Effects of Vinorelbine in Non Small Cell Lung Cancer

1. Effects of Vinorelbine in
Non Small Cell Lung Cancer
Nguyen Duc Truong, MD
Thong Nhat Hospital

2. Jemal, CA Cancer J Clin 2008; 58: 71
Cancer Incidence Deaths
Colon 108,070 49,960
Breast 184,450 40,930
Prostate 186,320 28,660
Total 478,840 119,550
NSCLC Epidemiology
Lung 215,020 161,840
Statistics for 2008

3. Epidemiology

4. 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.

6. 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
1970 1980 1990 2000
Median
overall
survival,
months
12+
~8–10
~6
~2–4
Best supportive care Single-agent platinum Doublets Bevacizumab + PC
Cisplatin*
1978
Carboplatin*
1989
Erlotinib
Pemetrexed
2004
Docetaxel
1999
Paclitaxel
Gemcitabine
1998
Vinorelbine
1994
Docetaxel
2002
Bevacizumab
2006
Gefitinib
2003
Standard Therapies

7. Chremotherapy for NSCLC
• Old agents
– Cisplatin
– Carboplatin
– Etoposid
– Vinblastin
• New agents
– Docetaxel
– Paclitaxel
– Vinorelbine
– Gemcitabine
– Irinotecan

8. 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 D1,8
Cisplatin 80 mg/m2 D1 80 mg/m2 D1
Paclitaxel 225 mg/m2 D1 135 mg/m2 D1
Cisplatin 80 mg/m2 D1 80 mg/m2 D1
Gemcitabine 1250 mg/m2 D1,8 600 mg/m2 D1,8
Cisplatin 80 mg/m2 D1 80 mg/m2 D1
CALGB study 9431: Vokes et al. JCO 2002;20:4191

9. New agents: Induction CT followed by
concomitant CT-RT
RR(CT) RR(CT-RT) 1yS 2yS 3yS
(%)
V+C 44% 73% 65 40 23
P+C 33% 67% 62 29 19
G+C 40% 74% 68 37 28
CALGB study 9431: Vokes et al. JCO 2002;20:4191

13. 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

14. BMJ Meta-analysis:
Adjuvant Cisplatin-based Chemotherapy
Overall Survival
at risk Months
706 590 462 371 295 206Surgery+CT
Surgery 688 548 433 353 258 177
S
u
r
v
i
v
a
l
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 316 688
298 706
Events Total
Surgery+CT
Survival benefit with cisplatin-
based chemotherapy:
3% at 2 years, 5% at 5 years
BMJ 311:899-901, 1995.

15. 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
R
a
n
d
o
m
i
z
e
Radiation optional, predetermined by N stage for each center

16. 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 mos
MDFS 40.2 mos 30.5 mos
NEJM 350; 351-60, 2004.

17. 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

18. 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
R
A
N
D
O
M
I
Z
E
q3 wk

19. TAX 326: Survival
Docetaxel/Cisplatin vs. Vinorelbine/Cisplatin
Fossella FV et al: JCO 2003
Docetaxel/Cisplatin
Vinorelbine/Cisplatin
CumulativeProbability
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-Rank
1-yr Survival 46 vs 41%
2-yr Survival 21 vs 14%

20. TAX 326: Survival for DOCETAXEL + CARBO
vs. VINORELBINE + CISPLATIN
Survival(%)
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
Docetaxel
Carboplatin
Vinorelbine
Cisplatin
P = 0.657
(adjusted log-rank)
N = 812

21. 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-Pac292 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-Pac159 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

22. NCIC-BR10
Select inclusion
criteria:
•Stage IB-II NSCLC
•Complete surgical
resection
•N=482
R
A
N
D
O
M
I
Z
E
Vinorelbine, IV, 25 mg/m2,
weekly  16 wk
Cisplatin, 50 mg/m2, d 1, 8
q 4 wk  4 cycles
No chemotherapy

23. 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
AtRisk
Observation
Vinorelbine
StratifiedLog-Rank:p=0.04
HR:0.780(0.613,0.993)
'
Observation Vinorelbine
Percentage
0
20
40
60
80
100
0
240
242
3
155
182
6
117
135
9
Time(Years)
58
67
12
9
12
15
0
0

24. 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 REGIMEN
MEDIANSURVIVALINMONTHS:
Vinorelbine Supportive Care

25. 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
MEDIANSURVIVALINMONTHS:
Vinorelbine + DDP Paclitaxel + Carbo

26. 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
PERCENTOFPATIENTS:
QL: Impoved QL: Stable

27. 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
MEDIANSURVIVALINMONTHS:
Cisplatin 100 mg/M2 Vinorelbine + Cisplatin

28. Which regimen?

29. 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

30. Schiller et al. NEJM.2002; 346:92-98.
Extrapolating Stage IV: It’s all the Same?

31. 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

32. ECOG 1505: Adjuvant Bevacizumab
R
A
N
D
O
M
I
Z
E
STRATIFIED:
Stage
Histology
Gender
Chemo
regimen*
Chemotherapy
X 4 cycles
ELIGIBLE:
Resected IB^-IIIA
Squamous
Allowed!
Lobectomy
No prior chemo
No planned XRT
No h/o CVA/TIA
No ATE w/in 1 yr
Chemotherapy
x 4 cycles
Plus
Bevacizumab
X 1 year
^ Now revised to exclude IB < 4cm
Completed accrual/study
closed Sept 20, 2013

33. ECOG 4599: Overall Survival
0.0
0.2
0.4
0.6
0.8
1.0
ProportionSurviving
0 6 42 4818 3012 24 36
Months
HR=0.80; P=0.013
BV/PC 12.3 mo
PC 10.3 mo
Median Survival
1-year survival
51% vs. 44%
2-year survival
23% vs. 15%
Sandler, et al. NEJM. 355;24. Dec 14 2006.

34. 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: OS
Secondary 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
R
A
N
D
O
M
I
Z
E
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.

35. 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
Pirker R, et al. Lancet 373(9674): 1525 – 1531, 2009.

36. 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]
Pirker R, et al. Lancet 373(9674): 1525 – 1531, 2009.

37. 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
Pirker R, et al. Lancet 373(9674): 1525 – 1531, 2009.

38. 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)
OverallSurvival(%)
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.
Pirker R, et al. Lancet 373(9674): 1525 – 1531, 2009.

39. CV + Cetuximab Any grade Grade 0
OS 15.0 mos 8.8 mos
RR 44% 28%
PFS 5.4 mos 4.3 mos
OverallSurvival(%)
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 Risk
Grade 0 228 145 88 54 15 0
Any Grade 290 238 163 101 38 3
*Landmark analysis.
FLEX: OS Early Acne-Like Rash
Pre-Planned Analysis
Gatzemeier et al, JTO 2008, Vol 3, No. 11, S4 (abstract 8)

40. 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 n1
CDDP 75 mg/m² n1
n
Median age
KPS 80-100
Stage IV
Adenoma / Squamous
190
59.4 age
99.5%
80.5%
41.6% / 34.2%
191
62.1 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.

41. GLOB 3: Vinorelbine I.V./Oral + CDDP vs DCT+ CDDP
Tan EH, et al. Ann Oncol 2009;20:1249-56.
Chemotherapy in Advanced NSCLC

42. GLOB 3: Adenocarcinoma group
GLOB 3
NVB Oral + CDDP arm
n= 190
Adenocarcinoma
41.6% patients
Other types
68.4% patients
OR
MS
29.1%
11.7 months
26.1%
9.0 months
GLOB 3: Vinorelbine I.V./Oral + CDDP vs DCT+ CDDP
Vinorelbine in NSCLC without Squamous type
Tan EH, et al. Ann Oncol 2009;20:1249-56.

43. The effects of Vinorelbine in NSCLC with Adenocarcinoma type
GLOB 3: Vinorelbine I.V./Oral + CDDP vs DCT+ CDDP
Vinorelbine in NSCLC without Squamous type
Tan EH, et al. Ann Oncol 2009;20:1249-56.
GLOB 3
Adenocarcinoma type All
NVB Oral +
CDDP
n= 79
DCT +
CDDP
n= 75
NVB Oral +
CDDP
n= 190
DCT +
CDDP
n= 191
OR 29.1% 22.7% 31.2% 29.6%
MS 11.7 mons 11.6 mons 9.9 mons 9.8 mons

44. NAVELBINE in Elderly Patients with
Advanced NSCLC

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. Chemotherapy in Elderly Patients with
Advanced NSCLC
13%4.576 15%Vinorelbine
30%*776 22%
Gemcitabine +
Vinorelbine
Frasci‡
14%4.976 ---BSC
32%*6.578 20%Vinorelbine
Gridelli*
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

52. 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
R
A
N
D
O
MI
ZE
ASCO 2001 Abstract 1230
Vinorelbine 30 mg/m2 d1,8
Q 3 weeks
Gemcitabine 1000 mg/m2 d1,8
Vinorelbine 25 mg/m2 d1,8
Q 3 weeks
Gemcitabine 1200 mg/m2 d1,8
Q 3 weeks

53. 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

54. 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

55. www.thongnhathospital.org.vn