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Background: BRAF inhibitors are effective against selected BRAF V600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity., Methods: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)., Results: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m 2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m 2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045)., Conclusions: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAF V600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors., (© 2018 American Cancer Society.)

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: One of the most common and deadly complications of melanoma is brain metastases. The outcomes of advanced melanoma patients who developed brain metastases were reviewed to identify significant prognostic factors for overall survival (OS)., Methods: An institutional database of advanced melanoma patients enrolled on clinical trials in the Department of Melanoma Medical Oncology from 1986 to 2004 was reviewed and patients who developed brain metastases were identified. Date of diagnosis, patient age, pattern of brain involvement, timing relative to extracranial metastases, prior response to systemic therapy, and treatments given for brain metastases were assessed as potential prognostic factors for OS., Results: Among 743 melanoma patients enrolled in clinical trials for regional or systemic metastatic disease, 330 (44%) patients developed brain metastases. The median OS after the diagnosis of brain metastases was 4.7 months. Diagnosis before 1996, increased number of parenchymal brain metastases, leptomeningeal involvement, and development of brain metastases after receiving systemic therapy for extracranial metastases were found to be significant prognostic factors for OS. Among patients who received systemic therapy as the initial treatment of brain metastases, patients who previously responded to systemic therapies had longer survival than patients who had not responded., Conclusions: The era, pattern, and timing of melanoma brain metastases were found to be strongly associated with survival. Previous responsiveness to systemic therapies did not predict better outcomes overall, but it did correlate with improved survival for patients with brain metastases who were treated with systemic therapies. These factors may be used in guiding patient management and for stratifying patients in clinical trials., (Copyright © 2010 American Cancer Society.)

Background: Preliminary studies suggesting that extended-dose temozolomide with thalidomide is safe and active in patients with metastatic melanoma have led to frequent use of this oral regimen. To confirm these observations the combination was tested in a multicenter Phase II trial in patients with melanoma brain metastases., Methods: Eligible patients had melanoma brain metastases, with or without systemic metastases. The primary endpoint was response rate in brain metastases. Patients received temozolomide at a dose of 75 mg/m2/day for 6 weeks with a 2-week rest between cycles, and thalidomide (escalated to 400 mg/day for patients age < 70 years or to 200 mg/day for patients age > or = 70 years). A 2-stage design required > or = 3 responses in the first 21 patients before enrolling 29 additional patients in the second stage., Results: Sixteen eligible patients were enrolled. No objective responses were observed. The median survival was 23.9 weeks. Seven patients withdrew because of tumor progression; 7 were removed during Cycle 1 because of adverse events, including allergic reaction (1 patient), severe fatigue (1 patient), sudden death (1 patient), and thromboembolic events (pulmonary embolism in 3 patients and deep vein thrombosis in 1 patient); 2 patients withdrew when the study was suspended and subsequently closed. No associations could be established between baseline characteristics and toxicity., Conclusions: The proportion of patients with lethal or potentially life-threatening adverse events was high (0.31, 95% confidence interval, 0.11-0.59), and the absence of objective responses made it unlikely that further accrual would demonstrate the efficacy of the regimen. These observations provide little support for the use of this combination for melanoma brain metastases unless safe and effective methods to prevent thrombosis are developed., (2006 American Cancer Society)

Background: Temozolomide and interferon-alpha-2b (IFN-alpha-2b) are both active in melanoma. Therefore, the efficacy and safety of temozolomide in combination with pegylated IFN-alpha-2b in patients with metastatic melanoma without brain metastases was investigated., Methods: Patients with histologically confirmed, unresectable, American Joint Committee on Cancer Stage IV melanoma were enrolled in an open-label, Phase II study. The primary endpoints were tumor response and safety. Patients received temozolomide (75 mg/m2/dayx6 weeks with a 2-week break between cycles) plus concomitant subcutaneous pegylated IFN-alpha-2b (0.5 microg/kg/wk, continuously). Treatment was continued until unacceptable toxicity or disease progression occurred., Results: Thirty-five patients (median age, 55 years) with Stage IV melanoma and a median of 3 metastatic sites were enrolled and received a median of 1 cycle (i.e., 8 weeks) of therapy (range, 0-6 cycles). Eleven patients (31%) (95% confidence interval, 16% to 47%) had an objective tumor response, including 3 with clinical complete response durations of 6 months, 20 months, and 32+ months and 8 with partial responses. Three patients with a partial or mixed response were subsequently rendered free of clinically detectable disease with surgery. The median survival was 12 months with a median follow-up among survivors of 16 months. No patient developed brain metastases while receiving study treatment. Treatment was generally well tolerated. Hematologic toxicity consisted mainly of lymphopenia and leukopenia (National Cancer Institute Common Toxicity Criteria Grades 1-3); no Grade 4 hematologic toxicity was observed., Conclusions: The combination of temozolomide plus pegylated IFN-alpha-2b had antitumor activity and was well tolerated in patients with metastatic melanoma. Therefore, further study is warranted., (Copyright (c) 2006 American Cancer Society.)