Melanoma genetic variants and targeted therapies
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This document summarizes genetic markers and targeted therapies for melanoma. It notes that BRAF mutations are present in 40-70% of melanomas and that drugs like vemurafenib and dabrafenib that target mutated BRAF have shown improved survival compared to chemotherapy in clinical trials. For melanomas with NRAS or KIT mutations, drugs targeting the MEK pathway or KIT, respectively, are under investigation. The document also reviews genetic markers and potential targeted therapies for different anatomical sites of melanoma like the skin, mucosa, and uveal melanoma.
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Melanoma genetic variants and targeted therapies
- 3. A journey to the world of melanoma genetic and treatment Lorenzo Alonso. Medical Oncology
- 4. 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).
- 9. 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
- 10. C-Kit Mucosal, acral ( 2% each melanomas) and chronic sun damaged areas. Mutación mope important than amplificatión Drugs: Gleevec, Nilotinib, Dasatinib 10
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- 13. “Killing” the “mad” BRAF loco Vemurafenib Dabrafenib 13
- 14. BREAK-3 Responses: Dabrafenib 50% DTIC 6% Median Progression-free survival: 5,1 vs 2,7 months for Dabrafenib Squamous cell carcinoma Vemurafenib 26% Dabrafenib 6% 14
- 15. N-RAS mutation (MEK 162) GNAQ
- 17. 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
- 18. MEK inhibitors .AZD6244: inhibe MEK1 y MEK2 .GSK1120212(trametinib)
- 19. 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 allowed Response rate: 22% vs 8% Flaherty,K. NEJM 2012; 367:107
- 20. Dabrafenib (antiBRAF) alone or combined with trametinib(MEK inh) Flaherty,K, NEJM 2012;367: 1694
- 21. The practical path Melanoma diagnosis ECOG 0-1 Ipili o “slow” vemura ipili Braf no Braf mut mut Clinical vemura agressive
- 22. Braf: Vemurafenib.Dabrafenib MEK: trametinib. MEK 162 cKit: Imanitinib. Dasatinib. NRAS: MEK162 GNAQ: MEK inh CSD: chronic sun damaged Uveal: GNAQ 55% GNA11 35%
- 23. Melanoma genetic variants and therapeutic Anatomical site Marker Drugs Trials Skin: non- Braf (60%) Vemurafenib Phase III chronic sun Dabrafenib MEK inh: damaged trametinib NRAS(10%) MEK162 Phase II Skin: sun Kit (25%) Imatinib damaged Braf (5%) Dasatinib Mucoses Kit (39%) Phase II NRAS (5%) Acral Kit (36%) Braf (15%) NRAS (10%) Uveal GNAQ MEK inh:trametinib