NSCLC - Stage IV STAGE IVNSCLC

NSCLC - Stage IV NSCLC Main Drugs  Stage IV NAVELBINE:The pivotal drug GEMZAR:Main competitor TAXOL:Still often prescribed TAXOTERE:New comer

NSCLC - Stage IV Patients candidate for poly CT NVB - Platinum 1 st Line Metastatic NSCLC Stage IV patients Patients not candidate for poly CT NVB single agent NVB - GEM or

NSCLC - Stage IV NAVELBINE + CDDP = THE 1 st LINE STANDARD TREATMENT

NSCLC - Stage IV NVB+CDDP = the 1 st line standard treatment EFFICACY ORMS1YS 25-44% 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 randomised phase III studies Around 2000 patients EXPERIENCE

NSCLC - Stage IV RANDOMIZATION Scagliotti, JCO patients, 81% stage IV NAVELBINE :25mg/m² week x 8 weeks then every 2 weeks CISPLATIN :100mg/m²D1every 4 weeks 201 patients, 82% stage IV PACLITAXEL :225 mg/m²D1 CARBOPLATIN : AUC 6D1, 205 patients, 81% stage IV GEMCITABINE :1250mg/m²D1, D8 CISPLATIN : 75mg/m²D2 Q3w NVB+CDDP vs TXL+CBDCA vs GEM+CDDP Phase III randomized trial

NSCLC - Stage IV NVB+CDDP vs TXL+CBDCA vs GEM+CDDP Phase III randomized trial Scagliotti, JCO 2002 No other drug did better than NVB-CDDP SURVIVAL NVB+CDDP TXL+CBDCAGEM+CDDP MS 9.5 m. 9.9 m. 9.8 m. 1YS 37% 43% 37%

NSCLC - Stage IV NVB+CDDP vs TXL+CBDCA vs GEM+CDDP Phase III randomized trial Scagliotti, JCO 2002 NVB-CDDPTXL-CBDCAGEM-CDDP Thrombocytopenia0.1 3*16* Neutropenia 44* 3416 Febrile Neutropenia310.5 Neurotoxicity7 30* 4 Alopecia11 52* 10 TOLERANCE (G 3-4) % of cycles % of patients * significant

NSCLC - Stage IV NVB+CDDP vs TXT+CDDP Phase III randomized trial Mattson, ESMO 2002 Taxotere – Prescribing information – Nov NVB-CDDPTXT- CDDPTXT-CBDCA n = OR24.5%31.6%23.9% TTP5.3 m.5 m.4.6 m. MS10.1 m.11.3 m.9.4 m. 1YS41%46%38% 2YS14%21%18% NVB25 mg/m²/weekTXT75 mg/m² D1 TXT75 mg/m²D1 CDDP 100 mg/m² D1CDDP 75 mg/m² D1CBDCA 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"

NSCLC - Stage IV NVB-CDDPTXT-GEM n OR38%32% TTP8 m.7 m. MS11.5 m.9 m. 1YS45.4%34.4% NVB-CDDP : a new schedule Phase III randomized trial Kakolyris, ASCO 2002 EFFICACY NVB-CDDP 3 week schedule : all the efficacy of NVB-CDDP NVB30 mg/m² D1, D8TXT100mg/m² D1 CDDP 80 mg/m² D8GEM 1000mg/m² D1, D8+ G-CSF Q3w vs Q3w

NSCLC - Stage IV Clegg, Thorax 2002 NAVELBINE + CDDP: always the best cost effectiveness ratio NVB-CDDP : treatment cost NVB + CDDP GEM + CDDP TXL + CDDP Average cost / (TXL 135 mg/m²) patient (£)7550(TXL 175 mg/m²) 8147(TXL 250 mg/m²) Average cost / (TXL 135 mg/m²) life years saved (£) 10281(TXL 175 mg/m²) 9776(TXL 250 mg/m²)

NSCLC - Stage IV NVB-CDDP Recommended dose NVB25mg/m 2 / week CDDP100mg/m 2 D1 Every 4 weeks NVB30mg/m 2 D1, D8 CDDP80mg/m 2 D1 Every 3 weeks or

NSCLC - Stage 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 benefit NVB mg/m²/week until progression Duration of treatment:

NSCLC - Stage IV Which 2 nd line after NVB-CDDP 1 st line ? NVBGEMTXLTXT OR0-20%0-21%0-38%7-27% MS3 m m m m. Ferrigno, Lung Cancer 2000; Huisman, JCO 2000 Efficacy of single agent in 2 nd line

NSCLC - Stage IV Which 2 nd line after NVB-CDDP 1 st line ? Conclusion on suitability for 2 nd line NVBGEMTXLTXT NoYesPossibleYes After NVB-CDDP 1 st line, 2 possibilities according to patient’s profile: Good PS  TXN 2 nd line Poor PS  GEM 2 nd line

NSCLC - Stage IV  GEM-CDDP  TXL-CBDCA  TXT-CDDP Which competitors on the market ?

NSCLC - Stage IV  The « standard » competitor  Intense marketing activity with many symposia!  Aggressive claims : « the emerging standard…» – « essential in 1 st line » - « unsurpassed efficacy »  Communication on D1,D8 schedule for GP  Communication on GEM-CBDCA Competitor: GEMZAR

NSCLC - Stage IV Competitor: GEMZAR Results from phase III – GEM-CDDP NVB-CDDPGEM-CDDP OR25-44%21-43% TTP4-8 m m. MS m m. 1YS33-45%32-39% G3-4, %,pts Neutropenia 41-81%40-64% Thombocytopenia3-6%36-64% Asthenia14-31% (G2/4)18% (Melo) 58% (Sandler) + pneumonitis + renal toxicity

NSCLC - Stage IV Competitor: 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

NSCLC - Stage IV Competitor: GEMZAR Results from phase III – GEM-CBDCA OR:27-47% MS: 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

NSCLC - Stage IV  Less present in the communication BUTinteresting 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

NSCLC - Stage IV Competitor: TAXOL Results from phase III NVB-CDDPTXL-Plat. OR25-44%17-32% TTP4-8 m m. MS m m. 1YS33-45%33-43% G3-4, %,pts Neutropenia 41-81%33-76% Neurotoxicity2-7%13-40% Arthralgia / Myalgia Premedication required

NSCLC - Stage IV  No improvement of survival nor QoL  vs CDDP  vs any doublet (EtoP-NP-GP-TP)  Clear clinical toxicities  Which recommended dose ? 135 mg/m ² ? 175 ? 200 ? 225 ?  High cost but generics !!!! Competitor: TAXOL Results in phase III – TAXOL-Platinum

NSCLC - Stage IV  TXT-CDDP just registered in 1 st line metastatic NSCLC  Aventis striking force : communication (symposia : ECCO – ICACT ) specific NSCLC field force in some countries huge budget allocated to NSCLC Competitor: TAXOTERE

NSCLC - Stage IV Competitor: TAXOTERE Results from phase III NVB-CDDPTXT-CDDP OR25-44%17-37% TTP4-8 m m. MS m m. 1YS33-45% % G3-4, %,pts Neutropenia 41-81%33-76% DiarrhoeaNR7-12% Asthenia14-31% (G2/4)12-30%

NSCLC - Stage IV  A growing experience in 1 st 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 2 nd line (2 phase III) Competitor: TAXOTERE

NSCLC - Stage IV NVB-GEM NVB GEM mg/m² D1, D81000 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. ptsMS1YS Gridelli m.31% Thompson m.42% Camps m.35% As effective as a platinum based regimen

NSCLC - Stage IV NVB-GEM facing competitors MS1YSMajor toxicities NVB-GEM m.31-42% Neutropenia TXL-GEM m.26-41%Neuropathy-Arthralgia/Myalgia GEM-CDDP m.33-37% Neutropenia-Thrombocytopenia TXT-GEM9 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

NSCLC - Stage IV About 1 st 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 2 nd line after NP 1 st line ?  GEM, TXL, TXT.

NSCLC - Stage IV Competitors Mono CT in 1 st line NSCLC nAge OR DC MS 1YS Gridelli-ELVIS NVB %50%6.5 m.32% (JNCI 99) BSC m.14% Gridelli-MILES NVB %48%8.6 m.41% (ASCO 2001) GEM %48%6.5 m.26% NVB +GEM %47%7.4 m.31% Anderson GEM % -5.7 m.25% (BJC 2000) BSC m.22% Ranson TXL796516% -6.8 m % (JNCI 2000) BSC m.- Roszkowski TXT %42%6 m.25% (Lung Cancer 2000) BSC m.16%

NSCLC - Stage IV Gridelli, ASCO 2001 NAVELBINE remains the standard for elderly patients n= 698 median age= 74, 71% stage IV MILES study Phase III NVBGEMNVB + GEM OR18.5%17.3%20% Disease Control47.7%48.2%47% MS8.6 m6.5 m7.4 m 1-YS41%26%31%

NSCLC - Stage IV Which treatment for stage IV patients ? NVB 30 mg/m² D1, D8 every 3 weeks with platinumNVB25 mg/m²/w every CDDP100 mg D1 4 weeks NVB30 mg/m² D1,D8every CDDP80 mg/m² D1 3 weeks NVB30 mg/m² D1, D8every CBDCA300 mg D1 or AUC5 D1 3 weeks followed by consolidation with NVB mg/m²/w w/o platinumNVB25-30 mg/m² D1, D8every GEM1000 mg/m² D1, D8 4 weeks Patients candidate to poly CT Patients not candidate to poly CT