No abstract

BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. RESULTS: Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose-related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. CONCLUSIONS: Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance.

Immunotherapy leads to significantly prolonged survival of patients with metastatic melanoma. Autoimmune side effects including colitis, dermatitis, and endocrine abnormalities are common in patients treated with ipilimumab [anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4)]. Antibodies such as pembrolizumab that interfere with the PD-1 (programmed cell death 1)/PD-L1 pathway show greater efficacy and less toxicity than ipilimumab. Here we report 2 cases of pembrolizumab-induced uveitis associated with complete or partial tumor response. We suggest that uveitis may serve as a surrogate marker for a tumor response to therapy with pembrolizumab.

Background: Treatment with immune checkpoint and BRAF/MEK inhibitors has significantly improved the survival of patients with advanced cutaneous melanoma and other metastatic malignancies. Therapy-related uveitis is a rare ocular adverse event, which may potentially lead to legal blindness. The epidemiology of treatment-related uveitis is currently insufficiently known. Patients and methods: In this cohort study, we asked whether exposure to either immune checkpoint or BRAF/MEK inhibitors was associated with a higher risk of developing uveitis compared with the general population. Based on a Bayesian framework, we estimated the probability of developing uveitis with a right-censored, exponential survival model using data from the Zurich Melanoma Registry. The registry included all adult patients treated for advanced cutaneous melanoma between January 2008 and December 2018 at the University Hospital of Zurich, Switzerland. Results: In total, 304 patients (64%) were treated with immune checkpoint and 186 patients (38%) with BRAF/MEK inhibitors. Median follow-up time was 74 days (interquartile range: 57e233 days). Eleven patients developed uveitis and 30 patients died. We estimated the probability of developing uveitis per year in the general population as 0.05% (95% credibility interval [

Melanoma can be classified based on the detection of relevant oncogenic driver mutations. These mutations partially determine a patient's treatment options. MEK inhibitors have demonstrated little efficacy in patients with NRAS‐mutated melanoma owing to primary and secondary resistance. We report two patients with NRAS‐mutant metastatic melanoma with long‐term response to intermittent MEK‐inhibitor binimetinib therapy. Intermittent dosing schedules could play a key role in preventing resistance to targeted therapy. This article highlights the efficacy of an intermittent dosing schedule, toxicities associated with binimetinib, and possible mechanisms preventing resistance in targeted therapy. Intermittent MEK‐inhibitor therapy may be considered in patients with NRAS‐mutated melanoma that have failed all standard therapies. Key Points Melanomas harbor NRAS mutations in 10%–30% of the cases. These mutations promote hyperactivation of the MAPK pathway, leading to proliferation and prolonged survival of tumor cells. Currently, drugs directly targeting NRAS are not available. Downstream inhibition of the MAPK pathway can be considered as a therapeutic option after immunotherapeutic failure. Intermittent administration of kinase inhibitors might be the way to partially overcome the development of drug resistance by (a) inducing a fitness deficit for drug‐resistant cells on treatment break, (b) increasing the immunogenicity, and (c) inducing apoptosis and cell cycle arrest. It also enhances expression of numerous immunomodulating molecules, and reduction of immunosuppressive factors, which suggests better access of the immune system to the tumor.