Transcript Cancer and Leukemia Group B 9730

ADVANCES FOR
TREATMENT OF LUNG CANCER
ASCO 2004, NOLA
Jennifer Garst, M. D.
Assistant Professor of Medicine
Thoracic Oncology Program
Duke University Medical Center
ADVANCES FOR
TREATMENT OF LUNG CANCER
ASCO 2004, NOLA
Non-Small Cell Lung Cancer
a. Early Stage Disease
b. Locally Advanced Disease
c. Advanced Disease
ASCO PRACTICE GUIDELINES
www.ASCO.org
Clinical Practice Guidelines for the
Treatment of Lung Cancer, 1997
Updated 2003 For Unresectable NSCLC
Stage I/II Non-Small Cell Lung
Cancer
ASCO GL (1997):
• Surgical resection if operable
• Role of neoadjuvant or adjuvant therapy
cannot be ascertained at this time
NCCN GL (2004):
• Surgical resection if operable
• Stage IA- Observation
• Stage IB/II- Adjuvant Chemotherapy
Stage I/II Non-Small Cell Lung
Cancer
Stereotactic Hypofractionated
High-Dose Irradiation for Stage I
Non-small Cell Lung Carcinoma:
Clinical Outcomes in 273 Cases
Of a Japanese Multi-Institutional Study
Onishi et al, Abstract #7003
Stage I/II Non-Small Cell Lung
Cancer
N=273
Med age 76yrs
T1N0(175),T2N0(98), 7-58mm (28mm)
62% inop 2ndCOPD
3D, stereotactic procedure
1800-7500cGy given in 7-22 fractions
Onishi et al, Abstract #7003
Stage I/II Non-Small Cell Lung
Cancer
2.9% with grade ¾ pulmonary compl
CR 71%, PR 59%
Local Progression in 12.5%
3yrS: 69% Bio Eff Dose<100Gy
95% BED >100Gy
Interesting new technology
Onishi et al, Abstract #7003
1995 Meta-Analysis
Adjuvant Cisplatin Trials n=1394
Percentage Survival
100
HR 0.87
p=0.08
80
60
40
Surgery plus Chemotherapy
Surgery
20
0
0
6
12
18
24
30
36
42
48
54
Time from Randomization (months)
BMJ 31: 899-908, 1995 Slide by Dr. Pisters
60
IALT - Overall Survival
NEJM 2003
Slide by Dr. Pisters
HR= 0.86 [0.76-0.98]
100%
p<0.03
80%
60%
___ Chemotherapy
___ Control
40%
20%
Years
0%
At risk
0
1
2
3
932
935
4
5
775
624
450
308
181
774
602
432
286
164
UFT Meta-Analysis
Hamada, ASCO 23:7002, 2004
JBR.10
Winton, ASCO 23:7018, 2004
CALGB 9633
Strauss, ASCO 23:7019, 2004
Slide by Dr. Pisters
UFT Meta-Analysis
Background

UFT: Uracil and Tegafur

Tegafur - prodrug of fluorouracil

Uracil - inhibits DPD,  serum FU

Studied extensively in Japan

Well tolerated oral agent, long-term

Possible anti-angiogenic properties
Slide by Dr. Pisters
UFT Meta-Analysis
Hamada, ASCO 23:7002, 2004
• 6 randomized trials
• Conducted in Japan
• 5 years follow-up
Surgery
UFT (no intravenous chemo)
Slide by Dr. Pisters
UFT Meta-Analysis
Patient Characteristics - 6 Trials
•
Stage I - 95%
•
Adenocarcinoma - 84%
•
Women - 45%
•
Median Age - 62
Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters
UFT Meta-Analysis
6 Trials: Intervention UFT*
Stage
1
2
3
4
5
6
I-III
I
I-II
I
I Ad-S
I Ad
n
201
332
219
172
100
979
Survival
+ 15%
+ 15%
+ 4%
+ 17%
- 1%
+ 3%
2003
Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters
p
.022
NS
NS
.045
NS
.04
Reference
JCO 96
(ECCO 01)
Lung Ca 03
(ASCO 02)
(Lu Ca 03)
NEJM 04
*400 mg PO daily x 1-2 years
UFT Meta-Analysis
Exploratory Analysis T1
< 2 cm, n=670
2 - 3 cm, n=599
1.0
.
0.8
1.0
0.6
0.6
0.8
p=0.357
0.4
0.4
0.2
0
p=0.0157
0.2
1
3
5
7
0
Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters
1
3
5
7
UFT Meta-Analysis Conclusions
Pisters
•
This meta-analysis showed that long-term
treatment with UFT is effective as
postoperative adjuvant therapy for…
•
stage I
•
T>2 cm
•
adenocarcinoma
•
a study population with 45% women
Slide by Dr. Pisters
NSCLC Randomized Cisplatin Adjuvant Trials
After the 1995 Meta-Analysis
Chemo
Survival
Trial
Stage
n
Japan
ALPI
IALT
III-N2
I-III
I-III
119
1209
1867
VdP
MVdP
Vinca or EP
No
No
Yes
BLT
I-III
381
Platin-based
No
NCIC
IB-II
482
VbP
Yes
CALGB
IB
344
PacCb
Yes
Lung Ca 04; JNCI 03; NEJM 04; Lung Cancer 03; ASCO 04; ASCO 04 Slide by Dr. Pisters
Prospective Randomized Trial of Adjuvant
Vinorelbine and Cisplatin in Completely
Resected Stage IB/II NSCLC (JBR10)
482 pts randomized after resection
(stage IB/II)
• Lobectomy or pneumonectomy, N2
sampling
• Vin (25mg/m2 weekly) + Cis
(50mg/m2 d1,8) q 4 weeks x 4 cycles
versus observation
• Stratified: N status, ras mutation
Winton TL, et al. ASCO Abstract 7018 Slide by D’Amico
NCIC JBR10
T2N0M0 (IB)
T1-2 N1(II)
NSCLC
(Complete
resection)
R
A
N
D
O
M
I
Z
E
Cisplatin (50mg/m2
d1,8)
Vinorelbine
(25mg/m2)
4 cycles
Observation
Winton TL, et al. ASCO Abstract 7018 Slide by D’Amico
Prospective Randomized Trial of Adjuvant
Vinorelbine and Cisplatin in Completely
Resected Stage IB/II NSCLC (JBR10)
• 59% received 3 or more cycles
• Limited toxicity (neuro)
• Overall survival improved Vin/Cis (94m vs
73 m)
• 5-year survival longer for Vin/Cis (69% vs
54%)
• 15% survival improvement at 5 years
• 30% reduction in risk of death (p=0.012)
Winton TL, et al. ASCO Abstract 7018 Slide by D’Amico
JBR.10 - Overall Survival
Winton, ASCO 23:7018, 2004
100
____ VbP
Per cen tage
80
____ Observation
60
40
HR 0.696 [.524-.923]
p=0.012
20
69%
54%
0
0.0
239
Slide by 243
Dr. Pisters
2.0
4.0
6.0
8.0
10.0
182
193
94
121
47
51
13
10
0
0
Randomized Clinical Trial of Adjuvant
Chemotherapy with Paclitaxel and Carboplatin
following Resection in Stage IB NSCLC
(CALGB 9633)
• High risk stage I patients (T2) after
resection
• Stratified by histology, differentiation,
mediastinoscopy
• Lobectomy or pneumonectomy; N2
sampling
• Closed by a planned interval analysis
• Accrual 344/384 planned (90%)
Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico
CALGB 9633
T2N0M0 (IB)
NSCLC
(Complete
resection)
R
A
N
D
O
M
I
Z
E
Carboplatin
(AUC=6)
Taxol (200mg/m2)
4 cycles/12 wk
Observation
Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico
CALGB 9633
Variable
Chemo (n=173)
Control
(n=171)
P
value
Age
PS=0
Sx present
size
61 yr (34-78)
55%
78%
4.7cm (0-15)
62 yr (40-81)
58%
74%
4.6cm (1-12)
0.42
0.92
0.39
0.87
Squam
Poorly diff
Mediastin
39%
50%
80%
39%
50%
79%
0.98
0.99
0.78
Lobectom
89%
89%
0.98
Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico
Randomized Clinical Trial of Adjuvant
Chemotherapy with Paclitaxel and Carboplatin
following Resection in Stage IB NSCLC
(CALGB 9633)
•
•
•
•
All 4 cycles delivered in 85%
Dose modification in 35%
55% received all 4 cycles at full dose
Chemo well tolerated: no toxicity
related deaths
• Grade 3-4 neutropenia in 36%
Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico
CALGB 9633 - Overall Survival
0.6
0.8
----- Chemotherapy
----- Observation
0.4
HR 0.62 [0.41-0.95]
p=0.028
0.2
Probability
1.0
Strauss, ASCO 23:7019, 2004
0.0
71%
59%
0
20
40
4 yr
Survival Time (Months)
Slide by Dr. Pisters
60
80
NCIC & CALGB Adjuvant Chemotherapy
Conclusions
Why are the NCIC/CALGB results better?
•
Patient Selection
 Earlier stage disease
 Uniform patient population
 1.5 x more women than IALT
•
Therapy
 2 drug regimen
 Inclusion of 3rd generation agent
 Better compliance (CALGB)
 Lack of radiation
Slide by Dr. Pisters
NCIC & CALGB Adjuvant Chemotherapy
Conclusions
•
The NCIC and CALGB studies
confirm the positive IALT findings of
a benefit for postoperative platinbased chemotherapy in completely
resected NSCLC.
Slide by Dr. Pisters
Adjuvant Chemotherapy 2004
Conclusions
• Consistent reductions in the risk of
death have been observed in recent
adjuvant platin-based trials and the 1995
meta-analysis.
• Adjuvant platin-based chemotherapy
should be recommended to completely
resected NSCLC patients with good
performance status.
Slide by Dr. Pisters
Resectable Stage III Non-Small Cell
Lung Cancer
ASCO GL 1997:
• Not addressed
• Importance of PS, PFT’s
• Imply that bulky N2 disease should not be
considered resectable.
Resectable Stage III Non-Small Cell
Lung Cancer
Cisplatin/Etoposide Followed by TwiceDaily Chemoradiation vs
Cisplatin/ Etoposide Alone Before Surgery
in Stage III Non-small Cell Lung Cancer:
A Randomized Phase III Trial of the German
Lung Cancer Cooperative Group
Thomas et al, Abstract #7004
Resectable Stage III Non-Small Cell
Lung Cancer
3 Cycles Cis/VP16BID
XRT4500cGySurgery
w/Carbo/Vin
VS
3 Cycles Cis/VP16 Surgery XRT
5400cGY
Abstract #7004
Resectable Stage III Non-Small Cell
Lung Cancer
N= 481, 18% women, med age 59yo, PS0-1,
32% Stage IIIA, 68% Stage IIIB
Neo Chemo->Chemo/XRT NeoChemo/Adj XRT
Esoph
15%
4%
IndResp 52%
47%
Resction 45%
50%
TxRlDeath 5.6%
5.3%
3yrS
24%
23%
Abstract #7004
Unresectable Stage III Non-Small Cell
Lung Cancer
ASCO GL 2003 Update:
• Chemotherapy in association with definitive thoracic
irradiation is appropriate for selected patients
(PS 0-1, ?2) with unresectable, locally advanced
NSCLC.
• XRT no less than 6000 cGy
• Duration of chemotherapy should be 2-8 cycles.
Unresectable Stage III Non-Small Cell
Lung Cancer
Induction Chemotherapy Followed By
Concommitant Chemoradiotherapy vs
CT/XRT Alone for Regionally Advanced
Unresectable Non-small Cell Lung Cancer:
Initial Analysis of a Randomized Phase III
CALGB Trial
Vokes, et al. Abstract #7005
Unresectable Stage III Non-Small Cell
Lung Cancer
2 Cycles CarboAUC6/Taxol200mg/m2
WeeklyCarbo/Taxol/XRT
VS
WeeklyCarboAUC2/Taxol50mg/m2/XRT66GY
Vokes, et al. Abstract #7005
Unresectable Stage III Non-Small Cell
Lung Cancer
N=366, 34%women, 63%>60yo
IndconcChemo/XRT
Chemo/XRT
ANC
27%
15%
Eso
35%
31%
SOB
19%
12%
4Tox
41%
24%
MS
14mo
11.4mo
1yrS
54%
48%
-Poor 1yrS in both arms, SWOG 76%1yS
-?Wrong Chemotx
or wrong design
Vokes, et al. Abstract #7005
Advanced Non-Small Cell
Lung Cancer
ASCO GL 2003:
• Platinum-based combination chemotherapy
• Alternative non-platinum doublet or single agent as
clinically indicated
• No more than 6 cycles
• Docetaxel 2nd line; Gefitinib (Iressa) 3rd line
• Consider treatment on a clinical trial
Advanced Non-Small Cell
Lung Cancer
Results of a Phase III Trial of Erlotinib
(Tarceva) Combined with Cisplatin and
Gemcitabine Chemotherapy in Advanced
Non-small Cell Lung Cancer
Gatzemeier et al, Abstract #7010
The ErbB Family and Ligands
EGF
TGF-
Amphiregulin
-cellulin
HB-EGF
Epiregulin
No Known
Ligands
Heregulins
HB-EGF
Heregulins
-cellulin
Extracellular
Tyrosine
Kinase
Domain
Intracellular
ErbB-1
HER1
EGFR
ErbB-2
HER2 neu
ErbB-3
HER3
ErbB-4
HER4
Turning Off the EGFR-TK Signal
At the Source1-3
• Inhibition of the EGFRTK itself—inside the
cell—completely
inhibits EGFR-TK
signaling regardless of
the triggering event
Inhibition
of
apoptosis
Metastasis
Proliferatio
n
Invasion
Angiogene
sis
1. Leserer M et al. IUBMB Life. 2000;49:405-409. 2. Raymond E et al. Drugs.
2000;60(suppl 1):15-23. 3. Prenzel N et al. Endocr Relat Cancer. 2001;8:11-31.
EGFR in NSCLC
• EGFR-TK plays a key role in growth,
invasion, and metastasis of NSCLC
• EGFR expression in up to 80% of
tumors in patients with NSCLC
• Novel EGFR-TK inhibitors target key
signal transduction pathways
• Once-daily oral EGFR-TK inhibitors
appear to be well tolerated
Advanced Non-Small Cell
Lung Cancer
N=1172
Chemo-naïve StageIIIB/IV, PS0-1
6 cycles Cis/Gem + drug/placebomaint tablet
Erlotinib 150mg qd po
Erlotinib
Placebo
Diarh 6%
<1%
Rash 10%
<1%
OS 10.8mo
11.2 mo
Gatzemeier et al, Abstract #7010
Advanced Non-Small Cell
Lung Cancer
A Phase III Trial of Erlotinib (Tarceva)
Combined with Carboplatin and Taxol
Chemotherapy in Advanced Non-small Cell
Lung Cancer
TRIBUTE
Herbst et al, Abstract #7011
Advanced Non-Small Cell
Lung Cancer
n=1059
Same design
Erlotinib
Placebo
OS 10.8mo
10.6mo
Proper sequencing of targeted therapies is
under study
Herbst et al, Abstract #7011
Advanced Non-Small Cell
Lung Cancer
A Randomized Placebo-Controlled Trial of
Erlotinib (Tarceva) in Patients with
Advanced Non-small Cell Lung Cancer
Following Failure of 1st or 2nd Line
Chemotherapy: an NCIC CTG Trial
Shepherd et al, Abstract #7022
Advanced Non-Small Cell
Lung Cancer
N=731, Stage IIIB/IV
36% women, PS 0-3, 1-2 previous chemo comb
2:1 erlotinib 150 mg po qd vs placebo
Erlotinib
Placebo
D/C 5%
2%
TTDS-c 4.9mo
3.68mo
TTDS-p 2.79mo
1.91mo
PFS 2.23mo
1.84mo
(p<0.001)
OS 6.7mo
4.7mo
(p<0.001)
Shepherd et al, Abstract #7022
Advanced Non-Small Cell
Lung Cancer
Gefitinib (Iressa) Therapy for Advanced
Bronchioloalveolar Lung Cancer (BAC):
SWOG S0126
West et el, Abstract #7014
Advanced Non-Small Cell
Lung Cancer
BAC is increasing in incidence esp in
young non-smoking women
May be a subset to respond well to EGFR
targeted tx
N=138 (102 chemo naïve, 36 previously
tx)
51% women, med age 68yr, 86% PS0-1
Gefitinib 500mg po qd, most dose
reduced to 250 mg
West et el, Abstract #7014
Advanced Non-Small Cell
Lung Cancer
Chemo naïve
Previously Tx
RR 21%, 6 %CR
RR 10%
1yrS 50%
50%
Rash
MS 12 mo vs no rash 5 mo
Women
MS 16 mo vs Men 5 mo
Pulm Tox 3 patients died, ?IPF vs PD
West et el, Abstract #7014
Advanced Non-Small Cell
Lung Cancer
Interstitial Lung Disease During
Gefitinib Treatment of Japanese
Patients with Non-small Cell Lung
Cancer
Abstract #7063
Advanced Non-Small Cell
Lung Cancer
N=325, retrospective chart analysis
32% women, med age 67yr, 34% PS 2-4
Hepato Tox 5%
Rash 2.2%
Diarrhea 0.6%
22pts (6.8%) developed ILD,10died (3.1%)
MTD 18 days s/p Iressa, ½ acute onset SOB
Risk factors: Poor PS, previous PF, possibly
men with history of smoking
Abstract # 7063
Advanced Non-Small Cell
Lung Cancer
A Multicenter Phase III Randomized Trial for
Stage IIIB/IV NSCLC of Weekly Paclitaxel
and Carboplatin vs Standard Paclitaxel and
Carboplatin Given Every Three Weeks
Followed by Weekly Paclitaxel
Belani et al, Abstract #7017
Advanced Non-Small Cell
Lung Cancer
Arm1 CarboAUC6 D1, Taxol 100mg/m2 D1,8,15
Arm2 CarboAUC6 D1, Taxol 225mg/m2 D1
Followed by maintenance weekly Taxol 70mg/m2
Weekly
Q3W
ANCgr4
4.6%
7.9%
FN3/4
0.9%
3.3%
Neuro
16%
24%
HCT
17%
7%
RR
20%
18%
Belani et al, Abstract #7017
Advances for the Treatment of
Lung Cancer
1. A New Standard of care: Adjuvant platin-based chemotherapy
should be recommended to completely resected NSCLC
patients with good performance status.
2. Multi-modality treatments may offer a modest survival benefit for
appropriately selected patients with resectable Stage III NSCLC.
More to learn about role and timing of chemo, XRT and surgery.
3. Concurrent chemotherapy/XRT appears to offer a survival benefit for
patients with Inoperable Stage III NSCLC although induction therapy
and Carbo/Taxol may not be the best therapeutic choices.
4. Targeted therapies are making an impact in advanced and relapsed
NSCLC. More to learn about sequencing, mutations, population
selection, other targets. Warning: Pulmonary tox risk in PS2, PF
5. Platinum-based combinations remain the standard of care for
advanced NSCLC. Q3 Week Carbo/Taxol is here to stay!