ADVANCED NSCLC

Corey J. Langer, M.D.Co-Director, Thoracic Oncology

Fox Chase Cancer CenterPhiladelphia, PA 19111

Special Populations PS 2 Elderly

PS 2 and ElderlyNSCLC

• NEGLECTED SUBSETS

• BASIC UNADDRESSED QUESTIONS

• CONSTITUTE > 2/3 OF NEWLY DX’D ADVANCED NSCLC

IS THERE OPTIMAL TXFOR THE ELDERLY WITH

ADVANCED NSCLC?

Objectives• Public Health Perspective• Cooperative Group Elderly NSCLC

Subanalyses• Isolating role of Platinum (Carbo)• Evidence-based literature: ELVIS, SICOG,

MILES, etc.• Future Directions

The U.S. Population Is Aging

0

50

100

150

200

250

300

350

1950 1990 2030

65 years65 years65 years65 years

Yancik R, et al. Hematol Oncol Clin North Am. 2000;14:17–23.

NumberNumberof personsof persons(in millions)(in millions)

8.1%12.7%

20.0%

Cancer Risk Increases With Age

00

1010

2020

3030

4040

5050

00––3939 4040––5959 6060––7979

MaleMale

FemaleFemale

Risk Risk (%)(%)

AgeAge

American Cancer Society. American Cancer Society. Cancer Facts & Figures 2000Cancer Facts & Figures 2000. Atlanta, GA; 2000.. Atlanta, GA; 2000.

33.733.7

9.29.28.28.2

1.91.91.61.6

22.222.2

Incidence of Lung Cancer Increases With AgeU.S. incidence of lung cancer by ageU.S. incidence of lung cancer by age

Yancik R, et al. Comprehensive Geriatric Oncology. 1998:95–104.

600600

500500

400400

300300

200200

100100

003535 4040 4545 5050 5555 6060 6565 7070 7575 8080 85+85+

AgeAge

MenMen

WomenWomen

Incidence(per 100,000)

Elderly Lung Cancer Patients are Under-Represented on Clinical Trials

• 60% of lung cancer patients are 60• 35% - 40% of lung cancer patients are 70• Elderly representation on N.A. Trials

Study % 70E5592 15%S9509/9305 19%E5594 20%

CALGB 9730 27%UNC 29%

Explanations for Under-Representation on Clinical Trials

• Therapeutic nihilism

• Misperception

• Societal pressure (UK > EUR > NA)

• Increased co-morbidity or “unfitness” (??)

ECOG 5592: Elderly Data

• RANDOMIZATION cDDP 75 mg/m2 &– Etoposide 100 mg/m2 d 1-3– Paclitaxel 135 mg/m2/24o d 2– Paclitaxel 250 mg/m2/24o d 2 + G-CSF

• BREAKDOWN by Elderly ( 70) v “Young” (<70)– Elderly: cardiovascular (p=0.0089) + resp (p=0.0441) co-morbidities

Age N RR(%) TTP (mo) MS (mo) 1 YS (%) 2YS (%)<70 488 21.5 4.37 9.05 38 1470 86 23.3 4.30 8.53 28 12P 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

Should Older Patients Receive Combination Chemotherapy For

Advanced Stage Non-Small Cell Lung Cancer (NSCLC)? An Analysis of

Southwest Oncology Trials 9509 and 9308

Karen Kelly, Sheryl Giarritta, Stephen Hayes, Wallace Akerley, Paul Hesketh, Antoinette

Wozniak, Kathy Albain, John Crowley, David R. Gandara

OBJECTIVES

To determine the effect of age > 70 on

survival, toxicity, and drug delivery in

patients with a good performance status

(PS) 0 - 1 receiving combination

chemotherapy for advanced stage NSCLC.

RATIONALE

1. Adults of advanced age constitute a growing proportion of patients with metastatic NSCLC.

2. Older lung cancer patients often present with a decreased PS and/or co-morbidities.

3. Appropriate treatment options must be

identified for this group of patients.

METHODS

A retrospective analysis was conducted on two recent SWOG trials in advanced NSCLC:

SWOG 9509Paclitaxel + Carboplatin versusVinorelbine + Cisplatin

SWOG 9308Vinorelbine + Cisplatin versus Cisplatin

METHODS

1. The analysis identified two age groups:

patients < 70 years of age and patients

> 70 years of age.

2. The cohorts were compared for:

a) baseline characteristics

b) efficacy of treatment

c) toxicity

d) drug delivery

RESULTS

Paclitaxel/Carbo (N = 202)

Vinorelbine/Cis* (N = 406)

Total (N = 608)

Age < 70 164 (82%) 327 (81%) 491 (71%)

Age > 70 38 (18%) 79 (19%) 117 (19%)

* Total number of patients from SWOG 9509 and 9308

Number of Evaluable Patients by Age and Treatment

RESULTS

Patient Characteristics

Patient characteristics were similar between the two groups except for stage of disease in which there was a trend toward higher stage in younger patients

Variable Age <70 Age 70 Total p-value

Stage IIIB 45 (9%) 17 (15%) 62 (10%) .08

IV 446 (91%) 100 (85%) 542 (90%)

PS 0 178 (37%) 37 (33%) 215 (36%) .45

1 309 (63%) 76 (67%) 385 (64%)

Weight loss <5% 261 (55%) 63 (56%) 324 (55%) .84

5% 216 (45%) 50 (44%) 266 (45%)

RESULTS

< 70(n=490)

> 70 (n=115) P-value

Hem Gr 0-2 119 (24%) 20 (17%)

Hem Gr 3-5 371 (76%) 95 (83%) .11*

Non-Hem Gr 0-2 225 (46%) 50 (44%)

Non-Hem Gr 3-5 265 (54%) 65 (56%) .63*

Max Tox Gr 0-2 60 (12%) 7 (6%)

Max Tox Gr 3-5 430 (88%) 108 (94%) .06*

Toxicity

* p-value for all grades of toxicities

RESULTS

< 70 (n=475) > 70 (n=112) P-value

% Planned Dose 57% 54% .32

Completed PCb 49/153 (32%) 12/34 (35%) .35*

Completed VC 32/322 (10%) 3/78 (4%)

Off for toxicity: PCb 418/165 (11%) 6/37 (16%) .37 VC 93/325 (29%) 36/78 (46%) .003

Drug Delivery: SWOG 9509, 9305

PCb - Paclitaxel + CarboplatinVC - Vinorelbine + Cisplatin* p-value for comparison by age

RESULTS: Elderly S9305, 9509Efficacy

<70 70(n=491) (n=117) p-value

TTP (mo) 4.2 3.9 .62

Median Survival (mo) 8.6 6.9 .06

1 Yr OS 40% 30% ----

2 Yr OS 16% 10% ----

In a multivariate analysis including age, treatment arm, stage, PS and weight loss, there was no effect of age on PFS (p=.74) or survival (p=.10) …Kelly et al., ASCO 2001, A-1313

CONCLUSIONS

1. Relatively few older patients (19%)

entered these cooperative group trials.

2. There was a trend toward shorter

survival in older patients (p=.06).

3. Grade 3-5 toxicities occurred more

frequently in older patients (p=.06).

CONCLUSIONS

4. Fewer patients of any age were able to

complete VC compared to PCb.

5. A significantly larger number of older

patients discontinued VC due to toxicity

as compared to PCb.

6. Trials should be specifically designed for

this population.

FUTURE PLANS

SWOG 0027 A phase II trial of vinorelbine followed by

docetaxel in advanced NSCLC patients with a PS of 2 or Age > 70 years old

Vinorelbine25 mg/m2, d 1 & 8 every 3 weeks x 3

Docetaxel35 mg/m2 weekly 3/4 weeks x 3

TAX326: Study Design

RANDOMIZE

Docetaxel 75 mg/m2 IV + Cisplatin 75 mg/m2 IV q 3 wk

Docetaxel 75 mg/m2 IV + Carboplatin AUC 6 IV q 3 wk

Vinorelbine 25 mg/m2 IV d 1, 8, 15, 22 + Cisplatin 100 mg/m2 IV d 1 q 4 wk

Premed: Dexamethasone 8 mg PO bid 6 doses (first dose 12 hours prior to Docetaxel infusion) for the Docetaxel groups.

: Stratification by

• Stage (IIIB or IV)

• Geographic region

Fossella FV. Eur J Cancer 2001;37(suppl 6):S154. (abstr & oral presentation 562)

Survival Time (Mos.)

Cu

mu

lati

ve P

rob

ab

ility

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

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

DocetaxelCisplatinVinorelbineCisplatin

P = 0.044(adjusted log-rank)

SURVIVAL All patients D+CIS VS. V+CIS: Non-inferiority vs improved survival

TAX326

Tax 326 Elderly SubanalysisDocetaxel-Cisplatin

All 65

N 408 148

OR% 32 NA

MS (mo) 10.9 12.6

1 yr OS% 38 52

2 yr OS% 21 24

Tax 326 Elderly SubanalysisDocetaxel-Carboplatin

All 65

N 406 114

OR% 24 NA

MS (mo) 9.1 9.0

1 yr OS% 38 52

2 yr OS% 16 17

Tax 326 Elderly SubanalysisVinorelbine-Cisplatin

All 65

N 404 126

OR% 25 NA

MS (mo) 10 10.3

1 yr OS% 42 41

2 yr OS% 14 17

% Grade 3/4 Nonhematologic Toxicity: Docetaxel/Cisplatin

169Neurotoxicity

86Diarrhea

127Infection

1411Asthenia

1213N/V

114287No.

Age 65Age <65

% Grade 3/4 Nonhematologic Toxicity: Docetaxel/Carboplatin

117Neurotoxicity

46Diarrhea

188Infection

1310Asthenia

39N/V

114 288No.

Age 65Age <65

% Grade 3/4 Nonhematologic Toxicity: Vinorelbine/Cisplatin

1614Neurotoxicity

33Diarrhea

107Infection

1713Asthenia

2618N/V

128 268No.

Age 65Age <65

TAX 326 Elderly Conclusions

• Survival benefit is independent of age

• Modest increase in toxicity in elderly

• Docetaxel/Carboplatin is well tolerated in elderly NSCLC patients

E1594 Schema

RANDOMIZE

Stratification Performance status0-1 vs. 2

Weight loss inprevious 6 months<5% vs. 5%

Disease stage IIIBor IV

Presence or absence of brain metastases

Arm A: Cisplatin + PaclitaxelPaclitaxel: 135 mg/m2 over 24 hours, day 1Cisplatin: 75 mg/m2 day 2 3-week cycle

Arm B: Cisplatin + GemcitabineGemcitabine: 1,000 mg/m2 days 1,8,15Cisplatin: 100 mg/m2 day 1 4-week cycle

Arm C: Cisplatin + DocetaxelDocetaxel: 75 mg/m2 day 1Cisplatin: 75 mg/m2 day 1 3-week cycle

Arm D: Carboplatin + PaclitaxelPaclitaxel: 225 mg/m2 over 3 hours, day 1Carboplatin: AUC 6.0 day 1 3-week cycle

0 5 10 15 20 25 30

Months

0.0

0.2

0.4

0.6

0.8

1.0

Survival by Treatment Group Stage IV

Cis/PaclitaxelCis/GemcitabineCis/DocetaxelCarbo/Paclitaxel

ECOG 1594

• 1207 pts enrolled• 227 (20%) 70 years; 9 (1%) 80 yrs• Demographics similar for pts 70 yrs and

<70 yrs• Septuagenarians: signif more cardiac

(p<0.0001) & other non-cardiorespiratory co-morbidities (p=0.008, Fisher’s exact test)

ECOG 1594: Outcome Based on AgeAge Cohort <70 yrs 70 yrs p value

No. 912 227

Completion of 6 cycles 34% 30% 0.36

Gr 4 toxicity 66% 71.2% 0.04

Median no. of cycles 4 3 0.24

OR(%) 22.1 24.5 0.76

PFS (mo) PS 0-1 3.71 3.75

PFS 1yr (%) 6.5 8.6 0.37

PFS 2yr (%) 0.5 2.2 0.04

MS (mo) 8.15 8.25

1yr OS(%) 32.8 35.2 0.53

2yr OS(%) 10.6 13.7 0.24

Outcome in Patients 80 Years of Age: E1594

Age range 70-79 80 p valueNo. 215 9Tx completion (6 cycles) 32.5 0*OR (%) 21.5 0 0.16PFS (mo) 3.7 2.2 0.16MS (mo) 8.2 4.2 0.09

CONCLUSION: Low numbers preclude broad inferences, but octogenarians with advanced NSCLC, even though fit, fared no better than PS 2 patients.

*Tx completion No.1 cycle 22 cycles 33 cycles 34 cycles 1

Elderly Subanalysis:PCb X 4 vs PCb (indef)

AGE <70 (n=163) 70 (n=67)

Gr 2 Toxicity (%)

Neutropenia 38 35

Anemia 9 13

Thrombocytopenia 7 9

Peripheral Neuropathy 13 16

Nausea/Vomiting 14 15

Myalgia 15 9

Fatigue 8 15

Outcome

Median Survival (mos) 7.8 7.1

1-Year Survival (%) 30 34

2-Year Survival (%) 15 9…Hensing, Socinski et al., Proc ASCO 2001, A-1382

CALGB 9730: CbT v T

RAND

Carboplatin AUC 6 Q 3 wkPaclitaxel 225 mg/m2 Q 3 wk

Paclitaxel 225 mg/m2 Q 3 wk

N=584 Tx-naïve advanced NSCLC; accrued 10/97 - 1/01

Well balanced with respect to stage (III vs IV), gender (M v F), PS (0/1 vs 2)

Demographics: 156 (27%) >70 yrs; 399 M; 100 PS 2…A-2 ASCO 2002, Lilenbaum

CALGB: Results

• Response rates significantly better for carboplatin/paclitaxel vs paclitaxel (30% vs 16%, P<.0001)

• Median survival after 12.5 m follow-up significantly better for carboplatin/paclitaxel vs paclitaxel (8.8 m vs 6.7 m, P<.023)

• 1-year survival not significantly different for carboplatin/paclitaxel (37% vs 33%)

Lilenbaum et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 2

CALGB 9730

Overall Elderly

P PCb P CbN 287 284 98 77

OR% 17 29 21 36FFP (m) 2.5 4.6 NA NA

MST (m)* 6.7 8.8 5.8 8.011 yr OS% 33 37 31 35

*p=0.1014

Role of SchedulePaclitaxel-Carbo (RP2)

R

A

N

D

Arm 1) PACLITAXEL 100 mg/m2 Q wk X 3 Q 4 wk CARBOPLATIN AUC 6 Q 4 wkArm 2) PACLITAXEL 100 mg/m2 Q wk X 3 Q 4 wk CARBOPLATIN AUC 2 Q wk X 3 Q 4 wkArm 3) PACLITAXEL 150 mg/m2 Q wk X 6 Q 8 wk CARBOPLATIN AUC 2 Q wk X 6 Q 8 wk

Arm 2

…Belani, ASCO 2001, A1287

Response Rates at 8 Week Follow-up

Arm 1 Arm 2 Arm 3

Week 8 CR-PR (%) 35 38 31

Week 16 CR-PR (%) 32 24 18

Median survival (wks) 49 30 40

Conclusion

• Arm 1: best Tx index

• Best survival with lowest inc. of FN; gr 3 neuropathy; N/V; fewest dose reductions

Phase III Scheduling Trial

R

A

N

D

Carbo AUC 6 Q 4 wkPaclitaxel 100 mg/m2 d1, 8, 15 Q 4 wk

Carbo AUC 6 Q 3 wkPaclitaxel 225 mg/m2 Q 3 wk

PI: C. Belani

NON-PLATINUM TXIN ELDERLY WITH NSCLC

Randomized Trials in Elderly NSCLC

Trial Group Comment

V vs BSC ELVIS Completed

GV vs V SICOG Completed

G vs V vs GV ITA-MILES Completed

ELVIS Trial• E.L.V.I.S.: Elderly Lung Vinorelbine Italian Study• Eligibility: St IIIB/IV NSCLC: PS 0-2• Outcome clearly favored vinorelbine

Arm N OR(%) MS(mo) 1y OS%

VNR 78 20 6.5 32%

BSC 76 - 4.9 14%• Statistically significant QoL benefit for patients receiving

VNR

…Gridelli, JCNI 1999; 85: 365-376

Navelbine in the Elderly: Summary

• E.L.V.I.S.: first Phase III trial demonstrating a survival advantage for single-agent chemotherapy vs BSC

• Navelbine is generally well tolerated in the elderly patient– Age does not appear to change or increase

toxicity– Greater sensitivity of some older individuals

cannot be ruled out

Gemcitabine in Advanced NSCLC• Phase II trials

– RR 21% - 26%– Median survival 7 - 12.3 months– One-year survival of 30% - 50%

• Phase III trials– Gemcitabine 1000 mg/m2 weekly in symptomatic patients

vs BSC– Improvement in symptom control 93% vs 67%

• Toxicities are mainly myelosuppression and fatigue– Rare pulmonary toxicity

Rationale for Combining Gemcitabine and Vinorelbine in NSCLC

• Both drugs have activity in NSCLC

• Nonoverlapping toxicities except myelosuppression

• Outpatient schedule

• Both drugs well tolerated by elderly

Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study

• Patients with Stage IIIB/IV NSCLC

• Age 70 years at diagnosis

• Randomized to:– Vinorelbine 30 mg/m2 d1, 8 q 3 weeks vs.– Vinorelbine 30 mg/m2 d 1, 8

– Gemcitabine 1250 mg/m2 d 1, d 8 administered q 3 weeks

Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study

GV V

N 76 76

Stage IV 60% 60%

PS 0-1 73% 78%

OR 22% 15%

SD 27% 12%

MST 29 wks 18 wks

1-yr survival 30% 13%*

*P<.01

Chemotherapy in Elderly Patients with Advanced NSCLC

13%4.576 15%Vinorelbine

30%*776 22% Gemcitabine + VinorelbineFrasci‡

14%4.976 ---BSC

32%*6.5 78 20%VinorelbineGridelli*

1 YRMS (mo) N ResponseRegimenAuthor

*Gridelli, J Natl Cancer Inst 1999; 85:365-376.

‡Frasci et al, Proc ASCO 2001, 19:A1895* p<0.05

The MILES Phase III Trial: Gemcitabine + Vinorelbine vs Vinorelbine and vs Gemcitabine in Elderly

Advanced NSCLC Patients Gridelli et al Multicenter Italian Lung Cancer in the Elderly Study

NSCLC

70+ years old

Chemotherapy naïve

Stage IIIB

(N3 or pleural effusion) or IV

PS 0-2

RANDOMIZE

ASCO 2001 Abstract 1230

Vinorelbine 30 mg/m2 d1,8Q 3 weeks

Gemcitabine 1000 mg/m2 d1,8Vinorelbine 25 mg/m2 d1,8

Q 3 weeks

Gemcitabine 1200 mg/m2 d1,8Q 3 weeks

MILES STUDY: ELDERLY NSCLC

VNR GEM VNR/GEM

# Patients (n) 233 233 232

Stage IIIB (%) 29 30 31

Response Rate (%) 18.5 17.3 20

TTP (wk) Median Survival (mo)

18

8.8

18

6.6

19

7.6

1 year Survival (%)

41%

26%

31%

…Gridelli et al., ASCO 2001, A-1230

Baseline Quality of Life and SurvivalPrediction in NSCLC Elderly

• Patients enrolled in MILES study

• Assessment at baseline– Activities of daily living (ADL)– Instrumental ADL– EORTC C30 global (items 29-30)

• Analysis using multivariate Cox model

• Data on 81% (566/698) of patients

Perrone et al. Proc Am Soc Clin Oncol 2002;21. Abstract 1346

Baseline Quality of Life and IADL PredictedSurvival in NSCLC Elderly: Results

20 (16-28)<42%

30 (26-34)42-67%

53 (46-76)>67%

QOL

21 (17-27)50%

32 (26-43)51-99%

43 (34-49)100%

IADL

Median Survival, weeks (95% CI)Score

Perrone et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346

Baseline Quality of Life and SurvivalPrediction in NSCLC Elderly: Results

• ADL has no prognostic value

• IADL and QoL have prognostic value– Independently: IADL P=.0006, QoL P<.0001– Together IADL P=.051, QoL P<.0006

Perrone et al. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346

MILES Trial - Conclusions

• Polychemotherapy with gemcitabine + vinorelbine does not improve outcomes compared to single-agent vinorelbine or gemcitabine

• Single-agent chemotherapy should remain a standard for advanced NSCLC elderly patients

• Baseline QoL predictive of outcome, though no difference observed in Qol or IADL between each arm

ASCO 2001 Abstract 1230 ORAL PRESENTATION

Chemotherapy in Elderly Patients with Advanced NSCLC

*Gridelli, J Natl Cancer Inst 1999; 85:365-376.‡Frasci et al, Proc ASCO 2000, 19:A1895 Gridelli, Proc ASCO 2001, 20: A-1230

* 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

Phase II/III Trials in the Elderly

Trial Group Comment

Oral Vinorelbine (V) NCCTG Open

VX3 DX3 SWOG Closed (?)

DG v D SCCC Open

V - vinorelbine, D - docetaxel, G - gemcitabine

Elderly: Adv NSCLCOutstanding Issues

• No elderly-specific phase III trial (yet) comparing single agent(s) +/- platinum

• Comprehensive analysis of co-morbidities and their influence on toxicity, Tx tolerance, QoL and survival (CRASH score)

• Sparse data for pts 80 yrs

Main Domains of Multidimensional Assessment in Elderly Cancer Patients

Measuring ToolDomains

Comorbidity Charlson comorbidity scaleCIRS-G

Functional Status ADLIADL

Depressive symptomsMental StatusNutritional State

GDSMMSEMini nutritional assessment

CIRS-G, cumulative illness rating scale-geriatric; ADL, activities of Daily living; IADL, instrumental activities of daily living; GDS, geriatric Depression scale; MMSE, mini mental state examination

Study Concepts: Elderly NSCLC

• MONOTHERAPY VS PLATINUM COMBINATIONS: e.g.,

– gemcitabine +/- cisplatin or carboplatin

– vinorelbine or gemcitabine +/- oxaliplatin

• COMBINATION CHEMO & TARGETED TX: e.g., vinorelbine +/- OSI-774 or other EGFr inhibitor

• MONOTHERAPY COMPARISONS: e.g., weekly vinorelbine vs weekly paclitaxel or docetaxel

• NESTED PHARMACOKINETIC ANALYSES

Randomized Trials with CT+/- Targeted Therapies

TRIAL TARGET CT GROUP COMMENT

ZD1839 EGFR GC AstraZeneca Closed, no benefit

ZD1839 EGFR TCb AstraZeneca Closed, no benefit

OSI 774 EGFR TCb Genentech/OSI Closed

ABXEGFR EGFR TCb Immunex Proposed

Herceptin Her-2/neu TCb ECOG Proposed

AG3340 MMP TCb Agouron Closed no benefit

AG3340 MMP GC Agouron Closed no benefit

BMS275291 MMP TCb BMSO Closed

TNP-470 Angiogenesis TCb MDACC Proposed (or ditched)

rhuMabVEGF Angiogenesis TCb ECOG Open

ISIS3521 PKC TCb ISIS Closed, no benefit

Deltaparin Metastases Std NCCTG Open

PS 2 NSCLC

What are the data?

Impact of PS on OutcomeECOG 1581

Performance Objective Median ToxicStatus Response (%) Survival (wks) Deaths (%)

0 26 36 3

1 25 26 2

2 - 10 10

Intact (N) Diminished (N)

PS-0Female 12.58 (111) 8.54 (15)Male 9.86 (219) 6.74 (50)

PS-1Female 7.77 (214) 6.95 (102)Male 6.70 (421) 5.08 (224)

PS-2Female 5.31 (24) 2.30 (27)Male 4.30 (64) 3.43 (100)

Median Survival MonthsAppetite

ECOG Recursive Partitioning Analysis Terminal Nodes

ECOG Recursive Partitioning Analysis Terminal Nodes

Jiroutek et al.

GEPC/98-02: Outcomes

Arm CG CGV GVIV Subgroups (MST)

OR(%) 43 38 26* PS 0-1 9.11

TTP (wk) 25 21 22 PS 2 4.79

MST (m) 8.7 7.9 8.1 ST IIIB 9.4

1y OS (%) 35 31 35 ST IV 8.1

*CG v GVIV (p=0.0003); CGV v GVIV (p=0.01)

…Alberola, ASCO 2001, A-1229

EORTC: TP v GP v TGOutcome Measures

T+P G+P T+G

OR% 31 36 27

PFS (m) 4.4 5.6 3.9 (0.08)

MST (m) 8.1 8.8 6.9

1 yr OS (%) 36 33 27 (.09)

…Van Meerbeeck et al. (EORTC), ASCO 20001, A-1228

EORTC: TP v GP v TGSubgroups: Median Survival

STAGE MST (m)

IIIB 9.5

IV 7.5

PS

0-1 8.6

2 3.3p <0.0001

HeCOG Trials: Outcome based on PS

Tax (175 vs 225) TTP (mo) MS (mo) 1 y OS %

PS 0-1 6.3 11.25 N/A

PS 2 2.4 3.8 N /A

PCb vs PG TTP (mo) MS (mo) 1 y OS %

PS 0-1 6.6 11.1 44.4

PS 2 3.8 5.9 20

Impact of PS on Toxicity in Elderly ptsELVIS Trial

Performance Grade 4 Grade 3/4Status Patients Neutropenia (%) Constipation (%)

0-1 53 3 (5.7) 4 (7.5)

2 18 0 0

Perrone F. Personal Communication to P. Hesketh

Impact of PS on OutcomeELVIS Trial

Group Patients Response (%) MS (wks)*

Overall

BSC 78 - 21

V 76 19.7 28

PS 2

BSC 19 - 8

V 18 0.0 26*P=0.03

Perrone F. Personal Communication to P. Hesketh

E1594 Schema

RANDOMIZE

Stratification Performance status0-1 vs. 2

Weight loss inprevious 6 months<5% vs. 5%

Disease stage IIIBor IV

Presence or absence of brain metastases

Arm A: Cisplatin + PaclitaxelPaclitaxel: 135 mg/m2 over 24 hours, day 1Cisplatin: 75 mg/m2 day 2 3-week cycle

Arm B: Cisplatin + GemcitabineGemcitabine: 1,000 mg/m2 days 1,8,15Cisplatin: 100 mg/m2 day 1 4-week cycle

Arm C: Cisplatin + DocetaxelDocetaxel: 75 mg/m2 day 1Cisplatin: 75 mg/m2 day 1 3-week cycle

Arm D: Carboplatin + PaclitaxelPaclitaxel: 225 mg/m2 over 3 hours, day 1Carboplatin: AUC 6.0 day 1 3-week cycle

0 5 10 15 20 25 30

Months

0.0

0.2

0.4

0.6

0.8

1.0

Survival by Treatment Group Stage IV

Cis/PaclitaxelCis/GemcitabineCis/DocetaxelCarbo/Paclitaxel

0 5 10 15 20 25 30

Months

0.0

0.2

0.4

0.6

0.8

1.0

Survival by Treatment Group Stage IIIB

Cis/PaclitaxelCis/GemcitabineCis/DocetaxelCarbo/Paclitaxel

ECOG 1594: PS 2 SubanalysisCONCLUSIONS

• 68 of 1207 pts enrolled had PS 2

• Accrual suspended b/o untoward inc. of Gr 4/5 AEs

• Overall toxicity rate, however, did not differ significantly from that observed in PS 0-1 pts

• 5 deaths (7.35% Grade 5 AE), but only two were directly attributable to Tx

• Med survival of 4.1 mo and 1-yr survival rate 19.1% likely 2o to disease process rather than toxicity

….Sweeney et al Cancer 2001, 92:2639-47

ECOG 1594: PS 2 Subanalysis% G3 Heme Tox (n=64)

PC GC DC PCb

N 18 13 18 15

ANC 60 58 59 47

PLT 0 50 0 7

H/H 25 33 6 20

NF 5 0 12* 0*1 gr 5

….Sweeney et al cancer 2001, 92:2639-47

ECOG 1594: PS 2 Subanalysis% Gr3 Non-Heme Tox (n=64)

PC GC DC PCb

Renal 6 24* 0 0

N/V 40 42 41 0

Diarrhea 5 8 18 0

Neuropathy 15 13 18 20

Allergy 6 0 12 0

Grade 5 0 8 6 0*One Gr 5 toxicity

….Sweeney et al Cancer 2001, 92:2639-47

ECOG 1594: PS 2 SubanalysisOUTCOME

PC GC DC PCb Overall

Total 21 13 19 15 68

Evaluable 18 13 18 15 64

OR(%) 17 23 6 13 14

TTP (mo) 1.4 4.6 1.4 1.5 1.7

MST (mo) 7.0 7.9 2.3 4.6 4.1

1yr OS(%) 19 38.5 10.5 13.3 19.1….Sweeney et al Cancer 2001, 92:2639-47

ECOG 1599RP2: CbT or GC in PS 2 Adv NSCLC

R

A

N

D

CARBOPLATIN AUC 6 Q 3 wkPACLITAXEL 200 mg/m2 Q 3 wk

GEMCITABINE 1gm/m2 d1, 8 Q 3 wkCISPLATIN 60 mg/m2 Q 3 wk

E1599: RP2 Adv NSCLC: Status Update 8/18/01

• Activated 5/31/00• Suspended 5/8/01 for interim toxicity analysis (n=47)

CbT GCNo. Evaluable (to date) 32 30% Gr 3(4) Toxicity ANC 44(28) 40(13) Plt 9(0) 37(7) H/H 9 13 N/V 6(0) 23(0) PNS 13 0 Worst 75(29) 80(28)

• Reopened 1/02; 103 accrued as of 11/15/02• 2 grade 5 toxicities to date (CbT)

Randomized HeCOG Phase II Trial PS 2 NSCLC

RANDOMIZE

Gemcitabine 1250 mg/m2 d 1 +15Carboplatin AUC 3 d 1+ 15

Gemcitabine 1250 mg/ms2 d 1+ 15

100 pts targeted; 4 cycles of Tx projectedEndpoint: clinical benefit

CALGB 9730

• Single agent Paclitaxel vs. combination chemotherapy Paclitaxel/Carboplatin in advanced NSCLC

• Select eligibility criteria:– Stage IIIB/IV NSCLC– Chemotherapy naïve– Performance status 0-2– No CNS disease– Measurable or evaluable disease

CALGB: Subanalysis

N

OR (%)

MST (mo)

1yr OS%*

2y OS%

P CbP P CbP All

78 77 50 49 99

21 36 10 24 17

5.8 8.0 2.4 4.7 3.1

31 35* 10 18 14

NA NA 0 9 5*Wilcoxon=0.1014 log rank p=0.0123

ss (<0.0001) vs PS 0-1

Elderly PS 2

Conclusion: PS 2 may benefit from combination, carboplatin-based tx

… Lillenbaum et al ASCO 2002, A-2;21

PS 2 NSCLC: Treatment Efficacy

Trial RR (%) TTP (mo) MS (m) 1y OS% ECOG 14 1.7 4.1 19.1 HeCOG -- 2.4 3.8 -- HeCOG 11 3.8 5.9 20.9 CALGB

PCb 24 -- 4.7 18 P 10 -- 2.4 10

Alternative Approach for PS 2 Patients with Advanced NSCLC

• Use “new” active single agents• Use schedules with demonstrated favorable

toxicity profiles• Use agents sequentially• Avoid cisplatin (off study) although carboplatin

combinations appear reasonable• Consider formal phase III study evaluating new

agent +/- carbo or new agent +/- targeted Tx• Integrate quality of life into any future efforts

Elderly vs “Poor Risk”Patients with Advanced NSCLC

• “Healthy” elderly fare as well as younger patients with standard chemotherapy approaches

• “Poor risk” patients (PS2 ± low albumin ± weight loss) fare poorly

• Tolerability and potential benefits of chemotherapy in “poor risk” patients remain to be determined