Teresa Amaral

Merkel cell carcinoma: Epidemiology, pathogenesis, diagnosis and therapy

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Incidence varies according to the geographic regions but is overall increasing. Different risk factors have been identified namely advanced age, immunosuppression, and ultraviolet light exposure. An association between MCC and polyomavirus infection is known. However, the exact mechanism that leads to carcinogenesis is yet to be fully understood. Surgery when feasible is the recommended treatment for localized disease, followed by adjuvant radiation or chemoradiation. In the metastatic setting, chemotherapy has been the standard treatment. However, two recently published trials with immune checkpoint inhibitors in first and second line showed promising results with a tolerable safety profile and these might become the standard therapy shortly. Somatostatin receptors are expressed in many MCC but such expression is not associated with disease severity. Presently there are no biomarkers predictive of response that could help to better select patients to these new therapies, and additional research is essential.

Non-melanoma skin cancer: new and future synthetic drug treatments

ABSTRACT Introduction: Non-melanoma skin cancers (NMSC) mainly comprise two different entities: basal cell carcinoma (BCC) and squamous cell carcinoma (SCC); beneath these two entities, Merkel cell carcinoma, adnexal tumors, dermatofibrosarcoma protuberans, angiosarcoma, and cutaneous lymphoma belong to NMSC. These rare skin tumors are not the topic of this review. BCC and SCC are the most common cancers diagnosed in humans. The preferred treatment is surgery, which in most cases is curative. Although a high recurrence rate is seen, these cancers rarely metastasize. Therefore, systemic treatments were not a priority for these patients. It is long known that the abnormal activation of Hedgehog and epidermal growth factor receptor pathways were involved in BCC and SCC. In the last decade, metastatic disease became an important area of research, mostly because new therapies that targeted components of these two pathways became available. Areas covered: Here we cover the available therapeutic options for patients diagnosed with BCC and SCC, focus on systemic and targeted therapies. Expert opinion: BCC and SCC are common cancers, with good prognosis. More than the metastatic disease, advanced local disease and recurrent disease pose clinicians a great challenge. Albeit there are promising results with targeted therapies, resistance development has already been described.

How to use neoadjuvant medical treatment to maximize surgery in melanoma

ABSTRACT 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.

Severe hepatitis under combined immunotherapy: Resolution under corticosteroids plus anti-thymocyte immunoglobulins

In the last 10 years, new therapies became available for patients with locally advanced or metastatic melanoma, namely target therapies and immune checkpoint inhibitors. These therapies have toxicities different from those associated with chemotherapy, which was previously the first line therapy. Treatment with immune checkpoint inhibitors can induce immune-related adverse events (AEs), which can be difficult to recognise for physicians not familiar with these therapies. Taking that in consideration, guidelines and treatment algorithms for these AE approach were elaborated. However, there are some patients who do not respond to the recommended therapies. In these cases, there is presently little experience on how to proceed. Here we present a clinical case of an autoimmune hepatitis after ipilimumab and nivolumab therapy, which did not respond to corticosteroids.

Immunotherapy in managing metastatic melanoma: which treatment when?

ABSTRACT Introduction: Ten to fifteen percent of melanoma patients develop distant or unresectable metastasis requiring systemic treatment. Around 45% of the patients diagnosed with metastatic cutaneous melanoma harbor a BRAFV600 mutation and derive benefit from combined targeted therapy with MAPK pathway inhibitors. These offer a rapid response that translates into improvement of symptoms and increased quality of life. However, resistance often develops with subsequent progressive disease. Immunotherapy with checkpoint inhibitors may be offered to BRAF-mutated and wild-type patients and is associated with longer and durable responses that can continue over years. Areas covered: In this review, the authors discuss the late evidence for targeted and immunotherapy in melanoma patients, as well as therapy sequencing. Immunotherapy in special populations is also addressed. Expert opinion: Effective treatments are currently available. However, there are still unanswered questions of the best therapy sequence, the clear superiority of combined immunotherapy versus monotherapy in all patients, and therapy duration. Since different promising treatments will become available, clinical trials comparing the diverse options in terms of safety, efficacy and cost- effectiveness are required to make the right decisions. Consequently, patients should be encouraged to participate in clinical trials, whenever possible.

Reply to ‘Recent advances in systemic targeted therapy for cutaneous T-cell lymphoma’

Dear Editor, We would like to thank you for the opportunity to comment on the letter to the editor written by Lewis et al. with the title: ‘Recent advances in systemic targeted therapy for cutaneous T-cell lymphoma.’ Nonmelanoma skin cancers comprise of basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Merkel cell carcinoma, adnexal tumors, dermatofibrosarcoma protuberans, angiosarcoma, and cutaneous lymphoma. Contrary to BCC and SCC, the other tumors are relatively rare. The advances recently made on the therapies available for these rare tumors were outside the scope of our article [1]. However, similar to BCC and SCC, treatment of the above mentioned rare tumors is currently changing, as pointed out by Lewis and colleagues. Targeted therapy, but also immunotherapy, will probably become a part of treatment options of ‘real-world patients,’ outside clinical trials in the near future (i.e. avelumab and pembrolizumab for the treatment of Merkel cell carcinoma) [2,3]. Although most advanced cutaneous T-cell lymphomas are currently incurable, the newly available therapies seem to hold the promise of changing patients’ outcomes. Intense investigation is currently being done in this field involving monoclonal antibodies and proteasome inhibitors among others. This exciting ongoing investigation is, in our opinion, very well described and summarized in the submitted letter. Undoubtedly, further multicenter and multinational clinical investigations are required in order to generate evidence-based treatment strategies for these rare cutaneous malignancies. Funding

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

ABSTRACT 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.