Systematic or Meta-analysis Studies
Network meta-analysis of therapies for previously untreated advanced BRAF-mutated melanoma
Michael J. Zorattia, Tahira Devjia, Oren Levinea,b, Lehana Thabanea, Feng Xiea,c,⁎
BRAF-mutated melanoma Targeted therapy
Immunotherapy Network meta-analysis
A B S T R A C T
Background: The spectrum of treatment options for patients with metastatic BRAF-mutated melanoma is broad, spanning multiple treatment classes. However, there is a lack of head-to-head evidence comparing targeted and immunotherapies. The purpose of this study is to conduct a network meta-analysis (NMA) in previously un- treated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this pa- tient population at the treatment level.
Methods: The literature review included searches of MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) to November 2018. Randomized controlled trials of previously untreated patients with advanced melanoma were eligible if at least one intervention was either a targeted or immune therapy. Relative treatment effects were estimated by fiXed effect Bayesian NMAs on progression-free survival (PFS) and overall survival (OS), based on the hazard ratio.
Results: Combination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combi- nation vemurafenib with cobimetinib (HR 0.22 [95% CrI 0.17, 0.29] vs dacarbazine) were likely to rank as the most favorable treatment options for PFS, while combination nivolumab with ipilimumab was likely to be the most efficacious in terms of OS (HR 0.33 [0.24, 0.47] vs dacarbazine).
Conclusions and relevance: The findings highlight the efficacy of combination PD-1 with CTLA-4 inhibitors and combination BRAF with MEK inhibitors in the treatment of advanced melanoma. However, as few trials in- formed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape.
Until recently, effective treatment options for patients with ad- vanced stage melanoma were limited. Indeed, according to a 2011 systematic review of treatment options in melanoma, patients with metastatic disease had a median survival of under one year . How- ever, recent developments in understanding molecular mechanisms of oncogenesis, including the role of the mitogen-activated protein kinase (MAPK) signaling pathway, have led to the introduction of a number of novel treatment options. ApproXimately 40–70% of advanced mela- noma cases harbor a BRAF mutation, causing constitutive activation of the MAPK pathway [1–4]. Among recent developments in treatment options are selective BRAF and MEK inhibitors, which have improved patient outcomes with respect to progression-free survival (PFS) and overall survival (OS) compared to cytotoXic chemotherapy [5–7]. Furthermore, advance- ments have led to the development of immune checkpoint inhibitors, with targets including the cytotoXic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). These molecules play a co-regulatory role in the down-regulation of T-cell activation, and inhibition of these targets has demonstrated clinical benefit over traditional chemotherapy [8–15]. However, no head-to-head rando- mized controlled trial (RCT) evidence currently exists between targeted therapies, such as selective BRAF and MEK inhibitors, and im- munotherapies. To address this knowledge gap, we recently undertook a systematic literature review and network meta-analysis (NMA) to evaluate the relative efficacy of treatments for patients with advanced BRAF-mutated melanoma . The findings suggested that combination BRAF with MEK inhibitors and PD-1 inhibitors were sta- tistically similar and associated with improved OS compared to most other treatment classes. Combination BRAF with MEK inhibitors were statistically superior to all other treatment classes with respect to PFS. However, as dual immune checkpoint inhibition may prove to be an important treatment option, the conclusions were cautious given the lack of long-term survival data for combination CTLA-4 with PD-1 in- hibitors at the time of the analysis. Additionally, comparisons were based on treatment class due to limited evidence and, thus, it is not possible to draw conclusions regarding the relative treatment effects of individual treatments. The purpose of this study was to update the literature search and explore the evidence base in previously untreated advanced BRAF- mutated melanoma by estimating the relative treatment effects between individual treatment options.
Identification of the evidence base
Our systematic literature review and NMA was updated to November 10, 2018. The complete search strategy, literature screening, and data extraction methods have been described previously . Briefly, RCTs which reported OS or PFS in previously untreated adult patients with unresectable lymph node metastasis (American Joint Committee on Cancer [AJCC] TNM Stage IIIc) or distant metastatic (AJCC TNM stage IV) melanoma were eligible if at least one interven- tion was a targeted (BRAF or MEK) or an immune checkpoint (CTLA-4 or PD-1) inhibitor.
Bayesian NMAs were conducted to estimate the hazard ratios (HRs), with corresponding 95% credible interval (CrIs), for PFS and OS at both the treatment class-level and individual treatment-level. Analyses were conducted based on the reported HRs between trial arms. In the case of multi-arm trials (i.e. trials with three or more interventions), adjust- ments were made to reflect the correlations between relative treatment effects by converting log-HRs to log-hazards [17,18]. Both fiXed effects and random effects models were fitted to the data using Markov Chain Monte Carlo (MCMC) methods. Model fit was as- sessed according to the deviance information criteria (DIC). A four- chain model with non-informative priors was run with an adaptation phase of 50,000 iterations followed by 400,000 model iterations. The thin ratio was set to 5. Non-convergence was assessed by the Gelman- Rubin statistic. Inconsistency was evaluated by edge-splitting, an approach that estimates relative treatment effects based on direct evidence (i.e. pairwise comparisons between treatments nodes) and indirect evidence (i.e. relative treatment effects estimated only using indirect evidence) separately. If a model is consistent, the direction and statistical im- portance of effect will be maintained. Relative treatment rankings were evaluated according to the surface under the cumulative ranking curve (SUCRA) method, which generates a value on 0–100% to indicate the probable worst and best treatment options, respectively, in the network . In this Bayesian context, the interpretation of HRs from the relative treatment effect estimates is similar to the frequentist framework, where statistical importance (i.e. statistical significance in the fre- quentist framework) is established when the 95% CrI does not contain.
The literature review identified 8 new publications [21–28], which were updates of previously included trials, generating an evidence base of 25 publications [5,12,14,21–43] describing 15 trials. However, two trials were only eligible for inclusion in the treatment-class level ana- lysis due to the network structure [42,43]. From the literature update, two-year OS results from the CheckMate-069 trial, where patients were randomized to combination ipilimumab with nivolumab or ipilimumab monotherapy, were identified. The median survival had not been reached in either group. Updated PFS and recently published OS out- comes in the three-arm CheckMate-067 trial were also identified . At the time of publishing, median OS had not been reached in the combination nivolumab with ipilimumab group but was 37.6 months in patients treated with nivolumab and 19.9 months in patients treated with ipilimumab. Recently published three-year efficacy outcomes, in- cluding both PFS and OS, for the COMBI-d trial  and CheckMate- 066  were also identified. Four-year survival outcomes from the CheckMate-067 trial , where median OS had not yet been reached in the combination nivolumab with ipilimumab group, were included. Lastly, the final protocol-specified survival analysis from the Keynote- 006 trial  was included.
No new trials were identified. vemurafenib with cobimetinib [5,22], vemurafenib monotherapy [5,22,25,30,32,40], combination dabrafenib with trametinib [27,29,32], dabrafenib monotherapy [27,29,35], combination selumetinib with dacarbazine , tremelimumab monotherapy (overall survival only) , dacarbazine monotherapy [14,25,26,30,31,33,35,36,40,41], combination ipilimumab with da- carbazine [14,41], nivolumab or pembrolizumab [23,24,26,28,33, 34,38], combination nivolumab with ipilimumab [12,21,23,28,38], ipilimumab monotherapy [12,21,23,24,28,34,37,38], and combination ipilimumab with sargramostim . While no head-to-head evidence is available for nivolumab and pembrolizumab, both exhibiting anti-PD-1 mechanism of action, indirect evidence suggests they perform similarly across multiple diseases [44,45]. Therefore, both monoclonal anti- bodies were considered clinically equivalent and included as a single treatment option in order to establish a critical connection in the evi- dence network. In Keynote-006 [24,34], outcomes were reported from two doses of pembrolizumab (10 mg/kg q3wk or 10 mg/kg q2wk). From this trial, we included only the ’10 mg q3wk’ dose of pem- brolizumab. As of June 2017, pembrolizumab 2 mg/kg q3wk is the only dose currently approved by the US Food and Drug Association (FDA) or Health Canada for unresectable or metastatic melanoma [46,47]. Fur- thermore, phase I evidence suggests that the 2 mg/kg and 10 mg/kg doses of pembrolizumab perform similarly in melanoma patients . Additional interventions were included in the treatment class-level analysis, but could not be connected in the individual treatment-level network: selumetinib (MEK) , selumetinib with docetaxel (MEK with chemotherapy) , docetaxel (chemotherapy) , and temo- zolomide (chemotherapy) . However, the authors considered these interventions to be of low clinical relevance for this patient population.
A summary of treatment categorization into treatment classes is pre- sented in Table A.1. Trial characteristics, as well as demographic and clinical char- acteristics of the enrolled patients, reported previously , were well matched across trials. The median age at enrollment was above 50 years in all trials, with males comprising the majority of patients. Most pa- tients had metastatic disease. Few patients demonstrated evidence of brain metastasis, which was often an exclusion criterion for enrolment among included trials. In the majority of trials, patient populations were either all BRAF-mutated or a miXture of BRAF-mutated and wild- type. Mutation status was not reported in two trials [36,37]. The re- ported PFS and OS outcomes from each trial are presented in Table A.2. Individual treatment-level outcomes The network diagram for the treatment-level analyses is presented in Fig. 1. Nearly all comparisons were informed by a single trial. Out- comes for tremelimumab were only available for OS . Relative treatment effects for both PFS and OS are presented in Table 1.Progression-free survival As most comparisons were informed by a single trial, and the DICs for the fiXed (21.15) and random (22.83) models were similar, the fiXed effects model was selected as the appropriate fit. Relative treatment effects with respect to PFS are presented below the diagonal in Table 1. Differences between treatments within the same treatment class (dabrafenib vs. vemurafenib; combination dabrafenib with trametinib vs. combination vemurafenib with cobimetinib) were not statistically important. Combination dabrafenib with trametinib was more effica- cious than most treatments in the network, though the relative effects compared to combination vemurafenib with cobimetinib (HR 0.98, CrI 0.73, 1.31) and to combination nivolumab with ipilimumab (HR 0.83, CrI 0.58, 1.18) were not statistically important. All treatments, with the exception of ipilimumab with sargramostim (HR 0.66, CrI 0.40, 1.07), were statistically superior to dacarbazine.
These findings are reflected in the SUCRA results (Table A.4), which suggest that dabrafenib with trametinib (SUCRA 94.1) and combination vemurafenib with cobimetinib (SUCRA 92.1) are likely to rank as the preferred treatments in the network. The results of the edge-splitting exercise revealed evidence of in- consistency in the network (Table A.5). Specifically, comparisons be- tween combination dabrafenib with trametinib and dabrafenib, com- bination dabrafenib with trametinib and vemurafenib, and between nivolumab or pembrolizumab and combination nivolumab with ipili- mumab were statistically important based only on direct evidence, but not based on indirect evidence. Although point estimates demonstrated consistent direction of effect, the CrIs for indirect evidence were wider and caused some discrepancies in the statistical importance of findings.
The relative treatment effects for OS (Table 1) were also estimated through a fiXed effects NMA, as most contrasts were informed by a single trial and the DICs for the fiXed (25.99) and random (27.19) ef- fects models were similar. Treatment with combination nivolumab with ipilimumab was sta- tistically superior compared to all other treatments with the exception of combination ipilimumab with sargramostim (HR 0.66, CrI 0.28, 1.57). Consistent with this, treatment with combination nivolumab with ipilimumab was likely to rank as the preferred treatment option (SUCRA 98.1) and dacarbazine was likely to be the least favorable treatment option (SUCRA 5.5). Differences in OS between treatments within the same treatment class were not statistically important. Complete SUCRA results are presented in Table A.4.
Inconsistency comparisons between direct and indirect evidence for OS (Table A.5) revealed that combination dabrafenib with trametinib and dabrafenib, combination dabrafenib with trametinib and vemur- afenib, combination nivolumab with ipilimumab and nivolumab or pembrolizumab, and dacarbazine and vemurafenib were statistically important based on only direct evidence. With the exception of com- bination nivolumab with ipilimumab compared to nivolumab or pem- brolizumab, the direction and magnitude of estimated effects remained consistent.
Updated treatment class-level analyses The updated fiXed effects class-level NMAs (Table A.3) generally upheld the conclusions of the previously published treatment class-level analyses on PFS and OS. However, the incorporation of recently pub- lished OS data for combination nivolumab with ipilimumab (PD- 1 + CTLA-4) suggested that this treatment class is statistically superior to every treatment class with respect to OS, with the exception of combination CTLA-4 with cytokine (HR 0.63, CrI 0.27, 1.49). Thus, combination PD-1 with CTLA-4 inhibitors was predicted to be the most preferred treatment class with respect to OS (SUCRA 98.1). With re- spect to PFS, combination BRAF with MEK inhibitors remained the most preferable treatment class in the network (SUCRA 97.6).
Recent developments in targeted therapies and immune checkpoint inhibitors have led to a range of improved treatment options for pa- tients with advanced melanoma. Consistent with our previous review and NMA, this analysis, based on individual treatments rather than on treatment class, supported the use of combination dabrafenib and tra- metinib (BRAF with MEK inhibitors) and combination nivolumab with ipilimumab (PD-1 with CTLA-4 inhibitors). Specifically, combination treatment with dabrafenib and trametinib was the preferred treatment for PFS while combination nivolumab with ipilimumab was the pre- ferred option for OS. The efficacy profiles of the two combination BRAF with MEK inhibitor treatments were similar, both with respect to each other and with respect to other treatments. Across both PFS and OS, dacarbazine (chemotherapy) was likely to rank as the least preferred treatment option.
At the time of our original treatment class-based review and NMA, OS data for combination PD-1 with CTLA-4 inhibitors was unavailable. However, the updated review identified recently published OS data from the CheckMate-066 [26,33], CheckMate-067 [23,28,38], Check- Mate-069 [12,21], and COMBI-d [27,29] trials. After incorporating these results in our NMA, we found that combination PD-1 with CTLA-4 inhibitors was statistically superior to every other treatment class, with the exception of combination CTLA-4 inhibitors with cytokine, with respect to OS. Our analyses and conclusions are based on evidence retrieved through an extensive search of the literature, including a recent update (November 2018). The included trials are of high quality and are considered to carry a low risk of bias, as reported previously . Si- milar inclusion criteria across the trials also added confidence in our ability to estimate comparisons across the network of evidence. How- ever, few trials were identified in the evidence base, leading to a sparse network, with most treatment contrasts informed by a single trial. Additionally, the inclusion of some miXed-population trials, where re- sults were not reported separately for BRAF-mutated and BRAF wild- type patients, may have introduced heterogeneity into the evidence base. The decision to include these trials was made in order to facilitate the development of a connected network that linked targeted therapies and immunotherapies and was supported by evidence suggesting that immunotherapies tend to demonstrate efficacy irrespective of BRAF mutation status [12,49,50]. The chance of heterogeneity from inclusion of miXed BRAF populations is reflected in subgroup analysis of the combination immune checkpoint inhibitor study CheckMate-067 [23,38], which raises the possibility of preferential benefit in the ex- perimental arm for BRAF-mutated versus wild-type tumors. Yet, use of targeted therapies as front-line treatment of BRAF-mutated melanoma may be preferred for highly symptomatic patients with bulky metastasis . Previously untreated patients included in the trials of immune checkpoint inhibitors may have been selected for more indolent disease, thus limiting the generalizability of our results in the BRAF-mutated population.
Comparisons between the treatment class-level and in- dividual treatment-level analyses may be inadvertently biased, as not all treatments could be included in both network scopes. However, the treatment class-level analysis was purposefully conducted based on all available evidence to comprehensively reflect the evidence landscape. Future analyses may incorporate disconnected trials or observational evidence in the NMA [52,53]. Finally, the current analysis was based on relative treatment effects estimated on the constant, rather than time- varying, hazard ratio . The limitations of this approach should be considered, such as the need to assume proportional hazards, and future investigations may examine the relative treatment effects of these in- terventions based on the shape and scale of their survival curves [54,55]. The evidence in favor of targeted therapies and immune checkpoint inhibitors to date is promising. For example, a pooled analysis of OS data from 10 prospective and two retrospective studies of ipilimumab found three-year survival rates of approXimately 22% . Similarly, in a phase I and II trial, BRAF inhibitor-naïve patients treated with dab- rafenib 150 mg twice daily with trametinib 2 mg daily were found to have PFS rates over 20% after 3 years, with a median OS of more than 2 years . The rapid response of targeted therapy is also attractive, particularly in the case of the patient with extensive tumor growth and a high symptom burden. However, the availability of these new treat- ment options necessitates clinicians and decision makers to gain a thorough understanding of the comparative clinical profiles. Thus, the intent of this treatment-level analysis was to further explore and de- scribe the relative treatment effects of targeted therapies and im- munotherapies. Based on our treatment-level analysis, combination BRAF with MEK inhibitor therapy (combination dabrafenib with tra- metinib; combination vemurafenib with cobimetinib) and combination PD-1 with CTLA-4 inhibitor therapy (combination nivolumab with ipilimumab) were associated with the most favorable outcomes with respect to PFS and OS, respectively. However, clinical decisions should also weight the toXicity profiles of available treatment options. While our understanding of the treatment landscape has evolved, the findings of our analysis are based on relatively few trials in a sparse network of evidence and thus should be interpreted with caution. Further research in the field of advanced melanoma, specifically in the context of emerging immunotherapies, is needed to reinforce these findings.
No funding was received for the purpose of this study.
The authors have declared no conflicts of interest.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ctrv.2019.02.001.
 Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist
 Davies H, Bignell GR, CoX C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949–54.
 Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. New Engl J Med 2005;353:2135–47.
 Flaherty KT. Chemotherapy and targeted therapy combinations in advanced mela- noma. Clin Cancer Res Off J Am Assoc Cancer Res 2006;12:2366s–70s.
 Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined
vemurafenib and cobimetinib in BRAF-mutated melanoma. New Engl J Med 2014;371:1867–76.
 Eroglu Z, Ribas A. Combination therapy with BRAF and MEK inhibitors for mela- noma: latest evidence and place in therapy. Therap Adv Med Oncol 2016;8:48–56.
 Welsh SJ, Rizos H, Scolyer RA, Long GV. Resistance to combination BRAF and MEK
inhibition in metastatic melanoma: where to next? Eur J Cancer (OXford England) 1990;2016(62):76–85.
 O’Day SJ, Hamid O, Urba WJ. Targeting cytotoXic T-lymphocyte antigen-4 (CTLA- 4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 2007;110:2614–27.
 Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med 2012;366:2443–54.
 Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo
toXicology in non-human primates. Cancer Immunol Res 2014;2:846–56.
 Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New
Engl J Med 2010;363:711–23.
 Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. New Engl J Med 2015;372:2006–17.
 Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al.
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol
 Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New Engl J Med 2011;364:2517–26.
 Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab
versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label,
phase 3 trial. Lancet Oncol 2015;16:375–84.
 Devji T, Levine O, Neupane B, Beyene J, Xie F. Systemic therapy for previously untreated advanced BRAF-mutated melanoma: a systematic review and network
meta-analysis of randomized clinical trials. JAMA Oncol 2017;3:366–73.
 Woods BS, Hawkins N, Scott DA. Network meta-analysis on the log-hazard scale,
combining count and hazard ratio statistics accounting for multi-arm trials: a tu- torial. BMC Med Res Method 2010;10:54.
 Salanti G, Higgins JP, Ades AE, Ioannidis JP. Evaluation of networks of randomized
trials. Stat Methods Med Res 2008;17:279–301.
 Salanti G, Ades A, Ioannidis J. Graphical methods and numerical summaries for
presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 2011;64:163–71.
 van Valkenhoef G, Kuiper J. gemtc: Network Meta-Analysis Using Bayesian
Methods. R package version 0.8-2.
 Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al.
Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, rando-
mised, controlled, phase 2 trial. Lancet Oncol 2016;17:1558–68.
 Ascierto PA, McArthur GA, Dreno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant mela-
noma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol 2016;17:1248–60.
 Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma.
New Engl J Med 2017;377:1345–56.
 Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a mul-
ticentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017.
 Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall sur- vival results of the randomized BRIM-3 study. Ann Oncol 2017;28:2581–7.
 Ascierto PA, Long GV, Robert C, Brady B, DutriauX C, Di Giacomo AM, et al.
Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized
phase 3 trial. JAMA Oncol 2018.
 Long GV, Flaherty KT, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with meta-
static BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol Off J Eur Soc Med Oncol 2017;28:1631–9.
 Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in ad-
vanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised,
phase 3 trial. Lancet Oncol 2018;19:1480–92.
 Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al.
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet
(London, England) 2015;386:444–51.
 McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive
melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323–32.
 Robert C, Dummer R, Gutzmer R, Lorigan P, Kim KB, Nyakas M, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-
mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet
 Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D,
et al. Improved overall survival in melanoma with combined dabrafenib and tra- metinib. New Engl J Med 2015;372:30–9.
 Robert C, Long GV, Brady B, DutriauX C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. New Engl J Med
 Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. New Engl J Med 2015;372:2521–32.
 Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label,
phase 3 randomised controlled trial. Lancet (London, England) 2012;380:358–65.
 Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III
randomized clinical trial comparing tremelimumab with standard-of-care che- motherapy in patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin
 Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic
melanoma: a randomized clinical trial. JAMA 2014;312:1744–53.
 Larkin JHAJ, Nathan P, Lebmeier M, Lee D. The predicted impact of ipilimumab usage on survival in previously treated advanced or metastatic melanoma in the UK. PLoS ONE 2015;10:e0145524.
 Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al.
Checkmate 067: A phase iii randomized double-blind study of nivolumab (NIVO) monotherapy or NIVO combined with ipilimumab (IPI) versus IPI monotherapy in
previously untreated patients (PTS) with advanced melanoma (MEL). Asia-Pacific J Clin Oncol 2015;11:68.
 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New Engl J Med 2011;364:2507–16.
 Maio M, Grob J-J, Aamdal S, Bondarenko I, Robert C, Thomas L, et al. Five-year survival rates for treatment-naive patients with advanced melanoma who received
Ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol 2015;33:1191–6.
 Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy
versus temozolomide in patients with advanced melanoma. Clin Cancer Res Off J Am Assoc Cancer Res 2012;18:555–67.
 Gupta A, Love S, Schuh A, Shanyinde M, Larkin JM, Plummer R, et al. DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in
wild-type BRAF advanced melanoma. Ann Oncol Off J Eur Soc Med Oncol
 Li X, Wang J, Yao Y, Yang L, Li Z, Yu C, et al. Comparative efficacy and safety of
immune checkpoint inhibitor-related therapies for advanced melanoma: a Bayesian network analysis. Oncotarget. 2017.
 Peng TR, Tsai FP, Wu TW. Indirect comparison between pembrolizumab and ni-
volumab for the treatment of non-small cell lung cancer: a meta-analysis of ran- domized clinical trials. Int Immunopharmacol 2017;49:85–94.
Health Canada. Keytruda (pembrolizumab): Product Monograph. Health Canada; 2017.
 U.S. Food & Drug Administration. Keytruda; 2017.
 Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-pro-
grammed-death-receptor-1 treatment with pembrolizumab in ipilimumab-re- fractory advanced melanoma: a randomised dose-comparison cohort of a phase 1
trial. Lancet (London, England) 2014;384:1109–17.
 Larkin J, Lao CD, Urba WJ, McDermott DF, Horak C, Jiang J, et al. Efficacy and safety of Nivolumab in patients with BRAF V600 mutant and BRAF wild-type ad-
vanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol 2015;1:433–40.
 Shahabi V, Whitney G, Hamid O, Schmidt H, Chasalow SD, Alaparthy S, et al.
Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother CII 2012;61:733–7.
 Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis G, Keilholz U. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-
up. Ann Oncol 2015;26:v126–32.
 Thom HHZ, Capkun G, Cerulli A, NiXon RM, Howard LS. Network meta-analysis combining individual patient and aggregate data from a miXture of study designs
with an application to pulmonary arterial hypertension. BMC Med Res Method 2015;15:34.
 Cameron C, Fireman B, Hutton B, Clifford T, Coyle D, Wells G, et al. Network meta- analysis incorporating randomized controlled trials and non-randomized com-
parative cohort studies for assessing the safety and effectiveness of medical treat-
ments: challenges and opportunities. Systemat Rev 2015;4:147.
 Ouwens MJ, Philips Z, Jansen JP. Network meta-analysis of parametric survival curves. Res Synth Methods 2010;1:258–71.
 Jansen JP, Cope S. Meta-regression models to address heterogeneity and incon-
sistency in network meta-analysis of survival outcomes. BMC Med Res Method 2012;12:152.
 Schadendorf D, Hodi FS, Robert C, Weber JS, Margolin K, Hamid O, et al. Pooled
analysis of long-term survival data from phase II and phase III trials of Ipilimumab in unresectable or metastatic melanoma. J Clin Oncol Off J Am Soc Clin Oncol
 Long GV, Weber JS, Infante JR, Kim KB, Daud A, Gonzalez R, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined PR-171 with trametinib. J Clin Oncol Off J Am Soc Clin Oncol 2016;34:871–8.