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STAGE IV

NSCLC. STAGE IV. Stage IV NAVELBINE : The pivotal drug GEMZAR : Main competitor TAXOL : Still often prescribed TAXOTERE : New comer. NSCLC Main Drugs. or. NVB - GEM. NVB single agent. Patients not candidate for poly CT. 1 st Line Metastatic NSCLC Stage IV patients.

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STAGE IV

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  1. NSCLC STAGE IV

  2. Stage IV NAVELBINE : The pivotal drug GEMZAR : Main competitor TAXOL : Still often prescribed TAXOTERE : New comer NSCLCMain Drugs

  3. or NVB - GEM NVB single agent Patients not candidate for poly CT 1st Line Metastatic NSCLCStage IV patients NVB - Platinum Patients candidate for poly CT

  4. NAVELBINE + CDDP = THE 1st LINE STANDARD TREATMENT

  5. 9 randomised phase III studies Around 2000 patients OR MS 1YS 25-44% 8-11.5 m. 33 (24)*-45% NVB+CDDP = the 1st line standard treatment EXPERIENCE EFFICACY 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

  6. NVB+CDDP vs TXL+CBDCA vs GEM+CDDPPhase III randomized trial RANDOMIZATION 201 patients, 81% stage IV NAVELBINE :25 mg/m² week x 8 weeks then every 2 weeks CISPLATIN :100 mg/m² D1 every 4 weeks 201 patients, 82% stage IV PACLITAXEL :225 mg/m² D1 CARBOPLATIN :AUC 6 D1, Q3w 205 patients, 81% stage IV GEMCITABINE :1250 mg/m² D1, D8 CISPLATIN :75 mg/m² D2 Q3w Scagliotti, JCO 2002

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

  8. NVB+CDDP vs TXL+CBDCA vs GEM+CDDPPhase III randomized trial TOLERANCE (G 3-4) 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 % of cycles % of patients * significant Scagliotti, JCO 2002

  9. NVB+CDDP vs TXT+CDDPPhase III randomized trial NVB 25 mg/m²/week TXT 75 mg/m² D1 TXT 75 mg/m² D1 CDDP 100 mg/m² D1 CDDP 75 mg/m² D1 CBDCA AUC6 D1 Q4w Q3w Q3w EFFICACY NVB-CDDP TXT- CDDPTXT-CBDCA n = 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% "TXT+CDDP did not result in a statistically significant superior survival compared to vinorelbine+cisplatin" NVB-CDDP : never overpassed by any new doublet Mattson, ESMO 2002 Taxotere – Prescribing information – Nov. 2002

  10. NVB-CDDP : a new schedulePhase III randomized trial Kakolyris, ASCO 2002 NVB 30 mg/m² D1, D8 TXT 100 mg/m² D1 CDDP 80 mg/m² D8 GEM 1000 mg/m² D1, D8 + G-CSF + G-CSF Q3w vs Q3w EFFICACY 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 3 week schedule : all the efficacy of NVB-CDDP

  11. 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) NAVELBINE + CDDP: always the best cost effectiveness ratio Clegg, Thorax 2002

  12. NVB-CDDPRecommended dose NVB 25 mg/m2 / week CDDP 100 mg/m2 D1 Every 4 weeks or NVB 30 mg/m2 D1, D8 CDDP 80 mg/m2 D1 Every 3 weeks

  13. Consolidation concept Duration of treatment: • 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)  To prolong the therapeutic benefit NVB 25-30 mg/m²/week until progression

  14. 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. Which 2nd line after NVB-CDDP 1st line ? Efficacy of single agent in 2nd line Ferrigno, Lung Cancer 2000; Huisman, JCO 2000

  15. Which 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

  16. Which competitors on the market ? • GEM-CDDP • TXL-CBDCA • TXT-CDDP

  17. Competitor: GEMZAR • 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

  18. Competitor: 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

  19. 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

  20. Competitor: GEMZARResults from phase III – GEM-CBDCA 5 studies, n= 617 Stage IV= 44-54% EFFICACY OR: 27-47% MS : 10.2-11.5 m 1YS : 36-44% GC> GEM > VBL-CDDP > MIP TOLERANCE (G3-4 %pts) Leucopenia : 2-32% Thrombocytopenia : 2-49% No severe clinical toxicities 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

  21. Competitor: TAXOL • Less present in the communication BUT interesting papers : Kosmidis – Schiller (ECOG 1594) – SWOG2still 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 ???

  22. Competitor: 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 / Myalgia Premedication required

  23. Competitor: TAXOLResults in phase III – TAXOL-Platinum • 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 !!!!

  24. Competitor: TAXOTERE • 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

  25. Competitor: 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%

  26. Competitor: TAXOTERE • 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)

  27. NVB-GEM NVB GEM 25-30 mg/m² D1, D8 1000 mg/m² D1, D8 every 3 weeks Phase III No. pts MS 1YS Gridelli 251 7.4 m. 31% Thompson 67 10.7 m. 42% Camps 177 8.1 m. 35% Tolerance WHO G3 % pts As effective as a platinumbased regimen Neutropenia: 14-19% Thrombocytopenia: 2-3% Camps, ECCO 2001; Thompson, ASCO 2001; Gridelli, ASCO 2002

  28. NVB-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

  29. About 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.

  30. n Age OR DC MS 1YS Gridelli-ELVISNVB 76 7420% 50% 6.5 m. 32% (JNCI 99)BSC 78 74 - - 4.8 m. 14% 0.03 Gridelli-MILESNVB 223 7418.5% 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. - 0.03 Roszkowski TXT 137 59 20% 42% 6 m. 25% (Lung Cancer 2000)BSC 70 59 - - 5.7 m. 16% 0.02 CompetitorsMono CT in 1st line NSCLC

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

  32. Which treatment for stage IV patients ? Patients candidate to poly CT 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 every CBDCA 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 not candidate to poly CT NVB 30 mg/m² D1, D8 every 3 weeks

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