LUNG CANCER: ASCO 2006 TOPICS

• Adjuvant therapy

• Clinical studies

• Meta-analysis

• ChemoXRT for stage III disease

• Advances in stage IV NSCLC

• New agents

• Predictive tests

Time from Randomization (Mo)

Pro

ba

bil

ity

of

Su

rviv

al

0 40 50 60 70 80 9010 20 30

0.0

0.2

0.4

0.6

0.8

1.0 Adjuvant CT

Control

P=0.56

Keller et al. NEJM 343:1217, 2000

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5P

rob

abili

ty o

f S

urv

ival

Time from Randomization (Yr)

Adjuvant CT

Control

P=0.589

Adjuvant CT in NSCLCE3590 & ALPI Survival

Time from Randomization (Mo)

Pro

bab

ilit

y of

Su

rviv

al

0 40 50 60 70 80 9010 20 30

0.0

0.2

0.4

0.6

0.8

1.0 Adjuvant CT

Control

P=0.56

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5P

roba

bilit

y of

Sur

viva

l

Time from Randomization (Yr)

Adjuvant CT

Control

P=0.589

M. Tonato et al. PASCO 21:290a, 2002

ADJUVANT CHEMOTHERAPY

NCI-C BR-10

No. Pts. 459

Stage IB-II

Survival*

Observation 54

Adj. Chemotx 69

HR (95% C.I.) 0.69 (0.52-0.92)

P-value 0.012

* 5 year survival

ANITA RESULTS

Cis + VNR Observation p value

No. pts. 407 433 0.002

RFS (months) 38.3 20.7 0.002

M.S.T. (months) 65.8 43.7 0.013

5 year surv. 51.% 43%

*Douillard JY, et al.: Proc ASCO 23:624, 2005

UPDATE OF CALGB 9633: STAGE IB NSCLC

• Initiated in 1996 with accrual target of 500

• Positive study when first reported

CALGB 9633: FAILURE-FREE SURVIVAL

adjuvant chemo

control P value Hazard Ratio [90% CI]

population 173 171

recurrence or death 74 (42.8%)

89(52.0%)

0.030 0.74[0.57 – 0.96]

1-year FFS 85% (80%, 89%)

81% (76%, 86%)

0.16

2-year FFS 75% (70%, 81%)

69% (63%, 75%)

0.12

3-year FFS 66% (60%, 72%)

57% (51%, 64%)

0.047

4-year FFS 61% (51%, 67%)

52% (46%, 59%)

0.07

5-year FFS 52%(45%, 59%)

48%(41%, 55%)

0.21

CALGB 9633: OVERALL SURVIVALadjuvant

chemocontrol P value Hazard Ratio

[90% CI]

population 173 171

died from any cause 64 (37.0%)

73(42.7%)

0.10 0.80[0.60 – 1.07]

1-year survival 94% (91%, 97%)

94% (91%, 97%)

0.500

2-year survival 90% (86%, 94%)

84% (79%, 89%)

0.050

3-year survival 79% (74%, 84%)

71% (65%, 77%)

0.043

4-year survival 69% (63%, 75%)

61% (55%, 68%)

0.081

5-year survival 59%(52%, 66%)

57%(50%, 64%)

0.375

CALGB 9633: OVERALL SURVIVAL

0 2 4 6 8

Survival Time (Years)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bilit

y

ObservationChemo

0 1 2 3 4 5 6 7 8 9

Chemotherapy Observation

median 95 months 78 months

P value 0.10

HR (90% CI) 0.80 (0.60-1.07)

OVERALL SURVIVALTHEN AND NOW

ASCO: 2004 ASCO: 2006

0 2 4 6 8

Survival Time (Years)

0.00.2

0.40.6

0.81.0

Prob

abilit

y

ObservationChemo

0 1 2 3 4 5 6 7 8 90 2 4 6 8

Survival Time (Years)

0.00.2

0.40.6

0.81.0

Prob

abilit

y

ObservationChemo

0 1 2 3 4 5 6 7 8 9

HR=0.62; 90% CI: 0.44-0.89 p=0.01

HR=0.80; 90% CI: 0.60-1.07 p=0.10

INFLUENCE OF AGE ON SURVIVAL WITH ADJUVANT THERAPY:

NCI-C BR 10*

• Overall Survival similar:– Age > 65: 66% vs. 46% favoring chemo (N = 155)

– Age < 65: 70% vs. 58% favoring chemo (N = 327)

– Age > 75: HR 2.35 favoring observation

• Only 23 patients in this analysis, however

* Pepe C, et al.: Proc ASCO 24:2006

LUNG ADJUVANT CISPLATIN EVALUATION (LACE)*

• Individual patient data from ALPI, ANITA, BLT, IALT and JBR10

• Median F/U 5.1 years

• Survival benefit 3.9% at 3 years and 5.3% at 5 years

H.R. 0.89 (0.82 – 0.96; p = 0.03)

• Improved DFS H.R. 0.84 (0.78 – 0.90; p < 0.001)

• Results by surgical stage

Stage H.R. (95% C.I.)

IA 1.41 (0.96 – 2.09)

IB 0.92 (0.78 – 1.10)

II 0.83 (0.73 – 0.95)

III 0.83 (0.73 – 0.95)

*Pignon JP, et al.: Proc ASCO 24:366, 2006

4781121161194224355991120163202

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5YearsNo at riskChemotherapy

Control

Control

Chemotherapy

Ove

rall

Su

rviv

al

Adjusted HR=0.65, 95% CI [0.50-0.86], p = 0.002Adjusted HR=0.65, 95% CI [0.50-0.86], p = 0.002

Effect of adjuvant chemotherapy on Effect of adjuvant chemotherapy on survival in patients with ERCC1 survival in patients with ERCC1

negative tumorsnegative tumors

Adjusted HR=1.14, 95% CI [0.84-1.55], P = 0.40Adjusted HR=1.14, 95% CI [0.84-1.55], P = 0.40

346285121147165336996127149170

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5YearsNo at risk

ChemotherapyControl

Ove

rall

Su

rviv

al

Control

Chemotherapy

Effect of adjuvant chemotherapy on Effect of adjuvant chemotherapy on survival in patients with ERCC1 survival in patients with ERCC1

positive tumorspositive tumors

H.O.G. LUN 01-24/USO 02-33

• SWOG 9504, a phase II study of cisplatin + etoposide + XRT with consolidation taxotere achieved M.S.T. of 26 months and 5 yr. survival 29% in 83 patients with stage IIIB NSCLC

• HOG LUN 01-24, a phase III study with and without consolidation taxotere

• Cisplatin 50 mg/M2 days 1, 8, 29, and 36 + etoposide 50 mg/M2 days 1-5 and 29-33 + concurrent XRT

59.4 Gy (1.8 Gy/fraction); C.R., P.R. and stable patients randomized to docetaxel 75 mg/M2 q 3 weeks x 3 versus observation 4 to 8 weeks after induction

CONSOLIDATION DOCETAXEL

• 33% of patients entering protocol did not randomize due to progression or

toxicity from chemoXRT

• 22% required dose modification with cycle 2 and/or 3

• Docetaxel doses:• 0 cycles: 7 %

• 1 cycle: 34%

• 2 cycles: 30%

• 3 cycles: 29%

GRADE 3-4 DOCETAXEL TOXICITIES HOG LUN 01-24

N = 73

Neutropenia 23%

GCP fever 8%

Pneumonitis 10%

Fatigue 7%

1 or more Gr 3-4 toxicity 45%

COMPARISON GRADE 3-4

TOXICITIES WITH DOCETAXEL

SWOG 9504 SWOG 0012 HOG LUN 01-24

(N = 65) (N = 343) (N = 73)

Neutropenia 57% 54% 23%

Infection --- 15% 3%

Pneumonitis 7% 7% 10%

Therapy-related

death 5% 5% 5%

• International patient data meta-analysis of randomized first-line chemotherapy comparing cisplatin versus carboplatin based chemotherapy

• Nine phase III trials with 2,968 patients analyzed

• Higher response rate with cisplatin (33%) versus carboplatin (26%) based chemotherapy (p < 0.001)

• Improved survival with cisplatin, but not statistically significant (HR = 1.07; 95% C.I. 0.99 – 1.15; p = 0.1); survival was statistically superior to carboplatin when a platinum compound combined with third generation drug (taxane, vinorelbine or gemcitabine); H.R. 1,106 with 95%

C.I. 1.05 to 1.106 (p = 0.039)

META-ANALYSIS OF CISPLATIN VERSUS CARBOPLATIN*

*Ardizzoni A, et al.: Proc ASCO 24:366, 2006

NEW TREATMENT NSCLC

No. Pts. Resp. rate M.S.T.

17 63% Too early

54 62% 53 weeks

CARBOPLATIN + PACLITAXEL

IN NSCLC*

1. CBDCA AUC 6 + Paclitaxel

225 mg/M2 over 3 hours

2. 17 of 27 responses (63%)

*Vafai D, Natale RB, et al.: Proc ASCO 14:353, 1995

PHASE II TRIAL OF PACLITAXEL PLUS CARBOPLATIN IN NSCLC*

• Paclitaxel 135 mg/M2 as a 24 hr. infusion plus Carboplatin AUC 7.5 with G-CSF administered

to 54 patients• Courses every 3 weeks x 6; 32 (59%) completed

all 6 courses• If < grade 4 myelosuppression, Paclitaxel escalated

to 175 mg/M2 and 215 mg/M2 • Objective response rate 62% including 9% C.R.

• M.S.T. 53 weeks

*Langer CJ, et al.: J Clin Oncol 13:1860-1870, 1995

• Simple

• Simple

• Unsophisticated

• Simple

• Unsophisticated

• One solution for all problems

• Simple

• Unsophisticated

• One solution for all problems

• Marketing

• Simple

• Simple

• Unsophisticated

• Simple

• Unsophisticated

• One solution for all problems

• Simple

• Unsophisticated

• One solution for all problems

• Marketing

METASTATIC NSCLC: NEW AGENTS

• Sorafenib

• Sunitinib

• ZD6474

Phase II Sorafenib in NSCLCGatzemeier U et al, ASCO 2006, Abstract 7002

• A multi-kinase inhibitor targeting Raf, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-, Flt-3, c-Kit, and p38

• All were ECOG PS 0-2, no significant bleeding, brain mets allowed

• Sorafenib 400 mg BID (28 day cycles)

• Approximately 2/3 had 1 prior regimen while about 1/3 had 2 or more prior regimens

• 54% adeno, 31% squamous cell

Efficacy

Response* (n = 51) No. of Patients (%)

Stable disease 30 (59)

Progressive disease 18 (35)

Not evaluated† 3 (6)

* By RECIST criteria†3 patients died prior to tumor measurement

PROGRESSION-FREE AND OVERALL SURVIVAL SUMMARY

• Median PFS of 2.7 months overall

(5.5 months in SD patients)

• MST 6.7 months

• 2 patients treated for 2 years with ongoing treatment in 1 patient

VEGFR-2

VEGFR-1

VEGFR-3

PDGFR-

RET

KIT FLT-3

PDGFR-

SunitinibSocinski et al, ASCO 2006, Abstract 7001

CH3

NH

O

NH

F

H3C

CH3

NH

O

N

CH3

Multi-kinase inhibitor

EFFICACY (RECIST)

Response No. patients (%)

(N = 63)

PR 6 (9.5)

SD 27 (42.9)

PD 14 (22.2)

NE* 16 (25.4)

-----------------------------------------------------------------------------------------------

Median duration of response,

weeks (range) 12.2 (4.3 – 30.3+)**

* Patients for whom scans were not evaluable or not available for review

** One patient with ongoing tumor response at 30.3 weeks

Progression-Free Survival

100

90

80

70

60

50

40

30

20

10

0

Est

imat

ed P

FS P

roba

bili

ty (

%)

Time (Weeks)

Median PFS: 11.3 weeks (95% CI 10.0-15.7)

0 5 10 15 20 25 30 35 40

Overall Survival

100

90

80

70

60

50

40

30

20

10

0

Est

imat

ed S

urvi

val P

rob

abil

ity

(%)

0 5 10 15 20 25 30 35 40 45 50

Time (Weeks)

Median Overall Survival: 23.9 Weeks (95% CI 17.0–28.3)

ZD6474 versus GefitinibNatale R et al, ASCO 2006, Abstract 7000

NS

CL

C 2

nd/3

rd-l

ine Gefitinib 250 mg

n=85

Part A

ZD6474 300 mgn=83

Dis

ease

pro

gres

sion

or

toxi

city

Part B

Gefitinib 250 mg

ZD6474 300 mg

Study designed to have an 75% power to detect a 33% PFS at a significance level of p <0.2

Pro

bab

ilit

y of

rem

aini

ng

prog

ress

ion-

free

Primary Endpoint in Part A: Progression-Free Survival

Hazard ratio = 0.69 (95% CI = 0.50 to 0.96)Two-sided P-value = 0.025

Progression-free survival in Part A (months)

Median PFS

ZD6474 = 11.0 weeks

Gefitinib = 8.1 weeks

Final data cut-off, July 2005

0.1

0.8

0.6

0.4

0.2

0.9

0.7

0.5

0.3

0

1.0

0 2 4 6 8 10531 97 11 12 1413 15 1716 18

Median survival

ZD6474 then gefitinib = 6.1 months

Gefitinib then ZD6474 = 7.4 months

Pro

bab

ilit

y of

rem

aini

ng

aliv

eSecondary Endpoint:

Overall Survival

0.1

0.8

0.6

0.4

0.2

0.9

0.7

0.5

0.3

0

1.0

Time to death (months)

240 6541 2 83 9 10 11 12 13 14 157 16 17 18 19 20 21 22 23

Hazard ratio = 1.19 (95% CI = 0.84 to 1.68)Two-sided P-value = 0.34

MOLECULAR PREDICTORS IN NSCLC

• Resected patients with Excision Repair Cross-Complementing 1 (ERCC-1) positive tumors do

not benefit from adjuvant cisplatin-based chemotherapy

• EGFR exon 19 or 21 mutation predicts response

and TTP, but not survival in patients with BAC treated with erlotonib

• K-ras mutation predicts resistance to erlotinib• Improved PFS with addition of bevacizumab to

carboplatin + paclitaxel occurred mainly in patients with low baseline intercellular adhesion molecule (ICAM) levels

CONCLUSIONS

• Adjuvant therapy

• ChemoXRT

• Stage IV disease

• Post-platinum doublet

• Pemetrexed, Docetaxel

• Erlotinib

• Sorafenib, Sunitinib, ZD6474

• Biology – especially adjuvant therapy