Update on BRAF and MEK inhibition for treatment of melanoma in metastatic,unresectable, and adjuvant settings

Introduction: Selective inhibition of the MAPK pathway with BRAF and MEK inhibitors has emerged as a key component of the treatment of BRAF-mutant unresectable/locally advanced metastatic melanoma.

Areas covered: Current data are presented on the efficacy and safety of BRAFi + MEKi combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) from phase I, II, and III trials in the unresectable/locally advanced metastatic setting, as well as neoadjuvant and adjuvant applications. The theoretical basis, pre-clinical findings, clinical trial results and current ongoing clinical studies of combined BRAF/MEK inhibition with immunotherapy, also known as ‘triplet therapy,’ are also explored.

Expert opinion: Combination therapy with BRAF and MEK inhibitors dramatically improves response rates, progression-free survival and overall survival in patients with BRAF-mutant metastatic melanoma compared to historical treatments such as chemotherapy. Some serious adverse effects, including cutaneous squamous cell carcinoma, are attenuated with combination therapy, while less severe and reversible effects including pyrexia, left ventricular dysfunction, and ocular events can be more common with combination therapy. Existing data are insufficient to recommend triplet therapy, or a particular treatment sequence, with respect to BRAF and MEK inhibitors and immune therapies, though results from multiple ongoing trials are anticipated.     

An overview of binimetinib for the treatment of melanoma

ABSTRACT

Introduction

Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma.     

Future of combination therapy with dabrafenib and trametinib in metastatic melanoma

Introduction: Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF^V600 mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib, and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.

Expert opinion: Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.     

Emerging BRAF inhibitors for melanoma

Introduction: The clinical activity of BRAF inhibitor (BRAF-I) therapy is a major breakthrough in the treatment of metastatic melanoma carrying BRAF mutations. However, the therapeutic efficacy of BRAF-I therapy is limited due to the onset of intrinsic and acquired drug resistance.

Areas covered: The role of wild-type BRAF in melanocytes and of the mutated BRAF in the pathogenesis of melanoma is described in this article. The results obtained with BRAF-I in patients with mutated BRAF are reviewed. The mechanisms driving the intrinsic and acquired BRAF-I resistance, the development of combinatorial strategies designed to overcome them and their potential limitations are discussed. Lastly, the many questions that have to be addressed to optimize therapy with BRAF-I are listed.

Expert opinion: Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The discovery of BRAF mutations which drive melanoma tumorigenesis and the development of agents which selectively inhibit mutant-activated BRAF represent a major breakthrough in the treatment of metastatic melanoma. However, the development of drug resistance underlies the need of more effective and individualized combinatorial treatments to counteract the multiple escape mechanisms utilized by BRAF-mutant melanoma. Although combinatorial strategies using agents which target different protumorigenic signaling pathway components have been shown to increase the clinical efficacy of BRAF-I, novel strategies which utilize different antitumor mechanisms are needed.     

BRAF and MEK inhibition in melanoma

Introduction: Selective inhibition of the MAPK pathway with either BRAF or MEK inhibition has emerged as a key component for the treatment of BRAF-mutant metastatic melanoma. New evidence suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival, while potentially attenuating some of the serious adverse events observed with monotherapy.

Areas covered: This review covers the current data on the efficacy and safety of the selective BRAF (vemurafenib and dabrafenib) and MEK (trametinib) inhibitors as well as the available data on BRAF inhibitor + MEK inhibitor combination therapy (dabrafenib + trametinib and vemurafenib + cobimetinib). The efficacy, safety and toxicity data are discussed from Phase I, Phase II and Phase III trials of these drugs.

Expert opinion: Combination therapy with the BRAF and MEK inhibitors improves response rates and progression-free survival in patients with BRAF-mutant metastatic melanoma. Some of the serious adverse events, in particular, the incidence of cutaneous squamous cell carcinoma, are attenuated with combination therapy, whereas milder side effects such as pyrexia can be more common with combination therapy. Although dose reductions and dose interruptions are slightly more common with combination therapy, overall data supports the notion that combination therapy is safe and improves the outcomes for patients compared to single agent BRAF inhibitors.     

Current and emerging systemic therapies for cutaneous metastatic melanoma

Introduction: Melanoma therapies have evolved rapidly, and initial successes have translated into survival gains for patients with advanced melanoma. Both targeted and immune-therapy now have evidence in earlier stage disease. There are many new agents and combinations of treatments in development as potential future treatment options. This highlights the need for a reflection on current treatment practice trends that are guiding the development of potential new therapies.

Areas covered: In this review, the authors discuss the evidence for currently approved therapies for cutaneous melanoma, including adjuvant therapy, potential new biomarkers, and emerging treatments with early phase clinical trial data. The authors have searched both the PubMed and clinicaltrials.gov databases for published clinical trials and discuss selected landmark trials of current therapies and of investigational treatment strategies with early evidence for the treatment of melanoma.

Expert opinion: Significant efficacy has been demonstrated with both immune checkpoint inhibitors and targeted therapies in treating advanced melanoma. A multitude of novel therapies are in development and there is need for instructive biomarker assessment to identify patients likely to respond or be refractory to current therapies, to identify mechanisms of resistance and to direct further treatment options to patients based on individual disease biology.     

BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma

Introduction: BRAF inhibition alone has achieved unprecedented efficacy results in patients affected by BRAF-mutated advanced melanoma. Since these findings, it was postulated that dual inhibition of BRAF and other components of the RAS/RAF/MEK/ERK MAPK pathway (such as MEK) would be superior to BRAF inhibition as monotherapy. A series of recent clinical trials have confirmed this hypothesis.

Areas covered: In this article, the biological rationale for both single and concomitant inhibitions of the MAPK pathway in BRAF mutant melanoma is provided. Moreover, available clinical data on the efficacy and toxicity of BRAF and MEK inhibition as single agents and in combination are extensively reviewed.

Expert opinion: Dual BRAF and MEK inhibition in advanced BRAF-mutated melanoma is superior to single inhibition in terms of efficacy without significant increase in toxicity. Therefore, BRAF plus MEK inhibition is expected to supersede single-agent BRAF inhibition in these patients in the near future.     

Cobimetinib and vemurafenib for the treatment of melanoma

Introduction: Cobimetinib combined with vemurafenib is a new approved MEK inhibitor for first line treatment of metastatic melanoma patients with BRAF V600 mutations. It improves tumor response rates and progression free survival compared to vemurafenib alone, while decreasing toxicities due to the paradoxical activation of the MAPK signaling pathway.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical and preclinical studies on cobimetinib. It also reports ongoing trials evaluating cobimetinib to better understand future developments for this drug.

Expert opinion: The combination of cobimetinib and vemurafenib seems to be more toxic than the combination therapy dabrafenib and trametinib even if these four drugs have never been compared in a randomized trial. The future of this combination depends on its capacity to be combined simultaneously or sequentially with immune based therapies to improve the durability of responses.     

Dabrafenib for the treatment of melanoma

Introduction: Approximately 50% of patients with cutaneous melanoma have an activating mutation in BRAF kinase, leading to constitutive activation of the mitogen-activated protein kinase pathway and unregulated cell growth. Selective inhibitors of the mutated BRAF kinase produce response rates of approximately 50% with median progression-free survival of 6 – 7 months. BRAF-blocking therapies work rapidly, with responses seen within 2 weeks after therapy initiation, and they are associated with generally mild toxicities. The BRAF inhibitor dabrafenib recently was approved for use in patients with BRAF V600-mutated metastatic melanoma.

Areas covered: This article discusses the mechanisms of action and pharmacokinetic and pharmacodynamic changes as well as clinical efficacy and safety of dabrafenib for treatment of patients with advanced melanoma including unresectable stage IIIc and stage IV patients who harbor a BRAF V600 mutation. Clinical trial data are reviewed, and efficacy of dabrafenib in patients with brain metastases and in combination with the MEK inhibitor trametinib is discussed.

Expert opinion: Despite rapid and significant tumor reduction in a majority of patients with BRAF-mutant metastatic melanoma who are treated with dabrafenib, this drug’s use as a single agent is limited because of its relatively short duration of response. Various combinations with drug(s) inhibiting other target kinases and/or with immunomodulating agent(s) will likely be the standard in the near future.     

The risk of dermatological toxicities of combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma patients: a systematic review and meta-analysis

Background: This meta-analysis was conducted to assess the risk of dermatological toxicities of combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma patients.

Methods: We considered relevant prospective randomized phase I, II, and III trials of melanoma patients on the combined BRAF and MEK inhibition versus BRAF inhibition, describing events of rash, photosensitivity reaction (PR), hyperkeratosis (HK), alopecia, cutaneous squamous-cell carcinom(cSCC), skin papilloma(SP), pruritus, and hand-foot syndrome(HFS), as eligible for inclusion.

Results: Eight trials comprising 3163 patients were included in the meta-analysis. The relative risks(RRs) of developing all-grade rash with combined BRAF and MEK inhibition versus BRAF inhibition was 1.59 (95%CI, 1.35–1.86, p?p?=?0.002), SP 0.09(95%CI, 0.04–0.24, p?p?p?p?p?p?=?0.21), HK 0.18(95%CI, 0.06–0.53, p?=?0.002), SP 0.14(95%CI, 0.02–1.16, p?=?0.07), alopecia 0.72(95%CI, 0.14–3.62, p?=?0.69), cSCC 0.23(95%CI, 0.17–0.33, p?<?0.00001), HFS 0.40(95%CI, 0.08–2.06, p?=?0.27), and PR 0.14(95%CI, 0.04–0.51, p?=?0.003), respectly.

Conclusion: Our analysis of data has demonstrated that combined BRAF and MEK inhibitor-based treatment is associated with an increased risk of all-grade rash and a decreased risk of all-grade and high-grade HK, SP, alopecia, cSCC, HFS, and PR compared with single BRAF inhibitor alone in melanoma patients. Appropriate prevention and management are recommended.     

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors

Objective: Currently, the treatment of BRAF V600-mutated metastatic melanoma with BRAF inhibitors gives a response rate of ～ 50% with a progression-free survival of ～ 6 – 7 months. In order to identify predictive biomarkers capable of stratifying BRAF-mutated patients at high risk of shorter response duration to anti-BRAF therapy, the authors analyzed the expression of 15 microRNAs (miRNAs) targeting crucial genes involved in melanoma biology and drug response.

Research design and methods: A total of 15 miRNAs and target gene expression were investigated in 43 patients (30 BRAF-mutated, and 13 BRAF wild-type). Moreover, 20 BRAF-mutated patients treated with vemurafenib were analyzed for miRNA expression in respect to time-to-progression.

Results: All miRNAs except miR-192 showed low expression in BRAF-mutated as compared with BRAF wild-type patients. In particular, miR-101, miR-221, miR-21, miR-338-3p and miR-191 resulted in significant downregulation in BRAF-mutated patients. Moreover, high expression of miR-192 and miR-193b* and low expression of miR-132 resulted in significant association with shorter progression.

Conclusion: Three miRNAs were significantly associated with clinical outcome in metastatic melanoma patients. An increased understanding of the molecular assessment of BRAF-mutated melanomas could allow development of specific molecular tests able to predict response duration.     

BRAF kinase inhibitors for treatment of melanoma: developments from early-stage animal studies to Phase II clinical trials

Introduction: Approximately, 30.4–66.0% of cutaneous melanomas possess a mutation in the BRAF gene that activates downstream signaling through the mitogen-activated protein (MAP) kinase pathway; this provides an attractive target for the treatment of advanced melanoma. Although BRAF inhibitors rapidly suppress melanoma growth, median progression-free survival remains unsatisfactory. Recent clinical trials have investigated drugs that can optimally enhance and prolong the anti-melanoma effects of BRAF inhibitors.

Area covered: This review discusses the development of BRAF inhibitor-based combination therapies for BRAF-mutant advanced melanoma.

Expert opinion: Future strategies for the treatment of advanced melanoma include novel combination therapies using BRAF/MEK inhibitors and immune checkpoints inhibitors or histone deacetylase inhibitors. These combination therapies might enhance antitumor responses against melanoma, prolonging survival in advanced melanoma patients. Further clinical studies are needed to optimize these novel combination therapies.     

Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma

The discovery of activating BRAF V600E mutations in 50% of all cutaneous melanomas has revolutionized the understanding of melanoma biology and provided new strategies for the therapeutic management of this deadly disease. Highly potent small molecule inhibitors of BRAF are now showing great promise as a novel therapeutic strategy for melanomas harboring activating BRAF V600E mutations and are associated with high levels of response. This commentary article discusses the latest data on the role of mutated BRAF in the development and progression of melanoma as the basis for understanding the mechanism of action of BRAF inhibitors in the preclinical and clinical settings. We further address the issue of BRAF inhibitor resistance and outline the latest insights into the mechanisms of therapeutic escape as well as describing approaches to prevent and abrogate the onset of both intrinsic and acquired drug resistance. It is likely that our evolving understanding of melanoma genetics and signaling will allow for the further personalization of melanoma therapy with the goal of improving clinical responses.     

Tyrosine kinase inhibitors in the treatment of unresectable or metastatic gastrointestinal stromal tumors

Introduction: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Proliferation of GIST is driven by activating mutations in the KIT or PDGFRA genes that found in most sporadic GISTs. Surgery is the main remedial measure for primary GIST, and imatinib is the principal therapeutic of choice for unresectable or metastatic GIST. Imatinib revolutionized treatment for unresectable or metastatic GISTs; however, resistance to imatinib has inevitably developed for most GIST patients.

Areas covered: PubMed was searched to find biological studies of GIST and clinical trials of molecularly targeted agents on unresectable or metastatic GISTs, and the key papers found have been reviewed. In this paper, the standard therapy which includes imatinib, sunitinib and regorafenib for unresectable or metastatic GIST has been reviewed and molecular mechanisms of resistance for tyrosine kinase inhibitors (TKIs) have been postulated and discussed. Treatment measures for resistant GIST and therapeutic choices after the standard therapy have also been described.

Expert opinion: The standard therapy for unresectable or metastatic GISTs is first-line imatinib, second-line sunitinib and third-line regorafenib. After standard therapy, best supportive care or clinical trials is recommended in the guidelines. However, patients may benefit from continuation of TKIs beyond disease progression and from rechallenge of TKIs used previously.     

Mitogen-activated protein kinase (MEK) inhibitors to treat melanoma alone or in combination with other kinase inhibitors

Introduction: Malignant melanoma (MM) is an aggressive disease with a rapidly rising incidence due to neoplasm of melanocytes. Molecular targeted therapies have demonstrated lower toxicity and improved overall survival versus conventional therapies of MM. The revealing of mutations in the BRAF/MEK/ERK pathway has led to the development of BRAF inhibitors such as vemurafenib and dabrafenib for the treatment of cutaneous MM. Though, progression of resistance to these agents has prompted attempts to target downstream proteins in this pathway. Trametinib, a MEK1/2 inhibitor, was approved in 2013 for the treatment of BRAF V600E/K mutation-positive unresectable or metastatic cutaneous melanoma patients.

Areas covered: The aim of the current review is to present an update on the role of MEK in progressive melanomas and summarize latest results of clinical studies with innovative MEK inhibitors and/or combined approaches with other kinase inhibitors such as BRAF inhibitors in the treatment of MM.

Expert opinion: Two combined treatments (i.e. trametinib plus dabrafenib and vemurafenib plus cobimetinib) target two different kinases in the BRAF/MEK/ERK pathway. The simultaneous prohibition of both MEK and BRAF is associated with more durable response rate than BRAF monotherapy and can overcome acquired resistance.     

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

ABSTRACT

Introduction: In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAF^V600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAF^V600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAF^V600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen.

Areas covered: Here we examine vemurafenib’s journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials.

Expert opinion: Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAF^V600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6–8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.     

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma

Introduction: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment.

Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs.

Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.     

Emerging insights into resistance to BRAF inhibitors in melanoma

Melanoma is the most aggressive form of skin cancer. The treatment of patients with advanced melanoma is rapidly evolving due to an improved understanding of molecular drivers of this disease. Somatic mutations in BRAF are the most common genetic alteration found in these tumors. Recently, two different mutant-selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, have gained regulatory approval based on positive results in randomized phase III trials. While the development of these agents represents a landmark in the treatment of melanoma, the benefit of these agents is limited by the frequent and rapid onset of resistance. The identification of several molecular mechanisms of resistance to BRAF inhibitors is rapidly leading to the clinical testing of combinatorial strategies to improve the clinical benefit of these agents. These mechanisms, and the lessons learned from the initial testing of the BRAF inhibitors, provide multiple insights that may facilitate the development of targeted therapies against other oncogenic mutations in melanoma, as well as in other cancers.     

Protein kinase inhibitors in melanoma

Introduction: The most commonly mutated oncogene identified to date in melanoma is BRAF (～ 50%), an upstream mediator of the mitogen-activated protein kinase (MAPK) pathway. Recently, BRAF-kinase inhibitors as well as MEK-kinase inhibitors were introduced into the clinics.

Areas covered: Substantial Phase II and III clinical trials were searched in patients with advanced melanoma treated with BRAF-kinase inhibitors, MEK-kinase inhibitors and cKIT inhibitors.

Expert opinion: For patients with a BRAF, NRAS or cKIT mutation the treatment with selective, targeted drugs is considered as feasible and results in a high rate of confirmed tumor responses. In patients with BRAF mutation the progression free survival and overall survival is prolonged in patients who were treated with BRAF kinase inhibitors or MEK kinase inhibitors compared to patients receiving chemotherapy with dacarbazine. A major problem is the development of resistance to the inhibitors through multiple different mechanisms. One approach to overcome resistance is to combine BRAF and MEK inhibitors. Treatments with kinase inhibitors are more efficacious than chemotherapies, however, they compete with the newly developed immune checkpoint blockers, and may in future be preferentially applied in second- or x-line.     

Molecular targeted therapy for patients with melanoma: the promise of MAPK pathway inhibition and beyond

Importance of the field: Recent discoveries have expanded the understanding of the molecular signaling events critical to melanomagenesis and led to the development of targeted therapeutic agents that are revolutionizing the treatment of patients with advanced melanoma.

Areas covered in this review: This article reviews current therapy and its limitations, describes the key pathogenic mechanisms in melanoma for which inhibitors have been tested, and summarizes the results of clinical trials involving molecularly targeted agents in this disease.

What the reader will gain: There has been an explosion of preclinical and clinical research aimed at targeting the key molecular alterations in melanoma for therapeutic benefit. These findings will be presented and placed in the proper clinical context, affording information regarding the current molecular targets in the melanoma and the activity and limitations of therapeutic agents directed against them.

Take home message: Greater understanding of the pathogenic mechanisms underlying melanoma development has prompted the development of new therapeutic approaches aimed at counteracting these processes. While progress made over the past few years has generated considerable excitement, the benefits of these new therapies are still limited by incomplete and transient tumor regressions. It is hoped that with further investigation, particularly into mechanisms of treatment de novo and acquired treatment resistance, these limitations can be overcome.