LUNG CANCER: ASCO 2006 TOPICS Adjuvant therapy Clinical studies Meta-analysis ChemoXRT for stage III...
-
Upload
joseph-marshall -
Category
Documents
-
view
214 -
download
0
Transcript of LUNG CANCER: ASCO 2006 TOPICS Adjuvant therapy Clinical studies Meta-analysis ChemoXRT for stage III...
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