title: Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges.
abstract: Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF(V600) driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.
authors: Siwen Hu-Lieskovan, Lidia Robert, Blanca Homet Moreno, and Antoni Ribas, University of California Los Angeles, Los Angeles, CA; and Blanca Homet Moreno, Carlos III Health Institute, Madrid, Spain.
authors: Siwen
authors: S
authors: Hu-Lieskovan
authors: Siwen Hu-Lieskovan, Lidia Robert, Blanca Homet Moreno, and Antoni Ribas, University of California Los Angeles, Los Angeles, CA; and Blanca Homet Moreno, Carlos III Health Institute, Madrid, Spain.
authors: Lidia
authors: L
authors: Robert
authors: Siwen Hu-Lieskovan, Lidia Robert, Blanca Homet Moreno, and Antoni Ribas, University of California Los Angeles, Los Angeles, CA; and Blanca Homet Moreno, Carlos III Health Institute, Madrid, Spain.
authors: Blanca
authors: B
authors: Homet Moreno
authors: Siwen Hu-Lieskovan, Lidia Robert, Blanca Homet Moreno, and Antoni Ribas, University of California Los Angeles, Los Angeles, CA; and Blanca Homet Moreno, Carlos III Health Institute, Madrid, Spain. aribas@mednet.ucla.edu.
authors: Antoni
authors: A
authors: Ribas
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000235:genetics / Q000628:therapy*; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf