update treatment of melanoma
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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. - PowerPoint PPT PresentationTRANSCRIPT
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.
• Ipilimumab:– IgG1 monoclonal Ab– Block CTLA-4=> Augments T cell activation and proliferation.
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
• Median over all survival: (P<0.001) – Ipi+ gp100= 10.0 m– Ipi alone = 10.1 m– Gp 100 alone = 6.4 m
NEJM 2010 Improved survival with ipilimumab in patients with metastatic melanoma
Ipi + gp100
IpiGp 100
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
• 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
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
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
NEJM 2011 Ipilimumab plus dacarbazine for previously untreated metastatic melanoma
Ipi + dacar
Dacar+ placebo
Ipi + dacar
Dacar+ placebo
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
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
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.
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
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
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
NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Vemurafenib
Dacarbazine
Vemurafenib
Dacarbazine
NEJM 2011 Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Vemurafenib
Dacarbazine
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
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