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Locally advanced non resectable disease (III A non resectable, III B , bulky N2)

NSCLC. CT and RT combination. Locally advanced non resectable disease (III A non resectable, III B , bulky N2). Chemotherapy + radiotherapy. 3 modalities of administration. Sequential CT-RT Concomitant CT-RT Radiosensitization. Stage IIIB RT/CT

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Locally advanced non resectable disease (III A non resectable, III B , bulky N2)

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  1. NSCLC CT and RT combination Locally advanced non resectable disease (IIIA non resectable, IIIB, bulky N2)

  2. Chemotherapy + radiotherapy 3 modalities of administration • Sequential CT-RT • Concomitant CT-RT • Radiosensitization

  3. Stage IIIB RT/CT NAVELBINE : Well established VP 16/CDDP : Still often prescribed GEMZAR : Re-entering ? TAXOL : Well established TAXOTERE : New comer NSCLCMain drugs

  4. Efficacy of NVB as a radiosensitizer Garst study Phase IIn= 36 inoperable pts NVB 4 mg/m²/day 2 hours before RT + 60 Gy EFFICACY OR: 56% MS : 20.7 m 1YS : 59% 2YS : 35% TOLERANCE (G3-4 %pts) Oesophagitis : 14/5% Radiation dermatitis : 8% Radiation pneumonitis : 3% NVB: Highly effective radiosensitizer also well tolerated Garst, ASCO 2002

  5. 0.006 Efficacy of Navelbine + CDDPin sequential CT-RT OR MS Distant Survivalafter CT after RT-CT relapses Felip 48 % - 13 m - - (n = 33) Viallet 46 % 74 % 12,2 m 3 YS : 26 %(n = 42) 24,2 m 66,7 % 22 %for responders non resp. responder Zatloukal* - 47 % 13,2 m - -(n = 50) Ishikura - 83 % not reached - 1 YS : 68 %(n = 30) 2 YS : 58 % Mornex* - 71 % 13,8 m - 1 YS : 56 % 2 YS : 23 % * Sequential arm Felip, ASCO 97; Viallet, Cancer 99; Zatloukal, ASCO 02; Ishikura, ASCO 02, Mornex, ECCO 01

  6. Tolerance of Navelbine + CDDPin sequential CT-RT Phase II studies WHO G/4, % ptsSequential NPRT Neutropenia38-88% Febrile Neutropenia2-12%rare complications Thrombocytopenia4-7%no risk of haemorrage Oesophagitis 1-17% Pneumonitis1-10% Good tolerance profile: no risk of delayed RT Zatloukal, ASCO 02; Viallet, Cancer 99; Felip, ASCO 97; Mornex, ECCO 01; Ishikura ASCO 02

  7. EFFICACY Arm 1 Arm 2 OR: 71% 63% MS : 13.8 m. 15 m. 1YS : 56% 56% NVB-CDDP experience in sequential CT-RTPhase III trial Mornex study n = 207 (24% IIIA, 76% IIIB) Arm 1: NVB-CDDP x 3 cycles  RT x 66 Gys Arm 2: VP16-CDDP x 2 cycles + RT x 66 Gys NVB-CDDP Efficacy confirmed in Phase III trial Mornex, Eur. J. Cancer, 2001

  8. NVB-CDDP sequential vs concomitantRandomized phase II studyStage IIIA-B Patients SEQUENTIAL NVB-CDDP  RT CONCOMITANT NVB-CDDP + RT Zatloukal study n 47 51 OR 47% 80% MS 13.2 months 20.6 months 2YS 15% 42% G 3-4 neutropenia 39.6% 64.7% G 3-4 esophagitis 4.2% 17.6% p = 0.02 p = 0.02 Zatloukal, ASCO 2002

  9. 0.02 0.001 Sequential or concomitant CT-RT Cox study Distant metastases - free survival at 3 years Loco-regional recurrence - free survival at 3 years Sequential CT-RT 65% 28% Concomitant CT-RT 42% 59% Induction CT followed by concomitant CT-RT is suggested Cox, Lung Cancer 2000

  10. NVB-CDDP in concomitant RT-CT RT 2 Gy/D (66 Gy) CALGB study (Vokes) D1 D22 D43 D64 D85 2 cycles of 3 weeks 2 cycles of 3 weeks INDUCTION CT CONCOMITANT CT-RT C1 + C2 C3 + C4 NVB 25 mg/m² 15 mg/m² D1, D8 + CDDP* (n= 58) D1, D8, D15 C1 D1, D8 C2 TXL 225 mg/m² D1 135 mg/m² D1 + CDDP* (n= 60) GEM 1250 mg/m² D1, D8 600 mg/m² D1, D8+ CDDP* (n= 63) 60%IIIB 48%IIIB 37%IIIB * CDDP used at 80mg/m² D1 in all arms Vokes, JCO 2002

  11. NVB-CDDP in concomitant RT-CTRandomized phase II study CALGB study (Vokes) OR AFTER OR AFTER MEDIAN 1-YEAR INDUCTION CT CONCO. CT-RT SURVIVAL SURVIVAL NVB - CDDP 44% 73% 17.7 months 65% TXL - CDDP 33% 67% 14.8 months 62% GEM - CDDP 40% 74% 18.3 months 68% Vokes, JCO 2002

  12. NVB-CDDP in concomitant RT-CT Tolerance WHO G3-4 % pts (concomitant phase) NEUTROPENIA THROMBO- OESOPHAGITIS CYTOPENIA NVB - CDDP 27% 2% 25% TXL - CDDP 53% 6% 39% GEM - CDDP 51% 56% 52% NVB-CDDP = the best efficacy / tolerability ratio. Vokes, JCO 2002

  13. Which competitors on the market ? • TXL • GEM • VP 16 • TXT

  14. Competitor: Taxol TXL-Platinum NVB-CDDP 9 studies (1 randomised) 11 studies (3 randomised) n= 417 n= 470 EFFICACY SequentialORCT = 23-30% ORCT-RT = 48-87% ORCT = 46-57% ORCT-RT = 47-83% MS= 12 m MS = 12.2 - > 16 m ConcomitantORCT = 24-53% ORCT-RT = 50-78% ORCT = 41-71% ORCT-RT = 68-80% MS= 12-26 m MS = 13.2-20.6 m TOXICITY* Neutropenia14-100% 25-88%FN 8-25% 2-12%Oesophagitis9-40% 1-24%Pneumonitis3-26% 1-10% NVB - CDDP : Major induction results Less Toxic Clear recommended schedules *G3-4, % pts

  15. Competitor: Gemcitabine GEM-CDDP NVB-CDDP 5 studies (1 randomised) 11 studies (3 randomised) n= 194 n= 470 EFFICACY SequentialORCT = 67% ORCT-RT = 63% ORCT = 46-57% ORCT-RT = 47-83% MS= 13 m MS = 12.2 - > 16 m ConcomitantORCT = 40-45% ORCT-RT = 64-74% ORCT = 41-71% ORCT-RT = 68-80% MS= 18.3 m MS = 13.2-20.6 m TOXICITY* Thrombocyto.15-56% 0-7%RBC 15% -Fatigue 30% 6-10%Oesophagitis10-52% 1-24%Pneumomitis18% 1-10% Need for 4 week wash-out before RT NVB - CDDP : More feasible Less Toxic Clear recommended schedules *G3-4, % pts

  16. Competitor: VP16 VP16-CDDP NVB-CDDP 2 studies 11 studies (3 randomised) n= 121 n= 470 EFFICACY SequentialORCT = ND ORCT-RT = 41-68% ORCT = 46-57% ORCT-RT = 47-83% MS= 8.2-14 m MS = 12.2 - > 16 m ConcomitantNo experience documented ORCT = 41-71% ORCT-RT = 68-80% MS = 13.2-20.6 m TOXICITY* Neutropenia12% cy. 25-88%FN 5% 2-12%Thrombocyto. 24% cy. 0-7%RBC transfus. 22% -Oesophagitis ND 1-24% NVB - CDDP : The benefit of a new combination with a major drug in NSCLC *G3-4, % pts

  17. Competitor: Taxotere TXT-Platinum NVB-CDDP 3 studies 11 studies (3 randomised) n= 213 n= 470 EFFICACY SequentialORCT = 43% ORCT-RT = 71% ORCT = 46-57% ORCT-RT = 47-83% MS= ND MS = 12.2 - > 16 m ConcomitantORCT = 43-52% ORCT-RT = 68-74% ORCT = 41-71% ORCT-RT = 68-80% MS= 15 m MS = 13.2-20.6 m TOXICITY* Neutropenia46% cy. 25-88%FN 3-11% cy. 2-12%Oesophagitis 7-15% 1-24% NVB - CDDP : Major experience in stage III patients No missing data *G3-4, % pts

  18. Recommended dose CT-RT SEQUENTIAL NVB 25-30 mg/m² D1, D8 followed by RT 60 Gy CDDP 80 mg/m² D1 3 cycles of 3 weeks CONCOMITANT NVB 25 mg/m² D1, D8, D15 C1 + NVB 15 mg/m² D1, D8 C3-4 25 mg/m² D1, D8 C2 CDDP 80 mg/m² D1 CDDP 80 mg/m² D1 + RT 66 Gy 2 cycles of 3 weeks 2 cycles of 3 weeks Induction Concomitant

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