Sur les nouveaux médicaments et les perspectives qu ils offrent (traitement à la carte et survie longue)

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1 Sur les nouveaux médicaments et les perspectives qu ils offrent (traitement à la carte et survie longue) Professeur Jean Trédaniel Unité de cancérologie thoracique Hôpital Saint-Louis

2 Comparison of Four Chemotherapy Regimens for Advanced Non Small-Cell Lung Cancer Schiller et al. NEJM 2002; 346: 92-98

3 NSCLC: l avenir? La chimiothérapie à la carte Les thérapies ciblées

4 Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non Small-Cell Lung Cancer NEJM 2004; 350:

5 DNA Repair by ERCC1 in Non Small-Cell Lung Cancer and Cisplatin-Based Adjuvant Chemotherapy NEJM :

6 Vinorelbine plus Cisplatin vs. Observation in Resected Non Small-Cell Lung Cancer NEJM 2005; 352:

7 Prognostic and Predictive Importance of p53 and RAS for Adjuvant Chemotherapy in Non Small-Cell Lung Cancer observation observation p53 p53 IHC IHC > > p53 IHC < J Clin Oncol 2007; 25: 5240

8 A Genomic Strategy to Refine Prognosis in Early-Stage Non Small-Cell Lung Cancer NEJM 2006; 355:

9 Cell 2000; 100: 57-70

10 Structure schématique des Récepteurs de la famille ErbB Bull Cancer 2006; hors série: 17-24

11 Bull Cancer 2007; 94 (Suppl FMC): F

12 Bull Cancer 2006; hors série: 17-24

13 Bull Cancer 2006; hors série: 17-24

14 Les récepteurs ErbB en tant que cibles «multi-sites» Récepteurs ErbB EGFR VEGF et VEGF-R les NIB les MAB les NIB les MAB Autres inhibiteurs erlotinib (Tarcéva ) cétuximab (Erbitux ) sorafénib (Nexavar ) bévacizumab (Avastin ) Thalidomide géfitinib (Iressa ) panitumumab (Vectibix ) sunitinib (Sutent ) Inhibiteurs des valatanib métalloprotéinases vandétanib Autres

15 Quelques exemples de molécules ciblant les récepteurs erbb

16 Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non Small-Cell Lung Cancer: A Phase III Trial INTACT 2 J Clin Oncol 2004; 22:

17 Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non Small-Cell Lung Cancer: A Phase III Trial INTACT 2 J Clin Oncol 2004; 22:

18 Erlotinib in Previously Treated Non Small-Cell Lung Cancer Previously treated pts after 1 or 2 lines chemotherapy n = 731 Erlotinib 150 mg / j Placebo NEJM 2005; 353:

19 Erlotinib in Previously Treated Non Small-Cell Lung Cancer NEJM 2005; 353:

20 Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) Lancet 2005; 366:

21 Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer) Lancet 2005; 366:

22 Comparison of hazard ratios from ISEL and BR21

23 Why gefitinib failed? Nature Reviews Cancer 7,

24 Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST).

25 Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST). gefitinib docetaxel n ORR (%) 9,1 7,6 HR = 1,22 (95%CI: 0,82 1,84) Median survival (mo) 7,6 8 1-year survival (%) HR = 1,02 (95%CI: 0,905 1,150) PFS (mo) 2,2 2,7 6 mo PFS (%) HR = 1,04

26 Gefitinib (IRESSA) versus docetaxel in patients with locally advanced or metastatic non-small cell lung cancer pre-treated with platinum-based chemotherapy: a randomized, open-label phase III study (INTEREST). gefitinib docetaxel Adverse event (%) 72,3 82,2 Serious adverse event (%) 3,2 18,2 Décès iatrogène (%) 0,8 2,1 Rash (%) 49,4 10,2 Diarrhée (%) 35 24,8 Alopécie (%) 3,2 35,5 Neurotoxicité (%) 6,7 23,9 Neutropénie fébrile (%) 1,2 10,1 Dry skin (%) 15,2 1,4 Conclusion: géfitinib, le retour?

27 Études de phase II évaluant le géfitinib ou l erlotinib chez des patients atteints d un CBNPC avec mutation de l EGFR

28 «Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer». 99 patients, randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (AUC = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32) treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months) bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns: minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. J Clin Oncol 2004;22:2184

29 Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) trial - E4599. previously untreated NON-SQUAMOUS NSCLC stage IIIB/IV pas d'hémoptysie macroscopique PS = 0/1 pas de pathologie thrombo-embolique ou hémorragique pas de métastase cérébrale P 200 mg/m2+ C AUC=6 every 3 weeks P 200 mg/m2+ C AUC=6 every 3 weeks + B 15 mg/kg d1 every 3 weeks n = 444 n = 434 Abst 4, ASCO 2005

30 Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) trial - E4599. IIIB 14 % 13 % neutropénie 16,4 % 24 % PC PCB p hémorragie 0,3 % 4,5 % < 0,01 HTA 0,7 % 6 % < 0,01 n tox grade (5 hémoptysies) CR 0 % 1,4 % PR 10 % 25,8 % ORR 10 % 27,2 % < 0,0001 PFS 4,5 mois 6,4 mois < 0,0001 MS 10,2 mois 12,5 mois 0, yr s 43,7 % 51,9 % 2-yr s 16,9 % 22,1 %

31 Paclitaxel Carboplatin Alone or with Bevacizumab for Non Small-Cell Lung Cancer Sandler et al. NEJM 2006; 355:

32 Paclitaxel Carboplatin Alone or with Bevacizumab for Non Small-Cell Lung Cancer Sandler et al. NEJM 2006; 355:

33 Paclitaxel Carboplatin Alone or with Bevacizumab for Non Small-Cell Lung Cancer Sandler et al. NEJM 2006; 355:

34 Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) trial - E4599. «PCB is now the ECOG reference standard for first line treatment of advanced non squamous nonsmall cell lung cancer»!!!

35 Science 2002; 297: 63-64

36 NSCLC stade IV: évolution schématique de la survie au fil du temps