RAMB - Setembro 2017

reatment

advanced

melanoma

– A

changing

landscape

ssoc

ras

2017; 63(9):814-823

821

pembrolizumab achieved an ORR of 57.1%, with 23.8%

having confirmed complete responses. This strategy is

now being further evaluated in an ongoing phase 3 clin-

ical trial (MASTERKEY265; NCT02263508).

Another attractive approach involves combining

anti-PD1/PDL-1 molecules with BRAF/MEK inhibitors.

In a phase 1 dose-escalation study, patients received at-

ezolizumab, an anti-PD-L1 agent, in association with

vemurafenib. The trial demonstrated a manageable toxic-

ity profile and promising antitumor activity, with an ORR

of 76% and a median PFS of 10.9 months.

The triplet

combination of pembrolizumab, dabrafenib and tra-

metinib has also been shown to be feasible: although 67%

of the patients experienced grade 3-4 adverse events, lead-

ing to discontinuation of treatment in 33% of the cases,

this combination resulted in an ORR of 60%.

urrent

treatment

options

for

patients with

advanced

melanoma

razil

– S

ame

disease

different

perspectives

Advances in the past 5 years have widened the treatment

possibilities for advanced melanoma patients, with an

undeniable impact on overall survival (Figure 3 and Table

1). In the USA and Europe, those with BRAF-mutated tu-

mors can be treated, in the first line setting, with the anti-

BRAF/MEK combinations vemurafenib/cobimetinib or

dabrafenib/trametinib. Also, as mentioned before, immu-

notherapy with nivolumab, pembrolizumab, ipilimumab/

nivolumab, ipilimumab or T-VEC is approved and available.

In Brazil, while nivolumab and pembrolizumab have

been approved in 2016, the combination of ipilimumab

and nivolumab has not been incorporated to date, and

ipilimumab has been approved only for patients who have

failed a first-line therapy. Similarly, for molecularly-se-

lected patients, additional options include dabrafenib

used as single-agent, vemurafenib as single agent or the

combination of vemurafenib and cobimetinib. Quite

concerning, however, is the fact that none of the men-

tioned approved therapies is available in the public health

system, in which treatment still relies on standard cyto-

toxic chemotherapies.

If it is true that predictive and prognostic biomarkers

can help in a better patient selection in a setting of sky-

rocketing costs associated with cancer care and often

limiting toxicities, the only validated biomarker ready for

unrestricted clinical use and that can direct treatment

decisions is the assessment of the BRAF status. Factors

involved in the antitumor immune response could po-

tentially identify the best candidates for immune-check-

point blockade, and many are being extensively investi-

gated: total tumor mutational load, tumor peptidome,

expression of PD-L1, clonality of the TCR, density and

quality of immune infiltrates, gene expression profiles

associated with an “inflamed” phenotype, genomic deter-

minants of antitumor immunity and even the character-

ization of commensal bacteria that could potentially

modulate cell-mediated responses. A better characteriza-

tion of the mechanisms involved in primary and second-

ary resistance to either immunotherapy or targeted ther-

apy is also mandatory for a rational development of future

treatment strategies and compounds.

onclusion

Therapies for patients with advanced melanoma have

rapidly evolved over the past few years, improving qual-

ity of life and life expectancy. Checkpoint inhibition with

antibodies directed against PD-1, nivolumab and pem-

brolizumab, alone or in combination with the anti-CTLA4

agent ipilimumab, has become the preferred approach

for patients with advanced melanoma not harboring BRAF

mutations. Molecularly-targeted therapies directed against

the MAPK pathway also provide additional options for

those with a BRAF V600 mutation, and the association

of MEK inhibitors to BRAF inhibitors produced increased

response rates, progression free survival and overall sur-

vival, and rational ways to combine and sequence this

armamentarium will most likely allow for an even great-

er impact on survival for these patients. Although di-

rected therapies have not been approved for non-BRAF

molecular aberrations, including KIT and NRAS muta-

tions, high expectations for the coming years are justifiable

by both ongoing pre-clinical and clinical development.

Translational research and future clinical trials are war-

ranted to address the large body of questions that remain

to be answered, and strategies to bring this reality to in a

cost-effective manner to countries with significant cost

contingency issues are mandatory.

onflict

interest

The authors have the following conflicts of interest (COI)

to disclose:

•

A.H. – No COI to disclose

•

A.S. – No COI to disclose

•

C.A.A – Honoraria (BMS, MSD, Roche); travel expenses

(MSD, Novartis, Roche); advisory role (BMS, MSD)

•

M.S. – Honoraria (MSD); advisory role (MSD, Roche);

travel expenses (BMS, MSD, Roche)

•

V.P.C. – Honoraria (BMS, MSD, Novartis)

•

B.G. – Honoraria (BMS, Janssen, MSD); advisory role

(BMS, Janssen, MSD)