advances for treatment of lung cancer

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

http://www.asco.org/

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


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


N=273Med age 76yrsT1N0(175),T2N0(98), 7-58mm (28mm)62% inop 2ndCOPD3D, stereotactic procedure1800-7500cGy given in 7-22 fractions



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


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


UFT Meta-Analysis

Hamada, ASCO 23:7002, 2004

• 6 randomized trials• Conducted in Japan• 5 years follow-up

Surgery

UFT (no intravenous chemo)


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


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


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)


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%


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


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


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%


CALGB 9633 - Overall SurvivalStrauss, ASCO 23:7019, 2004

----- Chemotherapy ----- Observation

HR 0.62 [0.41-0.95]p=0.028

71%59%4 yr


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


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.


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.


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.


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


3 Cycles Cis/VP16BID XRT4500cGySurgery

w/Carbo/Vin

VS

3 Cycles Cis/VP16 Surgery XRT 5400cGY

Abstract #7004


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.


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


2 Cycles CarboAUC6/Taxol200mg/m2

WeeklyCarbo/Taxol/XRT

VS

WeeklyCarboAUC2/Taxol50mg/m2/XRT66GY



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


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


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


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


n=1059

Same design

Erlotinib Placebo

OS 10.8mo 10.6mo

Proper sequencing of targeted therapies is under study

Herbst et al, Abstract #7011


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


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


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

West et el, Abstract #7014


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



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



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

Abstract #7063


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


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


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!

advances for treatment of lung cancer

Documents

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nonsmall cell lung carcinoma

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