NAVELBINE

in

Non Small Cell Lung Cancer

VINORELBINEThe tailored treatment:

From Curative to Palliative

settingNoorwati 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%NSCLCSchiller ASCO ‘00

Lung Cancer

• More than one-third cases in advanced

stageearly 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

• KemoterapiPengobatan kanker dengan zat

atau obat yang berkhasiat membunuh sel kanker

• Obat disebut sitostatikapenghambat kerja sel

yang sedang tumbuh (proliferasi).

– sistemik (ke seluruh sistem tubuh)

– regional

Chemotherapy

• Mechanism is affected the DNA killed

the cellAntimetabolites

DNA

DNA

transcription

DNA duplication

Mitosis

Alkylating agents

Spindle poisons

Intercalating

agents

Prinsip Dasar

• Mencegah sel kanker untuk bermultiplikasi, menginvasi, metastasis dan membunuhpenderitanya

• 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

• Chemoterapynot 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

Mucositis

Nausea/vomiting

Diarrhea

Cystitis

Sterility

Myalgia

Neuropathy

Alopecia

Pulmonary fibrosis

Cardiotoxicity

Local reaction

Renal failure

Myelosuppression

Phlebitis

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

Targeted Therapy

Regiment of Chemotherapy

• Cisplatin +vinorelbine

• Cisplatin+etoposide

• Cisplatin+vinblastin

• Cisplatin+Gemcitabine

• Cisplatin+Docetaxel

• Carboplatin +Paclitaxel

Mekanisme Aksi Agen Sitotoksik pada Level

Siklus SelAntibiotics

S

(2-6h)G2

(2-32h)

M

(0.5-2h)

Alkylating agents

G1

(2- h)

G0

Vinca alkaloids

Mitotic inhibitors

Taxoids

Antimetabolites

Kemoterapi Kombinasi

Kemoterapi

kombinasi penting

utk mencapai log

kill dimana

populasi sel tumor

tidak sensitif thd

obat tunggal

Tujuan Kemoterapi

KombinasiMeningkatkan Efikasi

Mekanisme kerja yang berbeda Efek Samping

Mekanisme resistensi yang berbeda

Aktivitas Keamanan

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

for mitotic spindle

microtubules

Weak affinity

for axonal

microtubules

Binet, Sem.Onc 1989

Low

neurotoxicity

Potent

anti-tumoral activity

CT+RT

combination

Treatment adapted to each stage of the disease

Treatments of NSCLC:

A strategy adapted to each case

Resectable

disease

I, II, IIIA

Unresectable

disease

IIIB

Unresectable

disease

IV

Adjuvant CTPre-operative CT

Palliative CT

Platinum-based or

Platinum-free regimens

ANITA: Adjuvant NAVELBINE® + CDDP vs Observation

Long-term survival benefit: 8.4% at 7 years

13ANITA

Overall survivalOverall survival -- ITT populationITT population

months

Surv

ival D

istr

ibution F

unction

1.00

0.75

0.50

0.25

0

0 20 40 60 80 100 120

ObsObs

NVB + CDDPNVB + CDDP

Douillard, Lancet Oncology 2006

Completely resected

stage Ib to IIIA patientsObservation

n= 433

NAVELBINE 30 mg/m²/w

CDDP 100 mg/m² D1

q 4 weeks - 4 cycles

n= 407

MS (m) 43.7 65.7

2-year survival

5-year survival

7-year survival

+4.7%

+8.6%

+8.4%

p= 0.017

Trial Median

Survival

5-Year

Survival

Hazard

Ratio

ALPI

MVP vs control

55.2 m

48 m p = 0.585

--

--

HR: 0.96

95% CI:

[ 0.81 – 1.13]

IALT

P-based vs control50.8 m

44.4 mp = 0.03

44.5%

40.4%

HR: 0.86

95% CI:

[ 0.76 - 0.98]

JBR10

NP vs control

94 m

73 mp = 0.04

69%

54%

HR: 0.69 95% CI:

[ 0.52 - 0.91]

CALGB 9633

PC vs control

95 m

78 mp= 0.37

59%

57%

HR: 0.80 95% CI:

[ 0.60 – 1.07]

ANITA

NP vs control65.7 m

43.7mp = 0.017

51.2%

42.6%

HR: 0.80 95% CI:

[ 0.66 - 0.96]

Efficacy in randomized platin-based adjuvant trials

3/5 adjuvant trials showed significant survival improvement with chemotherapy

+ 4%

+ 15%

+ 8%

LACE

meta-analysis

LACE NAVELBINE

meta-analysis

Population Patients with completely resected NSCLC

Inclusion criteria CDDP-based vs Obs

CDDP-based + PORT vs PORT

NVB+CDDP vs Obs

NVB+CDDP + PORT vs PORT

Included studies 5 studies included

ALPI, BLT, IALT, JBR10, ANITA

4 studies included

BLT, IALT, JBR10, ANITA

Pts

characteristics

N = 4584

IA: 8%, IB: 30%, II: 35%, III: 27%

N = 1888

IA: 2%, IB: 34%, II: 38%, III: 26%

Main objective Overall Survival of

CDDP-based regimens

Overall Survival of

NVB+CDDP regimens

PORT= post-operative RTPignon, ASCO 2006, Douillard, ESMO 2006

Lung Adjuvant Cisplatin Evaluation (LACE)

Contribution of NAVELBINE® in the adjuvant setting

NAVELBINE + cisplatin

Control

+8.9%

p=0.0007p=0.004

55

46.1

Time (years)

Su

rviv

al (%

)

0 1 2 3 4 5 ≥6

100

80

60

40

20

0

Chemotherapy

Control

61.0

57.148.8

43.5

Time (years)

Su

rviv

al (%

)0 1 2 3 4 5 ≥6

1.0

80

60

40

20

0

+5.3%

LACE LACE NAVELBINE®

• 5 trials• Absolute survival benefit of 5.3% at 5-years

Pignon, ASCO 2006

• 4 trials• Absolute survival benefit of 8.9% at 5-years

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

Mediansurvival

(p < 0.03)Observation 44.4 m

CT (27% NVB+CDDP) 50.8 m

IALT, NEJM 2004n=1867 (Stages I: 36%, II: 25%, III: 39%)

(p = 0.009)

JBR10, NEJM 2005n=482 (Stages IB: 45%, II: 55%)

Mediansurvival

Observation 73 m

NVB+CDDP 94 m

Observation 43.7 m

NVB+CDDP 65.7 m

ANITA, ASCO 2005n=840 (Stages I: 35%, II: 30%, IIIA: 35%)

Mediansurvival

(p = 0.01)

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

Spasova, Neoplasma 02

NVB-CDDP yields high resection rates

NAVELBINE + CDDP

as preoperative CT for stage III NSCLC

Phase II study

n= 56

IIIA 36%, IIIB 64%

NAVELBINE D1, D8 30 mg/m²

CISPLATIN D1 80 mg/m²

every 3 weeks

OR

Resection rate

Complete resection

MS

1-YS

2-YS

54%

77%

32% (27% T4 – 50% N3)

21.5 m

89% (Compl. Res.) vs 45% (Incompl. Res.)

61% (Compl. Res.) vs 10% (Incompl. Res.)

Gottfried, WCLC 2005

Effective triplet CT in patients with large LA NSCLC

NAVELBINE + IFO + CDDP

as preoperative CT

Phase III study

n= 155

IIB 27%, IIIA 65%, IIIB

8%

NAVELBINE D1, D5 25 mg/m²

IFOSFAMIDE D1 3000 mg/m²

CISPLATIN D1 80 mg/m²

every 3 weeks

OR

Resection rate

Complete resection

Time to surgery

58.7%

69%

74% (79/107 pts)

32 days

CT+RT

combination

Treatment adapted to each stage of the disease

Treatments of NSCLC

Resectable

disease

I, II, IIIA

Unresectable

disease

IIIB

Unresectable

disease

IV

Adjuvant CT

Pre-operative CT

Palliative CT

Platinum-based or

Platinum-free regimens

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

Concurrent NVB+CDDP and radiotherapy appears more efficacious

than sequential use of the same therapeutics…

n=102

IIIA 15%

IIIB 85%

NVB +CDDP

then RT (60 Gy)

NVB+CDDP + 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

But concurrent approach requires patient’s selection

to limit toxicity burdens

Phase III study

Gr 3-4, % pts

NVB +CDDP

then RT (60 Gy)

NVB+CDDP + RT

then NVB+CDDP

Neutropenia

Febrile neutropenia

Thrombocytopenia

Esophagitis

Nausea/Vomiting

Neurotoxicity

Pulmonary toxicity

40%

2%

4%

4%

15%

2%

2%

65%

8%

6%

18%

39%

4%

4%

NAVELBINE® + CDDP: Sequential CT and RT or concurrent CT+RT+ consolidation?

Zatloukal, Lung Cancer 2004

CT+RT

combination

Treatment adapted to each stage of the disease

Treatments of NSCLC

Resectable

disease

I, II, IIIA

Unresectable

disease

IIIB

Unresectable

disease

IV

Adjuvant CT

Pre-operative CT

Palliative CT

Platinum-based or

Platinum-free regimens

Major efficacy and significantly lower cost for NAVELBINE+CDDP

1st line NAVELBINE D1,D8 + CDDP versus

GEM+CDDP

Phase III study

n=272

1st line: NVB+CDDP q3w*

2nd line: GEM weekly

1st line: GEM+CDDP q3w*

2nd line: NVB weekly

Efficacy

OR 1st Line

MS

32.1%

11m

26.7%

11m

Toxicity (Gr 3-4, %pts)

Neutropenia

Thrombopenia

30.7%

0%

17.7%

9.3%

Cost

Total direct costs

per patient

882 € 2,900 €

Martoni, Eur. J. Cancer 2005

(p= 0.004)

(p< 0.0001)

(p= 0.017)

*Followed by maintenance of the same drug NVB or GEM as in a single agent for responding and stable disease patients

NVB D1,D8 +CDDP: of the most active combinations in 1st line NSCLC

Efficacy of third generation

CDDP-based chemotherapies

Phase III studies OR MS 1-YS Nb

studies

NVB weekly+CDDP

q4w25-36% 8.8-10.3m 33.-42% 7

NVB D1,D8+CDDPq3w

27-39% 9.6-11m 39-41% 4

GEM+CDDPq3-4 w

22-42% 8.1-11m 32-44% 8

PTX+CDDPq3w

21-41% 7.8-10m 31-43% 5

DCT+CDDPq3w

17-37% 7.4-11.4m 31-48% 4

Clinical benefit response in one third of the patients

NAVELBINE+Carboplatin

Phase III study

vs NVB+GEM

n=316

NVB 30 mg/m² D1,D8

CBDCA AUC 5 D1

every 3 weeks

OR (ITT)

Disease control

MS

1-YS

20.8%

66%

8.6 m

34.4%

Tan, Lung Cancer 2005

Tolerance %pts

Neutropenia Gr 3-4

Febrile neutropenia

Nausea/Vomiting Gr 3

Constipation Gr 3

44.5%

11%

4%

4%

Tolerance profile suitable for an outpatient treatment

(Tan, Lung Cancer 2005)

NAVELBINE + CBDCA

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

with the convenience of CBDCA

Studies with NAVELBINE+Carboplatin (n>50)

NAVELBINE + CBDCA n MS

Tan, Lung Cancer 2005

Maguire, WCLC 2003

Bretti, Onco. Rep. 2001

Santomaggio, Am. JCO 1998

Cremonesi, Oncol. 2003

Parente, EJC 1997

158

150

83

77

52

75

8.5 m

8.6 m

9 m

9.5 m

12.3 m

8 m

n= 595 MS= 8-12.3 m

NVB+CBDCA: An effective outpatient chemotherapy

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)

0

25

50

Quality of life of NAVELBINE + CDDP/CBDCA

NAVELBINE + CDDP/CBDCA= Improved quality of life

Tan, Lung Cancer 2005

0

25

50

37%

% pts

Kelly, JCO 2001

Quality of life improvement

32%

NAVELBINE + CDDP(n=202)

Clinical benefit response

NAVELBINE + CBDCA(n=111)

% pts

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 2007elderly

Age (years old) Male Female

<20 0 0

20-40 5 2

40-60 29 10

>60 27 12

61 (71%) 24 (29%)

39/85

46%

Elderly patients:

A population with specific requirements

Treatment must be adapted to each patient’s profile

Level of independence Therapeutic options

No need of rehabilitation:- complete functional independence (ADL, IADL)

- negligible co-morbidity

Poly CT can be feasible

Reversible with rehabilitation:- dependence in ADL

- function limiting co-morbidity

Mono CT should be preferred

Irreversible:- dependence in ADL

- severe co-morbidity

BSC is the best option

Adapted from Balducci, Management of Cancer in the older person: a practical approach; The Oncologist 2000

n= 154

median age= 74

73% stage IV

NVB 30 mg/m2

D1, D8

every 3 weeks

BSC

OR

Disease control

Median Survival

1-YS

20%

50%

6.5 m

32%

-

-

4.8 m

14%

Gridelli, JNCI 99

NAVELBINE improves Survival vs BSC

ELVIS Phase III study

p = 0.03

NAVELBINE single agent in elderly patients

Gridelli, JNCI 1999

ELVIS Phase III study

WHO G3/4, % pts

NVB 30 mg/m2 D1, D8

every 3 weeks

Neutropenia

Infection

Vomiting

Cardiac toxicity

Constipation

Alopecia

4% Gr 4

none

1 pt

1 pt Gr 2

5.6%

4% Gr 3

NAVELBINE single agent in elderly patients

Gridelli, JNCI 99

NAVELBINE improves Quality of Life

ELVIS Phase III study

NAVELBINE single agent in elderly patients

NVB 30 mg/m2

D1, D8 versus BSC

q3 weeks

EORTC - C30 scales

EORTC - LC13 modules

Significant improvement with NVB for:

cognitive function – pain

dyspnea - pain in shoulder - pain medication

Gridelli,JNCI 03

NAVELBINE is the standard for elderly patients

MILES Phase III study

NAVELBINE single agent in elderly patients

median age= 74

70% stage IV

PS 2= 19%

NVB 30 mg/m²

D1, D8 q3w(n = 233)

GEM(n = 233)

NVB + GEM(n = 232)

OR 18% 16% 21%

MS 8.3 m 6.5 m 6.9 m

1-YS 38% 28% 30%

NAVELBINE + CDDP in the Elderly

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

Phase II study

n= 33

St IIIA, IIIB, IV

Median age= 73

NAVELBINE D1, D8, D15 30 mg/m²

CISPLATIN D1, D8, D15 25 mg/m²

q4 weeks

OR

Disease control

Median duration response

MS

Cinical benefit

Neutropenia Gr 3-4

48%

77%

7 m

11 m

46% responders

44.5% pts including 1 toxic death

(PS2 / infection)Mattioli, ESMO 02

NAVELBINE + CBDCA in the Elderly

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

Phase II study

n= 72

St IV

Median age= 75

NAVELBINE 25 mg/m² D1, D8

CBDCA AUC 5 D1

q3 weeks

OR

Disease control

PFS

MS

Neutropenia Gr 3-4

Febrile neutropenia

Thrombocytopenia Gr 3-4

Fatigue

Neurotoxicity

31%

67%

6.7 m

8.8 m

28%

4%

8%

None

3%Depperman, ESMO 2004

NAVELBINE in the Elderly

Recommended dose

NAVELBINE 30mg/m² D1,D8

3-week cycles

From curative to palliative settings

NAVELBINE: a reference treatment for NSCLC

Unresectable

disease

IV

Unresectable

disease

IIIB

Resectable

disease

I, II, IIIA

NVB+CDDP

Adjuvant or

Pre-operative CT

NVB+CDDP+RT

Sequential and

concomitant

NVB+CDDP

NVB+CBDCA

NVB single agent

Palliative CT

NAVELBINE in practice

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

As a single-agent:

30 mg/m²/w

In combination:

25-30 mg/m² D1, D8 every 3 weeks

NAVELBINE: a reference treatment for NSCLC