Vemurafenib and radiation therapy in melanoma brain metastases.

Brain metastases in malignant melanoma carries a poor prognosis with minimal response to any therapy. The purpose of this pilot analysis was to find the effectiveness of vemurafenib, an oral BRAF inhibitor, and radiation therapy in V600 mutated melanoma with brain metastases. BRAF mutation status of the melanoma patients was determined by real-time PCR assay. Retrospective analysis was performed on twelve patients who had the mutation and were treated with either stereotactic radiosurgery or whole brain radiation therapy prior to or along with vemurafenib at a dose of 960 mg orally twice a day. Clinical and radiological responses, development of new brain metastases, overall survival and toxicity were assessed. Improvement in neurological symptoms was seen in 7/11 (64 %) following therapy. Radiographic responses were noted in 36/48 (75 %) of index lesions with 23 (48 %) complete responses and 13 (27 %) partial responses. Six month local control, freedom from new brain metastases and overall survival were 75, 57 and 92 %. Four patients had intra-tumoral bleed prior to therapy and two patients developed steroid dependence. One patient experienced radiation necrosis. This retrospective study suggests that melanoma patients with brain metastases harboring BRAF mutation appear to be a distinct sub-group with a favorable response to vemurafenib and radiation therapy and acceptable morbidity.

Ipilimumab-Induced Organizing Pneumonia on 18F-FDG PET/CT in a Patient With Malignant Melanoma.

A 60-year-old woman with history of vaginal malignant melanoma and inguinal nodal metastases underwent F-FDG PET/CT for restaging following ipilimumab (Yervoy) immunotherapy, a Food and Drug Administration-approved human monoclonal antibody targeting cytotoxic T-lymphocyte-associated antigen 4. PET/CT demonstrated mildly FDG-avid multifocal enlarging bilateral lung opacities. Within each lung lesion, there was circumferential uptake localizing to a high-attenuation rim with a photopenic ground-glass center on CT, consistent with "reversed halo sign." Patient was asymptomatic at the time of imaging. Ipilimumab was discontinued, and 3-month follow-up PET/CT revealed spontaneous complete resolution of the lung lesions, supporting the diagnosis of ipilimumab-induced organizing pneumonia.

Ipilimumab-induced hepatitis on 18F-FDG PET/CT in a patient with malignant melanoma.

A 78-year-old man with metastatic malignant melanoma underwent a restaging 18F-FDG PET/CT after initiation of ipilimumab therapy, a Food and Drug Administration-approved human monoclonal antibody targeting CTLA-4. PET/CT demonstrated intense FDG uptake fusing to poorly circumscribed hypodensities throughout the liver. Patient was experiencing high-grade fever, chills, and generalized fatigue at the time of imaging, as well as mildly elevated liver function tests. Patient was subsequently treated with corticosteroids for suspected ipilimumab-induced hepatitis, and the patient rapidly improved clinically. Follow-up PET/CT 2 months later revealed complete resolution of abnormal FDG uptake in the liver, confirming the diagnosis of ipilimumab-induced hepatitis.

Primer on immuno-oncology and immune response.

Advances in the understanding of the immunogenicity of tumors have provided the basis for immuno-oncology, the development of immunotherapeutic agents that augment the patient's antitumor immunity and disrupt the immune-regulatory circuits that allow tumors to evade the immune system. Two immunomodulatory agents recently have been introduced for the treatment of malignancy: sipuleucel-T and ipilimumab. Unlike cytotoxic chemotherapy, immunotherapies stimulate the patient's immune system to mount or augment existing endogenous antitumor immune responses. Both agents have demonstrated significant improvements in long-term overall survival in patients. Like other immunotherapies, sipuleucel-T and ipilimumab also are characterized by adverse events that manifest as immune-related inflammatory conditions that typically are low grade. Management guidelines have been developed and emphasize early recognition of the signs and symptoms of immune-related adverse events and treatment with corticosteroids. Because these events can manifest even after the cessation of therapy, patients treated with immunotherapies should continue to be followed by their oncology team and other healthcare providers.

Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial.

PURPOSE: The combination of oblimersen, a bcl-2 antisense oligonucleotide, and dacarbazine lead to superior progression-free survival in advanced melanoma patients. Albumin-bound paclitaxel (nab-paclitaxel) has single-agent activity in melanoma. METHODS: In a phase I trial, chemotherapy-naïve patients with metastatic melanoma and normal LDH levels were enrolled on 3 cohorts. The treatment regimen consisted of 56-day cycles of oblimersen (7 mg/kg/day continuous IV infusion on day 1-7 and 22-28 in cohort 1 and 2; 900 mg fixed dose, twice weekly in weeks 1-2, 4-5 for cohort 3), temozolomide (75 mg/m(2), days 1-42), and nab-paclitaxel (175 mg/m(2) in cohort 1 and 3, 260 mg/m(2) in cohort 2 on day 7 and 28). Apoptosis markers were tested in pre- and post-treatment specimens of a subset of patients. RESULTS: Six grade 3 events (neutropenia, renal insufficiency, hyponatremia, elevated creatinine, allergic reaction, and neuropathy) and 2 grade 4 events (neutropenia and thrombocytopenia) were seen in 32 patients. The objective response rate was 40.6% (2 complete responses and 11 partial responses) and 11 patients had stable disease, for a disease control rate of 75%. CONCLUSIONS: The combination of oblimersen, temozolomide, and nab-paclitaxel was well tolerated and demonstrated encouraging activity in patients with advanced melanoma.