1. Treatment Strategies in Elderly and PS2 Patients
Rogerio Lilenbaum, MD, FACP
Yale Cancer Center

2. Chronological Age Does Not Equal Functional Age

3. Chemotherapy in elderly patients (≥ 65)
SEER Database between 1997 and 2002
A First-line
n = 21285
B : 2nd line
n = 2026
% pts receiving CT :
20.4% in 1997
27.8% in 2002
Distribution by type of chemotherapy, elderly patients with advanced non–small-cell lung cancer. Chemotherapy designated as first line if initiated within 90 days of diagnosis. First-line chemotherapy includes all agents received during the first 30 days of therapy. Second-line chemotherapy designated when a new chemotherapy agent is received after the initial 30-day period. (A) First-line chemotherapy; and (B) second-line chemotherapy (n = 2,026). Source: Surveillance, Epidemiology and End Results–Medicare,
Davidoff A J et al. JCO 2010;28:

4. Elderly Patients with Advanced NSCLC
In practice, risk is not systematically assessed, and the decision-making process is based primarily on “gestalt”.
Clinicians need an objective, reliable, reproducible, and easy-to-administer “test” of risk that answers:
Can I treat this patient?
How?

5. Risk factors for Gr. 3-5 Toxicity Possible score range: 0-25
Predictive Model II
Risk factors for Gr. 3-5 Toxicity
OR (95% CI)
Score
Age ≥73 yrs vs. <73
1.8 ( ) 2
GI/GU cancer vs. other cancer
2.2 ( ) 3
Standard dose vs. Upfront dose reduction
2.1 ( )
Polychemotherapy vs. monochemotherapy
1.8 ( )
Hemoglobin (male: <11, female: <10)
2.2 ( )
Creatinine Clearance (Jelliffe –ideal wt) <34
2.5 ( )
1 or more falls in last 6 months
2.3 ( )
Hearing impairment (fair or worse)
1.6 ( )
Limited in walking 1 block (MOS)
1.8 ( )
Assistance required in medication intake
1.4 ( ) 1
Decreased social activity (MOS)
1.3 ( )
Possible score range: 0-25
Hurria et al, JCO 2012

6. Prevalence of Toxicity by Score
“High” 83%
( ≥12)
76%
92%
ROC: 0.72
“Mid” 53%
(6 to 11)
45%
63%
100%
80%
“Low” 27%
(0 to 5)
31%
21%
60%
Grade 3-5 Toxicities
40%
20% 0%
0 to 4 5
6 to 8
9 to 11
12 to 13
≥14
N=39
N=64
N=123
N=36
N=50
N=161
Total Score

7. Elderly Selection on Geriatric Index Assessment
ESOGIA-GFPC 08-02
Elderly Selection on Geriatric Index Assessment
Phase III, randomized, multicenter study comparing in elderly patients (≥70 years) with stage IV NSCL a standard strategy of treatment allocation (carboplatin based bi-therapy or monotherapy with docetaxel) based on PS and age with an experimental strategy allocating the same regimen or BSC according to a comprehensive geriatric assessment
Presenting author: R. Corre
Co-authors: C. Chouaid, L. Greillier, H. Le Caer, C. Audigier-Valette, N. Baize, H. Bérard, L. Falchero, I. Monnet, E. Dansin, A. Vergnenegre, M. Marcq, C. Decroisette, S. Bota, R.Lamy, B.Massuti, C. Dujon, G. Fraboulet, J. Minguet, C. Plassot, H. Lena
Presentation 01503

8. hepatic, renal functions
STUDY DESIGN
Non-squamous
Carbo-Pemetrexed
≤ 75 and
PS 0-1
Carbo-Gemcitabine
Squamous R A N D O M I Z T
Based on PS
and age
> 75 and/or
PS 2
Docetaxel
NSCLC > 70 y
PS 0, 1 or 2
Stage IV
No prior chemo
Adequate hemato,
hepatic, renal functions A
Carbo-Pemetrexed
Non-squamous
Fit subjects
Carbo-Gemcitabine B
Squamous
Pre-frailed subjects
Based on CGA
Docetaxel
PS: performance status
CGA: comprehensive geriatric assessment
BSC: Best supportive care
Frailed subjects
BSC
Primary endpoint: Treatment failure-free survival (TFFS) documented progression, death of any cause, exit for toxicity considered unacceptable, or withdrawal of consent
Secondary endpoints: ORR, toxicities, OS, QoL, survival adjusted on QoL
Planned sample size: 490 patients for an expected hazard ratio of 1.30, a power of 80%, a two-sided overall type 1 error of 5%, assuming 5% of dropout patients.

9. TREATMENT FAILURE FREE SURVIVAL (ITT)
OVERAL SURVIVAL (ITT)
Arm A: median OS 6.5 months (95% CI 4.93; 7.7)
Arm B: median OS 6.2 months (95% CI 4.9; 7.8)
p=0.7784
Arm A: median TFF 3.2 months (95% CI 2.91;4.13)
Arm B: median TFF 3.2 months (95% CI 2.66;4.43)
p=0.7149
Arm A (PS,age) n=241
Arm B (CGA) n=232
C-pem
N=62
(25%)
C-Gem
N=21
(9%)
Doc
N=158
(66%)
N=84
(36%)
N=25
(11%)
N=73
(32%)
BSC
N=50
(21%)
mTFF (months)
4.4
4.53
3.1
4.9
4.8
2.7
1.3
mOS (months)
8.9
6.3
5.9
10.2
8.4
2.9

10. Elderly Patients with Advanced NSCLC
MILES
G V GV
Swedish
G CG
CALGB
9730
P CP
Pts
ORR (%)
MST (mo)
1-Y Surv (%)
Gridelli et al. JNCI 2003; Sederholm et al. JCO 2006; Lilenbaum et al. JCO 2005

11. IFCT Study Schema R A N D O M NSCLC Stage III-IV Age 70-89 years
PS 0-2
n = 451 R A N D O M
Vinorelbine or
Gemcitabine*
Erlotinib**
150 mg/d
Carboplatin +
Paclitaxel
451 patients with advanced NSCLC aged between 70 and 89 years and a PS of 0 to 2 ,were randomised 1 to 1 between single agent therapy with either vinorelbine or gemcitabine and the doublet of carboplatin and paclitaxel. At progression or in case of excessive toxicity, both arms were switched to erlotinib 150 mg/d.
Stratification by centre, PS 0-1 vs. 2, age ≤80 vs. >80 and stage III vs. IV
*Choice of the center at the beginning of the study; ** In case of PD or excessive toxicity
Quoix E et al: Lancet Sep 17;378(9796): 11

12. Patients characteristics
All Patients
(N=451)
Single Arm
(N=226)
Doublet Arm
(N=225)
p-value
Sex
0.272
Male
333 (73.8)
172 (76.1)
161 (71.6)
Age
0.588
Median
77.1
76.9
77.4
Range
Performance status
0.916
0-1
327 (72.7)
163 (72.4)
164 (72.9)
2-3
123 (27.3)
62 (27.6)
61 (27.1)
Stage
0.703 IV
364 (80.7)
184 (81.4)
180 (80)
Histology
0.910
Squamous
151 (33.5)
74 (32.7)
77 (34.2)
ADC
229 (50.8)
115 (50.9)
114 (50.7)
Other
71 (15.7)
37 (16.4)
34 (15.1)
Smoking status
0.487
Never smoker
94 (20.9)
50 (22.2)
44 (19.6)
Patients characteristics were well balanced between the two arms ; almost three quarters were males, median age was 77.
More than seventy percent of the patients had a PS of 0 or 1 and 80% had stage IV disease. A third of the patients had squamous cell histology and 50% adenocarcinoma.
As usual in elderly patients neversmokers represented as many as 20% of the patients

13. Overall survival Doublet Single agent Doublet Singlep o b t y
MST = 10.3 months (95% CI
1-year survival 45.1% (95% CI )
Doublet
Single agent
MST = 6.2 months (95% CI )
1-year survival 26.9% (95% CI ) p=
Doublet
Single
This improvement in PFS is reflected in the overall survival with a benefit of 4 months in median overall survival time for the doublet arm, with 45% vs 27% of patients surviving 1 year.
As you can see, median overall survival time and one year survival time in the single agent arm were near those predicted by previous studies in elderly patients whereas the median survival time and one year survival in the doublet arm are at least as one would expect in a general population of ‘any age’, with advanced NSCLC and a PS 0 to 2.
Months 6 12 18 24 30 36 42
Single
226
112 45 11 4 1
Doublet
225
150 78 46 14 7 13

14. PointBreak
Randomized, open-label, phase III superiority study conducted in US
Pemetrexed 500 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg
Paclitaxel 200 mg/m2; Carboplatin AUC 6; Bevacizumab 15 mg/kg
Induction Phase 4 cycles, q21d
Maintenance Phase
q21d until PD
Inclusion:
- No prior systemic therapy for lung cancer
- ECOG PS 0/1
- Stage IIIB-IV NS-NSCLC
- Stable treated brain mets allowed
Exclusion:
Peripheral neuropathy ≥Grade 1
- Uncontrolled pleural effusions
Pemetrexed +
(folic acid & vitamin B12 )
Carboplatin +
Bevacizumab
Pemetrexed +
(folic acid & vitamin B12 ) Bevacizumab
R 1:1
450 patients each
Paclitaxel +
Carboplatin + Bevacizumab
Bevacizumab
Primary Endpoint: Overall Survival
Socinski M, et al. ASCO 2013

15. Progression-Free and Overall Survival
Pem+ Cb+Bev
Pac+ Cb+Bev
OS median (mo)
12.6
13.4
HR (95% CI); P value
1.00 (0.86, 1.16); P=0.949
Survival rate (%)
1-year
52.7
54.1
2-year
24.4
21.2
Pem+ Cb+Bev
Pac+ Cb+Bev
PFS median (mo)
6.0
5.6
HR (95% CI); P value
0.83 (0.71, 0.96); P=0.012
ORR (%)
34.1
33.0
Time from Induction (months)
Time from Induction (months)

16. Overall Survival in Age Subgroups
Median Survival Time (months)
Pem+Cb+Bev
Pac+Cb+Bev
≤70
12.55
(95% CI: 11.10, 14.03)
14.26
(95% CI: 12.42, 15.21)
>70
12.65
(95% CI: 10.41, 16.85)
11.47
(95% CI: 8.05, 14.29)
>75
11.83
(95% CI: 7.16, 16.10)
8.94
(95% CI: 7.03, 14.29)
─ Pem+Cb+Bev ≤70
─ Pem+Cb+Bev >70
─ Pem+Cb+Bev >75
▪▪▪ Pac+Cb+Bev ≤70
▪▪▪ Pac+Cb+Bev >70
▪▪▪ Pac+Cb+Bev >75

17. Efficacy and Safety of Paclitaxel and Carboplatin With Bevacizumab for the First-Line Treatment of Patients With Nonsquamous Non–Small Cell Lung Cancer (NSCLC): Analyses Based on Age in the Phase III E4599 and PointBreak Trials
CJ Langer,1 MA Socinski,2 JD Patel,3 AB Sandler,4 JH Schiller,5 L Leon,4 SJ Hazard,4 SS Ramalingam6
1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; 2University of Pittsburgh Medical Center, UPMC Cancer Pavilion, Pittsburgh, PA; 3Feinberg School of Medicine, Northwestern University, Chicago, IL; 4Genentech, Inc., South San Francisco, CA; 5Harold C. Simmons Cancer Center, University of Texas Southwestern, Dallas, TX; 6Winship Cancer Institute of Emory University, Atlanta, GA

18. Results: OS and PFS in the Pooled Population vs E4599
OS for pts treated with PC + Bev vs PC alone in the (A) pooled population of E4599 and PointBreak and in the (B) E4599 trial only PFS for pts treated with PC + Bev vs PC alone in the (A) pooled population of E4599 and PointBreak and in the (B) E4599 trial only A. B.
Age Group n HR
95% CI
<65
735
0.75
0.62–0.89
65–74
453
0.80
0.64–1.00
70–74
203
0.68
0.48–0.96
<75
1188
0.78
0.68–0.89
≥75
157
1.05
0.70–1.57
Age Group n HR
95% CI
<65
499
0.76
0.62–0.92
65–74
277
0.80
0.61–1.05
70–74
129
0.62
0.40–0.96
<75
776
0.78
0.66–0.92
≥75
102
1.18
0.76–1.83
0.4
0.6
0.8
1.0
1.2
1.4
1.6
0.4
0.6
0.8
1.0
1.2
1.4
1.6 A. B.
Age Group n HR
95% CI
<65
735
0.71
0.60–0.85
65–74
453
0.62
0.49–0.78
70–74
203
0.57
0.40–0.81
<75
1188
0.69
0.60–0.79
≥75
157
0.95
0.62–1.44
Age Group n HR
95% CI
<65
499
0.66
0.54–0.80
65–74
277
0.55
0.41–0.73
70–74
129
0.54
0.35–0.84
<75
776
0.63
0.54–0.74
≥75
102
0.91
0.57–1.43
0.4
0.6
0.8
1.0
1.2
1.4
1.6
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Bev, bevacizumab; CI, confidence interval; E4599, Eastern Cooperative Oncology Group 4599 ; HR, hazard ratio; OS, overall survival; PC, paclitaxel + carboplatin.

19. Results: Safety in E4599
Incidence of gr 3–5 AEs was significantly higher for PCB vs PC alone Rates for discontinuations due to AEs also higher for PC + Bev vs PC alone
Age
PC + Bev PC
Grade 3–5 toxicitya <75 years
63%
48%
Grade 3–5 toxicitya ≥75 years
81%
56%
Grade 5 toxicity ≥75 years 8% 2%
aP <.005
Age
PC + Bev PC
<75 years
17% (65/375)
12% (49/401)
≥75 years
29% (17/59)
19% (8/43)

20. ECOG PS in NSCLC patients at presentation
> 200,000 new cases diagnosed in US in 2008 according to ACS estimates
After D. Cella from BIOQOL/Q-SCORE database (n=493)

21. SWOG Phase II Trial of Sequential Vinorelbine + Docetaxel in Elderly or Poor PS Patients with Advanced NSCLC
Hesketh et al. JTO 2006

22. Erlotinib vs. Chemotherapy in PS 2 PatientsD O M I Z E
1:1
Erlotinib
150 mg daily
Stratified by:
Center
Age (< 70 vs > 70)
Extent of Disease (Stage IIIB vs IV)
Carboplatin AUC 6 +
Paclitaxel
200 mg/m2
Day 1 q 21 days x 4 cycles
Optional
Cross-over to Erlotinib
Lilenbaum et al. JCO 2008

23. Erlotinib vs. Chemotherapy in PS2 Patients
Arm
E = 52
CP = 51
OOR (%) 4 12
SD (%) 37 43
PD (%) 44 20
PFS (mo)
1.9
3.5
MST (mo)
6.6
9.5
1y OS (%) 21 45
Lilenbaum et al. JCO 2008

24. Phase III Randomized Trial Pemetrexed vs
Phase III Randomized Trial Pemetrexed vs. Carboplatin and Pemetrexed in Patients with Advanced NSCLC and PS of 2
Pemetrexed
500 mg/m2 IV Q3W
Arm A
Eligibility:
Stage IIIB/IV NSCLC
(malignant effusion)
ECOG PS 2
No prior chemotherapy
Stable CNS disease
Measurable disease
Adequate organ function
(including GFR≥ 45 ml/min)
Signed informed consent
R A N D O M
I Z A T I O N
1:1
Stratification factors:
Stage: IIIB vs IV
Age: ≥70 vs <70
Wt loss: ≥5% vs <5%
X 4 cycles
Pemetrexed
500 mg/m2 IV Q3W +
Carboplatin
AUC 5 IV Q3W
n=137*
Arm B
Primary endpoint:
Overall Survival PD
Secondary endpoints:
Progression-free survival
Overall response rate
Safety
Pre-medications:
Vitamin B12: 1mg IM Injection
Folic Acid: 350-1,000mcg po daily
Dexamethasone 4mg po BID the day
before, the day of, and the day after
Lilenbaum et al. ASCO 2012 5 24

25. Patient Characteristics
CP (n=103)
Median age (range)
≥70 y (%)
65 (40-86)
(35.2)
65 (41-90)
(36.8)
Male / Female (%)
58.8 / 41.2
63.1 / 36.9
Stage IIIB / IV (%)
4.9 / 95.1
5.8 / 94.2
≥5% Weight loss (%)
53.9
51.4
Histology (%)
Adenocarcinoma
Squamous cell
Unknown
80.4
10.8
4.9
81.6
2.9
5.8
Smoking Status (%)
Current
Former
Never
66.7
22.5
17.5
60.2
22.3
Co-Morbidities (%)
Hypertension
COPD
Diabetes Mellitus
45.1
17.6
7.8
44.7
11.7
12.6
p=0.123 25

26. OVERALL SURVIVAL P CP Median, months 5.6 9.1 OS at 6 months, % 50 6518 43
HR=0.57 (0.41–0.79); p=0.001 CP P

27. PS 2 Elderly Quoix et al Lilenbaum et al P CP Median, months 5.6 9.1
OS at 6 months, % 50 65
OS at 12 months, % 18 43
MST = 10.3 months
1-year survival 45.1%
MST = 6.2 months
1-year survival 26.9%

28. Bev in PS 2 Advanced NSCLC: TOPPS
Pemetrexed 500 mg/m2 IV q 21 days R A N D O M I Z E
Chemotherapy-naive
patients with stage IIIB (with pleural effusion) or IV NSCLC and ECOG PS 2
Pemetrexed 500 mg/m2 IV q 21 days
Bevacizumab 15 mg/kg IV q 21 days
Carboplatin AUC=5 IV q 21 days Pemetrexed 500 mg/m2 IV q 21 days
Bevacizumab 15mg/kg IV q 21 days
Primary Objective:
PFS Secondary Objectives: ORR
Toxicity OS
Spigel, Lilenbaum, et al. 28

29. Bevacizumab-Related Toxicity (N=106)
Number of Patients (%) G1 G2 G3 G4
ARM 2
ARM 3
Thromboembolic event
0.0% 3
5.8%
5.6% 4
7.7% 1
1.9% 2
3.8%
Hypertension
3.7%
7.4%
Hemorrhage 10
19.2% 2%
Proteinuria 7
13.0%
Wound-healing complication
Osteonecrosis of the Jaw
Perforation
Fistula
CHF

30. Progression Free Survival (N=163)
Arm 1 (N=48)
Arm 2 (N=59)
Arm 3 (N=56)
Pem Only
Pem + Bev
Pem + Bev+ Carbo
Median PFS (95% CI)
2.6 (1.5, 5.1)
3.5 (2.4, 5.1)
4.1 (3.0, 6.4)
12-month PFS (95% CI)
0.05 (0.01, 0.16)
0.10 (0.03, 0.22)
0.16 (0.06, 0.29)

31. Elderly and PS2 Patients
Assessment of risk in elderly patients can be done objectively by reproducible instruments
At this time, it does not appear that a CGA-directed treatment algorithm is superior to MD choice (based on age and PS)
For elderly and PS 2 patients, a carboplatin doublet leads to an improvement in survival compared to single agent therapy at the cost of increased toxicity
Targeted agents are best used in patients selected by molecular criteria
Bevacizumab can be safely used in PS 2 patients but not in the “old elderly”