NS

CL

C -

Sta

ge

IV STAGE IV

NSCLCNSCLC

NS

CL

C -

Sta

ge

IVNSCLCMain Drugs

Stage IV

NAVELBINE : The pivotal drug GEMZAR :

Main competitor

TAXOL : Still often prescribed

TAXOTERE : New comer

NS

CL

C -

Sta

ge

IV

Patients candidate for poly CT

NVB - Platinum

1st Line Metastatic NSCLCStage IV patients

Patients not candidate for poly CT

NVB single agent

NVB - GEMor

NS

CL

C -

Sta

ge

IV

NAVELBINE + CDDP

= THE 1st LINE STANDARD

TREATMENT

NS

CL

C -

Sta

ge

IVNVB+CDDP = the 1st line standard treatment

EFFICACY

OR MS 1YS

25-44% 8-11.5 m. 33 (24)*-45%

Le Chevalier, JCO 1994; Wozniak, JCO 1998; Souquet, Ann. Onco. 2002; Kelly, JCO 2001; Scagliotti, JCO 2002; Fossella, ECCO 2001; Kakolyris ASCO 2002; *Gebbia, Lung Cancer 2002; Coudert, ASCO 2002

9 randomised phase III studies

Around 2000 patients

EXPERIENCE

NS

CL

C -

Sta

ge

IV

RANDOMIZATION

Scagliotti, JCO 2002

201 patients, 81% stage IVNAVELBINE : 25 mg/m² week x 8 weeks then every 2 weeks

CISPLATIN : 100 mg/m² D1 every 4 weeks

201 patients, 82% stage IVPACLITAXEL : 225 mg/m² D1

CARBOPLATIN : AUC 6 D1,

205 patients, 81% stage IVGEMCITABINE : 1250 mg/m² D1, D8

CISPLATIN : 75 mg/m² D2

Q3w

Q3w

NVB+CDDP vs TXL+CBDCA vs GEM+CDDPPhase III randomized trial

NS

CL

C -

Sta

ge

IVNVB+CDDP vs TXL+CBDCA vs GEM+CDDPPhase III randomized trial

Scagliotti, JCO 2002

No other drug did better than NVB-CDDP

SURVIVAL

NVB+CDDP TXL+CBDCA GEM+CDDP

MS 9.5 m. 9.9 m. 9.8 m.

1YS 37% 43% 37%

NS

CL

C -

Sta

ge

IVNVB+CDDP vs TXL+CBDCA vs GEM+CDDPPhase III randomized trial

Scagliotti, JCO 2002

NVB-CDDP TXL-CBDCA GEM-CDDP

Thrombocytopenia 0.1 3* 16*

Neutropenia 44* 34 16

Febrile Neutropenia 3 1 0.5

Neurotoxicity 7 30* 4

Alopecia 11 52* 10

TOLERANCE (G 3-4)

% of cycles

% of patients

* significant

NS

CL

C -

Sta

ge

IVNVB+CDDP vs TXT+CDDPPhase III randomized trial

Mattson, ESMO 2002Taxotere – Prescribing information – Nov. 2002

NVB-CDDP TXT- CDDP TXT-CBDCAn = 404 408 408

OR 24.5% 31.6% 23.9%

TTP 5.3 m. 5 m. 4.6 m.

MS 10.1 m. 11.3 m. 9.4 m.

1YS 41% 46% 38%

2YS 14% 21% 18%

NVB 25 mg/m²/week TXT 75 mg/m² D1 TXT 75 mg/m² D1CDDP 100 mg/m² D1 CDDP 75 mg/m² D1 CBDCA AUC6 D1

Q4w Q3w Q3w

EFFICACY

NVB-CDDP : never overpassed by any new doublet

"TXT+CDDP did not result in a statistically significant superior survival compared to vinorelbine+cisplatin"

NS

CL

C -

Sta

ge

IV

NVB-CDDP TXT-GEM

n 146 167

OR 38% 32%

TTP 8 m. 7 m.

MS 11.5 m. 9 m.

1YS 45.4% 34.4%

NVB-CDDP : a new schedulePhase III randomized trial Kakolyris, ASCO 2002

EFFICACY

NVB-CDDP 3 week schedule : all the efficacy of NVB-CDDP

NVB 30 mg/m² D1, D8 TXT 100 mg/m² D1CDDP 80 mg/m² D8 GEM 1000 mg/m² D1, D8+ G-CSF + G-CSF

Q3w vs Q3w

NS

CL

C -

Sta

ge

IV

Clegg, Thorax 2002

NAVELBINE + CDDP: always the best cost effectiveness ratio

NVB-CDDP : treatment cost

NVB + CDDP GEM + CDDP TXL + CDDP

Average cost / 4736 6321 6304 (TXL 135 mg/m²)patient (£) 7550 (TXL 175 mg/m²)

8147 (TXL 250 mg/m²)

Average cost / 6726 8623 8048 (TXL 135 mg/m²)

life years saved (£) 10281 (TXL 175 mg/m²)9776 (TXL 250 mg/m²)

NS

CL

C -

Sta

ge

IVNVB-CDDPRecommended dose

NVB 25 mg/m2 / week

CDDP 100 mg/m2 D1Every 4 weeks

NVB 30 mg/m2 D1, D8

CDDP 80 mg/m2 D1Every 3 weeks

or

NS

CL

C -

Sta

ge

IV

CDDP cumulative toxicity

difficult to administer more than 4 cycles of

polyCT

Patients with OR or SD

interest to prolong treatment beyond 6 cycles

to improve survival (De Vita)

Consolidation concept

To prolong the therapeutic benefitNVB 25-30 mg/m²/week until progression

Duration of treatment:

NS

CL

C -

Sta

ge

IVWhich 2nd line after NVB-CDDP 1st line ?

NVB GEM TXL TXT

OR 0-20% 0-21% 0-38% 7-27%

MS 3 m. 5-8.3 m. 3.9-9.7 m. 5.5-9.7 m.

Ferrigno, Lung Cancer 2000; Huisman, JCO 2000

Efficacy of single agent in 2nd line

NS

CL

C -

Sta

ge

IVWhich 2nd line after NVB-CDDP 1st line ?

Conclusion on suitability for 2nd line

NVB GEM TXL TXT

No Yes Possible Yes

After NVB-CDDP 1st line, 2 possibilities according to patient’s profile:

• Good PS TXN 2nd line

• Poor PS GEM 2nd line

NS

CL

C -

Sta

ge

IV

GEM-CDDP

TXL-CBDCA

TXT-CDDP

Which competitors on the market ?

NS

CL

C -

Sta

ge

IV

The « standard » competitor

Intense marketing activity with many symposia!

Aggressive claims : « the emerging standard…» – « essential in 1st line » - « unsurpassed efficacy »

Communication on D1,D8 schedule for GP

Communication on GEM-CBDCA

Competitor: GEMZAR

NS

CL

C -

Sta

ge

IVCompetitor: GEMZARResults from phase III – GEM-CDDP

NVB-CDDP GEM-CDDP

OR 25-44% 21-43%

TTP 4-8 m. 4.2-6.9 m.

MS 8-11.5 m. 8.1-9.8 m.

1YS 33-45% 32-39%

G3-4, %,pts

Neutropenia 41-81% 40-64%

Thombocytopenia 3-6% 36-64%

Asthenia 14-31% (G2/4) 18% (Melo)

58% (Sandler)

+ pneumonitis+ renal toxicity

NS

CL

C -

Sta

ge

IVCompetitor: GEMZAR

The only significant criteria : TTP (Schiller and Cardenal)

Lilly : communication on it

No improvement of survival vs any doublet (EtoP-NP-TC-TP) vs any triplet (MIP-NGP) except vs CDDP single agent

No improvement of QoL vs any doublets or triplets

Haematological + clinical toxicities Lilly's communication on flu-like symptoms - N/V - alopecia

NS

CL

C -

Sta

ge

IVCompetitor: GEMZARResults from phase III – GEM-CBDCA

OR : 27-47%

MS : 10.2-11.5 m

1YS : 36-44%

EFFICACY

Leucopenia : 2-32%

Thrombocytopenia : 2-49%

No severe clinical toxicities

TOLERANCE (G3-4 %pts)

5 studies, n= 617

GC > GEM> VBL-CDDP> MIP

Stage IV= 44-54%

Platelet transfusion : 6% *Hospit. for treatment: 14% **Pulmonary tox. : 13% *

Grigorescu, Lung Cancer 2002; ** Rudd, Cancer Conf. 2002;

Danson, ASCO 2001; *Novakova, ASCO 2002; Sederholm, Cancer Conf. 2002

NS

CL

C -

Sta

ge

IV

Less present in the communication

BUT interesting papers : Kosmidis – Schiller (ECOG 1594) –

SWOG2

still an important field force

Lots of generics available (Europe – USA – Asia) can be a threat : paclitaxel-CBDCA low price

Development of an oral formulation : still a dream ???

Competitor: TAXOL

NS

CL

C -

Sta

ge

IVCompetitor: TAXOLResults from phase III

NVB-CDDP TXL-Plat.

OR 25-44% 17-32%

TTP 4-8 m. 3-5.5 m.

MS 8-11.5 m. 8.1-9.9 m.

1YS 33-45% 33-43%

G3-4, %,pts

Neutropenia 41-81% 33-76%

Neurotoxicity 2-7% 13-40%

Arthralgia / MyalgiaPremedication required

NS

CL

C -

Sta

ge

IV

No improvement of survival nor QoL

vs CDDP

vs any doublet (EtoP-NP-GP-TP)

Clear clinical toxicities

Which recommended dose ? 135 mg/m² ? 175 ? 200 ? 225 ?

High cost but generics !!!!

Competitor: TAXOLResults in phase III – TAXOL-Platinum

NS

CL

C -

Sta

ge

IV

TXT-CDDP just registered in 1st line metastatic NSCLC

Aventis striking force :

communication (symposia : ECCO – ICACT )

specific NSCLC field force in some countries

huge budget allocated to NSCLC

Competitor: TAXOTERE

NS

CL

C -

Sta

ge

IVCompetitor: TAXOTEREResults from phase III

NVB-CDDP TXT-CDDP

OR 25-44% 17-37%

TTP 4-8 m. 3.7-8 m.

MS 8-11.5 m. 7.4-11.4 m.

1YS 33-45% 31-47.7%

G3-4, %,pts

Neutropenia 41-81% 33-76%

Diarrhoea NR 7-12%

Asthenia 14-31% (G2/4) 12-30%

NS

CL

C -

Sta

ge

IV

A growing experience in 1st line

Non reproducible and questionable efficacy results : MS = 7,4 m (ECOG) or 11,3 m (Fossella) ?

TXT-CDDP = NVB-CDDP (Fossella)

As many neutropenia as NVB-CDDP

Active drug in 2nd line (2 phase III)

Competitor: TAXOTERE

NS

CL

C -

Sta

ge

IVNVB-GEM

NVB GEM

25-30 mg/m² D1, D8 1000 mg/m² D1, D8

every 3 weeks

Camps, ECCO 2001; Thompson, ASCO 2001; Gridelli, ASCO 2002

Tolerance WHO G3 % pts

Neutropenia: 14-19%

Thrombocytopenia: 2-3%

Phase III No. pts MS 1YS

Gridelli 251 7.4 m. 31%

Thompson 67 10.7 m. 42%

Camps 177 8.1 m. 35%

As effective as a platinumbased regimen

NS

CL

C -

Sta

ge

IVNVB-GEM facing competitors

MS 1YS Major toxicities

NVB-GEM 7.4-10.7 m. 31-42% Neutropenia

TXL-GEM 6.9-9.8 m. 26-41% Neuropathy-Arthralgia/Myalgia

GEM-CDDP 8.7-9.8 m. 33-37% Neutropenia-Thrombocytopenia

TXT-GEM 9 m. 34-38% Neutropenia-Asthenia

Camps, ECCO 2001; Thompson, ASCO 2001; Kosmidis, ECCO 2001; Van Meerbeck, ASCO 2001; Kakolyris, ASCO 2002; Georgoulias, ASCO 1999; Gridelli, ASCO 2002

NS

CL

C -

Sta

ge

IVAbout 1st line CT in advanced NSCLC

Which patients are not candidate for poly CT ?

Frail patients / elderly patients.

Patients with comorbidities, renal impairment.

How can you prolong therapeutic benefit ?

NVB single agent maintenance after 4-6 cycles NP.

Which 2nd line after NP 1st line ?

GEM, TXL, TXT.

NS

CL

C -

Sta

ge

IVCompetitorsMono CT in 1st line NSCLC

n Age OR DC MS 1YS

Gridelli-ELVIS NVB 76 74 20% 50% 6.5 m. 32%(JNCI 99) BSC 78 74 - - 4.8 m. 14%

Gridelli-MILES NVB 223 74 18.5% 48% 8.6 m. 41%(ASCO 2001) GEM 232 74 17% 48% 6.5 m. 26%

NVB + GEM 233 74 20% 47% 7.4 m. 31%

Anderson GEM 150 65 18.5% - 5.7 m. 25%(BJC 2000) BSC 150 65 - - 5.9 m. 22%

Ranson TXL 79 65 16% - 6.8 m. 20-41%(JNCI 2000) BSC 78 65 - - 4.8 m. -

Roszkowski TXT 137 59 20% 42% 6 m. 25%(Lung Cancer 2000) BSC 70 59 - - 5.7 m. 16%

0.03

0.03

0.02

NS

CL

C -

Sta

ge

IV

Gridelli, ASCO 2001

NAVELBINE remains the standard for elderly patients

n= 698 median age= 74, 71% stage IV

MILES studyPhase III

NVB GEM NVB + GEM

OR 18.5% 17.3% 20%

Disease Control 47.7% 48.2% 47%

MS 8.6 m 6.5 m 7.4 m

1-YS 41% 26% 31%

NS

CL

C -

Sta

ge

IVWhich treatment for stage IV patients ?

NVB 30 mg/m² D1, D8 every 3 weeks

with platinum NVB 25 mg/m²/w every CDDP 100 mg D1 4 weeks

NVB 30 mg/m² D1,D8 every CDDP 80 mg/m² D1 3 weeks

NVB 30 mg/m² D1, D8 everyCBDCA 300 mg D1 or AUC5 D1 3 weeks

followed by consolidation with NVB 25-30 mg/m²/w

w/o platinum NVB 25-30 mg/m² D1, D8 every GEM 1000 mg/m² D1, D8 4 weeks

Patients candidate to poly CT

Patients not candidate to poly CT