AVANCÉES RÉCENTES EN CANCÉROLOGIE 19 MARS 2013

Transcription

1 AVANCÉES RÉCENTES EN CANCÉROLOGIE 19 MARS 2013

2 Je vais commencer par le mélanome malin, ce qui me permet de parler du traitement ciblé au niveau anomalies génétiques (vemurafenib) et système immunitaire (ipilimumab; anti- PD1 et anti-pdl1). Le traitement du cancer du sein permettra de mentionner les anticorps monoclonaux (trastuzumab et pertuzumab ) de même que le T-DM1. Je parlerai de la prostate pour mentionner les divers traitements hormonaux nouveaux, du colon (regorafenib) et du poumon (crizotinib) L'idée est de parler des récentes avenues thérapeutiques à travers des exemples.

3 Mélanome malin cutané Traitement chirurgical Traitement adjuvant Traitement de la maladie métastatique

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9 MÉLANOME MÉTASTATIQUE: immunothérapie - Interferon, Interleukin 2 - Ipilimumab (Yervoy)

10 Site Web pour cette image Figure 1: Ipilimumab stimulates antitumor immunity by blocking CTLA4,... nature.com Image taille réelle (Même taillex plus grand), 57KB Autres tailles Recherche par image Images similaires Type : GIF Les images peuvent être soumises à des droits d'auteur.

11 Kaplan Meier Curves for Overall Survival and Progression-free Survival in the Intention-to- Treat Population Hodi FS et al. N Engl J Med 2010;363:

12 Adverse Events in the Safety Population Hodi FS et al. N Engl J Med 2010;363:

13 Ipilimumab: particularités Réponse différente de la chimiothérapie classique: - réponse différée - aggravation des lésions avant réponse - période prolongée de maladie stable sans réponse objective Critères d évaluation: - immune related complete response - immune related partial response (50%) - immune related stable disease - immune related progressive disease (25%) évaluation à 4 semaines d intervalle

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15 Study Overview Releasing T cells from inhibitory control has been a strategy exploited by the anti CTLA-4 antibody ipilimumab. Now an antibody against a second checkpoint molecule, programmed death 1 (PD-1), has also shown activity against cancers, including non small-cell lung cancer.

16 Conclusions Anti PD-1 antibody produced objective responses in approximately one in four to one in five patients with non small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response.

17 Conclusions Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non small-cell lung cancer, melanoma, and renal-cell cancer.

18 Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal- cell carcinomas.

19 Dlugosz AA, Talpaz M. N Engl J Med 2009;361:

20 Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients.

21 Photographs of Lesions before and during Treatment in Two Patients with Locally Advanced Basal-Cell Carcinoma. Sekulic A et al. N Engl J Med 2012;366:

22 CANCER DU SEIN Chirurgie Radiothérapie Traitement médical: adjuvant et néoadjuvant métastatique

23 Correspondence between Molecular Class and Clinicopathological Features of Breast Cancer. Sotiriou C, Pusztai L. N Engl J Med 2009;360:

24 Étude NeoALTTO Étude néoadjuvante phase 3 Lapatinib (TKI ) + trastuzumab en comparaison avec ces molécules seules Rémission complète supérieure dans le groupe avec double inhibition 51,3-29,5-24,7%

25 Original Article Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer Sunil Verma, M.D., David Miles, M.D., Luca Gianni, M.D., Ian E. Krop, M.D., Ph.D., Manfred Welslau, M.D., José Baselga, M.D., Ph.D., Mark Pegram, M.D., Do-Youn Oh, M.D., Ph.D., Véronique Diéras, M.D., Ellie Guardino, M.D., Ph.D., Liang Fang, Ph.D., Michael W. Lu, Pharm.D., Steven Olsen, M.D., Ph.D., Kim Blackwell, M.D., for the EMILIA Study Group N Engl J Med Volume 367(19): November 8, 2012

26 Study Overview Women with metastatic breast cancer that had progressed during treatment with trastuzumab plus a taxane were assigned to lapatinib plus capecitabine or to trastuzumab emtansine. The response rate and survival were significantly better with trastuzumab emtansine.

27 Progression-free Survival, as Assessed by an Independent Review Committee. Verma S et al. N Engl J Med 2012;367:

28 Conclusions T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2- positive advanced breast cancer previously treated with trastuzumab and a taxane.

29 Original Article Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer José Baselga, M.D., Ph.D., Javier Cortés, M.D., Sung-Bae Kim, M.D., Seock-Ah Im, M.D., Roberto Hegg, M.D., Young-Hyuck Im, M.D., Laslo Roman, M.D., José Luiz Pedrini, M.D., Tadeusz Pienkowski, M.D., Adam Knott, Ph.D., Emma Clark, M.Sc., Mark C. Benyunes, M.D., Graham Ross, F.F.P.M., Sandra M. Swain, M.D., for the CLEOPATRA Study Group N Engl J Med Volume 366(2): January 12, 2012

30 Human Epidermal Growth Factor Receptor (HER) Family of Receptors and Therapeutic Agents Currently Available or in Development. Gradishar WJ. N Engl J Med 2012;366:

31 Study Overview Pertuzumab, an anti-her2 antibody, recognizes a different epitope of HER2 than does trastuzumab and behaves differently. In patients with metastatic breast cancer, the combination of the two antibodies plus docetaxel significantly increased progression-free survival.

32 Baselga J et al. N Engl J Med 2012;366: Overall Survival.

33 Adverse Events in the Safety Population. Baselga J et al. N Engl J Med 2012;366:

34 Conclusions The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects.

35 Original Article Everolimus in Postmenopausal Hormone- Receptor Positive Advanced Breast Cancer José Baselga, M.D., Ph.D., Mario Campone, M.D., Ph.D., Martine Piccart, M.D., Ph.D., Howard A. Burris, III, M.D., Hope S. Rugo, M.D., Tarek Sahmoud, M.D., Ph.D., Shinzaburo Noguchi, M.D., Michael Gnant, M.D., Kathleen I. Pritchard, M.D., Fabienne Lebrun, M.D., J. Thaddeus Beck, M.D., Yoshinori Ito, M.D., Denise Yardley, M.D., Ines Deleu, M.D., Alejandra Perez, M.D., Thomas Bachelot, M.D., Ph.D., Luc Vittori, M.Sc., Zhiying Xu, Ph.D., Pabak Mukhopadhyay, Ph.D., David Lebwohl, M.D., and Gabriel N. Hortobagyi, M.D. N Engl J Med Volume 366(6): February 9, 2012

36 Study Overview Resistance to hormone therapy through activation of cellular pathways involving mtor can develop in postmenopausal hormone-receptor positive breast cancer. Adding an mtor inhibitor to an aromatase inhibitor improved outcomes in patients who had disease progression during hormone therapy.

37 Kaplan Meier Plot of Progression-free Survival. Baselga J et al. N Engl J Med 2012;366:

38 Adverse Events Irrespective of Relationship to Study Treatment (with at Least 10% Incidence in the Everolimus Exemestane Group). Baselga J et al. N Engl J Med 2012;366:

39 Conclusions Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors.

40 Mechanism of Cell Death from Synthetic Lethality, as Induced by Inhibition of Poly(Adenosine Diphosphate [ADP] Ribose) Polymerase 1 (PARP1). Iglehart JD, Silver DP. N Engl J Med 2009;361:

41 Cancer de la prostate Chirurgie Radiothérapie: radium 233 Traitement médical: Hormonothérapie: classical ADT; abiraterone enzalutamide Chimiothérapie: docetaxel; carbazitaxel

42 Cancer de la prostate Chirurgie Radiothérapie: radium 233 Traitement médical: Hormonothérapie: classical ADT; abiraterone enzalutamide Chimiothérapie: docetaxel; carbazitaxel

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46 Original Article Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy Howard I. Scher, M.D., Karim Fizazi, M.D., Ph.D., Fred Saad, M.D., Mary-Ellen Taplin, M.D., Cora N. Sternberg, M.D., Kurt Miller, M.D., Ronald de Wit, M.D., Peter Mulders, M.D., Ph.D., Kim N. Chi, M.D., Neal D. Shore, M.D., Andrew J. Armstrong, M.D., Thomas W. Flaig, M.D., Aude Fléchon, M.D., Ph.D., Paul Mainwaring, M.D., Mark Fleming, M.D., John D. Hainsworth, M.D., Mohammad Hirmand, M.D., Bryan Selby, M.S., Lynn Seely, M.D., Johann S. de Bono, M.B., Ch.B., Ph.D., for the AFFIRM Investigators N Engl J Med Volume 367(13): September 27, 2012

47 Study Overview In a study involving nearly 1200 men with metastatic prostate cancer who had progressive disease after chemotherapy, enzalutamide, a novel androgen-receptor blocker, extended the median survival by nearly 5 months, as compared with placebo (18 months vs. 13 months).

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49 Kaplan Meier Estimates of Primary and Secondary End Points in the Intention-to-Treat Population. Scher HI et al. N Engl J Med 2012;367:

50 Adverse Events, According to Grade. Scher HI et al. N Engl J Med 2012;367:

51 Conclusions Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy.

52 Original Article Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy Charles J. Ryan, M.D., Matthew R. Smith, M.D., Ph.D., Johann S. de Bono, M.B., Ch.B., Ph.D., Arturo Molina, M.D., Christopher J. Logothetis, M.D., Paul de Souza, M.B., Ph.D., Karim Fizazi, M.D., Ph.D., Paul Mainwaring, M.D., Josep M. Piulats, M.D., Ph.D., Siobhan Ng, M.D., Joan Carles, M.D., Peter F.A. Mulders, M.D., Ph.D., Ethan Basch, M.D., Eric J. Small, M.D., Fred Saad, M.D., Dirk Schrijvers, M.D., Ph.D., Hendrik Van Poppel, M.D., Ph.D., Som D. Mukherjee, M.D., Henrik Suttmann, M.D., Winald R. Gerritsen, M.D., Ph.D., Thomas W. Flaig, M.D., Daniel J. George, M.D., Evan Y. Yu, M.D., Eleni Efstathiou, M.D., Ph.D., Allan Pantuck, M.D., Eric Winquist, M.D., Celestia S. Higano, M.D., Mary-Ellen Taplin, M.D., Youn Park, Ph.D., Thian Kheoh, Ph.D., Thomas Griffin, M.D., Howard I. Scher, M.D., Dana E. Rathkopf, M.D., for the COU-AA-302 Investigators N Engl J Med Volume 368(2): January 10, 2013

53 Study Overview Abiraterone has been approved as second-line chemotherapy in patients with metastatic castration-resistant prostate cancer. This study shows significant improvement in progression-free survival with abiraterone as first-line chemotherapy in these patients.

54 Conclusions Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer.

55 Tumeurs gastro-intestinales Chirurgie: RT +CT mieux que chirurgie seule néo-oesophage et gastro-oesophagien Trastuzumab: Ca gastrique Her2 Neu + Regorafenib: colon métastatique Bevacizumab: continuer au-delà de la progression; colon métastatique FOLFOX-Cetuximab: inefficace comme traitement adjuvant du colon stade 3

56 Study Overview Weekly chemotherapy and concurrent radiotherapy for 5 weeks before curative resection in patients with esophageal or esophagogastricjunction cancer resulted in a pathologically complete response in 29% of patients and doubled the median overall survival to 4 years.

57 Regorafenib (BAY , Fluoro-Sorafenib) is a multitarget inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 Etude phase 3 CORRECT : 760 patients en progression après tous traitements standard Regorafenib seul versus placebo Survie globale: 6,4 mois versus 5 mois

58 Cancers du poumon Chirurgie Radiothérapie Chimiothérapie TRAITEMENTS CIBLÉS: EGFR mutation: erlotinib; gefitinib ALK/EML4: crizotinib

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60 Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF ), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Survie: 1 an 77% 2 ans 64% patients traités par crizotinib ALK + 73% 33% patients non traités ALK + 49% 33% patients non traités ALK Crizotinib multitargeted drug bloque les proteines des genes ALK,ROS1,MEK

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62 Lymphomes folliculaire et à cellules à manteau Bendamustine-R supérieur à CHOP-R PFS de 69,5 comparé à 45 mois Survie globale inchangée

63 Lenalidomide maintenance M.M.

64 Carfilzomib: nouveau inhibiteur du proteasome Pomalidomide: nouveau immunomodulateur

65 Cancer de l ovaire Étude AURELIA: Cancer ovaire récurrent, platine-résistant Bev+CT supérieur à CT seule Progression maladie après 6,7 mois comparé à 3,4mois

66 Study Overview Incorporating bevacizumab in a chemotherapy regimen (7.5 mg/kg every 3 weeks for five or six cycles) and then continuing bevacizumab alone for a total of 12 months of treatment extended progression-free survival in advanced and high-risk early-stage ovarian cancer.

67 Conclusions The use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer.

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69 Cancer de la thyroïde Carcinome médullaire de la thyroïde: carbozantinib inhibe les protéines MET, RET et VEGF récepteur 2 Progression de 4 (placebo) mois à 11,2 mois Carcinome métastatique thyroïde RAI resist selumetinib bloque MEK protéine

70 Original Article Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing Marco Gerlinger, M.D., Andrew J. Rowan, B.Sc., Stuart Horswell, M.Math., James Larkin, M.D., Ph.D., David Endesfelder, Dip.Math., Eva Gronroos, Ph.D., Pierre Martinez, Ph.D., Nicholas Matthews, B.Sc., Aengus Stewart, M.Sc., Patrick Tarpey, Ph.D., Ignacio Varela, Ph.D., Benjamin Phillimore, B.Sc., Sharmin Begum, M.Sc., Neil Q. McDonald, Ph.D., Adam Butler, B.Sc., David Jones, M.Sc., Keiran Raine, M.Sc., Calli Latimer, B.Sc., Claudio R. Santos, Ph.D., Mahrokh Nohadani, H.N.C., Aron C. Eklund, Ph.D., Bradley Spencer-Dene, Ph.D., Graham Clark, B.Sc., Lisa Pickering, M.D., Ph.D., Gordon Stamp, M.D., Martin Gore, M.D., Ph.D., Zoltan Szallasi, M.D., Julian Downward, Ph.D., P. Andrew Futreal, Ph.D., and Charles Swanton, M.D., Ph.D. N Engl J Med Volume 366(10): March 8, 2012

71 Study Overview Genetic analysis was applied to different regions of renal-cell cancers. The lesions noted in the tumor were not found in every sample, and regions of the tumor had different gene-expression patterns. This suggests that extrapolation from results of a single biopsy may be problematic.

72 Conclusions Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection.

73 CONCLUSION La bendamustine est le seul agent chimiothérapeutique discuté. L ère du traitement ciblé, personnalisé, basé sur les progrès de la biologie est définitivement arrivée.