Elderly and Performance Status 2 Patients With Advanced...

Management of Special Populations with

Advanced NSCLC:

The Elderly (age > 70) and

PS 2 Patients

Corey J Langer MD, FACP Professor of Medicine

Director of Thoracic Oncology University of Pennsylvania

Corey.langer@uphs.upenn.edu

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

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)

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

Stratification

Institution

Stage IV/IIIB

PS 0-1/2

Docetaxel (D)

Docetaxel

60 mg/m2

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

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

Stage III-IV

Age 70-89 years

PS 0-2

n = 451

Vinorelbine

Gemcitabine*

Carboplatin +

paclitaxel

Erlotinib**

150 mg/d

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

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

ARM B C

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)

Gender

129 (78.7%)

43 (69.4%)

172 (76.1%)

161 (71.6%)

Median age

70.1 - 88.8

70.1- 88.0

70.0 - 88.8

115 (70.1%)

49 (29.9%)

50 (80.6%)

12 (19.4%)

165 (73%)

61 (27%)

164 (72.9%)

61 (27.1%)

IIIA-B

35 (21.3%)

129 (78.7%)

7 (11.3%)

55 (88.7%)

42 (18.6%)

184 (81.4%)

46 (20.4%)

179 (79.6%)

Histology

Squamous

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%)

Never smokers 33 (20.2%) 17 (27.4%) 50 (22.2%) 44 (19.6%) 0.49

Patients characteristics (2) Single agent (n= 226)

G (n = 164) V (n = 62) All

Doublet

(n= 225)

Mini Mental S

25 (15.8%)

133 (84.2%)

9 (14.5%)

53 (85.5%)

34 (15.5%)

186 (84.5%)

36 (16.2%)

186 (83.8%)

ADL score

124 (80%)

31 (20%)

51 (83.6%)

10 (16.4%)

175 (81%)

41 (19%)

176 (79.3%)

46 (20.7%)

Charlson‟s Ind.

120 (79.5%)

31 (20.5%)

43 (71.7%)

17 (28.3%)

163 (77.3%)

48 (22.7%)

161 (74.9%)

54 (25.1%)

Weight loss

[5-10%]

58 (36.5%)

57 (35.8%)

44 (27.7%)

25 (41%)

15 (24.6%)

21 (34.4%

83 (37.7%)

72 (32.7%)

65 (29.5%)

115 (51.3%)

55 (24.6%)

54 (24.1%)

]20 - 25]

[26 – 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%)

Response rate at 6 weeks (ITT)

Single Agent

Arm A (n = 211)

Doublet

Arm B (n = 210)

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

Doublet

Neutropenia 7 (4.7%) 23

(37.7%)

(14.3%)

(54.3%)

< 10-5

Febrile neutropenia 0

(9.84%)

(2.9%)

(9.6%)

Anemia 3

(2.01%)

(9.84%)

(4.3%)

(7.7%)

Thrombocytopenia 2

(1.34%)

(6.3%)

*3 patients did not receive any dose of CT

Non hematological toxicity

(418 evaluable patients) Grade 3-4 Arm A Single agent

Gem VNR All

n =149 n=61 n=210

Doublet

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

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)

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)

Exploratory Sub-group analysis N HR 95%

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

Multivariate analysis of survival (Cox model)

N=407 (patients without any missing data)

Variables Hazard ratio [95% CI] p

0.639 [0.51-0.801]

0.0001

PS 0-1

0.580 [0.45-0.747]

0.00026

Smoking history

0.664 [0.488-0.90]

0.0092

Histology

Squamous

0.679 [0.497-0.929]

0.843 [0.507-1.17]

0.0155

0.3072

0.653 [0.495-0.861]

0.0025

Weight loss

≤ 5%

0.669 [0.527-0.85]

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

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)

(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

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

254 (49)

228 (44)

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

137 (26)

168 (32)

214 (41)

144 (27)

148 (28)

234 (44)

281 (27)

316 (30)

448 (43)

Primary Endpoint Results

Objective Responses – ITT

Response Ratio = 1.31

(1.082 – 1.593)

P = 0.005

Independent

Radiologic Review

Ab-P/C

) 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

26% 24% 25%

50% Ab-P/C

Interaction p-

Value for

Histology: 0.036

Squamous

Histology

Squamous

Histology

PFS – ITT Population P

Months

Pt at risk

Ab-P/carboplatin (N=521)

paclitaxel/carboplatin (N=531)

0 3 6 9 12 15 18 21 24 27 30 33

1.00 Ab-P/

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

Months

Pt at risk

148 98

Ab-P/carboplatin (N=521)

Paclitaxel/carboplatin (N=531)

0 3 6 9 12 15 18 21 24 27 30 33

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

North America

Russia/Ukraine

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

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

North America

Russia/Ukraine

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

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

Docetaxel alone (D)

Docetaxel

60 mg/m2

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

III / IV or relapse

<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 3 6 9 12 15 18 21 24 27

Months after randomization

*by stratified log-rank with age, one-sided

Abe et al ASCO 2011

Hematological Toxicity(CTCAE v3.0)

(N=134)

(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)

(N=131)

CR 0 0

PR 31 45

SD 66 48

PD 16 15

NE 3 9

[95% C.I.]

[17.4-33.1]

[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 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*

Data cut-off: Nov/2010 * log-rank test, one-sided

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

Months after randomization *stratified log-rank by age, one-sided

Data cut-off: Nov/2010

0 3 6 9 12 15 18 21 24 27

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 3 6 9 12 15 18 21 24 27

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

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

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

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 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

1-2 4.8

>2 3.7 82%

‡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

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)

Female 12.58 (111) 8.54 (15)

Male 9.86 (219) 6.74 (50)

Female 7.77 (214) 6.95 (102)

Male 6.70 (421) 5.08 (224)

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

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

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

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

Paclitaxel 225 mg/m2

Carboplatin (AUC 6)

Chemotherapy-

naïve PS2

patients with

advanced

NSCLC Stratified by:

History of brain mets

Geographic region

PPX 210 mg/m2

Carboplatin (AUC 6)

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

0 100 200 300 400 500 600 700 800

Time From Randomization (Days)

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)

STELLAR 4: Trial Design

Gemcitabine 1000 mg/m2

days 1, 8, and 15

every 28 days

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

400 500 600 700 800

Time From Randomization (Days)

PPX Gemcitabine/ Vinorelbine

PPX vs. Gemcitabine/Vinorelbine (Intent-to-Treat)

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

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

Erlotinib

150 mg daily

Carboplatin

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

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

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

Elderly and Performance Status 2 Patients With Advanced...

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