Melanoma genetics and treatment

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A summary about new treatments for melanoma, based in the diffrent genetic profile of this disease

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Melanoma genetics and treatment

  1. 1. A journey to the world of melanoma genetic and treatmentLorenzo Alonso. Medical Oncology
  2. 2. The Facts• Phase III vemurafenib vs DTIC: median OS 13,2 months vs 9,6 months(significant)• 12 months OS: vemurafenib 55% vs 43% for dacarbazine.• Duration of response limited due to development of resistance• Ipilimumab: objective response uncommon(10-20%). Median OS vs gp100 10 vs 6,4 months. In a second study vs DTIC 3 year estimated survival rates 21% vs 12% (HR 0,72).
  3. 3. Braf inhibitor resistance
  4. 4. Mutations “relevants” BRAF (40-70%) melanomas NRAS: 20% melanomas PTEN: 20-40% melanomas C-Kit: acral(36%), mucosas(39%) and CSD *((28%). GNAQ y GNA11: > 50% uveal melanomas. *CSD: Chronic sun damaged 9
  5. 5. C-Kit Mucosal, acral ( 2% each melanomas) and chronic sun damaged areas. Mutación mope important than amplificatión Drugs: Gleevec, Nilotinib, Dasatinib 10
  6. 6. 11
  7. 7. 12
  8. 8. “Killing” the “mad” BRAF loco Vemurafenib Dabrafenib 13
  9. 9. BREAK-3 Responses: Dabrafenib 50% DTIC 6% Median Progression-free survival: 5,1 vs 2,7 months for DabrafenibSquamous cell carcinomaVemurafenib 26%Dabrafenib 6% 14
  10. 10. N-RAS mutation (MEK 162)GNAQ
  11. 11. Lancet Oncology 2013; 14: 249 End-point response: 30patients 20%PR in NRAS mutated Previous treatment allowed: no MEK inh or Ipilimumab The most common grade 3-4 adverse event: an asymptomatic rise in CPK “Retinal events” also commons
  12. 12. MEK inhibitors.AZD6244: inhibe MEK1 y MEK2 .GSK1120212(trametinib)
  13. 13. METRIC: Trametinib vs chemotherapy (Braf mutated) Chemotherapy:DTIC or Taxol 47% chemotherapy arm crossed over to trametinib At least one previous regimen No Braf inh or Ipilimumab allowedResponse rate: 22% vs 8% Flaherty,K. NEJM 2012; 367:107
  14. 14. Dabrafenib (antiBRAF) alone or combined with trametinib(MEK inh) Flaherty,K, NEJM 2012;367: 1694
  15. 15. The practical path Melanoma diagnosis ECOG 0-1 Ipili o “slow” vemuraipili Braf no Braf mut mut Clinical vemura agressive
  16. 16. Braf: Vemurafenib.Dabrafenib MEK: trametinib. MEK 162 cKit: Imanitinib. Dasatinib. NRAS: MEK162 GNAQ: MEK inhCSD: chronic sundamagedUveal: GNAQ 55% GNA11 35%
  17. 17. Melanoma genetic variants and therapeuticAnatomicalsite Marker Drugs TrialsSkin: non- Braf (60%) Vemurafenib Phase IIIchronic sun Dabrafenib MEK inh:damaged trametinib NRAS(10%) MEK162 Phase IISkin: sun Kit (25%) Imatinibdamaged Braf (5%) DasatinibMucoses Kit (39%) Phase II NRAS (5%)Acral Kit (36%) Braf (15%) NRAS (10%)Uveal GNAQ MEK inh:trametinib
  18. 18. albamumabtrigafenib

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