Early Stage NSCLC: Imprimatur
of Adjuvant Therapy
Overview of Recent Data
Corey J Langer MD, FACP
Professor of Medicine
Director of Thoracic Oncology
Abramson Cancer Center
University of Pennsylvania
Philadelphia, PA 19104
Disclosures: Past 10 yrs
• Grant/Research Support:
– Bristol Myers Squibb, Pfizer, Imclone, Lilly, ScheringPlough Research Institute, Sanofi-Aventis, Amgen, Cell
Therapeutics, OrthoBiotech, Celgene, Vertex,
Genentech, OSI, AstraZeneca, Pfizer, Medimmune, GSK
• Scientific Advisor:
– Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer,
GlaxoSmithKline, Pharmacyclics, Amgen, AstraZeneca,
Novartis, Genentech, OSI, Savient, Bayer/Onyx, Abraxis,
Clarient, Morphotek, Biodesix, AVEO, Synta
• Speakers Bureau: curtailed as of 12/10
– Bristol Myers Squibb, Imclone, Sanofi-Aventis, Lilly,
Genentech, OSI
Welcome to Winter in NJ 2-14
3
Stage is Destiny!
New Staging System (IASLC ’07)
to be instituted 2009
UICC6 T/M Descriptor
Proposed T/M
N0
N1
N2
N3
T1 (< 2 cm)
T1a
IA
IIA
IIIA
IIIB
T1 (> 2-3 cm)
T1b
IA
IIA
IIIA
IIIB
T2 ( 3 to < 5 cm)
T2a
IB
IIA
IIIA
IIIB
T2 (>5-7)
T2b
IIA
IIB
IIIA
IIIB
T2 (> 7 cm)
T3
IIB
IIIA
IIIA
IIIB
T3 invasion
T3
IIB
IIIA
IIIA
IIIB
T4 (same lobe nodules)
T3
IIB
IIIA
IIIA
IIIB
T4 (extension)
T4
IIIA
IIIA
IIIB
IIIB
M1 (ipsilateral Lung)
T4
IIIA
IIIA
IIIB
IIIB
T4 (pleural effusion)
M1a
IV
IV
IV
IV
M1 (contralateral lung)
M1a
IV
IV
IV
IV
M1 (distant)
M1b
IV
IV
IV
IV
New Staging System (IASLC ’07)
Instituted 2009
UICC6 T/M Descriptor
Proposed T/M
N0
N1
N2
N3
T1 (< 2 cm)
T1a
IA
IIA
IIIA
IIIB
T1 (> 2-3 cm)
T1b
IA
IIA
IIIA
IIIB
T2 ( 3 to < 5 cm)
T2a
IB
IIA
IIIA
IIIB
T2 (>5-7)
T2b
IIA
IIB
IIIA
IIIB
T2 (> 7 cm)
T3
IIB
IIIA
IIIA
IIIB
T3 invasion
T3
IIB
IIIA
IIIA
IIIB
T4 (same lobe nodules)
T3
IIB
IIIA
IIIA
IIIB
T4 (extension)
T4
IIIA
IIIA
IIIB
IIIB
M1 (ipsilateral Lung)
T4
IIIA
IIIA
IIIB
IIIB
T4 (pleural effusion)
M1a
IV
IV
IV
IV
M1 (contralateral lung)
M1a
IV
IV
IV
IV
M1 (distant)
M1b
IV
IV
IV
IV
Limitations of Earlier Adjuvant
Trials
• Use of regimens with marginal activity in
advanced NSCLC
• Inclusion of patients with compromised
PS and multiple co-morbidities
• Difficulty administering systemic therapy
in the post-op setting
• Inadequate power or overly ambitious
survival endpoints
1995 Meta-Analysis
Adjuvant Cisplatin Trials n=1394
100
HR 0.87
p=0.08
Percentage Survival
80
60
40
Surgery plus Chemotherapy
Surgery
20
0
0
12
18
24
36
48
54
60
Time from Randomization (months)
BMJ 31: 899-908, 1995
5% absolute survival benefit at 5 years, NS
Plaitnum-Based Adjuvant Trials in
Resected NSCLC
Trial
BMJ meta
IALT
ALPI
E3590
BLT
BR-10
CALGB9633
ANITA
LACE meta
N. of Patients
1394
1867
1209
488
381
482
344
840
4584
HR (95%CI)
0.87 (0.74-1.02)
0.86 (0.76-0.98)
0.96 (0.81-1.13)
0.93 (0.74-1.18)
1.02 (0.77-1.35)
0.70 (0.53-0.92)
0.63 (0.60-1.07)
0.79 (0.66-0.95)
0.89 (0.82-0.96)
NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; ASCO 04+06; Lancet Oncology 06
Plaitnum-Based Adjuvant Trials in
Resected NSCLC: Longterm Results
Trial
BMJ meta
IALT
ALPI
E3590
BLT
BR-10
CALGB9633
ANITA
LACE meta
N. of Patients
1394
1867
1209
488
381
482
344
840
4584
HR (95%CI)
0.87 (0.74-1.02)
0.91 (0.81-1.02)
0.96 (0.81-1.13)
0.93 (0.74-1.18)
1.02 (0.77-1.35)
0.70 (0.53-0.92)
0.80 (0.60-1.07)
0.79 (0.66-0.95)
0.89 (0.82-0.96)
NEJM 00; JNCI 03; EuroJTS 04, NEJM 04; NEJM 05; ASCO 04+06; Lancet Oncology 06
Intl Adjuvant Lung Cancer Trial
(IALT) 1867 pts, I-III
• Randomized to obs vs. 4 cycles post-op chemo*
• Radiation therapy optional (~30%)
• 4.1% absolute benefit at 5 years, p<0.03†
– Stage III > Stage I benefit
• Diminished at 7 yr follow-up
• HR 0.86 [0.76-0.98]  0.91 [0.81-1.02];
– p = 0.04  0.1 after 5 yrs due to non-cancer deaths ^
*cisplatin + etoposide or vinca alkaloid
†Arriagado, NEJM 350:351, 2004,
^ Le Chevalier ASCO 2008
Randomized International Adjuvant Lung
Cancer Trial (IALT): Cisplatin-Based
Chemotherapy vs No Chemotherapy for
Resected NSCLC
Stage I-III NSCLC
Complete surgical
resection within 60 days
N=1867
R
A
N
D
O
M
IZ
E
Arm A*
Cisplatin 80 mg/m2  4 cycles OR
Cisplatin 100 mg/m2  3-4 cycles OR
Cisplatin 120 mg/m2  3 cycles
PLUS
Etoposide 100 mg/m2  3 days/cycle OR
Vinorelbine 30 mg/m2 weekly OR
Vinblastine 4 mg/m2 weekly OR
Vindesine 3 mg/m2 weekly
n=935
Arm B
Observation
± thoracic radiotherapy 60 Gy†
n=932
*Each center selected which chemotherapy it would use.
†Optional, but predefined by N stage at each center.
Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation;
Arriagada et al. N Engl J Med. 2004;350:351.
Adjuvant Chemotherapy
IALT
•
•
•
•
n=1867
• cDDP was 80 q 3 weeks X 4
100 q 4 weeks X 3-4
120 q 4 weeks X 3
56% + Etoposide 100
27% + Vinorelbine 30
11% + Vinblastine 4
6% + Vindesine 3
Le Chevalier, ASCO 2003 abstract 6, NEJM 2004
Adjuvant Chemotherapy
IALT (International Adjuvant Lung Trial) n=1867
•
•
•
•
•
•
1995-2000
33 countries, initial accrual goal was 3300
80/20 M/F
Mean age 59 (all < 75)
Squamous 47%, ACAs 40%
Chemo to start < 60 days after surgery
Median f/u: 56 months
Le Chevalier, ASCO 2003 abstract 6, NEJM 1/04
IALT: Cisplatin-Based Chemotherapy vs
No Chemotherapy for Resected NSCLC:
Overall Survival (Med F/U 56 mos)
100
HR=0.86 (0.76-0.98)
Chemotherapy
% Survival
80
Observation ± RT
P<0.03
60
40
20
0
0
12
24
36
48
Months
Le Chevalier et al. Proc Am Soc Clin Oncol. 2003;22:2. Abstract and oral presentation. NEJM 1/04
60
IALT Trial
ARM
Adjuvant chemo
Number of enrollees
935
Dead of disease progression 361
Tx-related deaths (n)
14
Compliance with RT (%)
71
Median DFS (mo)
39.4
2-yr DFS (%)
61
5-yr DFS (%)
39
Median Survival Time (mo)
50.8
2-yr OS (%)
70
5-yr OS (%)
44.5
Control
932
405
2
85
34.3
55
34
44.4
67
40.4
IALT: Cisplatin-Based Chemotherapy vs
No Chemotherapy for Resected NSCLC:
Overall Survival
• Benefit seen across all demographic variables
–
–
–
–
Gender
type of surgery
use of RT
geographical location
• Greatest benefit in stage III pts (~7.5%)
• In subgroup analyses, survival advantage for
stage I and II was not statistically significant
– Stage I
– Stage II
– Stage III
Adj
65.6
46.5
37.4
Control
64.9
43.2
29.9
Rel %↑
0.7
3.3
7.5
IALT: Cisplatin + a Vinca or Etoposide
2008 Update: 7.5-Year Median Follow-Up
100%
chemotherapy: 578 deaths
- 495 deaths before 5 years
- 83 deaths after 5 years
80%
60%
HR: 0.91 (0.81-1.02, P = 0.10)
40%
control 590 deaths
- 534 deaths before 5 years
- 56 deaths after 5 years
20%
0%
0
1
2
3
4
5
6
7
8 years
935
775
619
520
447
372
282
208
125
932
780
650
550
487
399
300
208
133
Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.
Criticisms of IALT
• Heterogenous staging, chemo and application of RT (HR
favored stage III, not stage I or II)
• Study actually closed earlier than planned because of
emerging interest in neoadjuvant Tx
• Potential Molecular Imbalances: Results of ERCC1
suggest that one can select a group more likely to benefit;
other bio-correlatives still pending
• Elderly (> 75) excluded; how do we address this
expanding cohort?
• Dissipation of survival benefit after 5 years
• Why was this trial positive when so many similar trials
proved negative?
Recent (-) Trials of Adjuvant
CT in Completely Resected NSCLC
Study
CT
Regimen
# of
Patients
Outcome
VP16-P x 4
462
Negative
ALPI/EORTC Italy/Europe
MVP x 3
1197
Negative
BLT
V-P x 4
481
Negative
INT 0115
Country
USA
International
on OS
2004: Paradigm Shift
2004: Paradigm Shift
Recently Completed (+) Randomized
Adjuvant Trials in Early Stage NSCLC
CALGB 9633
NCI-C*
Stage
IB
IB-II
No.
500
480
Intervention
Carboplatin/Paclitaxel
Cisplatin/Vinorelbine
2005: Paradigm Shift
Recently Completed (+) Randomized
Adjuvant Trials in Early Stage NSCLC
CALGB 9633
NCI-C*
ANITA
Stage
IB
IB-II
I-IIIA
No.
500
480
840
Intervention
Carboplatin/Paclitaxel
Cisplatin/Vinorelbine
Cisplatin/Vinorelbine
CALGB 9633 - 344 pts, stage IB
• 4 cycles carboplatin/paclitaxel
vs. observation
• Radiation therapy not allowed
• 2004 - HR 0.62; p = 0.028
• 2006 - HR 0.80; p = 0.10
Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2009
CALGB 9633 Overall Survival
by Tumor Size
Tumor ≥4 cm
Observation
Paclitaxel + Carboplatin
1.0
Observation
Paclitaxel + Carboplatin
1.0
0.8
0.8
n=97
Probability
Probability
Tumor <4 cm
0.6
n=99
0.4
0.2
n=74
n=74
0.6
0.4
0.2
HR = 0.66; 90% CI, 0.45-0.97; P=0.04
0
HR = 1.02; 90% CI, 0.67-1.55; P=0.51
0
0
1
2
3
4
5
6
7
8
9
0
1
Years
Strauss Proc ASCO 2004 abs 7019, 2006 abs 7007, JCO 2008
2
3
4
5
Years
6
7
8
9
JBR.10
ELIGIBLE:
Resected IB and II
T2N0, T1N1, or
T2N1
No prior chemo
No RT
R
A
N
D
O
M
I
Z
E
Stratification:
• Nodal status – N0 vs N1
• RAS status
Winton T, et al. N Engl J Med. 2005;352:2589-2597.
Observation
N = 240
Vinorelbine 25 mg/m2 weekly x 16
plus
Cisplatin 50 mg/m2 day 1 & 8 q4wk
x 4 cycles
N = 242
Primary endpoint = overall survival
NCIC-CTG JBR.10
482 pts, stage IB-II
•
•
•
•
Stage IB-II only
4 cycles of post-op cis/vin vs. observation
No radiation therapy
15% survival advantage at 5 years
– 54% vs 69% alive (NEJM paper)
• HR 0.69, p=.012 in 482 pts
• Benefit only in stage II in subset analysis
– Although post-hoc analysis shows a benefit in
IB > 4cm
Winton, Proc ASCO 2004 Abs:7018, 2004, NEJM 2005
Overall Survival by Treatment Arm
'
100
Observation
All Patients
Fig.1
80
Vinorelbine
Stratified Log-Rank: p=0.04
HR: 0.780(0.613, 0.993)
HR 0.69
5 yr: 69% vs 54%
Percentage
5 yr: 67% vs 56%
60
MST 94m vs 72m
40
MST 94 m vs 73 m
20
0
At Risk
Observation
Vinorelbine
Absolute improvement in 5 yr OS = 15%
(69% vs 54%)
Winton et al. NEJM 2005
0
3
6
240
242
155
182
117
135
9
Time(Years)
58
67
12
15
9
12
0
0
Absolute improvement in 5 yr OS = 11%
(67% vs 56%); benefit persists at 9+ yrs
Vincent, Butts et al, 2009, ASCO -7501
1.0
Cumulative Incidence Plots for Disease
and Non-disease Related Deaths
Test for Non-Disease Related Deaths
=============================
Log-Rank Test p-value = 0.660
Fine-Gray Test p-value = 0.622
-----------------------------------------------------
0.2
0.4
0.6
Test for Disease Related Deaths
========================
Log-Rank Test p-value = 0.027
Fine-Gray Test p-value = 0.023
--------------------------------------------
0.0
Cumulative Probability
0.8
Observation/Disease Related
Chemotherapy/Disease Related
Observation/Non-Disease Related
Chemotherapy/Non-Disease Related
0
2
4
6
Time(Years)
8
10
12
14
Stage IB Analysis
T ≥ 4 cm
T < 4 cm
HR OS
p
HR OS
p
CALGB 9633
1.02
.51
0.66
.04
JBR.10
1.73
.07
0.66
.13
No Chemo
Benefit
Strauss JCO 2008
Potential Chemo
Benefit
ANITA - 840 pts, stage IB-IIIA
• 1:1 Randomization post-resection
– Vinorelbine (30 mg/m2) Q wk X 16 +
Cisplatin 100 mg/m2 Q 4 wks X 4 vs
– Observation
• Radiation therapy allowed
• 8.6% survival advantage at 5 years
(persists at 7 yr)
– 42.6% vs 51.2% alive
• HR 0.7 [0.66-0.95], p =.013
• Benefit only in stage II and IIIA
Douillard Lancet Oncol. 7:719, 2006
ANITA: Rand Phase III Trial of Vinorelbine and
Cisplatin vs Obs in Resected stage I-III NSCLC:
Demographics
•
•
•
•
•
•
•
•
•
840 pts accrued from 12/94 through 12/00
Median F/U > 70 mos
Each arm well balanced
Median age 59 (18 – 75)
86% male
95% PS 0-1
59% Squamous ca
37% pneumonectomy
Stage
– I – 35%
– II – 30%
– III – 35%
Douillard Lancet Oncol. 7:719, 2006
Abstract #7013: ANITA Trial
Overall survival - ITT population
Survival Distribution Function
1.00
Median months
P-value
Hazard Ratio
0.75
OBS.
43.8
NVB + CDDP
65.8
0.013
0.79 [0.66 - 0.95]
0.50
Obs
0.25
NVB + CDDP
0
0
20
40
60
months
Douillard Lancet Oncol. 7:719, 2006
80
100
120
ANITA: Randomized Phase III Trial of
Vinorelbine and Cisplatin vs Observation
in resected stage I-III NSCLC
Arm
Observation
Adjuvant
No
433
407
RFS (mo)
21
36
Median Surv (mo)*
44
66
2 yr OS
63
68
5 yr OS
43
51
7 yr OS
37
48
Stage I
62
63
Stage II
39
52
Stage III
26
42
5 yr OS
* P =0.002, HR 0.76
Douillard Lancet Oncol. 7:719, 2006
ANITA: Randomized Phase III Trial of
Vinorelbine and Cisplatin vs Observation
in resected stage I-III NSCLC
Arm
Observation
Adjuvant
No
433
407
RFS (mo)
21
36
Median Surv (mo)*
44
66
2 yr OS
63
68
5 yr OS
43
51
7 yr OS
37
48
Stage I
62
63
Stage II
Stage III
39
26
52
42
5 yr OS
* P =0.002, HR 0.76
Douillard Lancet Oncol. 7:719, 2006
ANITA: Randomized Phase III Trial of Vinorelbine
and Cisplatin vs Obs in resected stage I-III NSCLC
Adjuvant Toxicities
Neutropenia Gr 3+4
86%
Febrile Neutropenia
12.5%
Nausea-Vomiting Gr 3+4
27%
Aesthenia
28%
Constipation
5%
Peripheral Neuropathy
3%
Drug-Related Fatality
1%
Douillard et al ASCO 2005, A-7013, p624
LACE:Trials and patients
•
•
•
•
•
5 trials including 4,584 patients
Median follow-up: 5.1 years (3.1 – 5.9)
80% male
Median age 59 years, 9% > 70 years old
Pathological Stage:
IA: 8%, IB: 30%, II: 35%, III: 27%
• Surgery: 31% pneumonectomy
• Histology:
49% squamous cell,
39% adenocarcinoma, 12% other
Pignon Proc ASCO 2006 abs 7008
Survival curve
100
Chemotherapy
No chemotherapy
Absolute difference
Survival (%)
80
at 3 years:
at 5 years:
3.9% + 1.5%
5.3% + 1.6%
61.0
60
57.1
40
48.8
43.5
20
0
0
1
2
3
4
5
>6
Time from randomization (Years)
CT effect & stage
Category
No. Deaths
/ No. Entered
Hazard ratio
Stage IA
102 / 347
1.41 [0.96;2.09]
Stage IB
509 / 1371
0.92 [0.78;1.10]
Stage II
880 / 1616
0.83 [0.73;0.95]
Stage III
865 / 1247
0.83 [0.73;0.95]
HR
(Chemotherapy / Control)
0.5
1.0
1.5
2.0
Chemotherapy better | Control better
Test for trend: p = 0.051
[95% CI]
2.5
CT may be detrimental for stage IA, but stage IA
patients were generally not given the potentially
best combination cisplatin+vinorelbine (13% of
stage IA patients versus ~43% for other stages)
CT effect & stage
Category
No. Deaths
/ No. Entered
Hazard ratio
Stage IA
102 / 347
1.41 [0.96;2.09]
Stage IB
509 / 1371
0.92 [0.78;1.10]
Stage II
880 / 1616
0.83 [0.73;0.95]
Stage III
865 / 1247
0.83 [0.73;0.95]
HR
(Chemotherapy / Control)
0.5
1.0
1.5
2.0
Chemotherapy better | Control better
Test for trend: p = 0.051
[95% CI]
2.5
CT may be detrimental for stage IA, but stage IA
patients were generally not given the potentially
best combination cisplatin+vinorelbine (13% of
stage IA patients versus ~43% for other stages)
Stage-Specific Hazard Ratios
Recent Adjuvant Trials
Trial
I < 4 cm
IALT
BR-10
I > 4 cm
0.95
1.73
ANITA
0.66
1.10
II
IIIA
0.93
0.79
0.59
N/A
0.71
0.69
CALGB
1.02
0.66
N/A
N/A
LACE
1.41*
0.91*
0.83
0.83
Negative
Positive
Indeterminate
Not studied
* 3 cm as cut point
Therapeutic Implications
• Short course adjuvant, platinum-based
therapy has emerged as standard
practice in resected stage Ib-IIIa NSCLC
• Ongoing controversies re:
–
–
–
–
–
–
–
Molecular Selection
Influence of Age on Outcome
Ideal platinating agent: carbo vs cisplatin
Choice of partner agent
Impact of Stage
Role of targeted agents
Utility of RT in IIIA (N2)
Disease Free Patients (%)
Potential Benefit
from Adjuvant Systemic Therapy
100
Patients with residual micrometastases
resistant to adjuvant therapy
80
Patients with
residual
micrometastases
sensitive to
adjuvant therapy
Predictive Markers ?
60
40
Patients cured with local regional therapy
Prognostic Markers ?
20
0
0
2
4
6
Years
8
10
Influence of Age on Outcome
Elderly Specific Analyses: BR10
Pepe et al ASCO ’06, A-7009
• 65: designated cut-off
– 327 younger pts (68 %)
– 155 older pts (32 %)
• Baseline demographics similar except
for histology and PS
Cohort
Adenoca
Squamous
PS 0
Younger
Older
P value
58%
32%
53%
43%
59%
42%
0.001
0.001
0.01
JBR-10 Outcomes by Age
• Worse PS in older; fewer PS 0 >65 (53% vs 41%, = 0.01)
• adeno>squam in younger, squam>adeno in older pts.
• Patients >65 received significantly less chemo
– no significant diff. in toxicity, or growth factor support
– more elderly patients refused treatment
• OS 46% vs. 66% for obs. vs. chemo in pts >65
– Overall Survival HR 0.61 [0.38-0.98], p =.04 in elderly
• OS 58% vs. 70% for obs. vs. chemo in pts <65
– Overall Survival HR 0.77 [0.54-10.9], p = 0.14 in young
• Older patients (>75)
– Worse survival regardless of Rx, but same when corrected for
disease-specific survival
– Benefit from chemo not seen in pts >75 (?harmful)
– However, patient numbers are too small to answer clearly
Pepe C, et al. Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study
JBR.10. J Clin Oncol. 2007 Apr 20;25(12):1553-61
BR10: Overall Survival by
Age Group
1.0
1.0
0-65
N = 327
H-R =2.38
66-70 N = 84
Log-Rank, p =0.0006
71-75 N = 48
0.8
Probability
0.8
>75
N = 23
0.6
0.6
63%
0.4
 75
0.4
N = 459
>75 N = 23
0.2
0.2
26%
0.0
0.0
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Time (Years)
Pepe C, et al Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada
and Intergroup Study JBR.10. J Clin Oncol. 2007 Apr 20;25(12):1553-61
Ideal Platinating Agent
Argument Favoring Carboplatin
• The best results obtained in stage IB have
been observed with CbPac (not with DDPbased regimens)
– Subset analysis in > 4 cm tumors
demonstrates a survival benefit
• CbPac has not been tested in stage II/IIIA
in the adjuvant setting
– Absence of data does not prove absence of
benefit (….absence of proof is not proof of
absence….)
• Finally, a substantial percentage of adj pts
are poor candidates for cisplatin-based
therapy due to age, co-morbidities, etc
Which Agents Partner Best
with Platinum
M. Kreuter, J. Vansteenkiste, J. Fischer, W. Eberhardt, H. Zabeck, J. Kollmeier, M. Serke, N.
Frickhofen, M. Reck, W. Engel-Riedel, S. Neumann, M. Thomeer, C. Schumann, P. De Leyn, T.
Graeter, G. Stamatis, I. Zuna, F. Griesinger and M. Thomas
on behalf of the TREAT investigators
Rationale: Dose delivery: Adjuvant CTX
LACE-Metaanalysis
NCIC-JBR .10
9%
4.5%
24 %
(≤ 2 cycles)
50%
(< 4 cycles)
• early death or progression
9%
5%
• toxicity
34%
13%
• patient refusal
35%
29%
No treatment
Treatment incomplete
Therapy delay
55%
Dose reductions
77%
TREAT Rationale:
• Adjuvant CTX: mainly Cisplatin / Vinorelbine
• Need: reduction of toxicity, improvement of dose delivery & compliance
• Cisplatin / Pemetrexed in thoracic malignancies: high dose intensity, low
toxicities
Pignon, JCO, 2008 ; Winton, N Engl J Med, 2005; Alam, Lung Cancer, 2005;
Vogelzang, JCO, 2003; Scagliotti, JCO, 2008; Schmid-Bindert, ASCO, 2009
TREAT: Design
Inclusion
• NSCLC stages IB, IIA, IIB, T3N1M0
• ≤ 42 Tage postoperatively, R0, systematic LN-dissection
• ECOG 0, 1
• amenable to Cisplatin treatment
Stratification
• Center
• Nodal status (N0 versus N1)
• Surgical procedure (lobectomy vs pneumonectomy)
Cisplatin / Vinorelbine (CVrb)
50 mg/m2 d1+8 / 25 mg/m2 d1, 8, 15, 22 q d 29 x 4
Winton et al., N Engl J Med (2005) 352: 258
R0
Cisplatin / Pemetrexed (CPx)
75 mg/m2 d1 /
500 mg/m2 d1 q d 22 x 4
TREAT: Conduct / endpoints
Study conduct
• Study concept 2005, Inclusion 10/2006-12/2009 (16 sites, 132
patients)
• Treatment until 2/2010, primary endpoint analysis 12/2010
Primary endpoint
Clinical Feasibility
• No death due to cancer, toxicity, comorbidity
• No Non-acceptance by patients leading to premature withdrawal
• No observation of DLT
Neutropenia
grade 4
>7d
Neutropenia
grade 3/4
with fever/infection
Thrombocytopenia
grade 4
>7d
Thrombocytopenia
any grade
with bleeding
Non-hematologic toxicity
grade 3/4
related to CTX
Secondary endpoints
Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse
Kreuter et al., BMC Cancer, 2007
TREAT: Conduct / endpoints
Study conduct
• Study concept 2005, Inclusion 10/2006-12/2009 (16 sites, 132
patients)
• Treatment until 2/2010, primary endpoint analysis 12/2010
Primary endpoint
Clinical Feasibility [considered promising if > 80%]
• No death due to cancer, toxicity, comorbidity
• No Non-acceptance by patients leading to premature withdrawal
• No observation of DLT
Neutropenia
grade 4
>7d
Neutropenia
grade 3/4
with fever/infection
Thrombocytopenia
grade 4
>7d
Thrombocytopenia
any grade
with bleeding
Non-hematologic toxicity
grade 3/4
related to CTX
Secondary endpoints
Dose delivery, safety, TTTF, RFS, OS, DMFS, LRFS, site of relapse
Kreuter et al., BMC Cancer, 2007
TREAT: Characteristics
Characteristics
Age (years [range])
Gender (%)
• male
• female
Smoking status (%)
• Smoker
• Ex-smoker
• Non-smoker
• Not available
CPx
CVb
Total
(n=67)
(n=65)
(n=132)
58 [40-73]
60 [38-74]
59 [38-74]
72
28
77
23
74
26
33
61
6
0
26
71
1.5
1.5
29
66
4
1
37
12
46
5
38
8
48
6
38
10
47
5
Stage (%)
IB
IIA
IIB
T3N1
TREAT : Characteristics
CPx
CVb
Total
(n=67)
(n=65)
(n=132)
Lobectomy
84
82
83
Pneumonectomy
12
15
14
Complex resections
4
3
3
Squamous cell carcinoma
45
42
43
Non-squamous
55
58
57
• Adenocarcinoma
• Large cell carcinoma
• Mixed cell carcinoma
37
9
9
44
9
5
41
9
7
Characteristics
Surgical procedures (%)
Histology (%)
Results: Primary endpoint - feasibility
Feasibility rate (%)
CPx
CVb
95.5
p = 0.0010 75.4
(CI 87.5-99.1)
(CI 63.1-85.2)
1.5
3.1
0
6.2
3.0
15.4
patients (n=2)
patients (n=10)
G4 neutropenia >7d
0
4
G4 thrombocytopenia >7d
G3/4 febrile neutropenia
Thrombocytopenia with bleeding
G3/4 non-hematologic toxicity
0
1
0
2
0
5
0
1
Death (%)
Withdrawal of consent (%)
DLT (%)
Reasons for DLT (events) *
* multiple
reasons possible
Results: End of therapy
EOT
CPx
CVb
Regular EOT (%)
77.6
36.9
Earlier termination of therapy (%)
22.4
63.1
patients (n=15)
patients (n=41)
• Unacceptable toxicity according to protocol**
4
19
• Unacceptable toxicity perceived by patient
6
7
• Relapse of disease
0
2
• Withdrawal of consent
0
4
1 (0)
2 (0)
• Non-compliance to protocol
0
2
• Medical decision by investigator
4
5
• Major protocol violation
0
1
• Other reasons
0
4
Reasons for earlier termination (events)*
• Death (therapy related)
*multiple reasons possible
**delay >2 weeks due to toxicity or in case of G3/4 non-hem toxicity
TREAT: Toxicity
Toxicity
Mean Number
(AE / SAE)
CPx
CVb
6.8 / 0.3
6.9 / 0.2
Hematologic
Toxicity G3/4 (%)
10.5
p<0.0001
76.5
Non-hematologic
Toxicity G3/4 (%)
33
p=0.7988
31
Hematologic
Toxicity (%)
G3/4
G3/4
Anemia
0
1.5
Thrombocytopenia
0
0
Neutropenia
9
69
1.5
6
Febrile Neutropenia
TREAT: Time to treatment failure
TtTF:
• AE
• progression /
relapse / death
• failure to return
to therapy
• refusal of
treatment /
withdrawal of
consent
Withdrawal probability
Time from surgery
to withdrawal due to
p<0.001
TREAT: Conclusions
• CPx safe and feasible
 less toxicity compared to CVb
 superior dose delivery compared to CVb
 high dose density (mg/m2/week)
• Dose delivery failure in CVb
mostly due to Vb (delivery d15, d22)
• Efficacy: longer follow up to be awaited
Molecular Selection
Immunohistochemical (IHC) Staining of the
Excision Repair Cross-Complementing 1
(ERCC1) Protein as Predictor of Benefit
from adjuvant chemotherapy (CT) in the
International Lung Cancer Trial (IALT)
 761 pts. (28 centers,14 countries) evaluable for ERCC1
expression
 ERCC1 repairs cisplatin-DNA adducts, so expression
indicates platinum resistance
 ERCC1 a “double-edged sword”; worse prognosis of NSCLC
if low expression, but more responsive to platinum
Soria, Proc ASCO 2006 A#7010; Olaussen K et al. N Engl J Med 2006;355:983-991
ERCC1-Negative:
Overall Survival
ERCC1-Positive:
Overall Survival
100%
100%
Control
80%
80%
47%
60%
Control
40%
20%
39%
Adjusted HR = 0.65
95% PI [0.50-0.86], p = 0.002
Overall Survival
Overall Survival
Chemotherapy
No at risk
Chemotherapy
40%
20%
0%
46%
60%
40%
Adjusted HR = 1.14,
95% CI [0.84-1.55], p = 0.40
0%
0
Chemotherapy
224
Control 202
1
2 Years 3
4
5
No at risk
194
163
161
120
81
59
47
35
Chemotherapy 165
Control
121
91
0
170
1
2 Years 3
147
149
121
127
Soria, Proc ASCO 2006 A#7010; Olaussen K et al. N Engl J Med 2006;355:983-991
85
96
4
5
62
69
34
33
IFCT-0801 TASTE
TAilored post-Surgical
Therapy in Early stage NSCLC
Principal Investigator
Jean-Charles SORIA
Institut Gustave Roussy - Villejuif
Biological Coordinator
Marie Wislez
Hôpital Tenon - Paris
TASTE design
Control Arm
CDDP - pemetrexed
EGFR
mutated
Experimental Arm
Customized
Erlotinib
ERCC1+
Observation
ERCC1-
CDDP-Pemetrexed
EGFR
wt
Non-SCC NSCLC stage II and IIIA (non-N2)
TASTE Results
•
•
•
•
•
•
150 pts randomized between May 2009 and July 2012,
74 in arm A (PEM/DDP) and 76 in arm B (Selected)
Most pts were male (61%), > 60 years (51%), and smokers (91%)
Pathological stage was IIA in 69 pt, IIB in 48 pt and IIIA in 32 pt.
ERCC1 was positive in 38 pts (19 in each arm) – only 25%, not 44% expected
EGFR mutation was identified in 10 pts (3 in arm A, 7 in arm B).
– Arm A, all pts received CP.
– Arm B,
• 7 pts received erlotinib,
• 53 pts received CP
• 16 were observed
•
•
•
Median exposure time to erlotinib was 276 days (10-365).
Out of 127 pts allocated to CP, 82% received the expected 4 cycles with a very good
tolerability profile (no febrile neutropenia).
Success
rate was 80% (120 out of 150 pts): appropriate Tx assignment and Tx
68
Soria J-C et al A-7505, ASCO ‘13
TASTE Conclusions
• Met its primary end point for the phase II component, demonstrating
feasibility of a national biology-driven trial in the adjuvant setting.
• Nevertheless, the phase III was canceled due to the unexpected
unreliability of the ERCC1 IHC read-out.
– Current commercial antibodies are unable to distinguish all
isoforms of ERCC1
TASTE Implications
• TASTE Needs to be redone with accurate ERCC1 IHC Ab
• May have been responsible for the (-) MadeIT phase III trial in advanced
NSCLC (relied on PCR mRNA probes and AQUA)
69
Soria J-C et al A-7505, ASCO ‘13
Role of Targeted Therapy
ECOG 1505: Adjuvant Bevacizumab
ELIGIBLE:
STRATIFIED:
Resected IB^-IIIA
Lobectomy
No prior chemo
No planned XRT
No h/o CVA/TIA
No ATE w/in 1 yr
Stage
Histology
Gender
Chemo
regimen*
R
A
N
D
O
M
I
Z
E
Chemotherapy
X 4 cycles
Chemotherapy
x 4 cycles
Plus
Bevacizumab
X 1 year
*Investigator Choice of 4 chemo regimens
^ Revised to exclude IB < 4cm
N >1500; closed to accrual summer 2013
ECOG 4599: Overall Survival
1.0
Proportion Surviving
0.8
Median Survival
PC
10.3 mo
BV/PC 12.3 mo
HR=0.80; P=0.013
1-year survival
51% vs 44%
0.6
2-year survival
23% vs 15%
0.4
0.2
0.0
0
6
12
18
24
30
36
Months
Sandler, et al. NEJM. 355;24. Dec 14 2006.
42
48
Chemotherapy Regimens
• Therapy to start 6-12 weeks post-operatively
– Investigator Choice of Chemo - 4 cycles (12 wks)
• Cisplatin/Vinorelbine
– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d
• Cisplatin/Docetaxel
– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d
• Cisplatin/Gemcitabine
– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d
• +/- Bevacizumab 15 mg/kg q 21 days x 12 mos
Chemotherapy Regimens:
amended 2010
• Therapy to start 6-12 weeks post-operatively
– Investigator Choice of Chemo - 4 cycles (12 wks)
• Cisplatin/Pemetrexed
– Cis 75 mg/m2 d1, Pemetrexed 500 mg/m2 d1
• Cisplatin/Vinorelbine
– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d
• Cisplatin/Docetaxel
– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d
• Cisplatin/Gemcitabine
– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d
• +/- Bevacizumab 15 mg/kg q 21 days x 12 mos
RADIANT Trial:
Adjuvant Trial of Erlotinib in NSCLC
Stage IB, II, or IIIA
NSCLC*
Complete surgical
resection
And subsequent
adjuvant chemo
No prior or concurrent
neoadjuvant or adjuvant
N=1654
*Enriched Population:
FISH and/or IHC (+)
R
A
2
N
Arm A
D
Erlotinib qd  2 years
O
M
I 1
Arm B
Z
Placebo qd  2 years
E
‫٭‬
RADIANT Trial:
Adjuvant Trial of Erlotinib in NSCLC
Stage IB, II, or IIIA
NSCLC*
Complete surgical
resection
And subsequent
adjuvant chemo
No prior or concurrent
neoadjuvant or adjuvant
N=1654
*Enriched Population:
FISH and/or IHC (+)
R
A
2
N
Arm A
D
Erlotinib qd  2 years
O
M
I 1
Arm B
Z
Placebo qd  2 years
E
‫٭‬
IPASS: Progression-free survival in EGFR
mutation positive and negative patients
EGFR mutation positive
EGFR mutation negative
Probability of progression-free
survival
1.0
0.8
0.6
0.4
Gefitinib (n=91)
Carboplatin/paclitaxel (n=85)
HR (95% CI) = 2.85 (2.05, 3.98)
p<0.0001
No. events gefitinib , 88 (96.7%)
No. events C/P, 70 (82.4%)
Median PFS G, 1.5 months
Median PFS C/P, 5.5 months
1.0
Probability of progression-free
survival
Gefitinib (n=132)
Carboplatin/paclitaxel (n=129)
HR (95% CI) = 0.48 (0.36, 0.64)
p<0.0001
No. events gefitinib, 97 (73.5%)
No. events C/P, 111 (86.0%)
Median PFS G, 9.5 months
Median PFS C/P, 6.3 months
0.8
0.6
0.4
0.2
0.2
0.0
0.0
0
Patients at risk :
Gefitinib 132
C/P
129
4
8
12
16
20
24
0
4
8
Months
108
103
71
37
31
7
12
16
20
24
1
0
0
0
0
0
Months
11
2
3
1
0
0
91
85
21
58
4
14
2
1
Treatment by subgroup interaction test, p<0.0001
Cox analysis with covariates; HR <1 implies a lower risk of progression on gefitinib; ITT population
Fukuoka et al, abstract 8006, ASCO 2009; Mok et al NEJM 2010
Phase II trial SELECT trial: adjuvant erlotinib in resected,
early stage NSCLC pts with EGFR mutations
PI L Sequist
TREATMENT PHASE
SCREENING PHASE
Resected stage
IA-IIIA NSCLC
Screen tumor for
activating EGFR
mutations (del
19, L858R)
N=100
Primary Endpoint: Two year
disease-free survival
+/adjuvant
chemo
Adjuvant erlotinib
x 2 years
Surveillance CT scans
and CTC analysis q 6
mos x 3 years then q
12 mos x 2 years
surveillance
Biopsy at recurrence,
sequence EGFR gene for
new mutations, FISH for
EGFR and MET copy
number
Enroll if:
screen + or documented EGFR mutation positive –andNo evidence recurrence on baseline CT scans
SELECT Trial: Adjuvant Erlotinib in Resected
NSCLC
Disease Free Survival
BR 19: Adjuvant Trial of
Gefitinib in NSCLC
Stage IB, II, or IIIA
NSCLC
Complete surgical
resection
No prior or concurrent
neoadjuvant or
adjuvant
N=1242
R
A
N
D
O
M
I
Z
E
‫٭‬
Arm A
Gefitinib qd  2 years
Arm B
Placebo qd  2 years
‫ ٭‬Modified 2004 to allow adjuvant chemotherapy
CAN-NCIC-BR19, CTSU, ECOG-CAN-NCIC-BR19, SWOG-CAN-NCIC-BR19 Protocol.
Clinical Trials (PDQ®). At: www.cancer.gov. Commenced October 2002.
* Trend toward impaired outcome for EGFR mutation pts receiving Gef [HR of OS: 1.51]
Goss ASCO 2010 Abstr LBA7005
ALCHEMIST
E4512
A081105
A151216
Target
ALK+
EGFRmut
Registry
Prevalence
~5%
~10%
All comers
n
336
410
6000-8000
DFS-OS
OS
--
Power
80%
85%
--
One-sided α
0.025
0.05
--
HR
0.67
0.67
--
Peripheral
screening for
ALK; RTPCR to
identify fusion
partners
Targeted
sequence and
kinome
analysis; PRO
and QOL
Extended
sequencing for
additional targets;
correlation with
local testing
Primary Endpt
Adjunct
Vaccines
MAGE-A3 Antigen
(melanoma antigen family A, 3)
• Truly tumor-specific
–Not expressed on normal cells (RT-PCR)
–Expressed by various tumor types
• Lung
• Bladder
• Head & Neck
• Melanoma
35-50%
35%
49%
74%
• Associated with poorer prognosis
(Bolli et al.,2002; Gure et al.,2005)
• Member of a large family of genes (portfolio)
MAGE A3 ASCI* randomized phase II
• Stage pIB or pII: double-blind, randomly assigned 2:1
to postoperative MAGE-A3 vaccination or placebo.
• Vaccination was started >6 weeks after surgery, with 5
vaccinations at 3-week intervals, followed by 8
vaccinations every 3 months.
• Other anti-cancer adjuvant therapy was not allowed.
• Primary endpoint was time-to-recurrence, other
endpoints were recurrence rates at different times,
and survival.
* antigen-specific cancer immune therapeutic
Vansteenkiste et al, ASCO 2006, abstract 7019
Safety Status
• 182 patients / 1214 MAGE-A3 doses
administered
• Well tolerated
• Mild grade 1 or 2 toxicities
• Local or systemic reactions,  48 hours
• 29 grade 3 or 4 adverse events in 21
patients
• Three grade 3 events, possibly related to
treatment
• Leading to withdrawal of 2 patients
–(local pain, COPD exacerbation)
Disease-Free Interval
HR=0.73
p=0.107
(95% CI = 0.44 - 1.2)
10% one-sided 
Vansteenkiste et al, ASCO 2006, abstract 7019
Efficacy Endpoints Overview
Final analysis 05 Oct, 2006
Cox regression model (95% confidence interval)
P-value from Cox regr. model adjusted for stratification covariates
HR with a 10% one-sided 
0.73
Disease-Free Interval
HR = 0.73 (0.44-1.20)
0.73
HR = 0.73 (0.45-1.16)
Disease-Free Survival
0.66
Overall Survival
0.00
2.00
0.50
« MAGE-A3 » better
HR = 0.66 (0.36-1.20)
1.00
1.50
Hazard ratio
« Control » better
P=0.107
MAGE Trial Design
Resectable
NSCLC
Surgery
Pathological stage IB, II, IIIA
Chemotherapy
(up to 4 cycles
platinum based
chemotherapy)
No chemotherapy
R
MAGE-A3
+AS15
Placebo
MAGE-A3 +AS15
MAGRIT Trial
R
Placebo
MAGRIT: Phase III
• Largest lung cancer study EVER
• Began in October 2007
• Goal: 2270 patients from 400 centers
in 33 countries in Europe, North and
South America, Asia, Australia
• 2289 ultimately enrolled
Role of Adjuvant RT in Stage II
and Stage IIIA
Should the pt receive adj RT?
1) Yes
2) No
3) Maybe
Adjuvant Radiotherapy:
Meta-analysis 1998
• Individual data from 9 randomized trials
including 2128 patients
• Treatment details (staging, surgery, RT)
highly variable among series
• PORT: better local control: 29% fewer local
recurrences - 195 LR vs 276 LR for no RT
• Overall HR = 1.21 (1.08-1.34) ~ survival
decrement of 7 % at two years (55% vs 48%)
• Increase risk greater for early stage
patients(Stage I/II vs. III)
Lancet 25 July 1998
PORT Meta-analysis
Survival Curves
Stewart et al Lancet 1998
PORT - Heterogeneity of Hazard
• No increased risk
for patients with N2
disease
• Patients with the
least to gain have
the most to lose
Stewart et al Lancet 1998
PORT Meta-analysis
Methodologic Flaws
• Variable and unspecified staging
• Variable and unspecified interval between resection and
PORT
• Inadequate RT
– Suboptimal doses; large fields
– Poor treatment planning
– Outmoded techniques (e.g.: use of low-energy photons or 60Co
for a substantial proportion of patients)
• Inclusion of N0 patients
• Unpublished data (2 of 9 studies)
• Relatively short F/U (< 4 yrs)
Stewart et al Lancet 1998
Risks of PORT with Modern
Technology
• Retrospective review
– 202 patients treated with surgery and
PORT for Stage II and III disease
– Median dose 55 Gy
– Actuarial rate of death from
intercurrent disease was 13.5%
compared to expected rate of 10%
Machtay et al JCO 2001
ANITA TRIAL: N2 Disease
– Influence of RT
Survival Distribution Function
1.00
CT RT
CT
RT
OBS
0.75
0.50
0.25
0.00
0
20
40
60
80
DURATION OF SURVIVAL (MONTHS)
100
120
IASLC 2005
ANITA TRIAL: N2 Disease
– Influence of RT
Survival Distribution Function
1.00
RT Effect? Or Serendipity?
0.75
CT RT
CT
RT
OBS
0.50
0.25
0.00
0
20
40
60
80
DURATION OF SURVIVAL (MONTHS)
100
120
IASLC 2005
ANITA - PORT Evaluation
• PORT: 33% on obs, 22% on chemo
• For all Chemo > XRT = chemo/XRT > 0
• For N2 Chemo/XRT > chemo > XRT > 0
XRT
No
No
Yes
Yes
Chemo
No
Yes
No
Yes
All pts MST
26mo
93mo
50mo
46mo
N2 MST
13mo
24mo
23mo
47mo
Rosell, IASLC 11, Abs Pr3, 2005
Plot of overall survival for N2 patients
stratified by postoperative radiotherapy
(PORT) use – SEER data
Lally, B. E. et al. J Clin Oncol; 24:2998-3006 2006
PORT Conclusions
• PORT has no role in N0 or N1 disease
• Role of PORT in N2 is controversial
– Recent subset and retrospective analyses hint
at benefit
– Ongoing “Lung ART” trial in France
• 700 pts with resected N2 randomized to PORT or not
• Adjuvant chemo allowed 1st
• Accrual sluggish
“Lung ART”
P.I. Dr Cécile Le Pechoux
Completely resected N2 NSCLC
Primary end-point: DFS (Sample size: 700 patients)
S
U
R
G
E
R
Y
Conformal RT
54 Gy/27-30 fxs
No post-op RT
Pre or post-op chemotherapy allowed
Concomitant chemo not allowed
Sponsors: FNCLCC, IFCT, LARS-G, EORTC
Conclusions: Adjuvant Therapy
• Adjuvant Platinum-based Chemotherapy is the
Standard of Care for Resected Stage II-IIIA NSCLC
– Improves OS 5%-15% at 5 years with newer drugs
• Fit elderly patients (< 75 yrs) benefit as much as
younger patients
• Ongoing trials with molecularly determined Tx,
erlotinib, bevacizumab, vaccines
• Controversies
–
–
–
–
Benefit in IB
Neoadjuvant vs adjuvant therapy
Which chemotherapy to use
PORT