NAVELBINE

Non Small Cell Lung Cancer

VINORELBINE
in treatment:
The tailored
From Curative to Palliative
setting
Noorwati Sutandyo
Divisi Hematologi-Onkologi Medik
Departemen Ilmu Penyakit Dalam FKUI/
RSUPN Cipto Mangunkusumo/RSKD
 Lung Cancer
Responsible for about
one-third of all cancer
deaths
Accounts for more
deaths than breast
cancer, prostate cancer,
and colon cancer
COMBINED
80-90% of patients who
develop lung cancer will
die of the disease
80-85%NSCLC
Schiller ASCO ‘00
 Lung Cancer

• More than one-third cases in advanced

stageearly detection is difficult to do
• Dharmais National cancer Centre 64% in
stage IV
• No curative treatment for advanced
stage only systemic therapy
• Sytemic therapy: chemoteherapy and
targeted therapy
 Kemoterapi

• KemoterapiPengobatan kanker dengan zat

atau obat yang berkhasiat membunuh sel kanker
• Obat disebut sitostatikapenghambat kerja sel
yang sedang tumbuh (proliferasi).
– sistemik (ke seluruh sistem tubuh)
– regional
 Chemotherapy
• Mechanism is affected the DNA killed
the cell
Antimetabolites

DNA Alkylating agents

DNA DNA duplication

transcription

Intercalating Mitosis
agents

Spindle poisons
 Prinsip Dasar
• Mencegah sel kanker untuk bermultiplikasi,
menginvasi, metastasis dan membunuh
penderitanya
• Mempengaruhi multiplikasi sel dan
pertumbuhan tumor, terutama sel yang
pertumbuhannya cepat
• Pemberian yang efektif: efikasi maksimal
dengan efek samping seminimal mungkin
Principle Of Chemotherapy
 Chemotherapy

• Chemoterapynot only kill

the cancer but also the
normal cell side effect
• But, the advantage of
chemotherapy relative
more cheaper than
targeted therapy
 Efek Samping Kemoterapi

Alopecia
Mucositis

Pulmonary fibrosis

Cardiotoxicity
Nausea/vomiting
Local reaction
Diarrhea
Renal failure
Cystitis
Myelosuppression
Sterility
Phlebitis
Myalgia
Neuropathy
Targeted Therapy
 Targeted Therapy

• Targeted therapy affected the

transduction signal pathway related
associated with proliferation or survival
cancer cell no affected the normal
cell more tolerable side effect
• But, the price more expensive
 Regiment of Chemotherapy

• Cisplatin +vinorelbine
• Cisplatin+etoposide
• Cisplatin+vinblastin
• Cisplatin+Gemcitabine
• Cisplatin+Docetaxel
• Carboplatin +Paclitaxel
Mekanisme Aksi Agen Sitotoksik pada Level
Siklus Sel
Antibiotics
Antimetabolites
S
(2-6h)
G2
(2-32h) Vinca alkaloids

M
(0.5-2h) Mitotic inhibitors

Alkylating agents Taxoids

G1
(2- h)

G0
Kemoterapi Kombinasi

Kemoterapi
kombinasi penting
utk mencapai log
kill dimana
populasi sel tumor
tidak sensitif thd
obat tunggal
 Tujuan Kemoterapi
Kombinasi
Meningkatkan Efikasi

Aktivitas Keamanan

Mekanisme kerja yang berbeda Efek Samping

Mekanisme resistensi yang berbeda
 Pemilihan kombinasi regimen

• Perlu dipilih regimen paling tepat untuk

memusnahkan kanker yang spesifik.
• Disebut regimen lini pertama/FIRST LINE
KEMOTERAPI
• Kadangkala disebut DRUG of CHOICE/obat
terpilih.
• Proses ini memerlukan penelitian uji klinik yang
cermat dan diperlukan contoh yang banyak.
• Regimen lini kedua  bila regimen lini pertama,
tidak mempan
 VINORELBINE
(Navelbine)

Inhibition of tubulin polymerization

with a differential affinity


Selective affinity

Weak affinity
for mitotic spindle for axonal
microtubules microtubules

  Binet, Sem.Onc 1989

Potent Low
anti-tumoral activity neurotoxicity
 Treatments of NSCLC:
A strategy adapted to each case

Resectable Unresectable Unresectable

disease disease disease
I, II, IIIA IIIB IV

  
Palliative CT
Adjuvant CT CT+RT
Platinum-based or
Pre-operative CT combination
Platinum-free regimens

Treatment adapted to each stage of the disease

 ANITA: Adjuvant NAVELBINE® + CDDP vs Observation
Completely resected Observation NAVELBINE 30 mg/m²/w
stage Ib to IIIA patients CDDP 100 mg/m² D1
q 4 weeks - 4 cycles
n= 433 n= 407
MS (m) 43.7 p= 0.017 65.7
2-year survival +4.7%
5-year survival +8.6%
Overall survival - ITT population
7-year survival +8.4%
1.00
Survival Distribution Function

0.75

0.50

Obs
0.25
NVB + CDDP

0
0 20 40 60 80 100 120
months
ANITA 13

Douillard, Lancet Oncology 2006

Long-term survival benefit: 8.4% at 7 years

 Efficacy in randomized platin-based adjuvant trials

Trial Median 5-Year Hazard

Survival Survival Ratio
ALPI 55.2 m -- HR: 0.96
MVP vs control 48 m -- 95% CI:
p = 0.585 [ 0.81 – 1.13]
IALT 50.8 m 44.5% HR: 0.86
+ 4%
P-based vs control 44.4 m 40.4% 95% CI:
p = 0.03 [ 0.76 - 0.98]
JBR10 94 m 69% HR: 0.69
54% + 15% 95% CI:
NP vs control 73 m
p = 0.04
[ 0.52 - 0.91]

CALGB 9633 95 m 59% HR: 0.80

95% CI:
PC vs control 78 m 57% [ 0.60 – 1.07]
p= 0.37

ANITA 65.7 m 51.2% HR: 0.80

NP vs control 43.7m 42.6% + 8% 95% CI:
p = 0.017 [ 0.66 - 0.96]

3/5 adjuvant trials showed significant survival improvement

with chemotherapy
 Lung Adjuvant Cisplatin Evaluation (LACE)

LACE LACE NAVELBINE

meta-analysis meta-analysis
Population Patients with completely resected NSCLC

Inclusion criteria CDDP-based vs Obs NVB+CDDP vs Obs

CDDP-based + PORT vs PORT NVB+CDDP + PORT vs PORT

Included studies 5 studies included 4 studies included

ALPI, BLT, IALT, JBR10, ANITA BLT, IALT, JBR10, ANITA

Pts N = 4584 N = 1888

characteristics IA: 8%, IB: 30%, II: 35%, III: 27% IA: 2%, IB: 34%, II: 38%, III: 26%

Main objective Overall Survival of Overall Survival of

CDDP-based regimens NVB+CDDP regimens
Pignon, ASCO 2006, Douillard, ESMO 2006
PORT= post-operative RT
 Contribution of NAVELBINE® in the adjuvant setting
LACE LACE NAVELBINE®
100 Chemotherapy 1.0 NAVELBINE + cisplatin
Control Control

80 80
+5.3%
61.0
+8.9%
60 60
55
Survival (%)

Survival (%)
48.8
40 57.1 40

46.1
43.5
20 20

0 0

p=0.004 p=0.0007

0 1 2 3 4 5 ≥6 0 1 2 3 4 5 ≥6

Time (years) Time (years)

• 5 trials • 4 trials
• Absolute survival benefit of 5.3% at 5-years • Absolute survival benefit of 8.9% at 5-years
Pignon, ASCO 2006 Douillard, ESMO 2006- ICACT 2007

NAVELBINE® + Cisplatin is the new standard of care

as adjuvant treatment for NSCLC
 Adjuvant NAVELBINE+CDDP:
a new standard of care

IALT, NEJM 2004

n=1867 (Stages I: 36%, II: 25%, III: 39%)
(p < 0.03)
Median Observation 44.4 m
survival CT (27% NVB+CDDP) 50.8 m

JBR10, NEJM 2005

n=482 (Stages IB: 45%, II: 55%)
(p = 0.009)
Median Observation 73 m
survival NVB+CDDP 94 m

ANITA, ASCO 2005

n=840 (Stages I: 35%, II: 30%, IIIA: 35%)
(p = 0.01)
Median Observation 43.7 m
survival NVB+CDDP 65.7 m

With 3 positive trials, NVB+CDDP has the largest experience

as adjuvant chemotherapy
 NAVELBINE + CDDP
as preoperative CT for stage III NSCLC

Phase II study
n= 56 NAVELBINE D1, D8 30 mg/m²
IIIA 36%, IIIB 64% CISPLATIN D1 80 mg/m²
every 3 weeks

OR 54%
Resection rate 77%
Complete resection 32% (27% T4 – 50% N3)
MS 21.5 m
1-YS 89% (Compl. Res.) vs 45% (Incompl. Res.)
2-YS 61% (Compl. Res.) vs 10% (Incompl. Res.)

Spasova, Neoplasma 02

NVB-CDDP yields high resection rates

 NAVELBINE + IFO + CDDP
as preoperative CT

Phase III study

n= 155 NAVELBINE D1, D5 25 mg/m²
IIB 27%, IIIA 65%, IIIB IFOSFAMIDE D1 3000 mg/m²
8% CISPLATIN D1 80 mg/m²
every 3 weeks
OR 58.7%
Resection rate 69%
Complete resection 74% (79/107 pts)
Time to surgery 32 days

Gottfried, WCLC 2005

Effective triplet CT in patients with large LA NSCLC

 Treatments of NSCLC

Resectable Unresectable Unresectable

disease disease disease
I, II, IIIA IIIB IV

  
Palliative CT
Adjuvant CT CT+RT
Platinum-based or
Pre-operative CT combination
Platinum-free regimens

Treatment adapted to each stage of the disease

 Unresectable stage III patients :
ASCO Guidelines for CT+RT

 CT plus RT prolongs survival compared to RT alone

 CT may best be started soon after the diagnosis of

unresectable NSCLC has been made

 Delaying CT may negate the survival benefits of treatment

 The duration of CT should be 2 to 4 cycles of initial

platinum-based CT
(Pfister, JCO 04)
 NAVELBINE® + CDDP:
Sequential CT and RT or concurrent CT+RT+ consolidation?

Randomised study

n=102
NVB +CDDP NVB+CDDP + RT (60 Gy)
IIIA 15%
IIIB 85% then RT (60 Gy) then NVB+CDDP

OR 47% 80%

CR 17% 21%

Median Survival 12.9 m 16.6 m

1-YS 53% 69%

2-YS 14% 34%

Zatloukal, Lung Cancer 2004

Concurrent NVB+CDDP and radiotherapy appears more efficacious

than sequential use of the same therapeutics…
 NAVELBINE® + CDDP:
Sequential CT and RT or concurrent CT+RT+ consolidation?

Phase III study NVB +CDDP NVB+CDDP + RT

Gr 3-4, % pts then RT (60 Gy) then NVB+CDDP
Neutropenia 40% 65%
Febrile neutropenia 2% 8%
Thrombocytopenia 4% 6%

Esophagitis 4% 18%
Nausea/Vomiting 15% 39%
Neurotoxicity 2% 4%
Pulmonary toxicity 2% 4%
Zatloukal, Lung Cancer 2004

But concurrent approach requires patient’s selection

to limit toxicity burdens
 Treatments of NSCLC

Resectable Unresectable Unresectable

disease disease disease
I, II, IIIA IIIB IV

  
Palliative CT
Adjuvant CT CT+RT
Platinum-based or
Pre-operative CT combination
Platinum-free regimens

Treatment adapted to each stage of the disease

 1st line NAVELBINE D1,D8 + CDDP versus
GEM+CDDP

Phase III study 1st line: NVB+CDDP q3w* 1st line: GEM+CDDP q3w*
n=272 2nd line: GEM weekly 2nd line: NVB weekly
Efficacy
OR 1st Line 32.1% 26.7%
MS 11m 11m
Toxicity (Gr 3-4, %pts)
Neutropenia 30.7% (p= 0.017) 17.7%
Thrombopenia 0% (p= 0.004) 9.3%
Cost
Total direct costs 882 € (p< 0.0001) 2,900 €
per patient
Martoni, Eur. J. Cancer 2005
*Followed by maintenance of the same drug NVB or GEM as in a single agent
for responding and stable disease patients

Major efficacy and significantly lower cost for NAVELBINE+CDDP

 Efficacy of third generation
CDDP-based chemotherapies
Phase III studies OR MS 1-YS Nb
studies

NVB weekly+CDDP 25-36% 8.8-10.3m 33.-42% 7

q4w
NVB D1,D8+CDDP 27-39% 9.6-11m 39-41% 4
q3w
GEM+CDDP 22-42% 8.1-11m 32-44% 8
q3-4 w
PTX+CDDP 21-41% 7.8-10m 31-43% 5
q3w
DCT+CDDP 17-37% 7.4-11.4m 31-48% 4
q3w

NVB D1,D8 +CDDP:

of the most active combinations in 1st line NSCLC
 NAVELBINE+Carboplatin

Phase III study NVB 30 mg/m² D1,D8

vs NVB+GEM CBDCA AUC 5 D1
n=316 every 3 weeks

OR (ITT) 20.8%
Disease control 66%
MS 8.6 m
1-YS 34.4%
Tan, Lung Cancer 2005

Clinical benefit response in one third of the patients

 NAVELBINE + CBDCA

Tolerance %pts

Neutropenia Gr 3-4 44.5%

Febrile neutropenia 11%
Nausea/Vomiting Gr 3 4%
Constipation Gr 3 4%
(Tan, Lung Cancer 2005)

Tolerance profile suitable for an outpatient treatment

 Studies with NAVELBINE+Carboplatin (n>50)

NAVELBINE + CBDCA n MS

Tan, Lung Cancer 2005 158 8.5 m

Maguire, WCLC 2003 150 8.6 m
Bretti, Onco. Rep. 2001 83 9m
Santomaggio, Am. JCO 1998 77 9.5 m
Cremonesi, Oncol. 2003 52 12.3 m
Parente, EJC 1997 75 8m
n= 595 MS= 8-12.3 m

NVB+CBDCA: the efficacy of a standard CDDP-based regimen

with the convenience of CBDCA
 Efficacy of third generation
CBDCA-based chemotherapies

Phase II and III studies OR MS 1-YS Nb

studies

NVB+CBDCA 21-45% 8-12.3m 34% 6*

GEM+CBDCA 29-42% 7.6-11m 32-44% 6

PTX+CBDCA 10-46% 8.1-11m 34-44% 7

DCT+CBDCA 24.5-34% 7.8-9.6m 38-39% 3

(*1 phase III)

NVB+CBDCA:
An effective outpatient chemotherapy
 Quality of life of NAVELBINE + CDDP/CBDCA

Quality of life improvement Clinical benefit response

% pts % pts
50 50
37%
32%

25 25

0 0
NAVELBINE + CDDP NAVELBINE + CBDCA
(n=202) (n=111)
Kelly, JCO 2001 Tan, Lung Cancer 2005

NAVELBINE + CDDP/CBDCA= Improved quality of life

NAVELBINE in platinum-based combinations
Recommended doses

NAVELBINE 30mg/m² D1,D8

CDDP 80mg/m² D1
3-week cycles

NAVELBINE 25-30mg/m² D1,D8

CBDCA AUC 5 D1
3-week cycles
 Elderly and Lung Cancer

• In Dharmais Hospital 2007elderly

Age (years old) Male Female

39/85
<20 0 0
20-40 5 2 46%
40-60 29 10
>60 27 12
61 (71%) 24 (29%)
 Elderly patients:
A population with specific requirements

Level of independence Therapeutic options

No need of rehabilitation:
- complete functional independence (ADL, IADL) Poly CT can be feasible
- negligible co-morbidity
Reversible with rehabilitation:
- dependence in ADL Mono CT should be preferred
- function limiting co-morbidity

Irreversible:
- dependence in ADL BSC is the best option
- severe co-morbidity
Adapted from Balducci, Management of Cancer in the older person: a practical approach; The Oncologist 2000

Treatment must be adapted to each patient’s profile

NAVELBINE single agent in elderly patients

ELVIS Phase III study

n= 154 NVB 30 mg/m2

median age= 74 D1, D8 BSC
73% stage IV every 3 weeks
OR 20% -
Disease control 50% -
Median Survival 6.5 m p = 0.03 4.8 m
1-YS 32% 14%

Gridelli, JNCI 99

NAVELBINE improves Survival vs BSC

NAVELBINE single agent in elderly patients

ELVIS Phase III study

NVB 30 mg/m2 D1, D8
WHO G3/4, % pts every 3 weeks
Neutropenia 4% Gr 4
Infection none
Vomiting 1 pt
Cardiac toxicity 1 pt Gr 2
Constipation 5.6%
Alopecia 4% Gr 3
Gridelli, JNCI 1999
NAVELBINE single agent in elderly patients

ELVIS Phase III study

NVB 30 mg/m2
D1, D8 versus BSC
q3 weeks

Significant improvement with NVB for:

EORTC - C30 scales cognitive function – pain

EORTC - LC13 modules dyspnea - pain in shoulder - pain medication

Gridelli, JNCI 99

NAVELBINE improves Quality of Life

NAVELBINE single agent in elderly patients

MILES Phase III study

median age= 74 NVB

70% stage IV 30 mg/m² GEM NVB + GEM
D1, D8 q3w (n = 233) (n = 232)
PS 2= 19% (n = 233)

OR 18% 16% 21%

MS 8.3 m 6.5 m 6.9 m

1-YS 38% 28% 30%

Gridelli,JNCI 03

NAVELBINE is the standard for elderly patients

 NAVELBINE + CDDP in the Elderly

Phase II study
n= 33 NAVELBINE D1, D8, D15 30 mg/m²
St IIIA, IIIB, IV CISPLATIN D1, D8, D15 25 mg/m²
Median age= 73 q4 weeks

OR 48%
Disease control 77%
Median duration response 7m
MS 11 m
Cinical benefit 46% responders
Neutropenia Gr 3-4 44.5% pts including 1 toxic death
(PS2 / infection)
Mattioli, ESMO 02

PolyCT NVB+CDDP is effective and feasible for fit elderly patients

 NAVELBINE + CBDCA in the Elderly
Phase II study
n= 72 NAVELBINE 25 mg/m² D1, D8
St IV CBDCA AUC 5 D1
Median age= 75 q3 weeks

OR 31%
Disease control 67%
PFS 6.7 m
MS 8.8 m
Neutropenia Gr 3-4 28%
Febrile neutropenia 4%
Thrombocytopenia Gr 3-4 8%
Fatigue None
Neurotoxicity 3%
Depperman, ESMO 2004

The efficacy and convenience of NVB+CBDCA for fit elderly patients

 NAVELBINE in the Elderly
Recommended dose

NAVELBINE 30mg/m² D1,D8

3-week cycles
 From curative to palliative settings

Resectable Unresectable Unresectable

disease disease disease
I, II, IIIA IIIB IV

  
NVB+CDDP
NVB+CDDP NVB+CDDP+RT
NVB+CBDCA
Adjuvant or Sequential and
NVB single agent
Pre-operative CT concomitant
Palliative CT

NAVELBINE: a reference treatment for NSCLC

 NAVELBINE in practice

As a single-agent:
30 mg/m²/w

In combination:
25-30 mg/m² D1, D8 every 3 weeks

 Perform blood count before any administration

 Short infusion (NAVELBINE diluted in 50-100 cc saline solution, 10’ infusion)
 NAVELBINE should be administered as the first cytotoxic given in a combination

NAVELBINE: a reference treatment for NSCLC