Transcript Adjuvant Chemotherapy

NSCLC Adiuvante
Dott. Domenico Galetta
Adjuvant Therapy Timeline
BLT
HR = 1.02
N=381
RADIANT
IALT
HR = .86
N=467
JBR.10
HR = .69
~
N=482
ANITA
HR = .76
N=840
20 03 2004
2005
2006
ALPI
HR = .96
N=1207
6
MAGRIT
20 08
20 13
CALGB 9633
HR = .83
N=344
E1505
Closed to
Accrual
2014
ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61
BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J Cardiothorcic Surg 2004;26:173-182
IALT–CDDP-based vs OBS Stage I-IIIA Arriagada R et al. N Engl J Med 2004; 350: 350-61
JBR.10–CDDP-VNR vs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97
ANITA–CDDP-VNR vs OBS Stage IB-IIIA Douilland JY et al. Lancet Oncol 2006; 7: 719-27
CALGB 9633–PAC-CARBO vs OBS Stage IB Strauss GM et al. J Clin Oncol 2008; 26: 5043-51
Adjuvant Therapy Timeline
BLT
HR = 1.02
N=381
IALT
HR = .86
N=467
2003
ALPI
HR = .96
N=1207
2004
RADIANT
JBR.10
HR = .69
N=482~
6
2005
ANITA
HR = .76
N=840
2006
MAGRIT
2008
2013
CALGB 9633
HR = .83
N=344
E1505
Closed to
Accrual
ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61
BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J Cardiothorcic Surg 2004;26:173-182
IALT–CDDP-based vs OBS Stage I-IIIA Arriagada R et al. N Engl J Med 2004; 350: 350-61
JBR.10–CDDP-VNR vs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97
ANITA–CDDP-VNR vs OBS Stage IB-IIIA Douilland JY et al. Lancet Oncol 2006; 7: 719-27
CALGB 9633–PAC-CARBO vs OBS Stage IB Strauss GM et al. J Clin Oncol 2008; 26: 5043-51
?
2014
ITACA
CALGB
30506
ALCHEMIS
T
CTONG11
04
Afatinib
Adjuv
EURECA
Adjuvant CT ± post-op RT, in operable NSCLC:
two meta-analyses of individual patient data
34 trials, 8447 patients
HR 0.86 (95 CI : 0.81-0.92)
P<0.0001
4% benefit
13 trials, 2660 patients
HR 0.88 (95 CI : 0.81-0.97)
P<0.009
NSCLC Meta-analyses Collaborative Group Lancet 2010; 375:1267
4% benefit
LACE Analysis by Stage
Adjuvant chemo has greatest benefit for
stage II and III and is detrimental for stage IA patients
Pignon JP, et al. J Clin Oncol 2008; 26:3552-9
Stage IB T Size Analysis
T ≥ 4 cm
T 3 - 4 cm
HR OS
p
HR OS
p
CALGB 9633
1.02
0.51
0.66
0.04
JBR.10
1.73
0.07
0.66
0.13
No Chemo Benefit
CALGB Stage IB and Tumor Diameter > 4 cm
7th edition of TNM staging
Tumors > 5 -7 cm are Stage IIA
Tumors > 7 cm are Stage IIB
Potential Chemo Benefit
JBR .10
Strauss GM,et al. J Clin Oncol 2008; 31: 5043-51
Butts CA, et al. J Clin Oncol 2010; 28: 29-34
What Have We Learned?
1. CDDP based adjuvant chemotherapy improves the
cure rate for patients with Stage II-IIIA NSCLC with a
PS of 0-1.
3. No role for adjuvant chemotherapy in patients with
a tumor size < 3 cm (Stage IA in both 6th and 7th
Staging classification).
2. Controversial role for adjuvant chemotherapy in
patients with a tumor size of > 4 cm with subset
analyses suggesting a benefit.
4. Non-cancer mortality may be increased in patients
receiving chemotherapy.
Early Stage NSCLC
No Biomarker, Unselected Population
Predictive Factors
P
r
o
b
a
b
i
l
i
t
y
Prognostic Factors
patients with residual
micrometastases
sensitive to adjuvant
therapy
Survival Time
Do «good prognosis»lung cancer exist?
T stage
(all N0M0)
T1a
T1b
T2a
T2b
T3
Primary
size
≤ 2 cm
> 2-3 cm
> 3-5 cm
> 5-7 cm
> 7 cm
N
1816
1583
2822
825
364
5 Year
Survival
Clinical
Stage
53%
47%
43%
36%
28%
5 year
survival
Pathological
stage
77%
71%
58%
49%
35%
Rami-Porta J Thor Oncology 2007
Prognostic factors in lung cancer
There are no “good prognosis lung cancers”
23% of patients with tumor less than 2 cm (stage
pT1aN0M0) are dead at 5 years.
All patients with breast cancer with this degree of risk are
reccomended additional therapy with primary treatment
• Phase II “proof of concept” studies less applicable to adjuvant setting.
• In adjuvant studies overall response rate is NOT an endpoint.
• Survival is much longer and potentially impacted by additional lines of
therapy at relapse.
• Quality of life issues and adverse events.
• Early stage NSCLC are less frequently reported than in other types of
tumors (e.g. breast).
Strategies to select Drugs for use with
surgery in Early Stage Lung Cancer
•
•
•
•
•
•
Gene expression profiles (microarrays)
Repair/Metabolism genotype
Immunotherapy
Molecular driven mutation
New targets
Assess radiographic response in induction
“window of opportunity”
Strategies to select Drugs for use with
surgery in Early Stage Lung Cancer
•
•
•
•
•
•
Gene expression profiles (microarrays)
Repair/Metabolism genotype
Immunotherapy
Molecular driven mutation
New targets
Assess radiographic response in induction
“window of opportunity”
Use of microarrays in NSCLC
•
•
•
•
•
•
Need for complicated methods.
Large number of genes used in gene profilings.
In most of the studies need of fresh tissue.
Lack of both reproducibility and independent
validation of the results.
Genes varied considerably and only few genes have
been consistently included.
Gene expression profiles can vary according to the
microarray platform and the analytic strategy used.
CALGB 30506 Schema (Stage IA/IB)
Resection T (1.75 to 4.0) N0 Patients + Array
N=1296
LM Score <0.55; 850
LM Score > 0.55; 446
Randomize
Randomize
Observation
N=425
Adjuvant
Chemotherapy
N=425
Observation
N=223
LM Scores Blinded to Investigators
Adjuvant
Chemotherapy
N=223
Gene Expression Survival Prediction in Lung
Adenocarcinoma : Validation Study
All stages
Stage I only
All stages with
covariates
Stage I only
with covariates
• Training-testing multi-institution validation study (UM,HLM,CAN/DF,MSK), 442 adenocarcinoma
• Eight Classifiers
Shedden K. et al. Nature Med. 2008; 14::822
Strategies to select Drugs for use with
surgery in Early Stage Lung Cancer
•
•
•
•
•
•
Gene expression profiles (microarrays)
Repair/Metabolism genotype
Immunotherapy
Molecular driven mutation
New targets
Assess radiographic response in induction
“window of opportunity”
Early Stage NSCLC
Prognostic Biomarkers
Reference
Marker
Trial
N
Marker
Status
HR for Survival
(P Value)
Fouret 2009[1]
MSH2
IALT
768
Positive
0.66 (.01)
Olaussen 2006[2]
ERCC1
IALT
761
Positive
0.66 (.009)
Filipits 2007[3]
MRP2
IALT
782
Positive
1.37 (.007)
p53
JBR.10
253
Positive
1.89 (.03)
Seve 2007, 2012[5]
β-tubulin
III
JBR.10
265
Positive
1.72 (.04)
Cappuzzo 2009[6]
MET
Retrospective
447
Negative
0.66 (.04)
BRCA1
Retrospective
126
58
Positive
1.98 (.02)
2.4 (.04)
Tsao 2007[4]
Rosell 2007[7]
1. Fouret P, et al. ASCO 2009. Abstract CRA7502. 2. Olaussen KA, et al. N Engl J Med. 2006;355:983-991. 3. Filipits M, et al. Clin Cancer
Res. 2007;13:3892-3898. 4. Tsao MS, et al. J Clin Oncol. 2007;25: 5240-5247. 5. Seve P, et al. Clin Cancer Res. 2007;13:994-999, Annals
Onc 2012. 6. Cappuzzo F, et al. J Clin Oncol. 2009;27:1667-1674. 7. Rosell R, et al. PLoS One. 2007;2:e1129.
TASTE -Adjuvant Trial IFCT0704:
Non Squamous Stage II and IIIA
ARM A
(Control)
CDDP pemetrexed
Erlotinib
EGFR
mutated
ARM B
(Experimental)
customized
ERCC1+
Observation
EGFR wt
ERCC1-
CDDP-Pemetrexed
TASTE: biomarker distribution
Biomarker distribution
Expected
EGFR
mutated
ARM B
(Experimental)
customized
Observed
10%
9%
ERCC1+
44%
25%
ERCC1-
56%
75%
EGFR WT
or UND
or UND
•
•
•
Study was stopped at 150 patients due to ERCC1 IHC which behavior during TASTE trial
was significantly different from the one observed in IALT-bio analysis1
Phase III did not proceed due to the unexpected lack of reliability of ERCC1 IHC 2
ERCC1 IHC is unable to distinguish the different isoforms. Only isoform 2 is active in DNA
repair. (Friboulet NEJM 2013)
1Olaussen
K et al. NEJM 2006
2Soria
JC ASCO 2013 Abst# 7507)
First analysis of toxicity and treament compliance in
customized postoperative chemotherapy based on BRCA1
levels after NSCLC resection: SCAT (Spanish Customized
Adjuvant Therapy) trial. Spanish Lung Cancer Group/GECP
Bartomeu Massuti1, Manuel Cobo2, Manuel Rodriguez-Paniagua1, Isabel Ballesteros3, Teresa Moran4, Ricardo Arrabal2, Jose Luis Gonzalez
Larriba5, Isidoro Barneto6, Yat Wah Pun3, Javier de. Castro Carpeño7, Lara Iglesias8, Carlos Baamonde6, Miguel Angel Muñoz9, Guillermo LopezVivanco10, JJ Rivas de Andres11, Dolores Isla12, Rafael Lopez13, Ramon De Las Peñas14, Delvis Rodriguez15, Pedro Lopez De Castro16, Angel
Artal17, Emilio Esteban Gonzalez18, Florentino Hernando Trancho19, Mariano Provencio20, J Valdivia21, Prudencio Diaz Agero7, Jose Luis Martin
De Nicolas8, Eva Pereira22, Jose Miguel Sanchez23, Rafael Rosell16;
1Alicante
University Hospital, Alicante/SPAIN, 2Hospital Carlos Haya, Malaga/SPAIN, 3Hospital La Princesa, Madrid/SPAIN, 4Catalan Institute of
Oncology, Badalona/SPAIN, 5Hospital Clínico San Carlos, Madrid/SPAIN, 6Hospital Reina Sofia, Cordoba/SPAIN, 7Hospital Universitario La Paz,
Madrid/SPAIN, 8Hospital 12 de Octubre, Madrid/SPAIN, 9Instituto Valenciano Oncología, Valencia/SPAIN, 10Hospital de Cruces de Barakaldo,
Vizcaya/SPAIN, 11Hospital Miguel Servet, Zaragoza/SPAIN, 12Hospital Lozano Blesa, Zaragoza/SPAIN, 13Hospital Clinico Universitario de
Santiago de Compostela, Santiago De Compostela/SPAIN, 14Hospital Provincial de Castellón, Castellón/SPAIN, 15Hospital Universitario Insular
de Gran Canaria, Las Palmas De Gran Canaria/SPAIN, 16Hospital Germans Trias i Pujol, Badalona/SPAIN, 17Hospital Universitario Miguel Servet,
Zaragoza/SPAIN, 18Hospital Universitario Central de Asturias, Oviedo/SPAIN, 19Hospital Clinico San Carlos, Madrid/SPAIN, 20Hospital Puerta de
Hierro, Madrid/SPAIN, 21Hospital Virgen de las Nieves, Granada/SPAIN, 22Grupo Español de Cancer de Pulmon (GECP), Barcelona/SPAIN, 23MD
Anderson Cancer Center, Madrid/SPAIN
Customized BRCA1 Adjuvant
Treatment in Stage II-II NSCLC (SCAT)
CONTROL
Resected
NSCLC
pN1 / pN2
Docetaxel/Cis
1
:
Q 1 BRCA1
Gem/Cis
Q2&3
BRCA1
Docetaxel/Cis
3
EXPERIMENTAL
Statification factors:
- Stage: N1 vs. N2
- Age <65 vs > 65 y
- Histology: Non-SCC vs. SCC
- Type of resection: Lobectomy vs Pneumonectomy
Q 4 BRCA1
Docetaxel
Planned number of patients: 432 (ammended)
CT should start until 8 weeks after surgery
PORT in N2 patients
Eudract: 2007-000067-15
NCTgov: 00478699
SCAT: BRCA1 expression
• Median mRNA BRCA1 levels: 15.78 (0.73-132)
• Quartiles distribution:
– Q1: 212 (42.4%)
– Q2-3: 150 (30%)
– Q4: 138 (27.6%)
• Mean BRCA1:
– Adenocarcinoma: 6.95 vs Squamous 20.29 (p<0.001)
• EGFR mut: 5.6% (incomplete data)
SCAT trial
ITACA Adjuvant Trial
Pharmacogenomics: Yes or No?
Standard
Chemotherapy
N= 700
HIGH ERCC1 & HIGH TS
Radically Resected
II-IIIA
No prior
Chemotherapy or
Radiation Therapy
prior surgery
R
Docetaxel
ERCC1 and TS
Assessment by RT-PCR
Standard
Chemotherapy
HIGH ERCC1 & LOW TS
R
Pemetrexed
Standard
Chemotherapy
Stratification Factors
Pathological stage
(II vs. III)
Smoking status
(current vs. former vs. never
smoker)
LOW ERCC1 & HIGH TS
R
Cisplatin/Gemcitabine
Standard
Chemotherapy
LOW ERCC1 & LOW TS
R
Cispplatin/Pemetrexed
Strategies to select Drugs for use with
surgery in Early Stage Lung Cancer
•
•
•
•
•
•
Gene expression profiles (microarrays)
Repair/Metabolism genotype
Immunotherapy
Molecular driven mutation
New targets
Assess radiographic response in induction
“window of opportunity”
Phase III Study in NSCLC: MAGRIT
MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR ImmunoTherapy
Resected MAGE-A3 (+) NSCLC
N= 2300
Pathological stage IB, II, IIIA
No chemo
Chemo
Randomization
Up to 4 cycles of
platinum-based chemo
MAGE-A3 ASCI
Randomization
Placebo
Powered for efficacy
MAGE-A3 ASCI
Placebo
Powered -for
27 -efficacy
2011 accrual completed
2014 ASCO results awaited
Strategies to select Drugs for use with
surgery in Early Stage Lung Cancer
•
•
•
•
•
•
Gene expression profiles (microarrays)
Repair/Metabolism genotype
Immunotherapy
Molecular driven mutation
New targets
Assess radiographic response in induction
“window of opportunity”
Adjuvant Gefitinib: JBR.19
Unselected for EGFR mut+
•Path stage IB - III NSCLC
•Complete surgical resection
•PS 0-2
•Adjuvant chemo and /or XRT
allowed
All patients
N = 503
Gefitinib
250 mg po q day
x 2 years
R
Placebo
PO q day
x 2 years
EGFR Mutated
Goss GD, et al. J Clin Oncol 2013; 31: 3320-26
Adjuvant Therapy: Erlotinib
Unselected for EGFR mut+
RADIANT
N = 945
Stage
IB-IIIA
Surgery
CTX4/
No CT
R*
* Selection
FISH + and/or IHC+
Primary endpoint: Disease Free Survival
Erlotinib
Placebo
EGFR mutation in early stage Lung
Cancer: Rationale
•
•
•
•
•
•
All stages need more cure
Eradicating metastases the goal
EGFR as target
Results in patients with early stages
Trials in progress
Seizing the opportunities
Adjuvant Imatinib in GIST
1 year vs 3 Years
Joensuu H et al JAMA. 2012;307(12):1265-1272. doi:10.1001/jama.2012.347
SELECT Trial
A multicenter phase II trial of
adjuvant erlotinib in 100 EGFRmutant lung cancer
EGFR mutation positive
Surgically resected
Stage I-IIIA NSCLC
< 6-9 months following adjuvant
chemo ± XRT
Initial 36, expanded to 100
ERLOTINIB 150 mg/daily, 2 years total
Scan every 6 months for 3 years,
annually yr 4-5
Primary End point : Disease Free Survival
Neil JW et al. J. Clin. Oncol. 2012;30 (abstr.7010)
SELECT: Adjuvant Erlotinib
Patients surgically reected stage I-IIIA harboring activating EGFR mutations
Neil JW et al. J. Clin. Oncol. 2012;30 (abstr.7010)
Further hurdles to be considered with
molecular alterations…..
• Is the alteration equally present in early
disease?
• Is the molecular alteration stable overtime?
• Is the targeted treatment equally effective as
adjuvant (maintenance) treatment or should
be reserved at relapse?
• Are long term toxicities tolerable?
TTP and OS from start of TKI retreatment, in patients who develop a recurrence of EGFRmutant lung cancer after stopping adjuvant TKI. A portion of patients gain durable disease
control on TKI despite prior adjuvant exposure.
Oxnard G R et al. Clin Cancer Res 2011;17:6322-6328
EURECA
Erlotinib Used as Adjuvant Therapy in
Resected EGFR mutant Lung Carcinoma
• Resected stage I-III EGFRmutation positive lung
cancer with activating EGFR
mutation(exon 19 deletion,
L858R, L861Q, G719X)
• Perioperative citotoxyc
chemotherapy and radiation
therapy as indicated
• Stratified by staging and
perioperative chemotherapy
N=286
Adjuvant erlotinib up to
24 months with CT
chest every 6 months
than yearly
N=190
CT chest every 6 months
than yearly
N=96
• CT scan at 30 months
• Follow patients for
recurrence or death
• Patients with recurrence
will be biopsed to confirm
recurrence and test for
molecular determination
of acquired resistance
• Record of subsequent
chemotherapies
Lung Cancer Mutation Consortium PI Cristopher Azzoli
Adjuvant Afatinib: 3 months vs 2 years
Baseline
CT need
Resected stage I-III
EGFR+ lung cancer
s/p completion of
standard adjuvant
chemotherapy +/- RT
R
A
N
D
O
M
I
Z
E
Afatinib
oral daily
x 3 months
CT Chest every 6 months x
3 years and then annualy
RFS at 5 years
Afatinib
oral daily
x 2 years
92 patients will be stratified for
pathological stage (I,II,III) powered to
detect a recurrence free survival
improvement of 20%
Adjuvant Afatinib PI Lecia Sequist
ALCHEMIST (Adjuvant Lung Cancer Enrichment
Marker Identification and Sequencing Trial)
Alliance
PI: Govindan R.
CLIA-approved LAB
•EGFR mutation test
Consent
& Register:
A151216
Screening
& Follow-up
Protocol
Pre-op
Cohort
•SOP-driven
FF/FFPE
•After resection,
buffy coat
•ALK rearrangement
E4512:
Crizotinib
ECOG 4512
PI: Ramalingam S.
Post-op
Cohort
•Assess FFPE
•buffy coat
TCGA
•Genomic sequencing
•Transciptome
•Methylation
Other
Adjuvant
Studies
ALCHEMIST (Adjuvant Lung Cancer Enrichment
Marker Identification and Sequencing Trial)
A151216 Registry Study
Screening and Follow up protocol
N= 6000 -8000
Actionable target and trial identified
E4512 N= 360
N = 410
A081105
Erlotinib
R*
Placebo
Primary Endpoint: OS
Adjuvant Therapy: Molecular Selection
Strategies to select Drugs for use with
surgery in Early Stage Lung Cancer
•
•
•
•
•
•
Gene expression profiles (microarrays)
Repair/Metabolism genotype
Immunotherapy
Molecular driven mutation
New targets
Assess radiographic response in induction
“window of opportunity”
WCLC 2013: what’s new
IFCT-0703: phase II study results
Adjuvant Therapy Timeline
BLT
HR = 1.02
N=381
IALT
HR = .86
N=467
2003
ALPI
HR = .96
N=1207
2004
RADIANT
JBR.10
HR = .69
N=482~
6
2005
ANITA
HR = .76
N=840
2006
MAGRIT
2008
2013
CALGB 9633
HR = .83
N=344
E1505
Closed to
Accrual
ALPI–MVP vs OBS Stage I-IIIA Scagliotti GV et al. J Natl Cancer Inst 2003; 95: 1453-61
BLT-CPPP-based vs OBS Stage I-III Waller D et al. Eur J Cardiothorcic Surg 2004;26:173-182
IALT–CDDP-based vs OBS Stage I-IIIA Arriagada R et al. N Engl J Med 2004; 350: 350-61
JBR.10–CDDP-VNR vs OBS Stage IB-II Winton T et al. N Engl J Med 2005; 352:2589-97
ANITA–CDDP-VNR vs OBS Stage IB-IIIA Douilland JY et al. Lancet Oncol 2006; 7: 719-27
CALGB 9633–PAC-CARBO vs OBS Stage IB Strauss GM et al. J Clin Oncol 2008; 26: 5043-51
?
Knowledge Gaps
2014
ITACA
CALGB
30506
ALCHEMIS
T
CTONG11
04
Afatinib
Adjuv
EURECA
<65
# Non-lung
cancer
deaths
>70
N
%
N
%
195
12
54
22
No treatment
interaction
Overall toxicities
grade 3-5
559
72
62
76
grade 4-5
470
34
65
41
0.7
3
1.9
Deaths from toxicities
grade 5
10
Elderly patients should receive adjuvant chemotherapy
Fruh M, et al. J Clin Oncol 2008; 26:3573-81
Adjuvant Chemotherapy – Optimal Regimen
Phase II Cis/Pemetrexed vs. Cis/Vinorelbine (TREAT)
Cis/Vb N-67
Cis/Pem N-65
Feasibility
74%
96%
Completion of Therapy
63%
22%
Grade 3-4 hematological toxicity
78%
11%
Grade 3-4 non-hematological toxicity
33%
31%
Cis 66%
Cis 90%
Vb 64%
Pem 90%
Dose Delivery (% Planned)
p =.001; p<.0001
Kueter M et al. Ann Oncol 24: 986-992;2012
Adjuvant Chemotherapy – Optimal Regimen
Most extensively studied regimen is Vinorelbine and Cisplatin
LACE meta-analysis showed a benefit of VNR/CDDP over
“other” CDDP regimens
E1505
pStage IB-IIIA
IB > 4 cm
R
A
N
D
O
M
I
Z
E
Primary endpoint: Overall Survival
Cisplatin – based
Chemotherapy
Cisplatin – based
Chemotherapy
Bevacizumab: 15 mg/kg
REGIMEN N= 636
% Use
Vinorelbine + CDDP
27%
Doxetaxel + CDDP
33%
Gemcitabine + CDDP
25%
Pemetrexed + CDDP
16%
Wakelee ASCO 2012, Abstr 7013
Lymphovascular Invasion in Stage I
Variables
HR
95% CI
N = 433 patients (1995-2010; 7th edition TNM staging)
P-value
Variables
HR
95% CI
P-value
Yanagawa N et al European J Cardio-Thoracic Surgery 44:e200-e206, 2013
Induction (Neoadjuvant) vs Adjuvant
Factors Favoring Induction
Chemotherapy
• Attacks micrometastases at earliest time
• Better drug delivery and tolerability
• Ability to assess sensitivity of agents used in
induction and planned for adjuvant
• Platform for new agent testing
• Surgical findings an outcome surrogate
• Time to identify unsuspected metastases and
comorbidities before local therapy
• Randomized trials equivalent or better
• Provide quick answers
Major pathologic response (≤10%
viable tumor) following
neoadjuvant chemotherapy as a
surrogate for overall survival in
patients with pathologically
documented stage IIIA (N2) lung
adenocarcinomas
Jamie E. Chaft1, Matthew D. Hellmann1, William
D. Travis2, Valerie Rusch3, Mark G. Kris1
Memorial Sloan-Kettering
Departments of 1Medicine, 2Pathology, 3Surgery
Major pathologic response as a surrogate for survival
Survival Results
Survival by Nodal Clearance
Survival by Nodal Downstaging
Percent survival
80
60
40
20
Nodal clearance
Persistant Nodal disease
100
Percent survival
Nodal downstaging
Persistent N2
100
80
60
40
20
0
0
0
12
24
36
48
60
72
0
12
24
36
48
60
72
Months
Months
Nodal
Clearance
N=14
Nodal
Persistent N2
Downstaging
N=16
N=30
Median
survival
Undefined
64 months
Hazard ratio
(95% CI)
1.4 (0.5 – 4.2) 0.7 (0.2 - 2.1)
Persistent
N2
N=32
Median
survival
Undefined
64 months
Hazard ratio
(95% CI)
1.0 (0.4 – 3.1) 0.9 (0.3 – 2.8)
Major pathologic response as a surrogate for survival
Survival Survival
by Major
Pathologic Response
by Major Pathologic Response
Percent survival
100
MPR (N=5)
>10% tumor cells (N=41)
80
60
40
20
0
0
12
24
36
48
60
72
Months
≥90% path response
N=5
<90% path response
N=41
Median survival
undefined
40.5 months
Hazard ratio (95% CI)
0.3 (0.07-0.95)
3.9 (1.1-14)
Adjuvant Therapy: Molecular Selection
Adjuvant chemotherapy uptake
~ 25%
Proportion of patients with surgically resected non–small-cell lung cancer diagnosed in
Ontario (N = 6,304) from 2001 to 2006 who received adjuvant chemotherapy.
Booth C M et al. JCO 2010;28:3472-3478
Conclusion
• Patient selection & drug selection based on gene
expression arrays, gene mutation and amplification
and/or proteomics will quite likely improve the efficacy
of adjuvant chemotherapy
• Phase II studies are marginally appropriate
• In this setting alternative efficacy outcomes instead of
OS are needed.
• Marker-based or marker by treatment interaction are
eagerly encouraged.
• In the context of rare oncogene-addicted tumors a
close multidisciplinary, international collaboration is
needed.