. .. Conclusion,

. .. Bibliographie,

. .. Annexes,

. .. Serment-d'hippocrate,

, ©Les cancers en France, 2015.

H. Davies, G. R. Bignell, and C. Cox, Mutations of the BRAF gene in human cancer, Nature, vol.417, issue.6892, pp.949-54, 2002.

C. Robert and C. Mateus, Traitement du mélanome par les inhibiteurs de BRAF, Correspondances en Onco-Théranostic, vol.1, issue.1, pp.24-28, 2012.

I. V. Fedorenko, K. Paraiso, and K. Smalley, Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma, Biochem. Pharmacol, vol.82, pp.201-209, 2011.
DOI : 10.1016/j.bcp.2011.05.015

URL : http://europepmc.org/articles/pmc4001781?pdf=render

K. T. Flaherty and G. Mcarthur, BRAF, a target in melanoma, Cancer, vol.116, pp.4902-4913, 2010.
DOI : 10.1002/cncr.25261

URL : https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.25261

G. Maurer, B. Tarkowski, and M. Baccarini, Raf kinases in cancer-roles and therapeutic opportunities, Oncogene, vol.30, pp.3477-3488, 2011.
DOI : 10.1038/onc.2011.160

URL : https://www.nature.com/articles/onc2011160.pdf

A. Ribas, K. B. Kim, and L. M. Schuchter, BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutation-positive melanoma, J Clin Oncol, vol.29, pp.8509-8509, 2011.

P. B. Chapman, A. Hauschild, and C. Robert, Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation, N Engl J Med, vol.364, pp.2507-2516, 2011.

P. B. Chapman, C. Robert, and J. Larkin, Vemurafenib in patients with BRAF V600 mutationpositive metastatic melanoma: final overall survival results of the randomized BRIM-3 study, Annals of Oncology, vol.28, pp.2581-2587, 2017.

A. Hauschild, J. J. Grob, and L. V. Demidov, Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial, Lancet, vol.380, pp.358-65, 2012.
DOI : 10.1016/s0140-6736(12)60868-x

K. Trunzer, A. C. Pavlick, and L. Schuchter, Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma, J Clin Oncol, vol.31, pp.1767-1774, 2013.

J. S. Wilmott, V. Tembe, and J. R. Howle, Intratumoral molecular heterogeneity in a BRAFmutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine, Mol Cancer Ther, vol.11, pp.2704-2708, 2012.

R. S. Lo, Receptor tyrosine kinases in cancer escape from BRAF inhibitors, Cell Res, vol.22, pp.945-947, 2012.
DOI : 10.1038/cr.2012.78

URL : https://www.nature.com/articles/cr201278.pdf

J. A. Mccubrey, L. S. Steelman, and S. L. Abrams, Emerging MEK inhibitors, Expert Opin Emerg Drugs, vol.15, issue.2, pp.203-226, 2010.

G. V. Long, D. L. Stroyakovsky, and H. Gogas, COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma, Conference: Annual Meeting of the, 2015.

J. Larkin, P. A. Ascierto, and B. Dréno, Combined Vemurafenib and Cobimetinib in BRAFMutated Melanoma, N Engl J Med, vol.371, pp.1867-1876, 2014.
DOI : 10.1056/nejmoa1408868

URL : http://espace.library.uq.edu.au/view/UQ:365371/UQ365371_OA.pdf

R. Dummer, P. A. Ascierto, and H. J. Gogas, Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial, Lancet, vol.19, pp.603-615, 2018.

R. Dummer, P. A. Ascierto, and H. J. Gogas, Overall survival in COLUMBUS: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) vs vemurafenib (VEM) or enco in BRAFmutant melanoma, J Clin Oncol, vol.36, 2018.

B. Moura, K. Homicsko, and G. Berthod, Nouvelles immunothérapies du mélanome: mécanismes d'action, efficacité et prise en charge des toxicités, Rev Med Suisse, vol.11, pp.1108-1122, 2015.

F. S. Hodi, S. J. O'day, and D. F. Mcdermott, Improved survival with ipilimumab in patients with metastatic melanoma, N Engl J Med, vol.363, issue.8, pp.711-734, 2010.

D. Schadendorf, F. S. Hodi, and C. Robert, Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma, J Clin Oncol, vol.33, pp.1889-1894, 2015.

E. Maverakis, L. A. Cornelius, and G. M. Bowen, Metastatic Melanoma -A Review of Current and Future Treatment Options, Acta Derm Venereol, vol.95, pp.516-524, 2015.

C. Robert, G. V. Long, and B. Brady, Nivolumab in Previously Untreated Melanoma without BRAF Mutation, N Engl J Med, vol.372, pp.320-330, 2015.

J. Larkin, V. Chiarion-sileni, and R. Gonzalez, Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma, N Engl J Med, vol.373, pp.23-34, 2015.

J. Schachter, A. Ribas, and G. V. Long, Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, openlabel phase 3 study (KEYNOTE-006), Lancet, vol.390, pp.1853-1862, 2017.

M. A. Postow, J. Chesney, and A. C. Pavlick, Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma, N Engl J Med, vol.372, pp.2006-2017, 2015.

J. S. Weber, G. Gibney, and R. J. Sullivan, Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial, Lancet Oncol, vol.17, issue.7, pp.943-955, 2016.

C. Garbe, T. K. Eigentler, U. Keilholz, A. Hauschild, and J. M. Kirkwood, Systematic review of medical treatment in melanoma: current status and future prospects, Oncologist, vol.16, pp.5-24, 2011.

C. Robert, J. Schachter, and G. V. Long, Pembrolizumab versus ipilimumab in advanced melanoma, N Engl J Med, vol.372, issue.26, pp.2521-2532, 2015.

A. Ribas, O. Hamid, and A. Daud, Association of pembrolizumab with tumor response and survival among patients with advanced melanoma, JAMA, vol.315, pp.1600-1609, 2016.

D. S. Shin, J. M. Zaretsky, and H. Escuin-ordinas, Primary resistance to PD-1 blockade mediated by JAK1/2 mutations, Cancer Discov, vol.7, issue.2, pp.188-201, 2017.

J. M. Zaretsky, A. Garcia-diaz, and D. S. Shin, Mutations associated with acquired resistance to PD-1 blockade in melanoma, N Engl J Med, vol.375, issue.9, pp.819-848, 2016.

J. S. Weber, R. R. Kudchadkar, and B. Yu, Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or naïve melanoma, J Clin Oncol, vol.31, pp.4311-4318, 2013.

P. Prithviraj, G. Mcarthur, and V. Atkinson, Updated efficacy and toxicity of treatment with anti-CTLA-4 antibody ipilimumab in metastatic melanoma patients previously treated with anti-PD-1 therapy, Journal for ImmunoTherapy of Cancer, vol.3, issue.2, p.126, 2015.

A. Jacobsoone-ulrich, P. Jamme, and S. Alkeraye, Ipilimumab in anti-PD1 refractory metastatic melanoma: a report of eight cases, Melanoma Res, vol.26, pp.153-159, 2016.

S. Bowyer, P. Prithviraj, and P. Lorigan, Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy, Br J Cancer, vol.114, issue.10, pp.1084-1093, 2016.

F. Aya, L. Gaba, and I. Victoria, Ipilimumab after progression on anti-PD-1 treatment in advanced melanoma, Future Oncol, vol.12, issue.23, pp.2683-2691, 2016.

L. Zimmer, S. Apuri, and Z. Eroglu, Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma, Eur J Cancer, vol.75, pp.47-55, 2017.

G. V. Long, C. Robert, and A. Arance, Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma in KEYNOTE-006, Eur J Cancer, vol.72, issue.1, pp.128-137, 2017.

Y. Fujisawa, K. Yoshino, and A. Otsuka, Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab : analysis of 60 japanese patients, J Dermatol Sci, vol.89, issue.1, pp.60-66, 2017.

M. Sato, H. Uhara, H. Koga, and R. Okuyama, Efficacy and toxicity of ipilimumab used after nivolumab in patients with melanoma, J Dermatol, 2018.

C. M. Balch, J. E. Gershenwald, and S. J. Soong, Final version of 2009 AJCC melanoma staging and classification, J Clin Oncol, vol.27, pp.6199-6206, 2009.

E. A. Eisenhauer, P. Therasse, and J. Bogaerts, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eur J Cancer, vol.45, issue.2, pp.228-275, 2009.

S. G. Downey, J. A. Klapper, and F. O. Smith, Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade, Clin Cancer Res, vol.13, issue.1, pp.6681-6688, 2007.

A. Aboudaram, A. Modesto, and L. Chaltiel, Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination, Melanoma Research, vol.27, pp.485-491, 2017.

M. A. Davies, P. Liu, and S. Mcintyre, Prognostic factors for survival in melanoma patients with brain metastases, Cancer, vol.117, pp.1687-96, 2011.

S. Kelderman, B. Heemskerk, and H. Van-tinteren, Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma, Cancer Immunol Immunother, vol.63, pp.449-458, 2014.

P. Tétu, J. Mangana, and R. Dummer, Benefit of the nivolumab and ipilimumab combination in pretreated advanced melanoma, Eur J Cancer, pp.1-3, 2018.

M. C. Kirchberger, A. Hauschild, G. Schuler, and L. Heinzerling, Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma, Eur J Cancer, vol.65, pp.182-184, 2016.

S. Ugurel, F. Kiecker, and S. Fröhling, Fulminant response to combined checkpoint inhibition with ipilimumab plus nivolumab after failure of nivolumab monotherapy in metastatic melanoma, Eur J Cancer, vol.83, pp.142-147, 2017.

L. Spain, T. Schmid, M. Gore, and J. Larkin, Efficacy of the combination of ipilimumab and nivolumab following progression on pembrolizumab in advanced melanoma with poor risk features, Eur J Cancer, vol.75, pp.243-247, 2017.

R. Garje, A. Chennamadhavuni, and S. Bell, Clinical parameters predicting response and outcomes to immunotherapy in metastatic cancers, J Clin Oncol, vol.36, 2018.

D. Olson, J. J. Luke, and S. Hallmeyer, Phase II trial of pembrolizumab (pembro) plus 1

, mg/kg ipilimumab (ipi) immediately following progression on anti-PD-1 Ab in melanoma

, J Clin Oncol, vol.36, 2018.

P. A. Ascierto, I. Melero, and S. Bhatia, Initial efficacy of anti-lymphocyte activation gene-3 (anti-LAG-3

, BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti-PD-1/PD-L1 therapy, J Clin Oncol, vol.35, 2017.

M. C. Kirchberger, B. Schilling, S. Haferkamp, A. Bosserhoff, G. Schuler et al., Can checkpoint inhibitor therapy improve response to chemotherapy?, J Clin Oncol, vol.35, 2017.

J. V. Aguilera, J. Paludo, and A. Bangalore, Chemoimmunotherapy combination after PD-1 inhibitor failure to improve clinical outcomes in metastatic melanoma patients, J Clin Oncol, vol.36, 2018.

P. D. Leger, S. Rothschild, E. Castellanos, R. N. Pillai, S. J. York et al., Response to salvage chemotherapy following exposure to immune checkpoint inhibitors in patients with non-small cell lung cancer, J Clin Oncol, vol.35, 2017.

S. S. Agarwala, S. J. Moschos, and M. L. Johnson, Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma progressing on or after a PD-1/L1 blocking antibody, J Clin Oncol, vol.36, 2018.

A. Diab, S. Rahimian, and C. L. Haymaker, A phase 2 study to evaluate the safety and efficacy of Intratumoral (IT) injection of the TLR9 agonist IMO-2125 (IMO) in combination with ipilimumab (ipi) in PD-1 inhibitor refractory melanoma, J Clin Oncol, vol.36, 2018.

C. Y. Xia, D. Y. Wang, and R. Mason, Activity of targeted therapy after failure of first-line immunotherapy in BRAF-mutant metastatic melanoma, J Clin Oncol, vol.36, 2018.

K. Saab, M. Mooradian, and D. Y. Wang, Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who have received PD-1 based therapy, J Clin Oncol, vol.36, 2018.

, Tableau 3 Taux de réponses objectives, de maladies stables et d'effets indésirables sévères parmi les neuf publications disponibles sous ipilimumab après anti-PD-1

, En présence des Maîtres de cette FACULTE et de mes chers CONDISCIPLES, je promets et je jure d'être fidèle aux lois de l'Honneur et de la Probité dans l

, Admis dans l'intérieur des maisons, mes yeux ne verront pas ce qui s'y passe, ma langue taira les secrets qui me seront confiés et mon état

, Respectueux et reconnaissant envers mes MAÎTRES, je rendrai à leurs enfants l'instruction que j'ai reçue de leurs pères

, Que les HOMMES m'accordent leur estime si je suis fidèle à mes promesses. Que je sois couvert d'OPPROBRE et méprisé de mes confrères si j'y manque

, Au moment d'être admis(e) à exercer la médecine, je promets et je jure d'être fidèle aux lois de l'honneur et de la probité

, Mon premier souci sera de rétablir, de préserver ou de promouvoir la santé dans tous ses éléments, physiques et mentaux

, Je respecterai toutes les personnes, leur autonomie et leur volonté, sans aucune discrimination selon leur état ou leurs convictions. J'interviendrai pour les protéger si elles sont affaiblies, vulnérables ou menacées dans leur intégrité ou leur dignité. Même sous la contrainte

, J'informerai les patients des décisions envisagées, de leurs raisons et de leurs

, Admis(e) dans l'intimité des personnes, je tairai les secrets qui me seront confiés