A journey to the world of melanoma genetic and treatment

Lorenzo Alonso. Medical Oncology

A journey to the world of melanoma genetic and treatment

Lorenzo Alonso. Medical Oncology

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).

Braf inhibitor resistanceBraf inhibitor resistance

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

10

C-Kit

Mucosal, acral ( 2% each melanomas) and chronic sun damaged areas.

Mutación mope important than amplificatión

Drugs: Gleevec, Nilotinib, Dasatinib

11

12

13

“Killing” the “mad” BRAF loco

Vemurafenib

Dabrafenib

14

Responses: Dabrafenib 50%

DTIC 6%

Median Progression-free survival:

5,1 vs 2,7 months for Dabrafenib

Responses: Dabrafenib 50%

DTIC 6%

Median Progression-free survival:

5,1 vs 2,7 months for Dabrafenib

Squamous cell carcinoma

Vemurafenib 26%

Dabrafenib 6%

Squamous cell carcinoma

Vemurafenib 26%

Dabrafenib 6%

BREAK-3BREAK-3

N-RAS mutation

(MEK 162)

GNAQ

Lancet Oncology 2013; 14: 249Lancet 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

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

MEK inhibitors

.AZD6244: inhibe MEK1 y MEK2.GSK1120212(trametinib)

METRIC: Trametinib vs chemotherapy (Braf mutated)

Flaherty,K.

NEJM 2012; 367:107

Flaherty,K.

NEJM 2012; 367:107

Chemotherapy:DTIC or Taxol

47% chemotherapy arm crossed over to trametinib

At least one previous regimen

No Braf inh or Ipilimumab allowed

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%Response rate: 22% vs 8%

Dabrafenib (antiBRAF) alone or combined with trametinib(MEK inh)

Flaherty,K, NEJM 2012;367: 1694

The practical path

Melanoma diagnosisMelanoma diagnosis

ECOG 0-1ECOG 0-1

Braf mutBraf mut

“slow”“slow”

Clinical

agressive

Clinical

agressive

vemuravemura

Ipili o

vemura

Ipili o

vemura

Braf no mutBraf no mut

ipiliipili

Braf: Vemurafenib.Dabrafenib

MEK: trametinib. MEK 162

cKit: Imanitinib. Dasatinib.

NRAS: MEK162

GNAQ: MEK inh

Uveal: GNAQ 55%

GNA11 35%

CSD: chronic sun damaged

Melanoma genetic variants and therapeutic

Anatomical site

Marker Drugs Trials

Skin: non-chronic sun damaged

Braf (60%)

NRAS(10%)

Vemurafenib

DabrafenibMEK inh: trametinib

MEK162

Phase III

Phase II

Skin: sun damaged

Kit (25%)

Braf (5%)Imatinib

Dasatinib

Mucoses Kit (39%)NRAS (5%)

Phase II

Acral Kit (36%)

Braf (15%)

NRAS (10%)

Uveal GNAQ MEK inh:trametinib

trigafenibtrigafenib

albamumabalbamumab