gdc-0973 and Brain-Neoplasms

During the past several years, targeted therapies have significantly improved outcomes in advanced basal cell carcinoma, psoriasis, and metastatic melanoma. This article reviews how advances in our understanding of the molecular pathogenesis of these diseases led to the development of targeted therapies and how these therapies are improving outcomes. Research is ongoing to address continuing challenges of drug resistance, adverse effects, and how best to use the new medications.

Topics: Adult; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azetidines; Brain Neoplasms; Carcinoma, Basal Cell; Dermatologic Agents; Dermatology; Etanercept; Female; Humans; Imidazoles; Indoles; Interleukin-17; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridines; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Necrosis Factor-alpha; Ustekinumab; Vemurafenib

Cobimetinib combined with vemurafenib was available in France in 2015 through a 'Temporary Authorization for Use' program (TAU, preapproval access pending its marketing on 2016) for patients with v-raf murine sarcoma viral oncogene homolog B1-mutant advanced melanoma. This study aimed to provide real-world outcomes in patients previously registered in this TAU. This noninterventional, ambispective, multicentre French study, conducted in patients previously registered in TAU, aimed to estimate overall survival (OS) and progression-free survival (PFS) and to describe the tolerability of the therapeutic combination. At first cobimetinib intake (in combination with vemurafenib), 88% of the 185 evaluable patients had disease stage IV (brain metastasis: 70% of them), 31% had elevated lactate dehydrogenases, and 10% had an Eastern Cooperative Oncology Group (ECOG) index ≥2. Median OS was 16.1 months (95% CI, 12.5-20.7). Brain metastasis ( P < 0.001), ECOG index ≥2 ( P = 0.007), and hepatic impairment ( P = 0.037) were found as independent factors significantly associated with shorter survival. Median PFS was 7.3 months (95% CI, 5.2-8.4). ECOG index ≥2 ( P = 0.006) was significantly associated with shorter PFS. Between cobimetinib start and inclusion, increased CPK (3% of patients), retinal serous detachment (3%), decreased left ventricular ejection fraction (3%), increased transaminases (3%), and rash (3%) were the most reported serious adverse events. This study provides real-world outcomes in France for the vemurafenib-cobimetinib combination available in patients with BRAF-mutant-advanced melanoma. Our data tend to confirm in the real-life setting that this combination therapy is effective in such patients, with a safety profile consistent with previous interventional studies.

Topics: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Humans; Melanoma; Mice; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Stroke Volume; Vemurafenib; Ventricular Function, Left

Post-surgical management of low grade gangliogliomas is controversial with paucity of data for the use of chemotherapy. BRAF mutations are present in a number of glioma subtypes and offer an opportunity for treatment with targeted therapy.. A 32-year-old man with an unresectable, BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial radiological and clinical response was noted after 13 weeks of treatment. Treatment complication with grade 2 skin and liver toxicity was resolved with dose interruption and reduction.. Combination BRAF and MEK inhibition present a safe and feasible treatment strategy in unresectable BRAF V600E mutant low grade ganglioglioma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Ganglioglioma; Humans; Male; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Drug Resistance, Neoplasm; Ganglioglioma; Humans; Male; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brain Neoplasms; Demyelinating Diseases; Female; Guillain-Barre Syndrome; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Piperidines; Polyradiculoneuropathy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib