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.

• 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


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)


• 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.


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.



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%


Ipilimumab

• Conclusions:

• Ipilimumab in combination with dacarbazine– improved overall survival in patients with

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)


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 )



Vemurafenib

Dacarbazine

Vemurafenib

Dacarbazine


Vemurafenib

Dacarbazine

Vemurafenib

• Adverse events:– arthralgia, rash, fatigue, alopecia, keratoacanthoma

or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea


Vemurafenib

• Conclusions: – improved rates of overall and progression-free

survival in patients with previously untreated melanoma with the BRAF V600E mutation.


update treatment of melanoma

Documents