RAMB - Setembro 2017

reatment

advanced

melanoma

– A

changing

landscape

ssoc

ras

2017; 63(9):814-823

817

tion).

In another 20% of the tumors harboring a BRAF

mutation, an alternate substitution of lysine for valine

occurs (the V600Kmutation).

9,11

Therapeutic manipulation

of the aberrantly activated MAPK pathway as a result of

those specific mutations has been proven to be an important

approach for the treatment of advancedmelanoma patients.

The first investigated anti-BRAF agent was the mul-

tikinase inhibitor sorafenib, which failed to show mean-

ingful clinical activity as a single agent or in combination

with chemotherapy.

Since then, vemurafenib and dab-

rafenib, more potent and selective BRAF inhibitors

(BRAFi), were developed. The clinical efficacy of orally-

administered BRAF inhibitor vemurafenib in patients

with BRAF V600-mutated melanoma has been established

in the phase 3 BRIM-3 trial, in which 675 patients with

metastatic/unresectable disease were randomly assigned

to either vemurafenib (960 mg twice daily) or dacarbazine

(1,000 mg/m

given intravenously every three weeks). The

updated objective response rate (ORR) confirmed by an

independent review was 47% among patients treated with

vemurafenib compared to 9% in the dacarbazine arm.

After

a median follow-up of 12.5 months, vemurafenib resulted

in a statistically significant improvement in overall survival

(OS) (13.6 vs. 9.7months; HR 0.70, 95CI 0.57-0.87; p=0.0008),

with 56% of the patients alive at 12 months. Progres-

sion-free survival (PFS) was also significantly prolonged

(6.9 vs. 1.6 months; HR 0.38, 95CI 0.32-0.46; p<0.0001).

Dabrafenib also demonstrated significant activity in

advancedmelanoma and has been approved for clinical use.

In a phase 3 trial, dabrafenib (150 mg taken orally twice

daily) was compared to dacarbazine (1,000 mg/m

given

intravenously every three weeks) in 250 patients with unre-

sectable stage III or stage IV melanoma harboring a BRAF

V600E mutation. Dabrafenib significantly prolonged the

median PFS (which was the primary endpoint of the study)

(5.1 vs. 2.7 months; HR 0.33; 95CI 0.20-0.54; p<0.0001),

resulting in an ORR of 50% versus 6%.

OS was updated

following a median follow-up of 13 to 15 months; while the

difference in survival was not statistically significant, cross-

over was permitted between the two groups and occurred

in 57 % of the patients initially treated with dacarbazine.

The most frequent toxicities associated with BRAF

inhibition were dermatologic (rash, photosensitivity and

hyperkeratosis), arthralgia, fatigue, nausea and diarrhea,

although differences in the toxicity profile of dabrafenib

and vemurafenib occur. Cutaneous squamous cell carci-

nomas (SCC) or keratoacanthoma may develop in up to

25% of patients treated with vemurafenib.

Conversely,

febrile reactions/pyrexia and severe hyperglycemia are

more frequent with dabrafenib and require attention.

14,15

Nevertheless, despite initial response, secondary re-

sistance often limits the benefit of single-agent BRAF

inhibitors, and underlying mechanisms involve reactiva-

tion of the MAPK pathway in almost 70% of the cases.

Hence, blockade of an immediate downstream signaling

component in the MAPK pathway, MEK, could poten-

tially result in significant antitumor effect. Initially test-

ed as single agent for patients who had not received prior

treatment with a BRAFi, trametinib, a selective blocker

of MEK1 and MEK2, was approved based on a survival

advantage in the phase 3 METRIC study (6-month sur-

vival rate 81% vs. 67%; 95CI 0.32-0.92; p=0.01). Objective

responses, despite comparing favorably to dacarbazine

(ORR 8%), occurred in only 22% of the patients.

The

rationale for the development of trials addressing dual

MAPK pathway blockade was based on the possibility of

minimizing the toxicity associated with paradoxical ac-

tivation of the MAPK pathway in the setting of BRAF

inhibition, delaying treatment resistance and enhancing

the antitumor effect. Based on early evidence that simul-

taneous, rather than sequential administration, could

represent the optimal approach, subsequent phase 3 stud-

ies evaluated BRAFi (vemurafenib or dabrafenib) given

concurrently with MEKi (cobimetinib or trametinib).

18,19

The combination dabrafenib (150 mg twice daily)

plus trametinib (2 mg once daily) was compared to single-

agent dabrafenib or vemurafenib in the COMBI-d and

COMBI-v trials, respectively.

18,20,21

Both studies have

consistently shown increased response rates, and gains

in PFS and OS favoring the use of the combination (Table

1), with updated 3-year survival rates of 44 and 45%.

22,23

In addition, the two trials confirmed that the incidences

of cutaneous squamous cell carcinoma and keratoacan-

thoma were significantly decreased with the combination

treatment by almost one third.

18,20,21

In the coBRIM trial,

another BRAFi/MEKi association was studied in 495

patients with previously untreated, BRAF-mutated, ad-

vanced melanoma. In this phase 3 trial, patients were

randomly assigned to vemurafenib (960 mg given twice

daily continuously, on days 1 to 28) plus cobimetinib (60

mg daily on days 1 to 21, followed by a 7-day interval) in

28-day cycles, or to vemurafenib plus placebo. Median

PFS, the primary endpoint of the study, was significant-

ly prolonged in the combination group (median PFS 12.3

vs. 7.2 months, HR 0.58; 95CI 0.46-0.72; p<0.0001). More

importantly, combined blockade resulted in gains in

overall survival (22.3 vs. 17.4 months, HR 0.70; 95CI

0.55-0.90; p=0.005) and ORR (70% vs. 50%).

These re-

sults have led to regulatory approvals of the aforemen-

tioned combinations.