Binimetinib for the treatment of NRAS-mutant melanoma

Introduction: Activating NRAS mutations occur in approximately 15–20% of melanomas and are the second most common oncogenic driver mutation in this disease, after BRAF mutations. There is an unmet medical need for new targeted therapy opportunities in metastatic patients whose tumors harbor an NRAS mutation. Binimetinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, has shown clinical activity in this group of patients.

Areas covered: The purpose of this paper was to review the safety, activity and efficacy of the MEK inhibitor binimetinib for the treatment of NRAS-mutant melanoma, as well as to discuss future therapeutic perspectives such as multiple pathways, targeted therapy, and combinations with immunotherapy.

Expert commentary: Only a modest progression-free survival (PFS) benefit was observed in NRAS-mutated patients who received binimetinib compared with dacarbazine in a randomized phase 3 clinical trial, with no improvement in overall survival. Nevertheless, binimetinib represents another promising treatment option for advanced melanoma and the first molecularly targeted therapy for the NRAS-mutant population. Binimetinib may also have a role in treating NRAS-mutated melanoma patients after failure of immunotherapy.     

Radiosurgery/stereotactic radiotherapy in combination with immunotherapy and targeted agents for melanoma brain metastases

Introduction: The clinical landscape of advanced melanoma drastically changed after the introduction of both targeted therapies and immunotherapy. This rapid development in systemic therapies led to a change in the management of patients with brain metastases, with the subsequent need to re-assess the role of local therapies, in particular stereotactic radiosurgery (SRS).

Areas covered: In this non-systematic review, we report on the current knowledge on the use of SRS in combination with immunotherapy and BRAF/MEK inhibitors for patients with melanoma brain metastases, as well as ongoing trials in this field.

Expert commentary: It is now more common to observe patients with melanoma brain metastases with better performance status and prolonged life expectancy. A combination of targeted therapy and immunotherapy, in different sequences, has been shown to be feasible and well tolerable, on the basis of retrospective reports. Additional data from ongoing prospective trials are however needed to confirm or not these findings and better explore the efficacy of the combination.     

The safety and efficacy of cobimetinib for the treatment of BRAF V600E or V600K melanoma

Introduction: In the recent years, melanoma patients’ outcome and survival improved, mainly because of systemic treatment improvement with targeted therapy and checkpoint blockade. Targeted therapy with BRAF and MEK inhibitors was approved to treat patients with unresectable or metastatic melanoma, harboring BRAF V600 mutations. This paper addresses the safety and efficacy of cobimetinib, when used in combination with vemurafenib, in the previous mentioned setting.

Areas covered: This article presents an overview on the rationale for clinical development of cobimetinib, as well as the mechanism of action, the efficacy and safety, and the most important trials that led to the approval of the combination therapy with vemurafenib. We searched the PubMed for published papers related to safety and efficacy of cobimetinib, and resistance mechanisms to BRAF inhibition. The abstract databases of the American Society of Clinical Oncology and European Society for Medical Oncology were also searched for updates on the mentioned clinical trials.

Expert commentary: Patients treated with targeted therapy experience a rapid tumor response. However, virtually all patients will develop resistance to treatment. Therapeutic combinations to overcome resistance mechanisms are currently addressed. In the future, targeted therapy strategy will include three or more drugs, probably from different therapeutic classes.     

Targeted therapy for metastatic colorectal cancer

Introduction: Outcomes in metastatic colorectal cancer are improving, with better understanding and use of targeted therapies.

Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This article reviews the current evidence for targeted therapies in advanced colorectal cancer, including up-to-date data regarding anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor (VEGF) agents, the relevance of primary tumor location and novel subgroups such as BRAF mutated, HER2 amplified, and mismatch-repair-deficient cancers.

Expert commentary: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for metastatic colorectal cancer (mCRC). The use of EGFR-targeted antibodies should be restricted to patients with extended RAS wild-type profiles, and there is evidence that they should be further restricted to patients with left-sided tumors. Clinically, mCRC can be divided into subgroups based on RAS, BRAF, HER2, and MMR status, each of which have distinct treatment pathways.     

Update on medical treatment of small intestinal neuroendocrine tumors

Introduction: Small intestinal (SI) neuroendocrine tumors (NETs) are relatively rare tumors. Due to the lack of symptom or specific symptoms, SI-NETs are often diagnosed at an advanced stage, making therapy challenging. The management of patients with advanced stage SI-NETS requires a multidisciplinary approach that combines surgical and medical treatment including novel targeted molecular therapies.

Areas covered: This article summarizes current strategies for the medical treatment of SI-NETS.

Expert commentary: The treatment plan of advanced-stage SI-NETs should be tailored in a case-by-case manner with the adoption of a multidisciplinary approach that combines different treatment options, including biological targeted therapies. In particular, we believe that the identification of the optimal treatment sequence(s), correct treatment timing and the selection of patients eligible to different treatments need specific investigation in controlled clinical trials.     

Intralesional therapy as a treatment for locoregionally metastatic melanoma

Introduction: The emergence of novel intralesional therapies have dramatically changed the treatment landscape for melanoma. The heterogeneous presentation of melanoma continues to pose challenges for clinicians, especially when dealing with advanced locoregional disease. Intralesional therapies have the benefit of causing local tumor destruction, while minimizing systemic toxicity. Moreover, the integration of immunotherapeutic agents into intralesional compounds has resulted in the additional benefit of a bystander effect, whereby untreated distant lesions also derive a benefit from treatment. Intralesional therapy has assumed an important role in the management of unresectable, locoregional disease for melanoma.

Areas covered: Multiple intralesional agents have been studied over the years, with only a few demonstrating promising results. This review will provide an overview of the different intralesional agents for melanoma. Mechanisms of action, clinical efficacy, and side effects will be the primary focus.

Expert commentary: Treatment options for advanced melanoma continue to evolve. Attractive new therapies delivered by an intralesional route has demonstrated promising results, with minimal side effects. The ideal treatment strategy for melanoma will remain a multimodal approach; intralesional therapy provides an additional tool in the treatment armamentarium for melanoma.     

Adjuvant therapy for advanced renal cell carcinoma

Introduction: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear.

Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors.

Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.     

How to use neoadjuvant medical treatment to maximize surgery in melanoma

Introduction: The aim of this work is to discuss the role of neoadjuvant therapy in melanoma patients, namely the potential to improve control and surgical resectability of locoregional disease. Moreover, potential survival benefits for high-risk stage III and IV melanoma patients will be addressed.

Areas covered: In this review, the different available neoadjuvant treatments including chemotherapy, bio-chemotherapy, targeted therapy, immunotherapy and local therapy will be presented and discussed. The PubMed published articles were identified and searched using the following terms located in the publication title: neoadjuvant therapy and melanoma. Studies investigating targeted therapy, immunotherapy and local melanoma treatments were included. Clinicaltrial.gov was also used as a source for recruiting or ongoing but not recruiting neoadjuvant clinical trials, for which no published results are available.

Expert commentary: Targeted therapy and immunotherapy in a neoadjuvant setting are still under investigation and not yet approved, however several neoadjuvant trials are ongoing. Shortly, results from these trials will answer the question whether neoadjuvant treatment translates into survival benefit and improves local disease control in stage III and IV melanoma patients. Immunotherapy and targeted therapy will play as relevant a role as in the metastatic setting, whereas chemotherapy will be used seldom.     

Ipilimumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors.

Areas covered: We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma

Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma.

The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.     

Second-line treatments of small-cell lung cancers

Introduction: Second-line therapies for relapsed small cell lung cancer (SCLC) patients remain a challenge, with limited clinical benefit because of rapid tumor growth, early dissemination and the development of drug resistance during the disease. Recent developments in genomic sequencing have provided further insight into the biology of the disease, identifying new targets and new pathways.

Areas covered: This review details chemotherapy, targeted therapies and immune-checkpoint blockades that have been investigated as second-line treatments for SCLC patients using a PubMed search (period 1990 – 2016, terms used: SCLC, treatments, second line, therapy).

Expert commentary: Recent genomic, proteomic and preclinical studies have identified novel therapeutic strategies currently being evaluated in clinical trials. Promising approaches for SCLC management include delta-like ligand-3 (DLL3)-targeted antibody–drug conjugate, combination targeted therapies, or targeted therapy–chemotherapy with an additive effect superior to the efficacy of single agents. The blockade of immune checkpoints has yielded promising preliminary results and is being investigated in ongoing trials. The inclusion of SCLC patients relapsing after platin-doublet induction in well-designed clinical trials remains a major challenge.     

Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck

Introduction: As epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of squamous cell carcinomas of the head and neck (SCCHN), several therapeutic agents that target EGFR have been evaluated for the treatment of SCCHN. Although patients with SCCHN derive clinical benefit from anti-EGFR agents, most notably the EGFR monoclonal antibody cetuximab, these patients eventually become resistant to EGFR-based therapies; preclinical studies have shown activation of secondary signaling pathways that lead to resistance to EGFR inhibition and, as such, serve as potential therapeutic targets to overcome resistance to EGFR inhibitors.

Areas covered: This review summarizes the results of recently completed trials of anti-EGFR agents in SCCHN, highlights the various mechanisms that drive resistance to EGFR inhibitors in SCCHN, and focuses on several novel targeted agents that could potentially help overcome resistance to EGFR-based therapies in SCCHN.

Expert commentary: Due to the development of resistance to EGFR-targeted therapies, novel treatment approaches to overcome resistance are a key unmet need for SCCHN.     

Therapeutic approaches for refractory germ cell cancer

Introduction: Most germ cell cancer patients with metastatic disease are cured by cisplatin-based combination chemotherapy. 30% of metastatic patients will develop relapse or progress despite adequate first-line treatment and will require salvage therapy, with about 10% of metastasized patients ultimately developing platinum-resistant and fatal disease.

Areas covered: Based on a comprehensive literature search of MEDLINE, EMBASE and conference proceedings of ESMO, ASCO and EAU meetings, this review provides an overview on current and potential future treatment options for platinum-refractory germ cell cancer patients including cytostatics and molecularly targeted therapies.

Expert commentary: Treatment of platinum-refractory disease remains challenging and long-term survival is rarely achieved despite multimodal treatment approaches. Targeted treatment approaches do not yet play a role in the treatment of platinum-refractory disease due to lacking efficacy in small, unselected clinical trials. Inclusion of patients into clinical trials is strongly recommended.     

Future applications of FGF/FGFR inhibitors in cancer

Introduction: Deregulation of the fibroblast growth factor (FGF)/FGF receptor (FGFR) network occurs frequently in tumors due to gene amplification, activating mutations, and oncogenic fusions. Thus, the development of FGF/FGFR-targeting therapies is the focus of several basic, preclinical, and clinical studies.

Areas covered: This review will recapitulate the status of current FGF/FGFR-targeted drugs.

Expert commentary: Non-selective FGF/FGFR inhibitors have been approved for cancer treatment but evidence highlights various complications affecting their use in the clinical practice. It appears mandatory to identify FGF/FGFR alterations and appropriate biomarkers that may predict and monitor response to treatment, to establish the contribution of the FGF/FGFR system to the onset of mechanisms of drug resistance, and to develop effective combinations of FGF/FGFR inhibitors with other targeted therapies.     

Therapeutic approaches for T790M mutation positive non-small-cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) is a subset of lung cancer with demonstrated response to targeted therapies. However, resistance to the first targeted approach usually occurs within the first year, and it is associated in 50–60% of cases to the T790M resistance mutation.

Areas covered: The review provides an overview on the significance of the presence of the T790M mutation, its detection, treatment options and subsequent mechanisms of resistance.

Expert commentary: Osimertinib is the current treatment option for T790M mutation positive NSCLC after progression to first or second-generation EGFR TKIs, with activity also on brain metastasis. However, the scenario is in continuous evolution and results from clinical trials are awaited in first-line setting and in combination strategies.     

The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care

Introduction: The eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging system was implemented in the United States on 1 January 2018.

Areas covered: This article provides an overview of important changes in the eighth edition AJCC staging system from the seventh edition based on analyses of a large international melanoma database. The clinical implications of these changes for melanoma treatment are also discussed.

Expert commentary: A standardized and contemporary cancer staging system that facilitates accurate risk stratification is essential to guide patient treatment. The eighth edition of the AJCC staging system is currently the most widely accepted approach to melanoma staging and classification at initial diagnosis.     

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has

significantly decreased mortality from breast cancer (BC).

Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase

recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops.

Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.     

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

Introduction: The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics.

Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function.

Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.     

Preventing central nervous system metastases in non-small cell lung cancer

Introduction: There are no effective central nervous system (CNS) metastases prevention methods in lung cancer patients. Prophylactic cranial irradiation has a limited effectiveness and relatively high toxicity. Systemic chemotherapy is not relevant in reducing the risk of CNS in lung cancer patients. The understanding of molecular background of brain metastases in non-small cell lung cancer (NSCLC) patients could contribute to the development of personalized treatments for such patients.

Areas covered: This article summarizes the latest clinical trials concerning the use of radiotherapy, chemotherapy, molecularly targeted therapies, and immunotherapy in lung cancer patients, with particular consideration of brain lung cancer metastasis prevention. The literature search was undertaken via PubMed and EMBASE searches and relevant articles are included in this review.

Expert commentary: The recent data supports that EGFR-TKIs and ALK inhibitors are clinically relevant for first-line treatment to prevent and treat CNS metastases in molecularly selected NSCLC patients. In the future, high hopes for the prevention of CNS metastases in NSCLC patients are associated with immunotherapy concerning immune check-points inhibitors.     

Recent advances in the management of pancreatic adenocarcinoma

Introduction: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly controversial. This review article aims to explore the current knowledge of pancreatic adenocarcinoma, focusing on diagnosis, treatment strategies, and the best supportive care.

Areas covered: The current literature on pancreatic adenocarcinoma treatment modalities has been summarized, with a focus on clinical trials and reviews. New treatment strategies and their impact on clinical practice have also been discussed.

Expert commentary: Despite many therapeutic developments, only modest improvements in survival rates have been achieved. There is an essential need to increase survival by developing more innovative treatment approaches for patients with PC.     

Optimizing treatment in recurrent epithelial ovarian cancer

Introduction: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients’ ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex.

Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC.

Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.