ADVANCES FOR TREATMENT OF LUNG CANCER

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ADVANCES FORTREATMENT OF LUNG CANCER

• ASCO 2004, NOLA
• Jennifer Garst, M. D.
• Assistant Professor of Medicine
• Thoracic Oncology Program
• Duke University Medical Center

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ADVANCES FORTREATMENT OF LUNG CANCER

• ASCO 2004, NOLA
• Non-Small Cell Lung Cancer
• a. Early Stage Disease
• b. Locally Advanced Disease
• c. Advanced Disease

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ASCO PRACTICE GUIDELINESwww.ASCO.org

• Clinical Practice Guidelines for the
• Treatment of Lung Cancer, 1997
• Updated 2003 For Unresectable NSCLC

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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

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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
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Stage I/II Non-Small Cell Lung Cancer

• N273
• 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
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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 Doselt100Gy
• 95 BED gt100Gy
• Interesting new technology

Onishi et al, Abstract 7003
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1995 Meta-Analysis Adjuvant Cisplatin Trials
n1394
100
HR 0.87 p0.08
80
60
Percentage Survival
40
Surgery plus Chemotherapy Surgery
20
0
6
12
18
24
30
36
42
48
54
60
0
Time from Randomization (months)
BMJ 31 899-908, 1995 Slide by Dr. Pisters
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IALT - Overall Survival NEJM 2003 Slide by Dr.
Pisters
___ Chemotherapy
___ Control
Years
181
308
450
775
932
624
At risk
164
286
432
602
935
774
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JBR.10 Winton, ASCO 237018, 2004
UFT Meta-AnalysisHamada, ASCO 237002, 2004

• CALGB 9633Strauss, ASCO 237019, 2004
• Slide by Dr. Pisters

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UFT Meta-AnalysisBackground

• 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
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UFT Meta-AnalysisHamada, ASCO 237002, 2004

• 6 randomized trials
• Conducted in Japan
• 5 years follow-up
• Surgery
• UFT (no intravenous chemo)

Slide by Dr. Pisters
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UFT Meta-AnalysisPatient Characteristics - 6
Trials

• Stage I - 95
• Adenocarcinoma - 84
• Women - 45
• Median Age - 62

Hamada, ASCO 237002, 2004 Slide by Dr. Pisters
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UFT Meta-Analysis 6 Trials Intervention UFT
Stage n Survival p Reference 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 04
2003
400 mg PO daily x 1-2 years
Hamada, ASCO 237002, 2004 Slide by Dr. Pisters
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UFT Meta-Analysis Exploratory Analysis T1
lt 2 cm, n670
2 - 3 cm, n599
1.0
1.0
.
0.8
0.8
0.6
0.6
p0.357
p0.0157
0.4
0.4
0.2
0.2
0
0
5
1
3
7
1
3
5
7
Hamada, ASCO 237002, 2004 Slide by Dr. Pisters
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UFT Meta-Analysis ConclusionsPisters

• This meta-analysis showed that long-term
  treatment with UFT is effective as postoperative
  adjuvant therapy for
• stage I
• Tgt2 cm
• adenocarcinoma
• a study population with 45 women

Slide by Dr. Pisters
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NSCLC Randomized Cisplatin Adjuvant TrialsAfter
the 1995 Meta-Analysis
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
Lung Ca 04 JNCI 03 NEJM 04 Lung Cancer 03
ASCO 04 ASCO 04 Slide by Dr. Pisters
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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
DAmico
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NCIC JBR10
Cisplatin (50mg/m2 d1,8) Vinorelbine (25mg/m2) 4
cycles
RANDOMIZE
T2N0M0 (IB) T1-2 N1(II) NSCLC (Complete resection)
Observation
Winton TL, et al. ASCO Abstract 7018 Slide by
DAmico
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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 (p0.012)

Winton TL, et al. ASCO Abstract 7018 Slide by
DAmico
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JBR.10 - Overall SurvivalWinton, ASCO 237018,
2004
____ VbP ____ Observation
HR 0.696 .524-.923 p0.012
69 54
Slide by Dr. Pisters
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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
DAmico
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CALGB 9633
RANDOMIZE
Carboplatin (AUC6) Taxol (200mg/m2) 4 cycles/12
wk
T2N0M0 (IB) NSCLC (Complete resection)
Observation
Strauss GM, et al. ASCO Abstract 7019 Slide by
DAmico
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CALGB 9633
Variable Chemo (n173) Control (n171) P value
Age 61 yr (34-78) 62 yr (40-81) 0.42
PS0 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
DAmico
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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
DAmico
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CALGB 9633 - Overall SurvivalStrauss, ASCO
237019, 2004
1.0
----- Chemotherapy ----- Observation
0.8
Probability
0.6
HR 0.62 0.41-0.95 p0.028
0.4
0.2
71 59
0.0
4 yr
0
20
40
60
80
Survival Time (Months)
Slide by Dr. Pisters
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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
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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
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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
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Resectable Stage III Non-Small CellLung Cancer

• ASCO GL 1997
• Not addressed
• Importance of PS, PFTs
• Imply that bulky N2 disease should not be
• considered resectable.

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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
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Resectable Stage III Non-Small CellLung Cancer

• 3 Cycles Cis/VP16?BID XRT4500cGy?Surgery
• w/Carbo/Vin
• VS
• 3 Cycles Cis/VP16? Surgery? XRT 5400cGY

Abstract 7004
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Resectable Stage III Non-Small CellLung Cancer

• N 481, 18 women, med age 59yo, PS0-1,
• 32 Stage IIIA, 68 Stage IIIB
• Neo Chemo-gtChemo/XRT NeoChemo/Adj XRT
• Esoph 15 4
• IndResp 52 47
• Resction 45 50
• TxRlDeath 5.6 5.3
• 3yrS 24 23

Abstract 7004
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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.

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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
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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
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Unresectable Stage III Non-Small CellLung Cancer

• N366, 34women, 63gt60yo
• 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 761yS
• -?Wrong Chemotx or wrong design

Vokes, et al. Abstract 7005
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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

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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
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The ErbB Family and Ligands
EGF TGF-? Amphiregulin ?-cellulin HB-EGF Epireguli
n
HB-EGF Heregulins ?-cellulin
No KnownLigands
Heregulins
Extracellular
Tyrosine Kinase Domain
Intracellular
ErbB-1HER1 EGFR
ErbB-2 HER2 neu
ErbB-3 HER3
ErbB-4 HER4
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Turning Off the EGFR-TK SignalAt the Source1-3

• Inhibition of the EGFR-TK itselfinside the
  cellcompletely inhibits EGFR-TK signaling
  regardless of the triggering event

Inhibitionof apoptosis
Proliferation
Invasion
Metastasis
Angiogenesis
1. Leserer M et al. IUBMB Life. 200049405-409.
2. Raymond E et al. Drugs. 200060(suppl
1)15-23. 3. Prenzel N et al. Endocr Relat
Cancer. 2001811-31.
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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

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Advanced Non-Small CellLung Cancer

• N1172
• Chemo-naïve StageIIIB/IV, PS0-1
• 6 cycles Cis/Gem drug/placebo?maint tablet
• Erlotinib 150mg qd po
• Erlotinib Placebo
• Diarh 6 lt1
• Rash 10 lt1
• OS 10.8mo 11.2 mo

Gatzemeier et al, Abstract 7010
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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
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Advanced Non-Small CellLung Cancer

• n1059
• Same design
• Erlotinib Placebo
• OS 10.8mo 10.6mo
• Proper sequencing of targeted therapies is under
  study

Herbst et al, Abstract 7011
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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
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Advanced Non-Small CellLung Cancer

• N731, Stage IIIB/IV
• 36 women, PS 0-3, 1-2 previous chemo comb
• 21 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 (plt0.001)
• OS 6.7mo 4.7mo (plt0.001)

Shepherd et al, Abstract 7022
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Advanced Non-Small CellLung Cancer

• Gefitinib (Iressa) Therapy for Advanced
  Bronchioloalveolar Lung Cancer (BAC) SWOG S0126

West et el, Abstract 7014
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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
• N138 (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
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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
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Advanced Non-Small CellLung Cancer

• Interstitial Lung Disease During Gefitinib
  Treatment of Japanese Patients with Non-small
  Cell Lung Cancer

Abstract 7063
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Advanced Non-Small CellLung Cancer

• N325, 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
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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
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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
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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.
• 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.
• 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.
• 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
• Platinum-based combinations remain the standard
  of care for advanced NSCLC. Q3 Week Carbo/Taxol
  is here to stay!

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