Targeted therapies: Improved outcomes for patients with metastatic melanoma

Recently published phase III trials involving interleukin-2, ipilimumab and vemurafenib redefine 'standard-of-care' for metastatic melanoma and demonstrate improved survival compared with dacarbazine. All three therapies are potential first-line options for patients with metastatic melanoma, with optimal treatment strategies evolving based on tumor mutation status, disease burden, performance status and comorbidities.     

Major therapeutic advances in the treatment of metastatic melanoma

The treatment of metastatic melanoma is presently in complete revolution. Two molecules have recently been authorized for this indication. These treatments have a very different mechanism of action compared to previous chemotherapies. Vemurafenib is a targeted therapy, which blocks BRAF selectively. This molecule induces objective responses in more than 50 % of the patients with V600E mutated melanoma and a benefit in terms of overall survival. However, many patients relapse after about 6 to 8 months of treatment. Many mechanisms are evoked to explain these secondary resistances to therapy. Ipilimumab is an immunotherapy that blocks CTLA4, a physiological brake of lymphocyte activation. With ipilimumab, the objective responses are less frequent than with vemurafenib but are more prolonged over time. Two phases III have demonstrated that ipilimumab treatment is effective on the overall survival of patients with metastatic melanoma. New combination therapies and additional targeted and immunotherapy agents are exciting perspectives that make us more optimistic for the future of metastatic melanoma treatment.     

Integrating New Therapies in the Treatment of Advanced Melanoma

OPINION STATEMENT: Treatments for advanced melanoma have evolved rapidly based on improved understanding of the pathways that determine T-cell responses and knowledge of growth-related mutations, which can be targeted with new classes of pharmacologic agents. The FDA approved ipilimumab and vemurafenib for advanced melanoma in 2011. Our practice is to evaluate all tumors from patients with metastatic disease for the presence of a BRAF mutation (Fig. 1). More than 20?years of follow-up show that responders to IL-2 can be cured of their melanoma. Therefore, we recommend high-dose IL-2 as first line therapy for patients with excellent functional status and normal cardiopulmonary reserve regardless of their BRAF mutation status. We use ipilimumab, which can induce durable tumor regressions and improved survival, as initial therapy for patients who refuse or are not candidates for IL-2, also regardless of their BRAF mutation status. Ipilimumab can be used as salvage therapy for patients with advanced disease after IL-2 or vemurafenib. Targeted therapies such as vemurafenib or imatinib can be offered to patients whose melanomas express the BRAF V600E or C-Kit mutations. Vemurafenib is particularly useful for patients whose disease is progressing rapidly, as clinical improvement can be obtained within days of starting therapy and response rates may be as high as 70?%. The major reason we do not recommend vemurafenib as first line treatment in all patients whose tumors have BRAF mutations is the short median duration of response of approximately 7?months. Enrollment in a clinical trial should always be considered for patients with metastatic melanoma. The clinical trial focus has changed from finding any agent with activity in melanoma, to overcoming mechanisms of resistance and enhancing the immunomodulatory activity of these new agents that confer therapeutic benefit. Selected patients can benefit from surgical resection or radiation to manage oligometastatic disease.     

Long-term survival with modern therapeutic agents against metastatic melanoma—vemurafenib and ipilimumab in a daily life setting

Despite new therapeutic options, metastatic melanoma remains to be one of the most fatal tumors. With the development of BRAF inhibitors and immune checkpoint inhibitors, overall survival could be prolonged significantly for the first time. Clinical studies implied that even long-term survival is possible with both types of drugs, but predictive markers are so far missing. In this study, we analyzed survival data from patients that received the first-in-class substances vemurafenib and ipilimumab, respectively, during the time period from registration of the drugs until availability of combination treatments. We aimed to evaluate the possibility of long-term survival in a daily life setting and to characterize patients that benefit from these drugs in order to gain insight into predictive attributes. Eighty patients were evaluated who were treated with either vemurafenib (n = 40) or ipilimumab (n = 40), and overall survival was analyzed. Subgroup analysis was performed for patients who were still alive 24 months after induction of therapy (long-term survival). Median overall survival (OS) was 8.0 months for patients treated with vemurafenib and 10.0 months for patients treated with ipilimumab (log-rank P value = 0.689). Long-term survival was achieved in 32.5% of patients (42.3% vemurafenib, 57.7% ipilimumab). Negative predictors of long-term survival in the vemurafenib group were brain and liver metastases, as well as elevated LDH, S100ß and liver enzymes. For ipilimumab, an increase in lymphocytes and eosinophils during course of treatment correlated with long-term survival. Our real-life experience shows that long-term survival is possible with using both therapeutic agents, vemurafenib and ipilimumab. Pattern of metastases and laboratory values might be of interest in decision making for a specific therapeutic approach. Combination of drugs and observational studies in larger patient cohorts are necessary to further validate our findings.     

Revisiting the role of systemic therapies in patients with metastatic melanoma to the CNS

The CNS is a common site of metastasis in patients with malignant melanoma. Locoregional control either with surgery or radiotherapy is first-line treatment for patients with brain metastasis should they be suitable candidates. For those patients who are not and those who progress after previous treatment, there is an unmet clinical need for effective systemic therapies. Systemic cytotoxics, such as temozolamide and fotemustine, have only modest activity, resulting in a median progression-free survival ranging from 1–2 months, in patients with metastatic melanoma to the brain. Newer systemic treatments such as vemurafenib and ipilimumab have been approved for the treatment of melanoma, but evidence regarding their activity in brain metastases is inconclusive due to the limited access of patients to clinical trials. This is now being revised and more data are emerging supporting the inclusion of patients with brain metastasis in trials. In this review, the authors present data regarding the efficacy of systemically administered therapies in patients with metastatic melanoma to the brain.     

A new era in the treatment of melanoma: from biology to clinical practice

Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treatment options for metastatic melanoma were scarce and without any overall survival benefi t. The emergence of new targeted therapies for BRAF mutant melanoma (vemurafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogenesis, and the direct translation into clinical practice.     

Surgery for distant melanoma metastasis

Traditionally, distant metastatic melanoma has a poor prognosis owing to lack of efficacious, U.S. Food and Drug Administration-approved systemic therapy and the limited use of surgical resection as a therapeutic option. More recently, new biological therapies such as vemurafenib (Zelboraf) and ipilimumab (Yervoy) have shown strong promise and dramatically improved the landscape of stage IV melanoma therapy. Although there are numerous single-institution studies advocating the role for therapeutic surgical intervention, many remain skeptical of nonpalliative surgery for metastatic melanoma. Surgical resection of advanced melanoma has been proven to be effective as long as all disease is removed (R0). Patient selection is paramount. The combination of newer systemic therapies and surgical resection is currently under investigation. Understanding the tumor biology of melanoma and its mechanism of metastatic spread is essential to developing the most efficacious treatment strategy.     

The use of systemic therapies for the treatment of brain metastases in metastatic melanoma: Opportunities and unanswered questions

The development of brain metastases is common in patients with metastatic melanoma and heralds a particularly poor prognosis. The development of the immunological agent ipilimumab and targeted treatments such as the selective BRAF inhibitor vemurafenib have revolutionised the treatment of metastatic disease. Evidence from clinical trials suggest these drugs may be effective in the treatment of brain metastases from melanoma. However efficacy may be limited by a lack of penetration of the blood brain barrier (BBB) and by multi substrate efflux pumps expressed on the BBB. The role and sequencing of radiotherapy, both whole brain and stereotactic radiotherapy, is yet to be determined but combinations of radiotherapy and systemic therapies may further increase the effects of these drugs on brain metastases. Considering the impact of brain metastases on morbidity and mortality in metastatic melanoma, future research into systemic drug therapy for the treatment of brain metastases and improvements in BBB penetrance should be a priority.     

Hirnmetastasen des Melanoms

Context

Brain metastases occur in the majority of patients with metastatic melanoma and are the most common cause of death. Until recently, local therapy (neurosurgery, radiosurgery and whole brain radiotherapy) was the only option for a chance of disease control in the brain. Systemic treatment options are now available.

Objective

The aim of this study is to discuss the treatment options for brain metastases from melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma and recent publications (Pubmed and manual search).

Results

In limited brain metastases, neurosurgery and radiosurgery are established treatments that can prolong survival. Immunotherapy with ipilimumab appears to have activity in patients with brain metastases, particularly when metastases are small and asymptomatic (response rate 16?% and median overall survival 7 months). The BRAF inhibitor dabrafenib achieved response rates of 30–40?% and a median overall survival of 7–8 months in patients with asymptomatic BRAF mutation brain metastases. The intracranial disease control rate was 80–90?%. In patients with symptomatic BRAF mutation brain metastases, the BRAF inhibitor vemurafenib showed activity with a disease control rate of >?80?% and a median overall survival of 5 months. In symptomatic multiple brain metastases, palliative whole brain radiotherapy is an established treatment even though it has failed to show an overall survival benefit. Corticosteroids and antiepileptic drugs are indicated for patients presenting with intracranial hypertension and epileptic seizures. Treatment of patients with metastatic melanoma and brain metastases should be discussed in a multidisciplinary team.

Conclusion

The therapeutic options for patients with brain metastases from melanoma have improved in recent years. Presently, there are several effective local and systemic treatments available.     

Adjuvant therapy for resected stage III melanoma patients: high-dose interferon-alpha versus ipilimumab combined with kinases inhibitors

High-dose interferon-alpha remains the first-line treatment in the adjuvant therapy of metastatic melanoma. More recently, high-dose pegylated interferon-alpha-2b has been approved by the US Food and Drug Administration. Actually, an adjuvant therapy alternative to high-dose interferon-alpha is represented by ipilimumab. Moreover, combination therapy of IFN-alpha or ipilimumab with tyrosine kinase inhibitors has been proved in patients with specific mutations. It is mandatory to understand what the best adjuvant treatment is for resected metastatic melanoma patients, particularly at stage III-N1, in terms of overall survival rather than recurrence-free survival. The ECOG 1609 clinical trial compared high-dose interferon-alpha and ipilimumab alone or combined with tyrosine kinase inhibitors for the treatment of early metastatic melanoma. In the past, ECOG 1684, 1690 and 1694 trials showed improvement in recurrence-free survival more than overall survival for high-risk melanoma patients (stage IIB-III) treated with high-dose interferon-alpha, whereas more recently the EORTC 18991 trial reported successful therapeutic results in terms of recurrence-free survival rather than overall survival for stage III-N1 melanoma patients treated with high-dose pegylated interferon-alpha-2b. Toxicity was more acceptable within one year of treatment. Randomized trials have demonstrated that ipilimumab as second-line therapy is able to increase dose-dependent overall survival rates in advanced melanoma patients despite severe but reversible immune-related adverse events. Old tyrosine kinase inhibitors have been used in combination with interferon for the treatment of advanced melanoma patients with moderate benefits and increased toxicity, but new selective drugs seem to be more efficacious. Early metastatic melanoma patients (stage III-N1) should be the principal subset to be treated with the most suitable adjuvant therapy to achieve the best overall survival. New schedules have to be tested with high-dose interferon-alpha and ipilimumab alone or combined with tyrosine kinase inhibitors while waiting for results from ECOG 1609.     

Treatment patterns in advanced melanoma: findings from a survey of European oncologists

With the emergence of new therapies, established patterns of treating advanced melanoma are changing. The aim of this study was to understand how advanced melanoma is treated in clinical practice in Europe following the introduction of ipilimumab and vemurafenib. An online survey was conducted between August and November 2012 with 150 oncologists and dermatologists, from France, Germany, Italy, Spain and the UK; respondents reported treating the majority of patients with one or two lines of therapy. For BRAF mutant melanoma, the most frequently used first‐line treatments were vemurafenib and dacarbazine. For BRAF wild‐type melanoma, the most frequently used first‐line treatment was dacarbazine. There was no single preferred agent for the second‐line treatment of BRAF mutant or BRAF wild‐type disease. Most sequencing from first‐ to second‐line was from conventional dacarbazine to newer agents such as ipilimumab and vemurafenib. The treatment of advanced melanoma is rapidly evolving due to the introduction of new agents. This study presents an early insight into access to the new agents, ipilimumab and vemurafenib, and clinical practice in several European countries.     

New drugs in melanoma: it's a whole new world

Current developments in systemic therapies for melanoma are spectacular. Over the last 40 years no one drug or combination of drugs demonstrated any impact on survival in metastatic melanoma. In contrast, in 2011 a number of new drugs will be approved. In 2011 immunomodulation with ipilimumab, a monoclonal antibody targeting the ligand CTLA-4, has been approved for patients with advanced melanoma in first- and second-line treatment by the Food and Drug Administration (FDA) and in second-line treatment by the European Medicines Agency (EMA). Also in 2011, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. Other monoclonal antibodies targeting T-cell ligands, such as programmed death-1 (PD-1), also show promise. Various inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) yield high response rates in patients harbouring the BRAF-V600E mutation. A significant impact on both progression-free and overall survival was demonstrated for vemurafenib compared with dacarbazine in a phase-III trial. Approval is expected in 2011. Both drugs had only modest effects of 2-3 months on median survival, so combination therapies must be explored. BRAF inhibitors in combination with mitogen-activated protein kinase (MEK) inhibitors show great potential. Moreover, combinations of immunomodulators and pathway inhibitors are expected to be very active, and phase-III trials are planned. Pegylated interferon-α2b was approved in 2011 on the basis of the results of the European Organisation for Research and Treatment of Cancer (EORTC) 18991 phase-III trial demonstrating a sustained impact on relapse-free survival in patients with lymph-node-positive melanoma. The efficacy of adjuvant therapy with ipilimumab is assessed in the now fully accrued EORTC18071 trial. Adjuvant trials with BRAF and MEK inhibitors are in the planning phase. Never was there a more exciting period in the world of melanoma treatment.     

Medikamentöse Systemtherapie des Melanoms

Context

Around 3000 melanoma patients are diagnosed with metastatic disease each year in Germany. For more than three decades no substantial therapeutic progress in the treatment of advanced melanoma was made; however, the use of targeted agents and immune modulating antibodies has changed the perception of melanoma as treatment-resistant tumor.

Objective

The aim of this article is to discuss the systemic treatment options for advanced metastatic melanoma.

Material and methods

Treatment recommendations are given in consideration of the S3 guidelines on diagnosis, therapy and follow-up of melanoma published in 2013 and other recent publications (PubMed and manual search).

Results

The CTLA-4 blocking antibody, ipilimumab, was the first medication to demonstrate an overall survival benefit in a prospective randomized clinical study of metastatic melanoma. Subsequently selective BRAF as well as MEK inhibitors were also shown to prolong overall survival leading to drug registration. Currently additional agents and antibodies, such as MEK inhibitors for NRAS mutations in melanoma and PD1 blocking antibodies are being tested in clinical phase III studies. Over the next years the combination and sequence of these new agents will further improve the treatment and prognosis of advanced melanoma. Treatment of metastatic melanoma always requires a multidisciplinary approach.

Conclusion

Therapy options for patients suffering from advanced metastatic melanoma have improved in recent years. Nevertheless, clinical studies still remain the best option to improve melanoma treatment and to offer patients innovative and promising treatment options despite the recently achieved progress.     

Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma

BackgroundHistorically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors.Patients and methodsWe analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival.ResultsMedian overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9–12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2–235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival.ConclusionLM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM.     

Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2012

Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumour and causes 90% of skin cancer mortality. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts’ experience. Diagnosis is made clinically and staging is based upon the AJCC system. CMs are excised with one to two centimetre safety margins. Sentinel lymph node dissection (SLND) is routinely offered as a staging procedure in patients with tumours more than 1 mm in thickness, although there is as yet no clear survival benefit for this approach. Interferon-α treatment may be offered to patients with stage II and III melanoma as an adjuvant therapy, as this treatment increases at least the disease-free survival (DFS) and less clear the overall survival (OS) time. The treatment is however associated with significant toxicity. In distant metastasis, all options of surgical therapy have to be considered thoroughly. In the absence of surgical options, systemic treatment is indicated. BRAF inhibitors like vemurafenib for BRAF mutated patients as well as the CTLA-4 antibody ipilimumab offer new therapeutic opportunities apart from conventional chemotherapy. Therapeutic decisions in stage IV patients should be primarily made by an interdisciplinary oncology team (‘tumour board’).     

Stratégies thérapeutiques et traitements systémiques des métastases cérébrales du mélanome

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.     

Network meta-analysis of therapies for previously untreated advanced BRAF-mutated melanoma

BackgroundThe 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 untreated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this patient population at the treatment level.MethodsThe 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.ResultsCombination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combination 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 relevanceThe 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 informed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape.     

Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma

Ipilimumab (MDX-010, Yervoy; Bristol-Myers Squibb), a fully human monoclonal antibody against CTL antigen 4 (CTLA-4), was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In both early- and late-phase trials, ipilimumab has shown consistent activity against melanoma. For example, in a randomized phase III trial that enrolled patients with previously treated metastatic disease, ipilimumab, with or without a peptide vaccine, improved overall survival: Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms, respectively, versus 6.4 months in the vaccine-alone group (hazard ratio, 0.68; P ≤ 0.003). Serious (grade 3-5) immune-related adverse events occurred in 10% to 15% of patients. Thus, although it provides a clear survival benefit, ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy. Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.     

Tumor-Infiltrating Lymphocytes in Melanoma

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) is arguably the most effective treatment for patients with metastatic melanoma. With higher response rates than ipilimumab or IL-2, and longer durations of response than vemurafenib, TIL therapy carries the potential to transform current outcomes in melanoma, while also defining the way cell-based immunotherapy gets incorporated into mainstream cancer treatment. This paper will review the current state of TIL therapy in melanoma, the strategies to improve its efficacy, the current obstacles, and future directions to expand the availability of TIL to the general patient population.     

Recent developments in the medical and surgical treatment of melanoma

Answer questions and earn CME/CNE Increasing knowledge of the biology of melanoma has led to significant advances in drug development to fight this disease. Surgery is the primary treatment for localized disease and is an integral part of management in patients with more advanced disease. The last decade has become the era of targeted therapy in melanoma and has revolutionized the treatment of this disease. Since 2011, 4 new agents have been approved for the treatment of patients with metastatic melanoma: ipilimumab, vemurafenib, dabrafenib, and trametinib. Several new agents are currently in phase 3 trials with hopes of even more agents being approved for this once “untreatable” disease. How to integrate surgical options with more effective systemic therapies has become a new challenge for physicians. This review will provide an update on current surgical options, highlight the pathway to the development of the newly approved agents, and further discuss new treatments that are on the horizon. CA Cancer J Clin 2014;64:171–185. ^© 2014 American Cancer Society.