Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma.

PURPOSE: Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. PATIENTS AND METHODS: We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. RESULTS: Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed. CONCLUSIONS: Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01355120.

BRAF, MEK and KIT inhibitors for melanoma: adverse events and their management.

The introduction of tyrosine kinase inhibitors for the treatment of malignant melanoma has led to unprecedented response rates with superior overall survival rates in patients with targetable kinase mutations. Even though targeted, the effects of these new therapies are not limited to the cancer cells and induce a wide array of different adverse events (AEs). Most toxicities are mild to moderate in severity and often only affect the skin, but quality of life of patients is still affected. To prevent dose reduction and/or interruption, a sound knowledge of potential AEs and their management is required. BRAF inhibitors should not be used in patients with known RAS-mutant tumour in the medical history. We review common AEs of BRAF, MEK and KIT inhibitors used for the treatment of malignant melanoma and their management.

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network.

BACKGROUND: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. METHODS AND FINDINGS: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patients delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. CONCLUSION: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Side effects of systemic oncological therapies in dermatology.

The discovery of specific gene mutations, termed "driver mutations", in different tumors has brought personalized medicine into the focus of cancer treatment. Targeted treatment agents generally are administered orally and have a tolerable adverse event profile; they have become widely used in both inpatient and outpatient settings. The approval of the selective BRAF inhibitor vemurafenib (Zelboraf®) as first-line therapy of metastatic melanoma in Europe in February 2012 as well as the increasing use of MEK inhibitors within clinical trials confronts dermatologists and oncologists with a new spectrum of side effects. Knowledge of these possible adverse events and their management will be crucial for optimized patient care. This article offers an overview of the most important adverse events of currently employed dermato-oncologic therapeutic agents.

Current advances and perspectives in the treatment of advanced melanoma.

Melanoma has long been considered as an extremely therapy-resistant tumour. Recent developments in the area of immunotherapy as well as targeted therapy showed rapid development and excellent results. The anti-CTLA-4 antibody ipilimumab, which was approved in the USA and Europe in 2011, was the first substance in melanoma therapy to demonstrate an overall survival benefit. Another approval is expected in Europe for the specific BRAF-inhibitor vemurafenib, which has shown a significant impact on progression-free survival and overall survival in patients with the BRAF(V600E) mutation. In this review the relevant agents in the substance classes of immunomodulatory drugs and small molecules are presented and discussed, and future prospects for combination therapies and developments in melanoma treatment are outlined.

Improved survival with ipilimumab in patients with metastatic melanoma.

BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

Adjuvant pegylated interferon α-2b therapy for melanoma.

Although adjuvant high-dose interferon α-2b therapy significantly improves recurrence-free survival vs. observation in high-risk resected melanoma, the overall survival benefit is presently unclear. Pegylation of interferon α-2b (peginterferon α-2b) allows for a reduction in the dosing frequency with increased drug exposure. Adjuvant peginterferon α-2b therapy has also been shown to provide a significant, sustained improvement in recurrence-free survival compared with observation in patients with stage III melanoma. We report on the use of adjuvant peginterferon α-2b (3 µg/kg/week) in clinical practice in a series of 8 patients treated at the Universitätsklinikum Essen in Germany following complete resection of primary melanoma at intermediate- and high-risk of recurrence (stage II-III). Treatment duration ranged from 2 to 29 months, with 4 patients receiving long-term therapy (≥24 months). Following treatment, 5 patients (stage II) remained disease-free at 33, 33, 37, 39 and 43 months from the time of diagnosis. In 2 patients, peginterferon α-2b was terminated 4 and 9 months after treatment initiation due to disease progression. Once-weekly subcutaneous administration of peginterferon α-2b was convenient in all patients. In 3 patients experiencing adverse events, dose reductions led to a resolution of symptoms and enabled treatment to continue long-term. Three further patients discontinued therapy due to adverse events at 2, 8 and 27 months of therapy (persistent elevation of γ-glutamyl transpeptidase, liver transaminase elevation and urosepsis); dose modifications were not applicable in these patients. Thus, long-term adjuvant peginterferon α-2b therapy was feasible in the clinical practice setting and was generally well tolerated in these intermediate- and high-risk melanoma patients.