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Update treatment of melanoma

Update treatment of melanoma. R4 陳三奇. 財團法人台灣癌症臨床研究發展基金會. Stage III. Stage III. Prognostic factor: the numbers of LNs. Stage IV. Systemic therapy for advanced or metastatic melanoma. Ipilimumab. CTLA-4 ( cytotoxic T-lymphocyte associated antigen 4 ) a negative regulator of T cells.

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Update treatment of melanoma

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  1. Update treatment of melanoma R4 陳三奇 財團法人台灣癌症臨床研究發展基金會

  2. Stage III Stage III

  3. Prognostic factor: the numbers of LNs

  4. Stage IV

  5. Systemic therapy for advanced or metastatic melanoma

  6. Ipilimumab • CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) • a negative regulator of T cells. • Ipilimumab: • IgG1 monoclonal Ab • Block CTLA-4 => Augments T cell activation and proliferation.

  7. Ipilimumab • 676 patients • unresectabe stage III or IV melanoma • With progressive disease while receiving treatment. • Randomized into (3:1:1 ) • A: Ipilimumab plus gp100. • B: Ipilimumab alone • C: Gp100 glone. NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma

  8. Median over all survival: (P<0.001) • Ipi+ gp100= 10.0 m • Ipi alone = 10.1 m • Gp 100 alone = 6.4 m Ipi Gp 100 Ipi + gp100 NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma

  9. Ipilimumab • Adverse events: • Ipilimumab group :Grade 3 or 4 immune-related adverse(10 – 15 %) • Gp100 alone: 3% . • 14 deaths • Related to the study drugs (2.1%) • Immune-related adverse events: 7 • Colitis, septicemia, bowel perforation, peritonitis, Guillain-Barre syndrome) NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma

  10. Conclusions: • Ipilimumab +/- gp100 peptide vaccine • improved overall survival in patients with previously treated metastatic melanoma. • Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma

  11. Dacarbazine • Dacarbazine: • the only chemotherapeutic agent approved by the FDA for the treatment of metastatic melanoma • response rate of 7 -12% • median overall survival of 5.6 - 7.8 months. NEJM 2011 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

  12. Ipilimumab • 502 patients • Untreated metastatic melanoma • Randomized into (1:1 ) • A: Ipilimumab (10mg/kg) plus dacarbazine. • B: Darcabazine (850mg/m2, q3w) alone. NEJM 2011 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

  13. Ipi + dacar Dacar+ placebo Ipi + dacar Dacar+ placebo NEJM 2011 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

  14. Ipilimumab • Median overall survival: (P<0.001) • Ipi + DTIC= 11.2 m • DTIC = 9.1 m • Adverse events, grade 3 or 4 : (P< 0.001) • Ipi + DTIC : 56% • (no drug related death or bowel perforation.) • DTIC = 27.5% NEJM 2011 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

  15. Ipilimumab • Conclusions: • Ipilimumab in combination with dacarbazine • improved overall survival in patients with previously untreated metastatic melanoma NEJM 2011 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma

  16. BRAF V600E • BRAF mutation: • in 40 to 60% of cutaneous melanomas • constitutive activation of downstream signaling through the MAPK pathway. • 90 %: substitution of glutamic acid for valine at codon 600 (BRAF V600E) • BRAF V600K and BRAF V600R.

  17. Vemurafenib (PLX4032) • A potent inhibitor of mutated BRAF. • Marked antitumor effects against melanoma cell lines with the BRAF V600E mutation. • Not against cells with wild-type BRAF. • Phase 1 trial :maximum tolerated dose to be 960 mg twice daily. • Phase 2 : response rate of 53%, with a median duration of response of 6.7 months. NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

  18. Vemurafenib • 675 patients • Untreated, metastatic melanoma with BRAF V600E mutation. • Randomized into (1:1 ) • A: Vemurafenib (960mg, oral twice daily). • B: Dacarbazine (1000mg/m2, q3w) NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

  19. Vemurafenib • 6 months, overall survival • Vemurafenib group: 84 % • Darcabazine group : 64 % • Vemurafenib • was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 ) NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

  20. Vemurafenib Dacarbazine Vemurafenib Dacarbazine NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

  21. Vemurafenib Dacarbazine NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

  22. Vemurafenib • Adverse events: • arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

  23. Vemurafenib • Conclusions: • improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

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