Transcript Elderly and Performance Status 2 Patients With Advanced NSCLC

Elderly Patients with Advanced NSCLC:
Emerging Role of Targeted Therapy
Corey J Langer MD, FACP
Professor of Medicine
Director of Thoracic Oncology
University of Pennsylvania,
Philadelphia, PA
[email protected]
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
S9509/9305
E1594
E4599
15%
19%
20%
26%
CALGB 9730
27%
Chemotherapy in the Elderly Patient:
Special Challenges
Higher frequency of comorbid conditions
Higher prevalence of polypharmacy increasing the risk of
adverse drug interactions
Reduced hepatic, renal, lung function, immune
competence and bone marrow reserve
Impaired social, emotional or 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, but
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 (though underpowered to show a statistically
significant benefit wrt OS)
Single Agent 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, JCO 2000; 18(13): 2529-2536
 Gridelli, J Natl Cancer Inst 2003; 95: No5
TREATMENT SCHEMA – WJTOG
2005
Stratification
Institution
Stage IV/IIIB
PS
0-1/2
R
A
N
D
O
M
I
Z
E
Docetaxel (D)
Day 1
8
15
22
29
8
15
22
29
Docetaxel
60 mg/m2
Vinorelbine (V)
Day 1
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
– V
14.3mo
9.9 mo
59%
37%
HR=0.780 (0.561-1.085)
p=0.138
WJTOG – ASCO 2005
Retrospective Analyses of Platinumbased 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
JCOG phase III randomized trial in
advanced NSCLC elderly patients
Age > 70 yrs
IIIB-IV NSCLC
PS 0- 1
Tsukada et al, ASCO ’07, A-7629
R
a
n
d
o
m
i
z
a
t
i
o
n
Weekly Docetaxel
DOC 25 mg/m2
day 1, 8, 15
every 4 weeks
Weekly
CDDP+ Docetaxel
CDDP 25 mg/m2
DOC 20 mg/m2
day 1, 8, 15
every 4 weeks
Phase II Trial of Cisplatin
+ Docetaxel in the Elderly
Schema:
Results:
CDDP 25 mg/m2
DOC 20 mg/m2
Days 1, 8, 15
Q 4 wks
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
JCOG phase III randomized trial in
advanced NSCLC elderly patients
Premature Termination
Trial aborted after DSMC determined that the 70-74
age group benefitted from DP over D
Arm
Doc
Doc-DDP
No
63
63
PFS (mo)
3.7
6.2
MS (mo)
10.7
17
1-yr OS (%)
45.2
66.6
Gr 3-4 ANC
4.9
13.1
Gr 3-4 HGB
1.6
16.4
Gr 3-4 Anorexia
8.3
24.2
0
1
TRD
Tsukada et al, ASCO ’07, A-7629
Molecularly Targeted Agents: Role in Elderly
Patients with Advanced NSCLC
Potential for increased use given “favorable” toxicity profile
Limited prospective data to date
Retrospective analysis of BR21 showed that age did not dilute the survival
benefit of erlotinib vs placebo in the 2nd and 3rd line setting
Prospective phase II trial with erlotinib suggests benefit
Subset analyses of extended access trials with single-agent gefitinib have
demonstrated clinical activity and modest toxicity
Phase II trial of gefitinib + gemcitabine or vinorelbine (Scagliotti ASCO
2004); antineoplastic activity not enhanced; excessive toxicity for vinorelbine
and gefitinib
Prospective phase III trial of gefitinib vs vinorelbine shows equivalent
survival, improved QoL (IASLC ’07)
Retrospective analysis of bevacizumab combined with chemotherapy
suggests caution
BR.21: overall survival
100
HR=0.70 (0.58–0.85)
Stratified log-rank p<0.001
Percentage
80
60
Erlotinib
Placebo
40
20
0
At risk
Erlotinib
Placebo
0
6
488
243
255
107
12
18
Time (months)
145
50
23
9
24
4
0
30
0
0
Shepherd F, et al. N Engl J Med 2005.
Forest plot of survival by subsets
erlotinib:placebo
PS 0–1
PS 2–3
Male
Female
<65 years
65 years
Adenocarcinoma
Squamous-cell carcinoma
Other histology
Prior weight loss <5%
Prior weight loss 5–10%
Prior weight loss >10%
Never-smoker
Current/ex-smoker
1 prior regimen
2+ prior regimens
0
1
2
HR
3
4
Forest plot of survival by subsets
erlotinib:placebo
PS 0–1
PS 2–3
Male
Female
<65 years
65 years
Adenocarcinoma
Squamous-cell carcinoma
Other histology
Prior weight loss <5%
Prior weight loss 5–10%
Prior weight loss >10%
Never-smoker
Current/ex-smoker
1 prior regimen
2+ prior regimens
0
1
2
HR
3
4
Erlotinib for advanced non-small-cell lung cancer in the
elderly: an analysis of the National Cancer Institute of
Canada Clinical Trials Group Study BR.21
No significant demographic differences between age groups randomly assigned to
erlotinib or placebo
Elderly
No
PFS
OS
Younger
No
PFS
OS
Erlotinib
112
3.0
7.6
Erlotinib
376
2.1
6.4
Placebo
51
2.1
5.0
Placebo
192
1.8
4.7
P value
0.009
0.67
P value
< 0.0001
0.014
HR (95% CI)
0.63 (0.44-0.90)
0.92 (0.64-1.34)
HR (95% CI)
0.64 (0.53-0.76)
0.73 (0.61-0.89)
Response rates were similar between age groups.
Elderly patients, compared with young patients, had significantly more overall and
severe (grade 3 and 4) toxicity (35% v 18%; P < .001), were more likely to discontinue
treatment as a result of treatment-related toxicity (12% v 3%; P < .0001), and had lower
relative dose-intensity (64% v 82% received > 90% planned dose; P < .001).
Conclusion: Elderly pts treated with erlotinib have similar survival and QOL benefits
compared to younger pts, with somewhat greater toxicity
J Wheatley-Price P, Ding K, Seymour L, Clark GM, Shepherd FA JCO 2008 May 10;26(14):2350-7.
Phase II Study of Erlotinib in Elderly Patients
with Previously Untreated Advanced NSCLC.
PIs: Janne, Jackman & Johnson MD
Location: Dana Farber and MGH
Regimen: single agent 150 mg/d in chemo-naïve, PS 0-2 pts
≥70yrs until PD or toxicity
N = 80; median age 76 (70-91); 63% Adenoca or BAC; 95%
never/former smokers
Toxicities: gr > 1 rash 79%; grade 3 rash (5); diarrhea 69%;
9 pts D/C for toxicity; ILD (4), 1 fatality
OR%: 10% -- of 8 responders, 5 female, 2 never and 6
former smokers; all had rash
DC%: 51%; TTP: 3.5 mos
Median Survival: 10.9 mos (95% CI 7.8 – 14.6 mo)
1yr OS: 46%: 2yr OS: 19%
EGFr Mutations: (+) in 9/43 tested, corelated with RR, DC,
TTP and OS
Jackman D ASCO-2005, A-7148, JCO ‘07
Conclusions: SA Erlotinib in
Elderly NSCLC
Single agent activity and survival in Txnaïve pts matches that observed with
conventional cytotoxics
Untoward toxicity not observed; no
unusual safety concerns
Jackman D ASCO-2005, A-7148, JCO ‘07
Gefitinib in Elderly NSCLC
(Japanese experience)
Retrospective comparison comparing toxicity, response and survival
outcomes for gefitinib in patients aged 75 years or older (elderly group) with
patients aged younger than 75 years.
350 patients were eligible for this analysis,
Age
Cohort
No
Gr 3-4
AEs
OR%
MST
Elderly
92
9%
17
7.6m
Young
258
9%
21
9.3m
Multivariate analysis revealed elderly patients with lower Brinkman index
tended to be more sensitive to gefitinib (odds ratio: 4.57, 95% confidence
interval: 0.91-22.72, p = 0.0642).
Conclusions: Tx with gefitinib appeared to be as safe and effective in
elderly patients (aged 75 or older) with NSCLC as in non-elderly patients
Hotta K, Ueoka H, Kiura K, Tabata M, Ogino A, Umenura S, Harita S, Gemba K, Yonei T, Bessho A, Maeda T, Tanimoto M
Acta Oncol. 2005;44(7):717-22 (Okayamo)
Gefitinib in the Elderly with NSCLC
Prospective study of gefitinib 250 mg/d in advanced chemo-exposed NSCLC pts >
70. From August 2001 to May 2003,
40 consecutive pts enrolled from three Italian institutions from 8/01 to 5/03
OR% - 5% (1 CR, 1 PR) 18 disease stabilizations (NC: 45%) lasting at least 2 mos
– six patients (15%) who had disease stabilisation of 6 months or longer,
– median duration of response was 4.4 months (range 1.7-9.2).
No data on PFS or OS
Side effects generally mild and consisted of diarrhoea and skin toxicity.
– Grade 1-2 diarrhoea in 23.6%; one pt experienced grade 4 diarrhoea, requiring
hospitalization.
– Grade 1-2 skin toxicity, including rash, pruritus, dry skin, and acne in 20 pts
(50%).
Conclusions: Gefitinib is safe and well tolerated in elderly pretreated NSCLC
patients with reasonable disease control rate.
Cappuzzo F, Bartolini S, Ceresili GL, Tamberi S, Spreafico A, Lombardo L, Gergorc V, Toschi L, Calandri C,
Villa E, Crino L Br J Cancer. 2004 Jan 12;90(1):82-6
INVITE trial in advanced NSCLC elderly
(>70 yrs) pts with PS < 2
Vinorelbine 30
mg/m2 days 1 + 8
RP2
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
INVITE trial in advanced NSCLC elderly
(>70 yrs) pts with PS < 2
Arm
VNR
GEF
No PS 2 DCR TOI
99 16% 54
11
97 24% 43
23
PSI
31
36
Gr 3-5
42%
13%
ANC Rash
44% 4%
0% 34%
*PSI – Pulmonary symptom improvement
HR for Gef vs Vnr
PFS: 1.19 (0.85, 1.69)
OS: 0.98 (0.66, 1.47)
HR for Vnr vs Gef for 54 FISH (+)
PFS: 3.13 (1.45, 6.73)
OS: 2.88 (1.21, 6.83)
Conclusions:
• Gefitinib and vinorelbine similar efficacy
• Gefitinib better tolerated
• Paradoxical benefit for VNR in FISH (+) pts
Crino et al IASLC ’07
Crino L, Cappuzzo F, Zatloukal R et al J Clin Oncol. 2008 Sep 10;26(26):4253-60
Phase II randomized trial of IRESSA +
GEM or VNR in elderly NSCLC pts
Accrual completed
GEM+Gefitinib
R
GEM 1200 mg/m2, i.v., d 1-8, q21
IRESSA 250 mg/die, p.o., until to PD
VNR+Gefitinib
VNR 30 mg/ m2, i.v., d 1-8, q21
IRESSA 250 mg/die p.o., until to PD
Study Coordinators: C. Gridelli – G.V. Scagliotti
Phase II randomized trial of IRESSA +
GEM or VNR in elderly NSCLC pts
Accrual completed
GEM+Gefitinib
R
GEM 1200 mg/m2, i.v., d 1-8, q21
IRESSA 250 mg/die, p.o., until to PD
VNR+Gefitinib
VNR 30 mg/ m2, i.v., d 1-8, q21
IRESSA 250 mg/die p.o., until to PD
Study Coordinators: C. Gridelli – G.V. Scagliotti
Randomized Phase II of Gefitinib in
Combination with Vinorelbine or
Gemcitabine in Elderly Pts with NSCLC
Gr 3-4 ADRs in 87.5% in the 1st 24 pts on VG
– Including 72% gr 3-4 neutropenia
– 3 deaths which may have been Tx-related (1 septic
shock and cerebral infarct)
Results
No
CR/PR
TTP (d)
MS (d)
VG
24
1/3
91
371
GG
35
3
94
275
Phase 2 trial of docetaxel and gefitinib in Txnaïve pts with advanced NSCLC > 70 yrs of age
Eligibility: chemotherapy-naïve NSCLC patients, 70 years of age or older
Tx Design:
– Docetaxel 75 mg/m(2) every 3 weeks - 2 cycles beyond maximal response
– Gefitinib 250 mg po until PD
Primary endpoint - response rate (RR); Secondary endpoints : OS and PFS
RESULTS: 44 patients initiated therapy between March 2003 and May 2005.
Seventeen patients (40%; 95% confidence interval [CI], 26%-57%) had a partial response
48% had stable disease.
Median PFS was 6.9 months (95% CI, 3.95-7.8 months).
Median survival time was 9.6 months (95% CI, 4.6-16.3 months).
Univariate analyses: sex; ECOG PS, and Charlson comorbidities index (CCI) score proved
predictors of improved survival
Multivariate analyses: female sex was a statistically significant predictor of survival.
– median survivals were 22.8 months in women and 4.8 months in men.
Most common adverse events being hyperglycemia, fatigue.
CONCLUSIONS: Combination docetaxel and gefitinib: active and well tolerated in patients
with advanced NSCLC who are 70 years of age and older; merits further investigation
especially in women
Simon et al Cancer. 2008 May 1;112(9):2021-9.
Randomised phase II trial in
NSCLC pts unsuitable for Platbased CT (Elderly or PS 2)
R
Cetuximab +
Gemcitabine X 6
cycles
Gemcitabine 
Cetuximab at PD
Gridelli C, Mencoboni M, Carrozza F et al. C225 and Gemcitabine
in elderly or adult PS 2 advanced NSCLC pts : the CALC-1 randomized phase II trials.
JCO 2008: 2(15S): 452s (A8117)
Results
Elderly (n=58)
Arm
PFS (mo)
MS
1 yr OS
G+C
3
6
41%
G  C*
4
9
31%
PS 2 (n=42)
Arm
PFS (mo)
MS
1 yr OS
G+C
5.7
10.2
27%
G  C*
2.2
6.5
35%
* 34% of elderly and 60% of PS 2 pts were unable to start C225
maintenance or 2nd line Tx.
Gridelli C, Mencoboni M, Carrozza F et al. C225 and Gemcitabine
in elderly or adult PS 2 advanced NSCLC pts : the CALC-1 randomized phase II trials.
JCO 2008: 2(15S): 452s (A8117)
NCCTG: N0422: Cetuximab (C225) and RT in Elderly
&/or Poor Performance Status Patients with Stage III
NSCLC: A Phase II Study to Evaluate Survival & Toxicity
Eligibility:
– >65 yrs old or younger and PS=2
– Stage III NSCLC
– Adequate organ function
Treatment
– Cetuximab, 400 mg/m2: Day 1
– Then, Cetuximab 250 mg/m2: Days 8, 15, 22, 29,
36, 43+ concurrent RT(60 Gy/30 fxs)
Major endpoint: survival
Inhibition of Tumor Vascularization:
Reduced Metastases and Tumor Volume
Tumors per liver, no.
VEGF mAb
250
Control mAb
226
200
150
100
22
50
0
Control
mAb
VEGF
mAb
Growth of experimental liver metastases
Human CRC xenograft model
– Anti-VEGF mAb–treated animals showed significant
reductions in the mean number of metastases per liver
(10-fold less) and tumor volume (nearly 20-fold less)
Warren et al. J Clin Invest. 1995;95:1789–1799.
rhuMAb VEGF (Recombinant
Humanized Monoclonal
Antibody to VEGF) aka
Bevacizumab
Humanized to avoid
immunogenicity (93%
human, 7% murine).
Recognizes all isoforms of
vascular endothelial growth
factor, Kd = 8 x 10-10 M
Terminal half life 17-21
days
Survival by Tx Arm
12 mo. 24 mo.
44.4% 15.4%
51.0% 22.0%
1.0
PC
PCB
Probability
0.8
P = 0.003
HR: 0.80 (0.65, 0.93)
0.6
Medians: 10.3, 12.3
0.4
0.2
0.0
0
6
12
18
24
30
36
Months
Sandler et al NEJM 12/06
E4599: Outcome*
Arm
RR %
PFS (mo)
MS (mo)
1yr OS %
2 y OS %
CbP
15
4.5
10.3
43.7
16.9
CbPB
35
6.2
12.3
51.9
22.1
* All Differences were statistically significant p< 0.05
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.
Introduction
Elderly patients (> 70 years) account for
approximately 50% of all cases of lung cancer
Elderly patients with a good performance status can
be treated with platin-based two drug combinations
Two drug combinations appear to have superior
efficacy when compared to monotherapy for the
elderly (Lilenbaum et al, J Clin Oncol 2005; Sederholm et
al J Clin Oncol 2005)
In general, when compared to younger patients, the
elderly have:
– Reduced hepatic and renal function
– Altered volume of distribution
– More co-morbid illness
Objectives
To compare the outcomes between carboplatin
and paclitaxel combination (PC) chemotherapy
and PC with Bevacizumab (PCB) for elderly
patients enrolled to ECOG 4599.
To study the differences in safety and efficacy
between elderly and younger patients treated
with PCB in ECOG 4599
Methods
Subset analysis of ECOG 4599 database
Elderly patients defined as those > 70 years of
age at the time of study entry
< 70 years comprised the non-elderly group
Data available as of November 1, 2005 (same
release date as that used for the final ECOG
technical report for the study)
Results
Eligible cases = 850 (PC : n=433; PCB : n=417)
> 70 years: n=224 (26%)
> 80 years: 1.6%
Median age:
– Non-elderly: 63 years
– Elderly: 74 years
Median number of cycles of therapy for patients > 70 yrs
– PC : 5 cycles
– PCB : 7 cycles
Baseline Characteristics
PC
PCB
< 70 yrs
> 70 yrs
< 70 yrs
> 70 yrs
N
320
113
306
111
Female
44%*
34%
53%*
41%
PS 1
61%
60%
56%
70%
Stage IIIB
13%
12%
12%
12%
Adeno/NOS
87%
91%
87%
89%
* Indicates statistically significant difference
Efficacy
Elderly (> 70)
Non-Elderly (< 70)
PC
PCB
PC
PCB
CR+PR
17%
29%
14%
36%
SD
50%
39%
50%
39%
Median
PFS
4.9 m
4.4 m
1-Yr
Survival
Median
survival
50%
5.9 m
P=0.063
46%
6.2 m
P<0.001
53%
11.3 m
P = 0.4
9.6 m
12.1 m
42%
12.8 m
P = 0.0027
PFS in Elderly: PCB vs. PC
Hazard ratio: 0.76 (0.57,1.01)
Overall Survival in Elderly: PCB vs. PC
Toxicity Data for Elderly Patients
Worst Grade Toxicity: PC: 61%; PCB: 87% (P < 0.001)
Grade 4
PC
PCB
P Value
Neutropenia
22%
34%
0.06
Fever with Neutropenia
0.9%
6.2%
0.03
0
3.5%
0.06
Thrombocytopenia
Non-Hematological Toxicity in
Elderly Patients
PC
PCB
P Value
0.9%
6.2%
0.03
0
7.9%
0.002
1.7%
7.9%
0.03
Nausea
0
4.4%
0.03
Anorexia
0.9%
7.9%
0.01
Fatigue
12.9%
20.2%
0.16
Hypertension
Proteinuria
Hemorrhage
Treatment-related Deaths among Elderly
Patients
PC
N = 2 (1.8%)
Infection (n=1)
Cardiac ischemia, Melena/GI bleeding, liver failure (n=1)
PCB
N = 7 (6.3%)*
Infection (n=2)
Hemoptysis (n=2)
Hematemesis (n=1)
Cerebrovascular ischemia (n=1)
Febrile neutropenia (n=1)
* P = not significant
Toxicity on PCB Arm: Elderly vs.
Non-Elderly
Grade 3/4
> 70 yrs
< 70 yrs
P
Neutropenia (Gr 4)
34%
22%
0.02
Melena/GI Bleed
3.5%
0.9%
0.005
Proteinuria
7.9%
1.3%
0.001
Muscle weakness
7.8%
2.2%
0.02
Motor neuropathy
3.5%
0.6%
0.05
Dizziness
7.9%
1.6%
0.003
Worst Grade
87%
70%
< 0.001
TRDs
6.3%
2.6%
0.08
Representation of Elderly Patients in
ECOG phase III Trials for NSCLC
Study
N
> 70 yrs
Proportion
MS
ECOG
5592
ECOG
1594
ECOG
4599
574
86
15%
8.5 m
1207
227
20%
8.2 m
850
224
26%
11.3 m
Conclusions: Elderly
enrolled in E 4599
Proportion of elderly patients on ECOG 4599 is the highest
recorded among ECOG phase III trials.
PCB is associated with higher degree of toxicity in elderly
patients, when compared to treatment with PC alone.
No significant improvement in survival or PFS was noted with
PCB over PC for the elderly (but PC out-performed historic
controls in this study).
When compared to younger patients, the elderly experienced
more toxicity and more TRDs with PCB.
The observations are limited by the post-hoc, retrospective
nature of this analysis.
The safety and efficacy of bevacizumab-chemotherapy
combinations in elderly patients with NSCLC merits further
scrutiny.
An Open-label, Phase II Trial of
nab-paclitaxel, Carboplatin, and
Bevacizumab in first-line
Patients with Advanced NonSquamous Non-Small Cell Lung
Cancer
Reynolds C, Barrera D, Vu DQ, et al.
ASCO 2007, Abstract # 7610
Study Design: ABX036
Open label, nonrandomized, multicenter Phase II study.
Intravenous (IV) Abraxane 300 mg/m2, carboplatin IV
AUC=6, and Bevacizumab 15 mg/kg on Day 1 of each 21day cycle.
Responding patients received minimum of 4 cycles of
treatment.
Bevacizumab was not continued after completion of
chemotherapy
Patients with progressive disease or intolerable toxicity
came off study. Responses were assessed every two
cycles
Patient Characteristics
Patient Characteristics
Overall Responses
Toxicities
Progression Free Survival
Estimated Median PFS (95% CI)
9.8 (6.1, 11.5) months
Survival
Medianoverall
overallsurvival
survival
Median
15.8months
months(95%
(95%CI:
CI:10.4,
10.4,NA))
NA))
15.8
Combination Bevacizumab
and Erlotinib: Results (n=40)
Overall response rate 20% in 2nd and 3rd line
setting
Median TTP = 7.0 months
– 38% FFP @ 12 mos
Median survival = 12.6 months
No unexpected toxicities
Herbst RS et al. J Clin Oncol. 2005;23:2544
Bevacizumab and Erlotinib
Phase II Trial in two separate Txnaïve cohorts:
– PS 2
– Elderly
Schema
– Erlotinib: 150 mg/d
– Bevacizumab: 10 mg/kg Q 2wks
– Tx until PD or unacceptable toxicity
PI: H Borghaei, CJ Langer
Bevacizumab and Erlotinib
Phase II Trial in two separate Txnaïve cohorts:
– PS 2
– Elderly
Schema
– Erlotinib: 150 mg/d
– Bevacizumab: 10 mg/kg Q 2wks
– Tx until PD or unacceptable toxicity
PI: H Borghaei, CJ Langer
Receptor Tyrosine Kinase Inhibitors
Inhibitor
Manufacturer
Vatalanib Novartis-Schering
PTK787/ZK222584
ZD2171
SU11248
Axitinib
AG013736
VEGFR1 VEGFR2 VEGFR3 PDGFR
cKIT
FGFR
+
+
+
+
+
+
+
+
+
+
+
Pfizer / Sugen
-
+
-
+
+
+
Pfizer
+
+
+
+
+
-
AstraZeneca
GW786034 GlaxoSmithKline
Sunitinib
Target
Other
+
BAY43-9006
(Sorafenib)
Bayer
-
+
-
+
RAF /
MEK
ERK
VandetanibZ
D6474
AstraZeneca
-
+
-
-
EGFR
Efficacy Comparison for Antiangiogenic Agents
(Without Chemotherapy)
n
PR (%) SD (%) DCR
PFS* OS†
83
85
8.0
1.0
-
45.0
34.0
11.0
8.1
Crossover
Sunitinib2
63
9.5
43
-
11.3
23.9
Sorafanib3
52
0.0
59
-
11.7
29.5
488
283
8.9
<1
-
45.0
-
9.7
7.7
29.0
20.3
19
0.0
-
NA
12
-
288
283
8.8
9.1
46.4
45.8
-
12.6
12.6
34.0
35.9
ZD64741
Erlotinib4
ZD6474
Gefitinib
Erlotinib
Placebo
Bevacizumab5
Docetaxel/
Premetrexed6
Docetaxel
Premetrexed
*Weeks; †Median weeks; 1Natale RB, ASCO 2006 (abstr 7000); 2Socinski AM, ASCO 2006 (abstr 7001);
3Gatzemeier U, ASCO 2006 (abstr 7002); 4Shepherd FA, NEJM 353(2):123-32, 2005;
5Johnson DH, J Clin Oncol 22(11):2184-88, 2004; 6Hannah N, J Clin Oncol 22(9):158997, 2004
-
Early Stage NSCLC in the
Elderly
Implications of the BR10 Subanalysis
LACE Meta-analysis
Ongoing Trials evaluating Targeted
Therapies
JBR.10 – Outcomes by Patient
Age
T1-2, N0-1 NSCLC
N2 nodes sampled
N = 482
Stratified by:
N0 vs N1
Ras pos, neg, or
unknown
R
A
N
D
O
M
I
Z
E
D
Cisplatin 50 mg/m2 d1, 8
Vinorelbine 30*25 mg/m2/wk x4
N = 242 (*-18 excl. for Vin 30/m2) = 224
Young (≤ 65 years) = 157
Elderly (> 65 years) = 67
No chemotherapy/Observation
N = 240
Young (≤ 65 years) = 162
Elderly (> 65 years) = 78
Pepe, J Clin Oncol. 2007 Apr 20;25(12):1553-61
JBR-10 Outcomes by Age
Worse PS in older; fewer PS0 >65 (53% vs 41%, = 0.01)
adeno>squam in younger, squam>adeno in older pts.
Patients >65 received significantly less chemo
– no significant diffs in toxicity, or growth factor support
– more elderly patients refused treatment
Older patients (>75) had worst survival regardless of Rx,
but same when corrected for disease-specific survival
OS 46% vs. 66% for obs. vs. chemo in pts. >65
OS 58% vs. 70% for obs. vs. chemo in pts <65
Benefit from chemo not seen in pts >75 (?harmful)
– However, patient numbers are too small to answer clearly
Pepe, J Clin Oncol. 2007 Apr 20;25(12):1553-61
Elderly Specific Analyses - BR10: Toxicity
Pepe et al ASCO ’06, A-7009
Cohort
Young (< 65)
Elderly (> 65)
P value
No
150
63
NA
Mean DI - VNR
13.2
9.9
0.0004
Mean DI - DDP
18
14.1
0.001
Non Ca COD
4.8%
16.9%
Other differences re: elderly
– Fewer doses of VNR (p=0.014) and DDP (p=0.006)
– Fewer completed Tx; more refused Tx (p=0.03)
– Less myalgias/arthralgias and mood alterations
No significant difference with respect to other toxicities,
G-CSF use, and hospitalizations
BR10: Overall Survival by Age
Group
1.0
1.0
0-65
N = 327
66-70 N = 84
H-R = 2.38
71-75 N = 48
0.8
Probability
0.8
>75
N = 23
Log-Rank, p = 0.0006
0.6
0.6
63%
0.4
 75
0.4
N = 459
>75 N = 23
0.2
0.2
26%
0.0
0.0
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Time (Years)
Pepe, J Clin Oncol. 2007 Apr 20;25(12):1553-61
E1505: Phase III Trial of Adjuvant
Chemotherapy +/- Bevacizumab
Eligibility:
#Resected IB - IIIA
Lobectomy
No prior chemo
No planned XRT
No h/o CVA/TIA
No ATE w/in 12 mo
Stratification:
Stage
Histology
Gender
Type of Chemo
N=1500
.
*Specified regimens
• Cisplatin and docetaxel
• Cisplatin and vinorelbine
• Cisplatin and gemcitabine
• Cisplatin and pemetrexed
^ > 4 cm
R
A
N
D
O
M
I
Z
E
Chemotherapy*
X 4 cycles
Chemo* x 4 cycles
+
Bevacizumab
x 1 year
• Primary endpoint: overall survival
- 1500 pts to detect 26.5 % difference in Med OS with
85% power and 2.5% type 1 significance level
• Secondary endpoints: disease-free survival, safety
[bleeding and arterial thromboembolic events (ATEs)]
• Biomolecular correlatives
• No age cut-offs
Elderly patients with Advanced
NSCLC: Treatment Principles
Age alone should not be a criterion for treatment
selection in advanced disease
PS is the primary determinant of prognosis in
elderly patients with advanced NSCLC
Dedicated trials in patients aged 70 to 79 with PS
0-1 may no longer be necessary, but we have yet
to show the superiority of a platinum-based
regimen compared to a single agent in an elderly
specific trial
Dedicated studies are urgently needed in
octogenarians
Assessment of co-morbidities and potential
impact on outcome is an important research goal
Targeted Tx in Elderly Patients with
Advanced NSCLC: Basic Tenets
Erlotinib as a single agent is safe and feasible in both
the Tx-naïve setting and in the 2nd/3rd line venue
Bevacizumab in combination with standard
chemotherapy in Tx-naïve NSCLC yields
– improved OR% and a trend toward increased PFS, but
– demonstrates no survival advantage in post-hoc analysis
– And it causes significantly more toxicity, including
neutropenia, FN, GI bleeding, proteinuria, motor neuropathy,
dizziness, and TRDs.
E1505, while it allows elderly pts to be enrolled, does
not permit carboplatin-based therapy.
The role of other molecular-targeted agents and angioinhibitory agents merits further investigation in the
adjuvant setting, especially in the elderly, who are
likely to be under-represented in current chemo-based
adjuvant efforts
You
You are
are never
never too
too old
old to
to
sign
sign up
up for
for this
this protocol
protocol !!
Doc, Give me
the pen……..
You
You are
are never
nevertoo
too old
old to
to
sign
sign up
up for
forthis
this protocol
protocol !!
But first
I have to
sign
those
damn
HIPAA
forms