ADVANCES FORTREATMENT OF LUNG CANCER
ASCO 2004, NOLA
Jennifer Garst, M. D.
Assistant Professor of Medicine
Thoracic Oncology Program
Duke University Medical Center
ADVANCES FORTREATMENT OF LUNG CANCER
ASCO 2004, NOLA
Non-Small Cell Lung Cancer
a. Early Stage Disease
b. Locally Advanced Disease
c. Advanced Disease
ASCO PRACTICE GUIDELINESwww.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=273Med age 76yrsT1N0(175),T2N0(98), 7-58mm (28mm)62% inop 2ndCOPD3D, stereotactic procedure1800-7500cGy 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
Surgery plus Chemotherapy
Surgery
0
20
40
60
80
100P
erce
nta
ge
Su
rviv
al
Time from Randomization (months)
6 12 18 24 30 36 42 48 54 600
BMJ 31: 899-908, 1995 Slide by Dr. Pisters
1995 Meta-AnalysisAdjuvant Cisplatin Trials n=1394
HR 0.87p=0.08
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5
HR= 0.86 [0.76-0.98] p<0.03
IALT - Overall SurvivalNEJM 2003 Slide by Dr. Pisters
___ Control
___ Chemotherapy
Years
164286432602774935
181308450624775932At risk
JBR.10 Winton, ASCO 23:7018, 2004
CALGB 9633Strauss, ASCO 23:7019, 2004
Slide by Dr. Pisters
UFT Meta-AnalysisHamada, ASCO 23:7002, 2004
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 n Survival pReference
1 I-III 201 + 15% .022 JCO 96
2 I 332 + 15% NS (ECCO 01)
3 I-II 219 + 4% NS Lung Ca 03
4 I 172 + 17% .045 (ASCO 02)
5 I Ad-S 100 - 1% NS (Lu Ca
03)
6 I Ad 979 + 3% .04 NEJM 04Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters
*400 mg PO daily x 1-2 years2003
1.0.
0.8
0.6
0.4
0.2
01 3 5 7
< 2 cm, n=6701.0
0.8
0.6
0.4
0.2
01 3 5 7
2 - 3 cm, n=599
UFT Meta-Analysis
Exploratory Analysis T1
p=0.357 p=0.0157
Hamada, ASCO 23:7002, 2004 Slide by Dr. Pisters
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
Lung Ca 04; JNCI 03; NEJM 04; Lung Cancer 03; ASCO 04; ASCO 04 Slide by Dr. Pisters
Trial Stage n Chemo Survival
Japan III-N2 119 VdP No
ALPI I-III 1209 MVdP No
IALT I-III 1867 Vinca or EP Yes
BLT I-III 381 Platin-based No
NCIC IB-II 482 VbP Yes
CALGB IB 344 PacCb Yes
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)T2N0M0 (IB)T1-2 N1(II)T1-2 N1(II)
NSCLCNSCLC(Complete (Complete resection)resection)
ObservationObservation
Cisplatin (50mg/m2 Cisplatin (50mg/m2 d1,8)d1,8)
Vinorelbine Vinorelbine (25mg/m2)(25mg/m2)
4 cycles4 cycles
RRAANNDDOOMMIIZZEE
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
SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0164Wilcoxon test for equality of groups: p=0.0100Survival rate at 5 years for Observation: 54% - % C.I. ( 48%, 61%)Survival rate at 5 years for Vinorelbine: 69% - % C.I. ( 62%, 75%)
Observation Vinorelbine
Perc
enta
ge
0
20
40
60
80
100
Time (years) # At Risk(Observation) # At Risk(Vinorelbine)
0.0239243
2.0182193
4.094
121
6.04751
8.01310
10.000
____ VbP
____ Observation
HR 0.696 [.524-.923]p=0.012
69%54%
Slide by Dr. Pisters
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)T2N0M0 (IB)NSCLCNSCLC
(Complete (Complete resection)resection)
ObservationObservation
Carboplatin Carboplatin (AUC=6)(AUC=6)
Taxol (200mg/m2)Taxol (200mg/m2)4 cycles/12 wk4 cycles/12 wk
RRAANNDDOOMMIIZZEE
Strauss GM, et al. ASCO Abstract 7019 Slide by D’Amico
CALGB 9633
Variable Chemo (n=173) Control (n=171)
P value
Age 61 yr (34-78) 62 yr (40-81) 0.42
PS=0 55% 58% 0.92
Sx present 78% 74% 0.39
size 4.7cm (0-15) 4.6cm (1-12) 0.87
Squam 39% 39% 0.98
Poorly diff 50% 50% 0.99
Mediastin 80% 79% 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 SurvivalStrauss, ASCO 23:7019, 2004
----- Chemotherapy ----- Observation
HR 0.62 [0.41-0.95]p=0.028
71%59%4 yr
Slide by Dr. Pisters
0 20 40 60 80
Survival Time (Months)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ility
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 platin-based 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 CellLung 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 CellLung Cancer
Cisplatin/Etoposide Followed by Twice-Daily 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 CellLung Cancer
3 Cycles Cis/VP16BID XRT4500cGySurgery
w/Carbo/Vin
VS
3 Cycles Cis/VP16 Surgery XRT 5400cGY
Abstract #7004
Resectable Stage III Non-Small CellLung 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%
Resction45% 50%
TxRlDeath 5.6% 5.3%
3yrS 24% 23%
Abstract #7004
Unresectable Stage III Non-Small CellLung 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 CellLung 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 CellLung Cancer
2 Cycles CarboAUC6/Taxol200mg/m2
WeeklyCarbo/Taxol/XRT
VS
WeeklyCarboAUC2/Taxol50mg/m2/XRT66GY
Vokes, et al. Abstract #7005
Unresectable Stage III Non-Small CellLung Cancer
N=366, 34%women, 63%>60yoIndconcChemo/XRT Chemo/XRTANC 27% 15%Eso 35% 31%SOB 19% 12%4Tox 41% 24%MS 14mo 11.4mo1yrS 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 CellLung 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
EGFTGF-
Amphiregulin-cellulinHB-EGF
Epiregulin Heregulins
HB-EGFHeregulins-cellulin
Tyrosine KinaseDomain
ErbB-1HER1EGFR
ErbB-2HER2 neu
ErbB-3HER3
ErbB-4HER4
Extracellular
Intracellular
No KnownLigands
The ErbB Family and Ligands
Proliferation
InvasionAngiogenesis
Metastasis
Inhibitionof apoptosis
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.
Turning Off the EGFR-TK SignalAt the Source1-3
• Inhibition of the EGFR-TK itself—inside the cell—completely inhibits EGFR-TK signaling regardless of the triggering event
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 CellLung Cancer
N=1172
Chemo-naïve StageIIIB/IV, PS0-1
6 cycles Cis/Gem + drug/placebomaint 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 CellLung 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 CellLung 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 CellLung 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 CellLung Cancer
N=731, Stage IIIB/IV36% women, PS 0-3, 1-2 previous chemo comb2:1 erlotinib 150 mg po qd vs placeboErlotinib PlaceboD/C 5% 2%TTDS-c 4.9mo 3.68moTTDS-p 2.79mo 1.91moPFS 2.23mo 1.84mo (p<0.001)OS 6.7mo 4.7mo (p<0.001)
Shepherd et al, Abstract #7022
Advanced Non-Small CellLung Cancer
Gefitinib (Iressa) Therapy for Advanced Bronchioloalveolar Lung Cancer (BAC): SWOG S0126
West et el, Abstract #7014
Advanced Non-Small CellLung 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% PS0-1Gefitinib 500mg po qd, most dose
reduced to 250 mg
West et el, Abstract #7014
Advanced Non-Small CellLung 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 CellLung Cancer
Interstitial Lung Disease During Gefitinib Treatment of Japanese Patients with Non-small Cell Lung Cancer
Abstract #7063
Advanced Non-Small CellLung Cancer
N=325, retrospective chart analysis32% women, med age 67yr, 34% PS 2-4Hepato 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 SOBRisk factors: Poor PS, previous PF, possibly
men with history of smoking
Abstract # 7063
Advanced Non-Small CellLung 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 CellLung 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!
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