 (219) 6.74 (50)
PS1
Female 7.77 (214) 6.95 (102)
Male 6.70 (421) 5.08 (224)
PS2
Female 5.31 (24) 2.30 (27)
Male 4.30 (64) 3.43 (100)
Retrospective Analyses of the Role
of Chemotherapy in PS 2 Patients
with Advanced NSCLC
Survival benefit with single agent vinorelbine in PS 2
subset of ELVIS trial (26 weeks vs. 8 weeks with BSC)
Conflicting data on the possible superiority of platinum-
based doublets vs. single agents
– CALGB 9730*: survival 4.7 mos vs. 2.2 mos with
carboplatin/paclitaxel and paclitaxel respectively
– Le Chevalier:** no difference in survival between platinum-vinca
combination vs. vinorelbine alone
*Lilenbaum R J Clin Oncol, 2005; 23:190-196
**Le Chevalier T J Clin Oncol,1994;12:360-367
BMJ Meta-analysis
BMJ 1995;311:899-909
Cisplatin-based Therapy
CALGB 9730: PS 2 Subset
Analysis
N
OR (%)
MST (mos)
1-yr OS%*
2-yr OS%
P CbP P CbP All
277 284 50 49 99
17 30 10 24 17
6.7 8.8 2.4 4.7 3.1
32 37 10 18† 14
NA NA 0 9 5
*Wilcoxon = .1014; †Log rank P = .0123; SS (< .0001) vs PS 0-1
Total PS 2
Lilenbaum RC, et al. JCO 2005
Randomized Phase III, US Oncology
Trial in PS 2 NSCLC
R
A
N
D
O
M
I
Z
E
Gemcitabine 1000 mg/m2 d 1 + 8
Carboplatin AUC 5 d 1
Gemcitabine 1000 mg/m2 d 1+ 8
6 cycles of Tx projected
1°Endpoint: median survival
Obasaju et al ASCO ‟07, A-7533
Randomized Phase II Trial of Gemcitabine or
Gemcitabine/Carboplatin in PS 2, Adv NSCLC
Arm Gem Gem/Carbo
No (Eval) 85 (81) 85 (79)
Mean # cycles 3.3 3.9
% Pts with dose omissions 22% 35%
% Pts with dose recuctions 35% 57%
RDI - Gem 91% 71%
RDI - Carbo N/A 90%
G 3/4 Neutropenia 10% 27%
G 3/4 Thrombocytopenia 2% 22%
G 3/4 Anemia 2% 6%
Randomized Phase II Trial of Gemcitabine or
Gemcitabine/Carboplatin in PS 2, Adv NSCLC
Arm Gem Gem/Carbo
No (Eval) 85 (81) 85 (79)
OR % 11.5% 36%
PFS (mo) 2.79 4.01
MS (mo) 5.2 6.9
1 yr OS N/A N/A
Mean change in FACT-L -8.0 -0.9
Mean change in TOI -6.3 -1.7
Obasaju et al ASCO ‟07, A-7533
PS 2 Specific Trials through 2006
ECOG 1599
STELLAR 3
STELLAR 4
OSI: Erlotinib; CbP
PS 2 Specific Trials through 2006
ECOG 1599: first dedicated, PS-2 specific randomized phase II, cooperative group trial
STELLAR 3: first PS-2 specific, randomized phase III trial in NSCLC
STELLAR 4: second PS-2 specific, randomized phase III trial in NSCLC
OSI: Erlotinib; CbP: first trial to test EGFr TKI in PS 2 pts upfront
ECOG 1599: Dose-Attenuated CbP or
GC in PS2 Advanced NSCLC
Tester, Langer et al. ASCO 2004, JCO „07
R
A
N
D
O
M
I
Z
E
Carboplatin AUC 6 q3wk
Paclitaxel 200 mg/m2 q3wk
Gemcitabine 1 g/m2
days 1, 8 q3wk
Cisplatin 60 mg/m2 q3wk
ECOG 1599: Outcomes of
Doublet Therapy in PS2 Patients
Arm GC PCb
CR (%) 2 0
PR (%) 20 13
SD (%) 29 38
MS (mo) 6.7 6.1
PFS (mo) 3.0 3.9
1y OS (%) 25 19
N = 102
Tester, Langer et al. ASCO 2004, JCO „07
New Agents
Cytotoxics (with improved toxicity profiles)
Targeted agents (often non-toxic or
minimally toxic)
STELLAR 3: Trial Design
R
A
N
D
O
M
I
Z
E
Paclitaxel 225 mg/m2
Carboplatin (AUC 6)
q3w
N=201
Chemotherapy-
naïve PS2
patients with
advanced
NSCLC Stratified by:
Stage
Sex
History of brain mets
Geographic region
PPX 210 mg/m2
Carboplatin (AUC 6)
q3w
N = 199
Langer et al ASCO „05
N Median 1 yr 18 mo 2 yrs
PPX 199 7.8 mo 31% 20% 13%
Paclitaxel 201 7.9 mo 31% 11% 11%
HR=0.97
Log-rank P value=0.769
0.0
0.1
0.2
1.0
0.4
0.5
0.8
0.9
0.3
0.6
0.7
0 100 200 300 400 500 600 700 800
Time From Randomization (Days)
Pro
bab
ilit
y o
f S
urv
ival
STELLAR 3: Overall Survival
PPX/Carboplatin Paclitaxel/ Carboplatin
N Median 1 yr 18 mo 2 yrs
PPX/Carboplatin 199 7.8 mo 31% 20% 13%
Paclitaxel/Carboplatin 201 7.9 mo 31% 11% 11%
(Intent-to-Treat)
7 11
STELLAR 4: Trial Design
R
A
N
D
O
M
I
Z
E
Gemcitabine 1000 mg/m2
days 1, 8, and 15
every 28 days
or
Vinorelbine 30 mg/m2
days 1, 8, and 15
every 21 days
(N=190)
Eligibility Requirements:
• Chemotherapy-naïve
• Advanced NSCLC
• PS2 Stratified by:
• Stage
• Sex
• History of brain
metastasis
• Geographic region
PPX 175 mg/m2
every 3 weeks
(N=191)
80% power to detect 1.5-month difference (4-5.5); hazard ratio (HR)=1.37
N Median 1 yr 18 mo 24 mo
PPX 191 7.3 mo 26% 15% 15%
Gemcitabine/ 190 6.6 mo 26% 13% 10% Vinorelbine
STELLAR 4: Overall Survival
HR=0.95
Log-rank P value=0.686
0.0
0.1
0.2
1.0
0.4
0.5
0.8
0.9
0.3
0.6
0.7
0
100
200
300
400 500 600 700 800
Time From Randomization (Days)
Pro
bab
ilit
y o
f S
urv
ival
PPX Gemcitabine/ Vinorelbine
1.
0
PPX vs. Gemcitabine/Vinorelbine (Intent-to-Treat)
5
Multivariate Analysis: STELLAR 3 and 4
Factor Chi Square P value
Albumin < 3.5 vs > 3.5 39.8 <0.0001
Extrathoracic Tumor (excluding CNS mets)
19.9 <0.0001
Number of Comorbidities
> 2
10.1 0.0014
Smoking Hx 5.9 0.015
What is the Role of EGFR
TKI in PS 2 NSCLC?
Erlotinib vs. Chemotherapy in PS2
Patients
R
A
N
D
O
M
I
Z
E
1:1
Erlotinib
150 mg daily
Carboplatin
AUC 6
+
Paclitaxel
200 mg/m2
Day 1 q 21
days x 4 cycles
Stratified by:
Center
Age (< 70 vs > 70)
Extent of Disease (Stage IIIB vs IV)
Optional
Cross-over
to Erlotinib
Lilenbaum et al ASCO ‟06, J Clin Oncol 26:863–869, 2008
Overall Survival
Lilenbaum et al ASCO ‟06, J Clin Oncol 26:863–869, 2008
Studies Evaluating EGFR TKI in
Pts with Compromised PS
Trial Lilenbaum Hesketh Inoue*
PS 2 2 2-4
Mutation Status Unselected Unselected All (+)
Mut (+) 0% NA 100%
No. 52 81 30
OR% 4 8 66
PFS (mo) 1.9 2.5 6.5
MS (mo) 6.6 5.0 17.8
Akira Inoue, Kunihiko Kobayashi, Kazuhiro Usui, Makoto Maemondo, Shoji Okinaga, Iwao Mikami, Masahiro Ando, Koichi Yamazaki, Yasuo Saijo, Akihiko Gemma,
Hitoshi Miyazawa, Tomoaki Tanaka, Kenji Ikebuchi, Toshihiro Nukiwa, Satoshi Morita, and Koichi Hagiwara First-Line Gefitinib for Patients With Advanced
Non–Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Without Indication for Chemotherapy
JCO 2009 27: 1394-1400
Lilenbaum et al ASCO ‟06, J Clin Oncol 26:863–869, 2008
Hesketh et al, ASCO ’07, A-7536, J Thorac Oncol 3:1026–1031, 2008
Perspectives on PS
Performance status trumps age
Mutation status trumps PS
Management of PS 2 Patients
With Advanced NSCLC (1)
PS 2 patients represent a sizable percentage of our practice. – Expanding number of PS 2 – specific trials; but a relative paucity
of evidence-based, prospective data are available
– Treatment practices vary considerably
– Prognosis remains poor
Reliable and reproducible scales for assessing PS and relationship with co-morbidities are prime research goals
Combination chemotherapy may have its greatest impact on patients with PS 2 who are symptomatic from their cancer, whereas single agents may be best in those with co-morbidities
STELLAR trials, though (-), have enriched the literature and identified a number of prognostic variables that should be used as stratification factors in future studies: serum albumin, extrathoracic involvement, co-morbidities, smoking hx