Treatment Options For Metastatic Melanoma Research Articles

Lifileucel: FDA-approved T-cell therapy for melanoma.

This commentary reports on the history of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy and where TIL fits into the treatment options for metastatic melanoma.

Synergetic effect of high dose rate radiations (10× FFF/2400 MU/min/10 MV x-rays) and paclitaxel selectively eliminates melanoma cells.

Melanoma is one of the most aggressive cancers, with 1.6% of total cancer deaths in the United States. In recent years treatment options for metastatic melanoma have been improved by the FDA approval of new therapeutic agents. However, these inhibitors-based therapies are non-specific and have severe toxicities, including hyperkeratosis, photosensitivity, hepatitis, arthralgia, and fatigue. The aim of this study is to determine the synthetic lethal effect (paclitaxel and radiations) on melanoma cells and reduce the total radiation doses by increasing the dose rates up to 2400 MU/min. We previously reported a radiation treatment (10 MV x-rays, 10X-FFF, dose rate 2400MU/min, low total dose 0.5 Gy) that kills melanoma cells with 80% survival of normal HEM in vitro. In this study, we extended the radiation cycle up to four and included paclitaxel treatment to study the synthetic lethal effect on melanoma and two other normal primary cells, HDF and HEK. Cells were treated with paclitaxel prior to the radiation at a dose rate of 400 and 2400 MU/min with a total radiation dose of only 0.5 Gy. Mitochondrial respiration assay, DNA damage assay, and colony formation assays were performed to study apoptosis and cell death induction. Four days of consequent radiation treatment with paclitaxel significantly reduces the survival of melanoma cells by inducing apoptosis and mitochondrial damage. After treatment, excessive DNA damage in melanoma cells leads to an increase in the expression of pro-apoptotic genes (Caspase-3) and a decrease in the expression of DNA repair gene (PARP1) and anti-apoptotic gene (Bcl-2) to activate the apoptosis pathway. The combination of paclitaxel and radiation reduces the survival of melanoma cells colonies compared to radiation alone. Our study indicates that radiations with paclitaxel have a potential synthetic lethal effect on melanoma cells and can be developed as a melanoma therapy without toxicities or harmful effects on normal primary skin cells.

LRG1 Promotes Metastatic Dissemination of Melanoma through Regulating EGFR/STAT3 Signalling.

Simple SummaryMelanoma is a highly metastatic and lethal form of skin cancer. Currently, there is no effective treatment available once melanoma cells spread to other parts of the body. Our study demonstrated that LRG1 regulates multiple aspects of melanoma metastasis through modulating EGFR/STAT3 signalling. Targeting LRG1 may offer an alternative way to control the metastatic spread of melanoma cells.Although less common, melanoma is the deadliest form of skin cancer largely due to its highly metastatic nature. Currently, there are limited treatment options for metastatic melanoma and many of them could cause serious side effects. A better understanding of the molecular mechanisms underlying the complex disease pathophysiology of metastatic melanoma may lead to the identification of novel therapeutic targets and facilitate the development of targeted therapeutics. In this study, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in melanoma development and progression. We first established the association between LRG1 and melanoma in both human patient biopsies and mouse melanoma cell lines and revealed a significant induction of LRG1 expression in metastatic melanoma cells. We then showed no change in tumour cell growth, proliferation, and angiogenesis in the absence of the host Lrg1. On the other hand, there was reduced melanoma cell metastasis to the lungs in Lrg1-deficient mice. This observation was supported by the promoting effect of LRG1 in melanoma cell migration, invasion, and adhesion. Mechanistically, LRG1 mediates melanoma cell invasiveness in an EGFR/STAT3-dependent manner. Taken together, our studies provided compelling evidence that LRG1 is required for melanoma metastasis but not growth. Targeting LRG1 may offer an alternative strategy to control malignant melanoma.

Development and validation of a web-based patient decision aid for immunotherapy for patients with metastatic melanoma: study protocol for a multicenter randomized trial

BackgroundPatients with metastatic melanoma and their physicians are confronted with a complex decision regarding first-line therapy. Risks and benefits vary considerably between various treatment options. With this in mind, we aim to develop and evaluate a patient decision aid (PtDA) to inform patients about the risks and benefits of treatment options, namely, immunotherapy as monotherapy, immunotherapy as combination therapy, and treatment with BRAF/MEK inhibitors. We aim to test whether the use of this PtDA before medical consultation will increase patients’ knowledge of treatment options and thus promote shared decision-making (SDM) and patient decision satisfaction.MethodsIn total, 128 patients with metastatic melanoma from two German cancer centers will be randomized to the intervention group (IG), receiving access to the PtDA before medical consultation, or the control group (CG), receiving treatment as usual (TAU), i.e., medical consultation alone. There will be three major assessment points (before intervention, T0; after intervention, T1; and 3 months after intervention, T2). The main outcome is the patient’s knowledge of their treatment options, measured by a self-developed, piloted multiple-choice test at T1. Secondary outcome measures will include the extent of SDM during medical consultation, assessed by Observer OPTION 5, and patient decision satisfaction, assessed by the Satisfaction with Decision Scale (SwD), at T1 and T2.DiscussionThis trial will assess the effectiveness of a developed PtDA to enhance patient knowledge of treatment options for metastatic melanoma, SDM, and patient decision satisfaction. If the efficacy can be proven, the PtDA will be implemented nationwide in Germany to close a relevant gap in the education and care of patients with metastatic melanoma.Trial registrationClinicalTrials.gov NCT04240717. Registered on 27 January 2020

Comparative efficacy of dabrafenib+trametinib versus treatment options for metastatic melanoma in first-line settings.

Aim: The objective was to systematically review the literature and assess the relative efficacy of agents approved in first-line settings via network meta-analysis. Materials & methods: A literature review was conducted via searching different medical databases. The eligibility criteria included Phase II or III randomized controlled trialsthat had enrolled treatment-naive adult patients with advanced/metastatic melanoma. Results: The network meta-analysis results suggested that dabrafenib+trametinib significantly prolongs the survival outcomes compared with the monotherapies and had comparable efficacy profile compared with encorafenib+binimetinib and cobimetinib+vemurafenib. In comparison with immunotherapies, the results varied for progression-free survivaland overall survival.Conclusion: Long-term survival data of dabrafenib+trametinib establishes the combination as one of the preferred treatment optionsfor previously untreated melanoma patients.

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

Trends in the prognosis of metastatic melanoma in the era of targeted therapy and immunotherapy: A single-institution survey in Japan.

Advances in anticancer therapy, including the development of targeted therapy and immunotherapy, have drastically changed treatment options for metastatic melanoma. However, to date, only a few studies have been published that directly compare overall survival (OS) before and after introduction of these new therapeutic options in Japan. We retrospectively surveyed patients with metastatic melanoma treated in our hospital between 1989 and 2019 to investigate the OS benefit of the new therapies. A total of 115 patients with metastatic melanoma (cutaneous origin, 92; mucosal, 14; uveal, two) were included in the study. Kaplan-Meier analysis showed that the patient group receiving targeted therapy/immunotherapy (TT/IT) (n=47) had a median OS of 19.0months, which was longer than that in patients receiving conventional chemotherapy (n=42, 8.0months) or no treatment (n=26, 6.0months) (P<0.001). In the subgroup analysis performed for the TT/IT group, patients of younger age and with the BRAF mutation had significantly improved OS. As the number of treatment lines increased, the median OS tended to become longer. Our real-world data confirmed an improvement of median OS upon the introduction of the new therapies for metastatic melanoma. However, the long-term OS benefit was limited, possibly because of racial differences in some of the clinical characteristics. To improve the overall melanoma prognosis, the entire treatment strategy, including perioperative therapy needs strengthening.

Rapid evolution of acute kidney injury after initial infusion of pembrolizumab in a melanoma patient concurrently treated with RAF/MEK inhibitors.

The use of either immune checkpoint blockade or RAF/MEK inhibitors represents standard of care treatment options for metastatic melanoma. Each class of these drugs has distinct response kinetics, adverse effects, and unique clinical challenges. Combination of immune checkpoint blockade and RAF/MEK inhibitors may result in rapid and durable responses, however, the potential adverse effects of such combinations are poorly characterized. Here, we describe the case of a patient with BRAF-mutant melanoma who received an initial infusion of anti-PD-1 therapy while taking RAF/MEK inhibitors and experienced severe acute kidney injury, an otherwise infrequent side effect of any of these drugs alone. Treatment with corticosteroids rapidly reversed this process, indicating an underlying immune-mediated complication. A deeper understanding of potential adverse effects of combination therapies and their potential mechanisms should be carefully considered in the treatment landscape for melanoma and other cancers.

Current status of gene therapy in melanoma treatment

Melanoma is the deadliest type of skin cancer and which has a high ability of metastasis. Surgery is an effective method to treat I or II stage melanoma patients. However, there are few treatment options for metastatic melanoma. Gene therapy is one of the attractive options and is considered as the future direction for treating melanoma. This review mainly discusses the properties and challenges of the various gene therapies in melanoma, especially the delivery systems and gene targeting.

Current and emerging treatment options for metastatic melanoma: a focused review

Melanoma is responsible for nearly 9,000 deaths each year in the United States. Until the early 2000s, chemotherapeutic agents were the mainstay of treatment for metastatic disease. Currently approved treatments include therapies that block signal transduction pathways (BRAF inhibition), increase anti-tumor immune responses (CTLA-4 blockade), or stimulate tumor-infiltrating T cells (IL2). In recent years, various new strategies have emerged. Radiation therapy has been widely underutilized, but it can prime tumor cells that are distant from the field of radiation, a phenomenon termed the abscopal effect. Other therapies such as pembrolizumab disrupt the tumor cells' typical mechanisms of T-cell avoidance. Various other treatments involving imiquimod, adoptive T-cell therapy, and vaccines are currently being studied and can play a role in metastatic melanoma treatment in the future. Herein, we review the past treatment modalities, currently approved treatments, and potentially effective options for the future. We also provide strengths of recommendation and level of evidence for each treatment.

Melanoma of unknown primary origin in the novel therapy era: a Dutch population-based study

Background: Over the past decade, there has been tremendous progress in treatment options for metastatic melanoma, with most improvements reported in clinical trials. Approximately 3% of the melanoma patients present with melanoma of unknown primary (MUP). In most trials with novel agents, outcomes in MUP patients have not been reported specifically. We aimed to describe the epidemiology of Dutch MUP patients and assess changes in survival after introduction of novel therapy in clinical practice.

Progression patterns under BRAF inhibitor treatment and treatment beyond progression in patients with metastatic melanoma.

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF‐mutant metastatic melanoma who had progressed on treatment with single‐agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra‐ and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progression‐free survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti‐PD‐1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD‐1 inhibitors.

Recent Successes and Future Directions in Immunotherapy of Cutaneous Melanoma.

The global health burden associated with melanoma continues to increase while treatment options for metastatic melanoma are limited. Nevertheless, in the past decade, the field of cancer immunotherapy has witnessed remarkable advances for the treatment of a number of malignancies including metastatic melanoma. Although the earliest observations of an immunological antitumor response were made nearly a century ago, it was only in the past 30 years, that immunotherapy emerged as a viable therapeutic option, in particular for cutaneous melanoma. As such, melanoma remains the focus of various preclinical and clinical studies to understand the immunobiology of cancer and to test various tumor immunotherapies. Here, we review key recent developments in the field of immune-mediated therapy of melanoma. Our primary focus is on therapies that have received regulatory approval. Thus, a brief overview of the pathophysiology of melanoma is provided. The purported functions of various tumor-infiltrating immune cell subsets are described, in particular the recently described roles of intratumoral dendritic cells. The section on immunotherapies focuses on strategies that have proved to be the most clinically successful such as immune checkpoint blockade. Prospects for novel therapeutics and the potential for combinatorial approaches are delineated. Finally, we briefly discuss nanotechnology-based platforms which can in theory, activate multiple arms of immune system to fight cancer. The promising advances in the field of immunotherapy signal the dawn of a new era in cancer treatment and warrant further investigation to understand the opportunities and barriers for future progress.

PCN28 - Number Needed to Treat (NNT) and Cost of Preventing an Event (COPE) Comparison Between the Association of Cobimetinib and Vemurafenib Among Other Treatment Options for Metastatic Melanoma With BRAF V600 Mutation

PCN28 - Number Needed to Treat (NNT) and Cost of Preventing an Event (COPE) Comparison Between the Association of Cobimetinib and Vemurafenib Among Other Treatment Options for Metastatic Melanoma With BRAF V600 Mutation

Clinical practice guidelines for the diagnosis and management of melanoma: melanomas that lack classical clinical features.

A Cancer Council Australia multidisciplinary working group is currently revising and updating the 2008 evidence-based clinical practice guidelines for the management of cutaneous melanoma. While there have been many recent improvements in treatment options for metastatic melanoma, early diagnosis remains critical to reducing mortality from the disease. Improved awareness of the atypical presentations of this common malignancy is required to achieve this. A chapter of the new guidelines was therefore developed to aid recognition of atypical melanomas. Main recommendations: Because thick, life-threatening melanomas may lack the more classical ABCD (asymmetry, border irregularity, colour variegation, diameter > 6 mm) features of melanoma, a thorough history of the lesion with regard to change in morphology and growth over time is essential. Any lesion that is changing in morphology or growing over a period of more than one month should be excised or referred for prompt expert opinion. Changes in management as a result of the guidelines: These guidelines provide greater emphasis on improved recognition of the atypical presentations of melanoma, in particular nodular, desmoplastic and acral lentiginous subtypes, with particular awareness of hypomelanotic and amelanotic lesions.

The impact of checkpoint blockade prior to adoptive cell therapy using tumor-infiltrating lymphocytes for metastatic melanoma: An update from MD Anderson Cancer Center.

138 Background: Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can produce long lasting treatment responses in patients (pts) with metastatic melanoma. In our initial report of 31 treated pts, we demonstrated overall response rate (ORR) of 48%. Due to the evolution of treatment options for metastatic melanoma with heavy reliance on immunomodulatory therapies, we sought to re-evaluate responses in the era of checkpoint blockade. Methods: Pts receive treatment consisting of 7 days of lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. High dose interleukin-2 (720,000 IU/kg IV q 8 hrs up to 15 doses) was infused after TIL infusion. Responses were assessed by imaging per irRC. Results: A total of 74 pts have been treated in our initial TIL study with an updated ORR assessment of 43%. Stratification of pts according to their checkpoint blockade immune-modulator therapy prior to TIL ACT, demonstrated that prior Ipilimumab (Ipi) decreased ORR to 33% compared to 51% in checkpoint naïve pts and decreased overall survival (OS) post-TIL therapy (median 7.7 vs 24.6 months respectively). There were too few pts to assess the impact of anti-PD1 as a single agent. A multiparametric analysis revealed that LDH levels at the time of therapy mainly influences OS and ORR to TIL but still could not invalidate the impact of Ipi prior to TIL ACT. The durability of the response was also found to be different between the 2 groups (30% for Ipi prior and 50% No Ipi prior). This new reality also impacted previously reported parameters that correlated with ORR to TIL ACT such as the expression of B-and-T lymphocyte attenuator (BTLA) on CD8+ TIL. Interestingly, assessment of mutation load (ML) of the tumors prior to TIL ACT showed that the check point naïve group display a high ML ( &gt; 100) within their tumor whereas some patients who had Ipi prior to TIL have a low ML ( &lt; 100). Conclusions: Our preliminary analysis shows that pre-treatment with Ipi decreases ORR to TIL ACT. Understanding how prior ipi modifies TIL, the tumor and microenvironment will help to define the full extent of the impact and how to best treat Ipi refractory pts with TIL. Clinical trial information: NCT00338377.

Abstract B022: Intratumoral CD40 activation and checkpoint blockade induces systemic anti-melanoma immunity that eradicates disseminated tumors

Abstract Although surgical resection is a reliable treatment for localized melanoma, treatment options for metastatic melanoma are limited. Melanoma Brain metastasis (MBM) is a major clinical problem in patients with advanced melanoma, and the incidence of brain metastasis is increasing every year. Thus, there is a significant unmet need for effective therapies for metastatic melanoma and MBM patients. Agonistic CD40 antibodies generate strong tumor specific CD8 T cell response and anti-tumor activity; however systemic anti-CD40 therapy has been associated with cytokine release syndrome and liver toxicity. We studied the anti-melanoma activity and mechanism of action of a non-replicating adenovirus encoding a CD40-targeting chimeric immunostimulatory protein (ISF35) by local intratumoral delivery approach to treat local and distant melanoma. Mice bearing established B16 melanomas on both right and left flanks or on right flank and in brain were treated intratumorally with ISF35 or rAd.empty to the right flank tumor and received anti-PD1 plus anti-CTLA-4 systemically. Anti-tumor effects of mono or combination therapies were determined by mice survival and tumor growth measurement. The mechanistic contribution of immune cells to this therapy was determined by using antibody blockades. Immune cell infiltrates in tumor and expression of activation markers on these cells were analyzed by flow cytometry. Intratumoral administration of ISF35 generates systemic anti-tumor immunity mediates by CD8 T cells and suppress both injected and distant uninjected wild-type B16.F10 melanomas. However, tumors did not completely regress after therapy. When combined with checkpoint inhibitors, ISF35 generates synergistic systemic anti-melanoma immunity that eradicates both injected and uninjected distant subcutaneous melanoma and uninjected brain melanoma with 40% of mice cured. The systemic anti-tumor activity of ISF35/anti-PD-1/anti-CTLA-4 was associated with greater production of melanoma-specific CD8 T cells with an activated phenotype. Immunotherapy based on intratumoral CD40 activation is potentiated by PD-1 and CTLA-4 blockade and this combination generates functional and long-lasting anti-tumor CD8 T cell immunity that systemically suppresses melanoma metastases. This approach will be a better option for treatment of patients with metastatic melanoma that does not respond to checkpoint blockage monotherapy. Citation Format: Manisha Singh, Christina Vianden, Adi Diab, Patrick Hwu, Willem W. Overwijk. Intratumoral CD40 activation and checkpoint blockade induces systemic anti-melanoma immunity that eradicates disseminated tumors [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B022.

Current treatments for advanced melanoma and introduction of a promising novel gene therapy for melanoma (Review).

Metastatic melanoma is a fatal form of skin cancer that has a tendency to proliferate more rapidly than any other solid tumor. Since 2010, treatment options for metastatic melanoma have been developed including chemotherapies, checkpoint inhibition immunotherapies, e.g., anti‑cytotoxic T‑lymphocyte antigen‑4(CTLA‑4) and anti‑programmed death‑1(PD‑1), and molecular-targeted therapies, e.g., BRAF and MEK inhibitors. These treatments have shown not only high response rates yet also side‑effects and limitations. Notwithstanding its limitations, stem cell therapy has emerged as a new auspicious therapy for various tumor types. Since stem cells possess the ability to serve as a novel vehicle for delivering therapeutic or suicide genes to primary or metastatic cancer sites, these cells can function as part of gene‑directed enzyme prodrug therapy(GDEPT). This review focuses on introducing engineered neural stem cells(NSCs), which have tumor‑tropic behavior that allows NSCs to selectively approach primary and invasive tumor foci, as a potential gene therapy for melanoma. Therapy using engineered NSCs with cytotoxic agents resulted in markedly reduced tumor volumes and significantly prolonged survival rates in preclinical models of various tumor types. This review elucidates current treatment options for metastatic melanoma and introduces a promising NSC therapy.

Current metastatic melanoma treatment patterns in academic oncology.

e20119 Background: Treatment options for metastatic melanoma have changed rapidly over the past few years. Little evidence on patient experiences and outcomes in routine academic practice is availa...

Combination therapy of melanoma using kinase inhibitors.

Treatment options for metastatic melanoma depend on the clinical course of the disease and the molecular profile such as mutations of the BRAF gene. In this article, we review the current state of targeted therapy with kinase inhibitors. Despite major advancements in targeted therapy of metastatic melanoma, most patients relapse and show progressive disease after 5-7 months with single inhibition of BRAF or MEK. Acquired resistance is virtually universal and mediated by diverse mitogen-activated protein kinase-dependent or independent mechanisms. Recent evidence favours concurrent targeting of BRAF and MEK in patients with BRAFV600-mutated melanoma instead of BRAF inhibitor monotherapy. The combination delays the onset of acquired resistance, resulting in increased progression-free and overall survival. A growing number of early trials evaluate the efficacy of inhibitors targeting additional pathways such as phospho-inositide 3-kinase/AKT in conjunction with BRAF or MEK. Even though consistent and mature phase III study results are not yet available for these combinations, the repertoire of targeted therapy in metastatic melanoma is wide and promising. The short era of single BRAF inhibition in BRAF-mutated melanoma is soon taken over by dual concurrent inhibition of MEK and BRAF.