bai bao cao vinorelbine

Effects of Vinorelbine in Non Small Cell Lung Cancer

Nguyen Duc Truong, MDThong Nhat Hospital

Jemal, CA Cancer J Clin 2008; 58: 71

Cancer Incidence Deaths

Colon 108,07049,960

Breast 184,45040,930

Prostate186,320 28,660

Total 478,840 119,550

NSCLC Epidemiology

Lung215,020

161,840

Statistics for 2008

Epidemiology

NSCLC: Stage at Diagnosis

Stage IV 40%

Stage I 10%

Stage II 20%

Stage IIIA 15%Stage IIIB 15%

Ettinger et al. Oncology. 1996;10:81-111.

Food and Drug Administration. At http://www.fda.gov/cder/cancer/druglistframe.htm. Accessed August 28, 2006.; National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology. Non-small cell lung cancer v2.2006. Accessed August 28, 2006. Schrump et al.

Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

History of Therapy in Advanced NSCLC: FDA Approval Dates

*Label does not include NSCLC-specific indication

First-line

Second-line

Third-line

Not approved

First-line

Second-line

Third-line

Not approved

1970 1980 1990 2000

Medianoverallsurvival,months

12+

~8–10~6

~2–4

Best supportive careBest supportive care Single-agent platinumSingle-agent platinum DoubletsDoublets Bevacizumab + PCBevacizumab + PC

Cisplatin*1978

Carboplatin*1989

ErlotinibPemetrexed

2004

Docetaxel1999

PaclitaxelGemcitabine

1998

Vinorelbine1994

Docetaxel2002

Bevacizumab2006

Gefitinib2003

Standard Therapies

Chremotherapy for NSCLC

• Old agents

– Cisplatin

– Carboplatin

– Etoposid

– Vinblastin

• New agents

– Docetaxel

– Paclitaxel

– Vinorelbine

– Gemcitabine

– Irinotecan

New agents: Induction CT followed by concomitant CT-RT

Induction (2 cycles)Concomitant (2 cycles)

Vinorelbine 25 mg/m2 D1,8,(15) 15 mg/m2 D1,8Cisplatin 80 mg/m2 D1 80 mg/m2 D1

Paclitaxel225 mg/m2 D1 135 mg/m2 D1Cisplatin 80 mg/m2 D1 80 mg/m2 D1

Gemcitabine 1250 mg/m2 D1,8 600 mg/m2

D1,8Cisplatin 80 mg/m2 D1 80 mg/m2 D1

CALGB study 9431: Vokes et al. JCO 2002;20:4191

New agents: Induction CT followed by concomitant CT-RT

RR(CT) RR(CT-RT) 1yS 2yS 3yS (%)

V+C 44% 73% 6540 23

P+C 33% 67% 6229 19

G+C 40% 74% 6837 28

CALGB study 9431: Vokes et al. JCO 2002;20:4191

FDA Approved Chemotherapy Regimens for Advanced

NSCLC• First-Line

– Cisplatin + paclitaxel (24 hour infusion)– Cisplatin + vinorelbine (4 week)– Cisplatin + gemcitabine (3 or 4 week)– Cisplatin + docetaxel (3 week)– Bevacizumab + carboplatin + paclitaxel

• Second-Line– Docetaxel– Pemetrexed – Erlotinib

BMJ Meta-analysis: Adjuvant Cisplatin-based Chemotherapy

Overall Survival

at risk Months706 590 462 371 295 206Surgery+CT

Surgery 688 548 433 353 258 177

Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1.0

0.9

0 12 24 36 48 60

Surgery 316 688298 706Events Total

Surgery+CT

Survival benefit with cisplatin-based chemotherapy:

3% at 2 years, 5% at 5 years

BMJ 311:899-901, 1995.

IALT Schema

Surgically resected non-small cell lung cancer

Observation

Cisplatin 300-400mg/m2 over 3-4 cycles

with

Etoposide, vinorelbine, vinblastine, or vindesine

Within 60 days post-op

Randomize

Radiation optional, predetermined by N stage for each center

IALT Results

Chemo (932) No Chemo (935)5 yr OS 44.5% 40.4%

5 yr DFS 39.4% 34.3%MS 50.8 mos 44.4 mosMDFS 40.2 mos30.5 mos

NEJM 350; 351-60, 2004.

935 775 619 520 447 372 282 208 125

932 780 650 550 487 399 300 208 133

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8 years

chemotherapy: 578 deaths

- 495 deaths before 5 years

- 83 deaths after 5 years

control 590 deaths - 534 deaths before 5 years - 56 deaths after 5 years

HR: 0.91 (0.81-1.02, P = 0.10)

Le Chevalier T, et al. J Clin Oncol. 2008(May 20 suppl). Abstract 7507.

IALT: 7.5-Year Median Follow-Up

TAX 326: Schema

Fossella FV et al: JCO 2003

Docetaxel: 75 mg/m2 IV + Cisplatin: 75 mg/m2 IV

Docetaxel: 75 mg/m2 IV + Carboplatin: AUC 6 IV

Vinorelbine: 25 mg/m2 IV d 1, 8, 15, 22 + Cisplatin: 100 mg/m2 IV d 1

Premed: Dexamethasone 8 mg PO bid 6 doses (first dose on evening prior to docetaxel infusion) for the docetaxel groups.

Stratification by: • Stage IIIB or IV• Geographic region

q3 wk

q4 wk

RANDOMIZE

q3 wk

TAX 326: SurvivalDocetaxel/Cisplatin vs. Vinorelbine/Cisplatin

Fossella FV et al: JCO 2003

Docetaxel/Cisplatin

Vinorelbine/Cisplatin

Cu

mu

lati

ve P

rob

ab

ilit

y

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 3 6 9 12 15 18 21 24 27 30 33

Survival Time (months)

P = .044, Adjusted Log-Rank1-yr Survival 46 vs 41%2-yr Survival 21 vs 14%

TAX 326: Survival for DOCETAXEL + CARBO vs. VINORELBINE + CISPLATIN

Su

rviv

al (

%)

Time (months)

100

90

80

70

60

50

40

30

20

10

0

0 3 6 9 12 15 18 21 24 27 30 33

DocetaxelCarboplatin

VinorelbineCisplatin

P = 0.657(adjusted log-rank)

N = 812

The Bottom Line: Metastatic NSCLC Study N ORR(%) MST (mos) SWOG 9509 Carbo-Pac 208 25 8.0 Cis-Vino 202 28 8.0

EGOG 1594 Cis-Pac 292 21.3 8.1 Cis-Gem 288 21 8.1 Cis-Doce 293 17.3 7.4 Carbo-Pac 290 15.3 8.3

Italian Study Cis-Gem 205 30 9.8 Carbo-Pac 201 32 9.9 Cis-Vino 201 30 9.5

EORTC 08975 Cis-Pac 159 31 8.1 Cis-Gem 160 36 8.8 Gem-Pac 161 27 6.9

TAX 326 Doce-Cis 408 NA 10.9 Doce-Carbo 406 NA 9.1 Cis-Vino 404 NA 10.0

NCIC-BR10

Select inclusion criteria:

•Stage IB-II NSCLC

•Complete surgical resection

•N=482

RANDOMIZE

Vinorelbine, IV, 25 mg/m2, weekly 16 wk

Cisplatin, 50 mg/m2, d 1, 8 q 4 wk 4 cycles

No chemotherapy

Overall Survival by Treatment Arm

Absolute improvement in 5 yr OS = 11% (67% vs. 56%); benefit persists at 9+ yrs

Vincent, Butts et al, 2009.

All Patients

Absolute improvement in 5 yr OS = 15% (69% vs. 54%) Winton et al. NEJM 2005.

HR 0.69

5 yr: 69% vs 54%

MST 94 m vs 73 m

5 yr: 67% vs 56%

MST 94m vs 72m

At RiskObservationVinorelbine

Stratified Log-Rank: p=0.04HR: 0.780(0.613, 0.993)

'

Observation Vinorelbine

Perc

enta

ge

0

20

40

60

80

100

0

240242

3

155182

6

117135

9Time(Years)

5867

12

912

15

00

NON-SMALL CELL LUNG CANCER- Single Agent Vinorelbine vs Supportive Care -

- In Patients > Age 70: A Prospective Randomized Trial -

Gridelli et al JNCI 1999, p = 0.04

6.2

4.7

0

2

4

6

8

10

12

CHEMOTHERAPY REGIMENME

DIA

N S

UR

VIV

AL

IN M

ON

TH

S:

Vinorelbine Supportive Care

NON-SMALL CELL LUNG CANCER- SWOG 95-09 Randomized Trial in 410 Patients -

Kelly J Clin Oncol 2001; Survival: 1 YR 36%/38%, 2 YR 15%/16%; Resp Rate: 28%/25%

8 8

0

2

4

6

8

10

12

CHEMOTHERAPY REGIMEN

ME

DIA

N S

UR

VIV

AL

IN M

ON

TH

S:

Vinorelbine + DDP Paclitaxel + Carbo

NON-SMALL CELL LUNG CANCER- SWOG Randomized Trial: Quality of Life -

Kelly J Clin Oncol 2001. (N = 410). Baseline Compared with Week 25 (Using FACT-L)

0

10

20

30

40

50

60

70

80

90

100

Vinorelbine + Cisplatin Paclitaxel + Carboplatin

PE

RC

EN

T O

F P

AT

IEN

TS

:

QL: Impoved QL: Stable

NON-SMALL CELL LUNG CANCER- SWOG Randomized Trial in 415 Patients -

Wozniak et al J Clin Oncol 1999; Survival: 1 YR 36%/20% 2 YR 12%/6% p = 0.0018

6

8

0

2

4

6

8

10

12

CHEMOTHERAPY REGIMEN

ME

DIA

N S

UR

VIV

AL

IN M

ON

TH

S:

Cisplatin 100 mg/M2 Vinorelbine + Cisplatin

Which regimen?

Regimens: LACE Meta-analysis

• Cisplatin/vinorelbine: regimen for 41% LACE pts– Regimen for Anita and JBR10– 86% patients received >300mg/m2 cisplatin– 13% of IA’s cis/vinorelbine vs. 43% other stages

• Drugs used with cisplatin other studies– IALT: vinorelbine, vindesine, vinblastin, etoposide– BLT: vinorelbine, vindesine, mitomycin/vindesine,

mitomycin/ifosfamide– ALPI: vindesine/mitomycin

.04

.02

.10

.09

Schiller et al. NEJM.2002; 346:92-98.

Extrapolating Stage IV: It’s all the Same?

E1505 Chemotherapy Regimens

• Therapy to start 6-12 weeks post-operatively– Investigator Choice of Chemo - 4 cycles (12

wks)• Cisplatin/Vinorelbine

– Cis 75 mg/m2 d 1, Vin 25 mg/m2 d1,8 q21 d• Cisplatin/Docetaxel

– Cis 75 mg/m2 d 1, Docetaxel 75 mg/m2 d 1 q21 d• Cisplatin/Gemcitabine

– Cis 75 mg/m2 d 1, Gem 1250 mg/m2 d1,8 q 21 d• Cisplatin/Pemetrexed

– Cis 75 mg/m2 d 1; Pem 500 mg/m2 d 1 Q 21 d

• Bevacizumab 15 mg/kg q 21 days x 12 months

ECOG 1505: Adjuvant Bevacizumab

RANDOM IZE

STRATIFIED:

StageHistologyGenderChemo regimen*

ChemotherapyX 4 cycles

ELIGIBLE:

Resected IB^-IIIA

Squamous Allowed!³LobectomyNo prior chemoNo planned XRTNo h/o CVA/TIANo ATE w/in 1 yr

Chemotherapyx 4 cyclesPlusBevacizumabX 1 year

^ Now revised to exclude IB < 4cmCompleted accrual/study closed Sept 20, 2013

ECOG 4599: Overall Survival

0.0

0.2

0.4

0.6

0.8

1.0

Pro

port

ion

Su

rviv

ing

0 6 42 4818 3012 24 36

Months

HR=0.80; P=0.013

BV/PC 12.3 moPC 10.3 mo

Median Survival

1-year survival51% vs. 44%

2-year survival23% vs. 15%

Sandler, et al. NEJM. 355;24. Dec 14 2006.

Chemotherapy-naïve advanced

NSCLC

Vinorelbine 25 mg/m2 d1,8

+ cisplatin 80 mg/m2 d1, Q3W

FLEX: Pivotal Trial Cetuximab + Chemotherapy in 1st-Line Advanced NSCLC

Primary endpoint: OSSecondary endpoints: PFS, ORR, DCR, QoL, Safety, PK

n=557

n=568

Cetuximab 400 mg/m2 d1 wk1, then 250 mg/m2, QW

+ Vinorelbine 25 mg/m2 d1,8

+ cisplatin 80 mg/m2 d1, Q3W

RANDOMIZE

Up to 6 cycles of chemotherapy; patients not progressing continue on cetuximab maintenance

Stratified by IIIB or IV ECOG PS 0,1

or 2

All histologic subtypes included ECOG PS 0–2 No known brain metastases EGFR expression by IHC (≥1 positive tumor cells)

Pirker R, et al. Lancet 373(9674): 1525 – 1531, 2009.

FLEX: Results

CV + Cetuximab CV P

RR 36% 29% 0.012

PFS 4.8 mos 4.8 mos NS

TTF 4.2 mos 3.7 mos 0.015

NS=not significant; TTF=time to treatment failure.

Months

OS

(%

)

Median OS 1-Yr Surv.

CV + Cetuximab 11.3 mos 47%

CV 10.1 mos 42%

HR: 0.871; P=0.044


FLEX: Differences in Ethnicity

Caucasian (N=946)

Asian(N=121)

Prognostic Factors

Adenocarcinoma 44% 72%

Female 27% 46%

Never smoker 17% 52%

ECOG PS 0/1 81% 94%

Poststudy Treatment

EGFR TKIs 17% 61%

Median OS 9.6 mos 19.5 mos

[95% CI] [9.0–10.4] [16.4–23.3]


FLEX: Asian Subgroup (N=121)

CV + Cetuximab (N=62)

CV(N=59)

P Value

Baseline Prognostic Factors

Adenocarcinoma 65% 80%

Post-Study Treatment

EGFR TKIs 50% 73%

OS 17.6 mos 20.4 mos NS

RR 50% 44% NS

Cannot draw definitive conclusions because of small sample size (10% of total), differences in histology and differences in post-study EGFR TKI treatment


Median OS 1-Year Survival

CV + Cetuximab(N=466) 10.5 mos 45%

CV(N=480) 9.1 mos 37%

HR=0.803; P=0.003

FLEX: OS – Caucasians (N=946)Prespecified Analysis

Months

P value: stratified log-rank test (2-sided)

Ove

rall

Su

rviv

al (

%)

Median OS CV + Cetuximab CV HR

Caucasians (N=946) 10.5 mos 9.1 mos 0.803

Adenocarcinoma (N=413) 12.0 mos 10.3 mos 0.815

Squamous Cell (N=347) 10.2 mos 8.9 mos 0.794

Other (N=185) 9.0 mos 8.2 mos 0.807

CV=cisplatin/vinorelbine.


CV + Cetuximab Any grade Grade 0

OS 15.0 mos 8.8 mos

RR 44% 28%

PFS 5.4 mos 4.3 mos

Ove

rall

Su

rviv

al (

%)

Months

Any grade: CT + Cetuximab(N=290)

Grade 0: CT + Cetuximab(N=228)

HR=0.631 (95% CI: 0.515-0.774)*P<0.001

Patients at RiskGrade 0 228 145 88 54 15 0Any Grade 290 238 163 101 38 3

*Landmark analysis.

FLEX: OS Early Acne-Like RashPre-Planned Analysis

Gatzemeier et al, JTO 2008, Vol 3, No. 11, S4 (abstract 8)

GLOB 3: Vinorelbine I.V./Oral + CDDP vs DCT+ CDDP

GLOB 3

Q3W x 6 cycles

NVB I.V. 30 mg/m² n1*NVB Oral 80 mg/m²

n8*CDDP 80 mg/m² n1(*The first cycle is 25 mg/m² and next cycles 60 mg/m² )

DCT 75 mg/m² n1CDDP 75 mg/m² n1

nMedian ageKPS 80-100Stage IVAdenoma / Squamous

19059.4 age99.5%80.5%

41.6% / 34.2%

19162.1 age

100%84.8%

39.3% / 33.5%

OR

MS

1 YS

27.4%

9.9 m

39.4%

27.2%

9.8 m

40.9%

ns

ns

ns

Chemotherapy in Advanced NSCLC

Tan EH, et al. Ann Oncol 2009;20:1249-56.



Chemotherapy in Advanced NSCLC

GLOB 3: Adenocarcinoma group

GLOB 3 NVB Oral + CDDP arm

n= 190

Adenocarcinoma 41.6% patients

Other types68.4% patients

OR

MS

29.1%

11.7 months

26.1%

9.0 months


Vinorelbine in NSCLC without Squamous type


The effects of Vinorelbine in NSCLC with Adenocarcinoma type


Vinorelbine in NSCLC without Squamous type


GLOB 3

Adenocarcinoma type All

NVB Oral +CDDPn= 79

DCT +CDDPn= 75

NVB Oral +CDDPn= 190

DCT +CDDPn= 191

OR 29.1% 22.7% 31.2% 29.6%

MS 11.7 mons 11.6 mons 9.9 mons 9.8 mons

NAVELBINE in Elderly Patients with Advanced NSCLC

Navelbine in the Elderly: Summary

• E.L.V.I.S.: first Phase III trial demonstrating a survival advantage for single-agent chemotherapy vs BSC

• Navelbine is generally well tolerated in the elderly patient– Age does not appear to change or increase

toxicity– Greater sensitivity of some older individuals

cannot be ruled out

Rationale for Combining Gemcitabine and Vinorelbine in NSCLC

• Both drugs have activity in NSCLC

• Nonoverlapping toxicities except myelosuppression

• Outpatient schedule

• Both drugs well tolerated by elderly

Gemcitabine in Advanced NSCLC

• Phase II trials– RR 21% - 26%– Median survival 7 - 12.3 months– One-year survival of 30% - 50%

• Phase III trials– Gemcitabine 1000 mg/m2 weekly in

symptomatic patients vs BSC– Improvement in symptom control 93% vs

67%• Toxicities are mainly myelosuppression and fatigue

– Rare pulmonary toxicity

Rationale for Combining Gemcitabine and Vinorelbine in NSCLC

• Both drugs have activity in NSCLC

• Nonoverlapping toxicities except myelosuppression

• Outpatient schedule

• Both drugs well tolerated by elderly

Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study

• Patients with Stage IIIB/IV NSCLC• Age 70 years at diagnosis• Randomized to:

– Vinorelbine 30 mg/m2 d1, 8 q 3 weeks vs.– Vinorelbine 30 mg/m2 d 1, 8– Gemcitabine 1250 mg/m2 d 1, d 8

administered q 3 weeks

Gemcitabine Plus Vinorelbine vs Vinorelbine Alone in Patients with NSCLC: SICOG Study

GV V

N 76 76

Stage IV 60% 60%

PS 0-1 73% 78%

OR 22% 15%

SD 27% 12%

MST 29 wks 18 wks

1-yr survival 30% 13%*

*P<.01

Chemotherapy in Elderly Patients with Advanced NSCLC

13%4.576 15%Vinorelbine

30%*776 22% Gemcitabine + VinorelbineFrasci‡

14%4.976 ---BSC

32%*6.5 78 20%VinorelbineGridelli*

1 YRMS (mo) N ResponseRegimenAuthor

*Gridelli, J Natl Cancer Inst 1999; 85:365-376.

‡Frasci et al, Proc ASCO 2001, 19:A1895* p<0.05

The MILES Phase III Trial: Gemcitabine + Vinorelbine vs Vinorelbine and vs Gemcitabine in Elderly

Advanced NSCLC Patients Gridelli et al Multicenter Italian Lung Cancer in the Elderly Study

NSCLC

70+ years old

Chemotherapy naïve

Stage IIIB

(N3 or pleural effusion) or IV

PS 0-2

RANDOMIZE

ASCO 2001 Abstract 1230

Vinorelbine 30 mg/m2 d1,8Q 3 weeks

Gemcitabine 1000 mg/m2 d1,8Vinorelbine 25 mg/m2 d1,8

Q 3 weeks

Gemcitabine 1200 mg/m2 d1,8Q 3 weeks

MILES STUDY: ELDERLY NSCLC

VNR GEM VNR/GEM

# Patients (n) 233 233 232

Stage IIIB (%) 29 30 31

Response Rate (%) 18.5 17.3 20

TTP (wk) Median Survival (mo)

18

8.8

18

6.6

19

7.6

1 year Survival (%)

41%

26%

31%

…Gridelli et al., ASCO 2001, A-1230

MILES Trial - Conclusions

• Polychemotherapy with gemcitabine + vinorelbine does not improve outcomes compared to single-agent vinorelbine or gemcitabine

• Single-agent chemotherapy should remain a standard for advanced NSCLC elderly patients

• Baseline QoL predictive of outcome, though no difference observed in Qol or IADL between each arm

ASCO 2001 Abstract 1230 ORAL PRESENTATION

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bai bao cao vinorelbine

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