Research

JAMA Oncology | Original Investigation

Systemic Therapy for Previously Untreated Advanced

BRAF-Mutated Melanoma
A Systematic Review and Network Meta-Analysis
of Randomized Clinical Trials
Tahira Devji, BSc; Oren Levine, MD; Binod Neupane, PhD; Joseph Beyene, PhD; Feng Xie, PhD

Supplemental content
IMPORTANCE Multiple effective first-line systemic treatment options are available for patients
with advanced BRAF-mutated melanoma. A lack of head-to-head randomized clinical trials
(RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal
first-line treatment.

OBJECTIVE To estimate the relative efficacy and safety of systemic therapies for advanced,
treatment-naive, BRAF-mutated melanoma.

DATA SOURCES We searched MEDLINE, Embase, and the Cochrane Central Registry of
Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016.

STUDY SELECTION We included RCTs in which at least 1 intervention was a targeted (BRAF or
MEK) or an immune checkpoint (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] or
programmed cell death 1 [PD-1]) inhibitor.

DATA EXTRACTION AND SYNTHESIS Two reviewers performed study selection, data
abstraction, and risk of bias assessment. We performed a Bayesian network meta-analysis
using a fixed-effect model to combine direct comparisons with indirect evidence. We
estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS),
and odds ratios (OR) for objective response rate (ORR) and serious adverse events.

RESULTS Sixteen eligible articles reporting 15 RCTs involving 6662 patients assigned to 1 of 10
treatment strategies were included. Both BRAF/MEK and PD-1 were associated with improved
OS benefit compared with all other treatments except CTLA-4/granulocyte macrophage
colony-stimulating factor. There was no significant difference in OS between BRAF/MEK and
PD-1 (HR, 1.02; 95% credible interval [CrI], 0.72-1.45). The network meta-analysis showed a
significant advantage of BRAF/MEK compared with all other treatment strategies for PFS.
BRAF/MEK was associated with higher ORR (OR, 2.00; 95% CrI, 1.64-2.45) compared with
BRAF alone, with both being superior in achieving ORR compared with other treatments.
Chemotherapy and PD-1 were associated with lowest risk of serious adverse events. There
was no significant difference in the risk of serious adverse events between chemotherapy and
PD-1 (OR, 1.00; 95% CrI, 0.74-1.34). Author Affiliations: Department of
Clinical Epidemiology & Biostatistics,
McMaster University, Hamilton,
CONCLUSIONS AND RELEVANCE Compared with other treatments, BRAF/MEK and PD-1 Ontario, Canada (Devji, Levine,
inhibition significantly improved OS. The favorable safety profile of PD-1 inhibitors supports Neupane, Beyene, Xie); Department
of Oncology, McMaster University,
using this option as first-line therapy in circumstances where rapid response is not a priority.
Hamilton, Ontario, Canada (Levine);
Father Sean O’Sullivan Research
Centre, St Joseph’s
Healthcare-Hamilton, Hamilton,
Ontario, Canada (Xie).
Corresponding Author: Feng Xie,
PhD, Department of Clinical
Epidemiology & Biostatistics,
McMaster University, 50 Charlton
Ave E, Rm H306 Martha Wing,
JAMA Oncol. doi:10.1001/jamaoncol.2016.4877 Hamilton L8N 4A6 (fengxie
Published online October 27, 2016. @mcmaster.ca).

(Reprinted) E1

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 Research Original Investigation
C
utaneous melanoma is an aggressive and deadly form
of skin cancer. Incidence rates of melanoma have
rapidly risen over the last 30 years with an annual in-
crease of 3% to 7% worldwide.1,2 Early stage melanoma is of-
ten cured with surgery alone; however, most patients present-
ing with advanced-stage disease are not candidates for surgical
resection and thus systemic therapy is the main treatment mo-
dality. Prognosis for patients with unresectable or metastatic
melanoma is poor, with a 5-year survival rate of 24% to 29%
and 10% to 19% for patients with stage IIIC and IV disease,
respectively.3 Until recently, treatment options were limited
for advanced disease. Multiple developments in understand-
ing the molecular mechanisms of melanoma oncogenesis and
immune evasion have revolutionized the standard of care for
patients with advanced melanoma.
The mitogen-activated protein (MAP) kinase signaling
pathway is an important mediator of cell proliferation and dif-
ferentiation in melanoma.4,5 Approximately 40% to 60% of cu-
taneous melanomas harbor a mutation in the BRAF gene that
leads to constitutive activation of downstream signaling
through the MAP kinase pathway.6,7 In addition, immune
checkpoint inhibitors including cytotoxic T-lymphocyte–
associated antigen 4 (CTLA-4) and programmed cell death pro-
tein 1 (PD-1) have been identified as key coregulatory mol-
ecules responsible for down-regulation of T-cell activation.8-10
Targeted therapies, including selective BRAF and MEK in-
hibitors, have drastically improved rates of progression-free
survival (PFS) and overall survival (OS) in patients with meta-
static melanoma harboring a BRAF V600 mutation.11-15 Im-
mune checkpoint inhibitors have also shown significant ben-
efit over conventional chemotherapies in randomized trials,16-21
regardless of BRAF mutation status.18,22,23 Thus, in the case
of advanced BRAF-mutated melanoma, multiple effective
first-line treatment options are available. No head-to-head ran-
domized trials of targeted agents and immunotherapies have
been conducted, and thus the optimal treatment is un-
known. Our aim was to systematically review the literature and
determine the relative efficacy and safety of systemic treat-
ment options for advanced BRAF-mutated melanoma in the
first-line setting. To obtain the estimates of relative treat-
ment effects for all possible comparisons, we employed a net-
work meta-analysis (NMA) technique, which simultaneously
integrates direct evidence from head-to-head trials and indi-
rect evidence (relative treatment effects between 2 treat-
ments derived from a common comparator).24,25
Methods
Literature Search
We conducted this study according to the methods outlined
in the Cochrane Handbook for Systematic Reviews of
Interventions.26 MEDLINE, EMBASE, and Cochrane Central
Registry of Controlled Trials (CENTRAL) were systematically
searched from inception up to and including April 29, 2016.
Search terms included extensive controlled vocabulary (MeSH
and EMTREE) in various combinations, supplemented with
keywords including melanoma, targeted therapy, and immu-
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Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma
Key Points
Question What is the relative efficacy and safety of systemic
therapies for advanced, treatment-naive, BRAF-mutated
melanoma?
Findings In this systematic review and network meta-analysis,
BRAF/MEK and programmed cell death protein 1 (PD-1) inhibition
were associated with improved overall survival benefit compared
with all treatments except cytotoxic T-lymphocyte–associated
antigen 4/granulocyte macrophage colony–stimulating factor.
There was no significant difference in overall survival between
BRAF/MEK and PD-1; BRAF/MEK conferred a significant advantage
over all other treatments for progression-free survival;
chemotherapy and PD-1 were associated with lowest risk of
serious adverse events, with no significant difference in risk
between treatments.
Meaning The favorable efficacy and safety profile of PD-1
inhibitors supports using this option as first-line therapy.
notherapy (eTable 1 in the Supplement). We limited our search
to randomized clinical trials (RCTs) by applying a filter devel-
oped by the Health Information Research Unit at McMaster
University.27 There were no language or date restrictions made.
We manually searched the reference lists of included studies
and consulted with experts to search for additional studies.
Study Selection
We included phase 2 or 3 RCTs that met the following criteria:
(1) the study enrolled treatment-naive adult patients with un-
resectable lymph node metastasis (American Joint Commit-
tee on Cancer [AJCC] TNM Stage IIIC) or distant metastatic
(AJCC TNM stage IV) melanoma; (2) at least 1 of the interven-
tions compared in the trial was either a targeted (BRAF or MEK)
or an immune checkpoint (CTLA-4 or PD-1) inhibitor; and (3)
the study reported on at least 1 of the following outcomes: OS,
PFS, objective response rate (ORR), and/or serious adverse
events (SAEs) defined as greater than or equal to grade 3 ac-
cording to the National Cancer Institute Common Terminol-
ogy Criteria for Adverse Events.28
Although our population of interest is BRAF-mutated mela-
noma, we did not restrict study eligibility by BRAF mutation
status. Targeted therapies (BRAF or MEK inhibitors) have gen-
erally been studied in a selected population of patients with
tumors harboring the mutation of interest. Immunothera-
pies (CTLA-4 or PD-1 inhibitors) have been studied either in a
mixed population or in a BRAF wild-type population. Based
on proven efficacy of immunotherapy in melanoma regard-
less of BRAF mutation status,18,22,23 these treatments have be-
come important options even for the BRAF-mutated cancers.
To generate a comprehensive network of trials comparing all
treatment options of current clinical relevance, it was neces-
sary to capture immunotherapy trials. Hence, we were inclu-
sive of trials irrespective of the BRAF mutation status.
Two reviewers (T.D. and O.L.) independently screened
titles and abstracts in duplicate, obtained full texts of articles
that either reviewer considered potentially eligible, and de-
termined eligibility from the full texts independently and in
duplicate. All discrepancies were resolved by consensus or with
jamaoncology.com
 Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma
a third adjudicator (F.X.). Interobserver agreement for the re-
viewers’ assessments of study eligibility was calculated with
the Cohen κ coefficient of agreement.
Data Extraction and Risk of Bias Assessment
The same 2 reviewers used a pilot-tested, standardized form to
independently extract information from each eligible study. Data
regarding study and population characteristics, as well as treat-
ments and outcomes (PFS, OS, ORR, and SAEs) were ab-
stracted. For PFS and OS, we extracted the hazard ratio (HR) and
confidence interval (CI) when available. When HRs and corre-
sponding CIs were not reported, we estimated them by recon-
structing individual patient data from published Kaplan-
Meier cur ves with methods desc ribed by Guyot and
colleagues.29 Authors of included studies were contacted if im-
portant data were unclear or not reported. For multiple reports
of the same trial, we used longest follow-up data for analysis.
Risk of bias of individual studies was assessed independently
by the reviewers (T.D. and O.L.) using the Cochrane Collabora-
tion risk-of-bias tool,26 and interrater agreement was calcu-
lated by weighted κ.30,31 Any disagreements were resolved by
consensus.
Data Synthesis and Analysis
Given the limited number of RCTs for any individual treat-
ment, we categorized therapies by drug class: targeted therapy
(BRAF, MEK, combined BRAF and MEK [BRAF/MEK]), immu-
notherapy (CTLA-4, PD-1, CTLA-4/PD-1), chemotherapy, and
combinations of these treatment groups (MEK/CHEMO, CTLA-
4/CHEMO, CTLA-4/granulocyte macrophage colony–
stimulating factor [GM-CSF]). We synthesized evidence for 4
outcomes: PFS, OS, ORR, and any SAEs. For each outcome, we
performed a Bayesian NMA using a Markov Chain Monte Carlo
(MCMC) simulation technique with 100 000 iterations in each
of the 4 chains. Noninformative priors (ie, N[0, 10000]) were
chosen for the effect parameters. The analysis was per-
formed under the fixed-effect model, as only 1 trial provided
direct evidence for most of the treatment comparisons. How-
ever, a random-effects (RE) model was also performed as sen-
sitivity analysis and model fits were compared using devi-
ance information criteria (DIC).32 In the comparison of any 2
models, we deemed a better fit model if its DIC was less than
the DIC of the other model by at least 5. Heterogeneity in the
network was assessed with the Cochrane Q (χ2) test and quan-
tified using the I2 statistic within each pairwise comparison
when 2 or more trials were available for the comparison.33 Be-
cause it was uncommon to have both direct and indirect evi-
dence for most comparisons in our networks, we assumed co-
herence for our analysis (ie, direct and indirect evidence, when
both available for a given comparison, were statistically simi-
lar). To test the robustness of this assumption we used the
node-splitting method to assess whether there was incoher-
ence in any closed loops.32,34
Relative effects of treatments are reported as HR for sur-
vival outcomes (PFS and OS) and odds ratio (OR) for binary
outcomes (ORR and SAEs) along with corresponding 95% cred-
ible intervals (CrIs), the Bayesian equivalent of 95% CIs. We
estimated the overall ranks of treatments by calculating the
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Original Investigation Research
surface under the cumulative ranking curve (SUCRA) for each.35
The SUCRA index ranges between 0 (or 0%) and 1 (or 100%),
where the treatments with highest and lowest SUCRA are con-
sidered to be the best and worst treatments, respectively.
We combined different drugs of the same class within a
single treatment category, which may have introduced hetero-
geneity in our NMA. In the trial by Ribas et al,36 tremeli-
mumab, a fully human monoclonal antibody against CTLA-4,
did not show significant benefit for OS over chemotherapy. This
trial is discordant with results of ipilimumab, a similar CTLA-
4-directed molecule. Tremelimumab was administered ev-
ery 90 days, and based on early progression most patients re-
ceived only 1 dose.36 At the time, risk of pseudo-progression
and immune-related response criteria had not been well
established.37 The dosing schedule and early discontinuation
of treatment may have limited the benefit of tremelimumab.38
We performed a sensitivity analysis excluding this trial from
the network to determine the impact of combining results for
both CTLA-4 agents.
Network meta-analysis was performed in WinBUGS soft-
ware (version 1.4.3, MRC Biostatistics Unit) interfacing through
R software.
Results
Study Characteristics
Of the 2546 citations identified through our literature search
(1848 after duplicates were removed), 1750 were deemed in-
eligible after title and abstract screening, leaving 98 studies
plus 1 identified from the relevant article search for full-text
review (eFigure 1 in the Supplement). Sixteen eligible publi-
cations reporting 15 RCTs12-15,17,18,20,36,39-45 were included in
the review and NMA (eTable 2 in the Supplement). Overall
agreement between the 2 reviewers for final eligibility was ex-
cellent (κ = 0.87;, 95% CI, 0.79-0.94).
eTable 2 in the Supplement summarizes the characteris-
tics of the 15 RCTs involving 6662 patients. All studies were
multicenter (13 conducted internationally) and published be-
tween 2011 and 2015. Five RCTs17,18,20,41,44 focused on both pa-
tients with BRAF mutations and wild-type tumors, 2 RCTs39,44
on patients with wild-type tumors only, 6 RCTs12-15,42,43 on pa-
tients with BRAF mutations, and 2 trials36,40 did not specify
the BRAF status. Ten treatment strategies were compared. No
RCTs directly compared immunotherapies with targeted thera-
pies; eFigure 2 in the Supplement provides the network
geometries for all 4 outcomes.
Quality of Evidence
The overall risk of bias was low and agreement between re-
viewers in this assessment was excellent (κ = 0.90; 95% CI,
0.80-0.96). The detailed risk of bias assessment can be found
in eFigure 3 in the Supplement. For all outcomes, most of the
direct treatment comparisons had only 1 trial providing evi-
dence; hence heterogeneity was not estimable for such
comparisons. We found minimal heterogeneity (I2 = 0%) in all
direct comparisons with 2 or more trials in the OS and PFS net-
works. However, heterogeneity was detected for the PD-1/
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 Research Original Investigation
CTLA-4 vs CTLA-4 comparison (I2 = 51%, 2 trials) in the ORR
network, and for the BRAF/MEK vs BRAF comparison
(I2 = 88%, 2 trials) in the SAEs network. The fit of the fixed-
effect model was similar or better than that of RE model in the
OS, PFS and ORR networks. Although the RE model was a bet-
ter fit for the SAEs network, 8 of 9 direct comparisons each had
just 1 trial, hence heterogeneity was driven entirely by the com-
parison of BRAF/MEK vs BRAF from just 2 trials. Therefore,
the fixed-effect model was a practical choice for analysis of all
outcomes including SAEs.
Overall Survival
Thirteen trials (5361 patients) comparing 9 treatments were in-
cluded in the OS analysis (eFigure 2A in the Supplement). We
obtained extended follow-up (5-year) data of 1 trial20 from a
second publication.46 Both BRAF/MEK and PD-1 were associ-
ated with improved OS benefit compared with all other treat-
ments except CTLA-4/GM-CSF (key comparisons include
BRAF/MEK vs BRAF: HR, 0.69; 95% CrI, 0.59-0.82 and PD-1
vs CTLA-4: HR, 0.58; 95% CrI, 0.47-0.71) (Figure, A). There was
no significant difference in OS between BRAF/MEK and PD-1
(HR, 1.02; 95% CrI, 0.72-1.45). The SUCRA values of 92% and
90% for BRAF/MEK and PD-1, respectively, suggested that
these were the 2 treatments with the highest chance of im-
proving OS in advanced melanoma (eTable 3 in the Supple-
ment). The sensitivity analysis by removing the Ribas et al36
trial resulted in a ranking order with PD-1 higher than BRAF/
MEK, SUCRA of 93% and 84%, respectively. The analysis of this
outcome does not include CTLA-4/PD-1 because OS data are
awaited from landmark trials.
Progression-Free Survival
Fourteen trials (6738 patients) comparing 10 treatments were
included in the PFS analysis (eFigure 2B in the Supplement).
The results of NMA showed a significant advantage of BRAF/
MEK compared with all other treatment strategies for PFS
(Figure, B). Overall, PD-1/CTLA-4 showed a significant im-
provement in PFS compared with PD-1 alone (HR, 0.75; 95%
CrI, 0.62-0.91) and all other treatments except BRAF/MEK (HR,
1.49; 95% CrI, 1.03-2.18). For PFS, BRAF/MEK was most likely
the best treatment (SUCRA: 100%), followed by PD-1/CTLA-4
(SUCRA: 87%) and BRAF (SUCRA: 78%), whereas MEK was least
likely to be the best treatment strategy (SUCRA: 7%) (eTable 3
in the Supplement).
Objective Response Rate
Thirteen trials (5580 patients) comparing 9 treatment strat-
egies were included in the ORR analysis (eFigure 2C in the
Supplement). As shown in Figure, C, BRAF/MEK was associ-
ated with a higher ORR compared with BRAF alone (OR,
2.00; 95% CrI, 1.64-2.45); both treatments, however, con-
ferred a significant improvement in ORR compared with all
other interventions included in the network (BRAF/MEK vs
PD-1/CTLA-4 OR, 0.26; 95% CrI 0.14-0.48). Among the
immunotherapies, PD-1/CTLA-4 was associated with higher
ORR when compared with PD-1 alone (OR, 1.82; 95% CrI,
1.34-2.47), which in turn was better than CTLA-4 (with or
without chemotherapy). The SUCRA analysis suggested that
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Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma
BRAF/MEK is likely the best treatment in achieving an
objective response (SUCRA: 100%) followed by BRAF
(SUCRA: 87%) and PD-1/CTLA-4 (SUCRA: 75%) (eTable 3 in
the Supplement). Sensitivity analysis with the removal of
the Ribas et al36 trial did not affect the results of our pri-
mary analysis.
Serious Adverse Events
Only 8 trials (4395 patients) comparing 8 treatment strategies
reported adverse events of grade 3 or higher (eFigure 2D in the
Supplement). Rates of SAEs ranged from 38.4% for chemo-
therapy to 68.7% for CTLA-4/PD-1 (eTable 4 in the Supple-
ment). As shown in eTable 5 in the Supplement, chemo-
therapy and PD-1 were associated with lowest risk of SAEs
compared with all other treatments. There was no significant
difference in the risk of SAEs between chemotherapy and PD-1
(OR, 1.00; 95% CrI, 0.74-1.34). Among the immunothera-
pies, CTLA-4/PD-1 was associated with higher risk of SAEs
compared with CTLA-4 (OR, 1.63; 95% CrI, 1.19-2.26) and
PD-1 (OR, 2.99; 95% CrI, 2.18-4.12). Among the targeted
therapies, BRAF/MEK was associated with lower risk of
SAEs compared with BRAF (OR, 0.84; 95% CrI, 0.66-1.06).
The SUCRA analysis suggested that chemotherapy and PD-1
had the lowest risk of SAEs with SUCRA values of 93%
(eTable 3 in the Supplement).
Discussion
Until recently, therapeutic options for patients with ad-
vanced melanoma were limited, and the prognosis was guarded
at best. With the advent of targeted therapies and immune
checkpoint inhibitors, the treatment landscape has changed
dramatically, complicating decision making for patients and
clinicians. In this systematic review and NMA focusing on tar-
geted and immunotherapies for treatment-naive patients with
advanced BRAF-mutated melanoma, we found that BRAF/
MEK and PD-1 inhibitors showed significant survival benefit
over all other treatments with the only exception of CTLA-4/
GM-CSF therapy where there was no difference in OS. In our
primary and sensitivity analyses of OS, there was no statisti-
cally significant difference between BRAF/MEK and PD-1 in-
hibitors. We therefore conclude that these treatment strate-
gies should be considered equivalent with respect to survival
benefit based on current evidence. A caveat in interpreting our
analysis is the lack of OS data for CTLA-4/PD-1. The combina-
tion immunotherapy shows promise in early outcomes and
could change the treatment landscape once longer-term re-
sults are published.
Only 1 randomized phase 2 trial addressed CTLA-4/GM-
CSF treatment showing an OS benefit with the addition of sar-
gramostim to ipilimumab. There is potential synergy be-
tween GM-CSF (which augments antigen presentation) and
CTLA4 inhibition (which promotes T-cell proliferation) in im-
mune response. Additionally, reduced toxic effects with the
combination compared to CTLA-4 monotherapy likely con-
tributes to improved survival. Further phase 3 evidence will
be required to confirm the efficacy of this therapy.40
jamaoncology.com
 Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma Original Investigation Research

Figure. Pooled Estimates for All Possible Treatment Effects for Each Outcome
A Overall survival

BRAF

0.69
BRAF/MEK
(0.59-0.82)
1.22 1.76
CTLA-4
(0.94-1.58) (1.29-2.40)

0.99 1.43 0.81

CTLA-4/CHEMO
(0.75-1.32) (1.03-2.00) (0.64-1.05)
0.90 1.31 0.74 0.91
CTLA-4/GM-CSF
(0.50-1.64) (0.70-2.43) (0.44-1.26) (0.51-1.64)
1.94 2.81 1.59 1.96 2.15
MEK
(1.29-2.92) (1.80-4.37) (1.08-2.34) (1.31-2.92) (1.12-4.13)
1.47 2.12 1.20 1.47 1.62 0.75
MEK/CHEMO
(0.96-2.26) (1.33-3.36) (0.80-1.80) (0.97-2.26) (0.83-3.15) (0.45-1.27)

0.71 1.02 0.58 0.71 0.78 0.36 0.48

PD-1
(0.52-0.96) (0.72-1.45) (0.47-0.71) (0.53-0.96) (0.44-1.38) (0.24-0.55) (0.31-0.75)

1.44 2.08 1.18 1.45 1.59 0.74 0.98 2.04

CHEMO
(1.17-1.77) (1.59-2.71) (1.01-1.38) (1.19-1.76) (0.92-2.76) (0.52-1.06) (0.68-1.42) (1.62-2.57)

B Progression-free survival

BRAF

0.58
BRAF/MEK
(0.51-0.66)
2.13 3.65
CTLA-4
(1.52-2.97) (2.56-5.21)

2.05 3.52 0.96

CTLA-4/CHEMO
(1.58-2.66) (2.63-4.71) (0.68-1.36)
2.19 3.76 1.03 1.07
CTLA-4/GM-CSF
(1.30-3.69) (2.19-6.44) (0.69-1.54) (0.63-1.82)
2.89 4.96 1.36 1.41 1.32
MEK
(1.99-4.17) (3.34-7.32) (0.88-2.09) (0.96-2.07) (0.73-2.39)
1.84 3.15 0.86 0.90 0.84 0.64
MEK/CHEMO
(1.27-2.66) (2.13-4.68) (0.56-1.33) (0.61-1.31) (0.46-1.52) (0.40-1.01)

1.16 1.99 0.55 0.57 0.53 0.40 0.63

PD-1
(0.86-1.57) (1.44-2.76) (0.48-0.63) (0.41-0.77) (0.35-0.82) (0.27-0.61) (0.42-0.96)

0.87 1.49 0.41 0.42 0.40 0.30 0.98 0.75 PD-1/CTL A-4
(0.61-1.24) (1.03-2.18) (0.34-0.49) (0.29-0.61) (0.26-0.62) (0.19-0.47) (0.30-0.75) (0.62-0.91)

2.70 4.63 1.27 1.32 1.23 0.93 1.47 2.32 3.11 CHEMO
(2.27-3.20) (3.73-5.74) (0.95-1.69) (1.08-1.60) (0.75-2.03) (0.67-1.30) (1.06-2.04) (1.81-2.98) (2.26-4.25)

C Objective response rate

BRAF

2.00
BRAF/MEK
(1.64-2.45)
0.08 0.04
CTLA-4
(0.05-0.14) (0.02-0.07)

0.11 0.05 1.35

CTLA-4/CHEMO
(0.06-0.21) (0.03-0.11) (0.70-2.65)
0.04 0.02 0.50 0.37
MEK
(0.01-0.13) (0.01-0.07) (0.15-1.58) (0.11-1.24)
0.16 0.08 1.95 1.45 3.89
MEK/CHEMO
(0.07-0.35) (0.03-0.18) (0.90-4.36) (0.60-3.49) (1.08-15.01)

0.28 0.14 3.54 2.62 7.03 1.82

PD-1
(0.16-0.49) (0.08-0.25) (2.59-4.86) (1.35-5.08) (2.24-23.68) (0.81-3.97)

0.52 0.26 6.45 4.77 12.82 3.30 1.82

PD-1/CTLA-4
(0.28-0.94) (0.14-0.48) (4.67-8.94) (2.37-9.57) (3.99-43.88) (1.44-7.50) (1.34-2.47)

0.07 0.03 0.87 0.64 1.72 0.44 0.24 0.13

CHEMO
(0.05-0.10) (0.02-0.05) (0.59-1.28) (0.37-1.09) (0.58-5.47) (0.22-0.88) (0.17-0.36) (0.09-0.21)

Effect estimates reflect comparison of the treatment in the row heading being compared to the column heading. Overall survival and progression-free survival are
presented with hazard ratios. Objective response rates (C) are presented with odds ratios. Numbers in parentheses are 95% credible intervals. Chemo indicates
chemotherapy; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; GM-CSF, granulocyte macrophage colony–stimulating factor; PD-1, programmed cell death
protein 1.

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 Research Original Investigation
BRAF/MEK inhibition was most effective with respect to
PFS followed by CTLA-4/PD-1 inhibition. Unlike OS, PFS is
not influenced by crossover or postprogression therapies.
Yet, given the variability in response patterns using
immunotherapies,37 PFS may be less robust as an outcome
measure in this setting.
Survival benefit must be balanced against risk of toxic ef-
fects. In the setting of advanced disease, systemic treatment
is noncurative for most, and thus quality of life is a priority.
Rates of SAEs were high for all treatment strategies with the
exception of PD-1 inhibitors, which showed no increased risk
compared with chemotherapy. Among immunotherapies,
CTLA-4/PD-1 was associated with a significantly increased
risk of toxic effects compared with either monotherapy.
Each immune checkpoint inhibitor activates T cells by a
unique mechanism, and to see higher rates of immune-
related toxic effects is expected with the combination. With
respect to targeted therapy, BRAF/MEK was less toxic than
BRAF monotherapy. This is consistent with results of pri-
mary trials and reflects the BRAF-inhibitor–induced para-
doxical activation of the MAP kinase pathway, which causes
skin-related toxic effects, including secondary cutaneous
malignancy.47,48
Our analysis of ORR showed best results with BRAF/MEK
inhibition. This supports first-line use of combination tar-
geted therapy for patients with bulky or highly symptomatic
disease, when rapid reduction in tumor volume is necessary
to improve health status. This may also influence choice of
treatment in the setting of nondisseminated but unresect-
able disease. Our analysis does not address resection rates fol-
lowing use of systemic treatment, thus clinical significance for
locally advanced disease is tentative.
There are several strengths of our study. Our safety analy-
sis helps provide a uniform assessment of risks of toxic ef-
fects across treatment categories. An inadequate number of
trials (n = 4) reported treatment–related adverse events to pro-
vide a meaningful comparison across treatment categories. For
a more comprehensive comparison, we analyzed rates of any
SAE. Treatment-related adverse event rate is a clinically rel-
evant safety outcome, but the rate of any adverse event is a
more conservative and pragmatic metric.
Our analysis is also strengthened by high quality and low
risk of bias in the primary trials. Although the included ran-
domized phase 2 trials offer less precise estimates due to
smaller sample sizes, these studies allow for a comprehen-
sive overview of the current treatment landscape for patients
with advanced melanoma. We considered only treatment-
naive patients in an attempt to standardize baseline progno-
sis. Moreover, inclusion criteria for primary trials were very
similar, producing a homogeneous population for the meta-
analysis with the exception of the BRAF status of eligible pa-
tients. The inclusion of patients with BRAF wild-type tumors
receiving immunotherapy is justified by the efficacy of im-
mune checkpoint inhibitors regardless of mutation status.17,18,23
For trials that included a mixed BRAF population, subgroups
based on mutation status were often not reported. Had we lim-
ited our analysis to patients who were BRAF mutation posi-
tive there would be no common reference trial linking tar-
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Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma
geted and immunotherapies in our network, making
comparison impossible. Some reports suggest BRAF muta-
tion may be a negative prognostic indicator.49,50 In our NMA,
studies that included BRAF wild-type tumors were predomi-
nantly immunotherapy trials. The indirect comparisons could
therefore be biased by prognostic differences in study popu-
lations. However, evidence regarding the prognostic impor-
tance of BRAF status in advanced melanoma is mixed,51 and
the influence on our analysis is uncertain.
We classified treatments by mechanism of action. This re-
sulted in a concise network often with multiple trials contrib-
uting to a comparison between 2 treatment categories. We feel
this is more informative compared with an alternate design in
which each drug is considered separately yielding a very sparse
network. The inclusion of various drugs within a single net-
work node is a potential source of heterogeneity, although sig-
nificant heterogeneity was not detected or not assessable for
most direct comparisons.
Limitations
Our analysis is limited by sparse networks for all outcomes.
Imprecise estimates of treatment effects are likely even when
the magnitude of the estimates are important since direct
evidence for each network was limited. Most direct compari-
sons were based on evidence from a single trial, and around
three-fourths of all treatment comparisons were derived
from indirect evidence alone, which must be considered
when making inferences from our study findings. We did not
suspect indirectness (related to the question or due to transi-
tivity) because trial populations and study characteristics
were very comparable to the target population of our NMA.
Indirect evidence for most comparisons was derived from the
common comparator of chemotherapy. Chemotherapy dose
and frequency was similar in all trials, so it is reasonable to
assume transitivity. All networks had an almost star-shaped
geometry, and there were no more than 2 closed loops of evi-
dence formed by different independent trials in these net-
works. The node splitting analysis did not detect incoherence
in any closed loop. Publication bias could not be formally
assessed due to the small number of trials available for direct
comparisons.
Conclusions
Our systematic review and NMA provides the first compari-
son between targeted therapies and immune checkpoint in-
hibitors for treatment-naive, BRAF-mutated advanced mela-
nomas. In the absence of a compelling clinical circumstance
to guide choice of treatment, it has been unclear which treat-
ment strategy is optimal for patient-important outcomes.
Though limited by a sparse network and a lack of OS data for
CTLA-4/PD-1, this analysis provides an evidence-based frame-
work to inform clinical decision making. Our results show that
OS is best with either PD-1 or combined BRAF/MEK inhibi-
tion. The favorable safety profile of PD-1 inhibitors supports
using this treatment option as first-line therapy in circum-
stances where rapid response is not a priority.
jamaoncology.com
 Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma
ARTICLE INFORMATION
Accepted for Publication: August 30, 2016.
Published Online: October 27, 2016.
doi:10.1001/jamaoncol.2016.4877
Author Contributions: Dr Xie and Ms Devji had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Devji, Levine, Xie.
Acquisition, analysis, or interpretation of data: All
Authors.
Drafting of the manuscript: Devji, Levine, Neupane.
Critical revision of the manuscript for important
intellectual content: All Authors.
Statistical analysis: Devji, Neupane, Beyene, Xie.
Administrative, technical, or material support: Xie.
Study supervision: Devji, Xie.
Conflict of Interest Disclosures: None reported.
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