BRAF Inhibitors in Non-Small Cell Lung Cancer

Simple Summary The identification of BRAF mutations in 1.5-3.5% of NSCLC patients represents a step forward towards new targeted agents for tackling NSCLC. The positive results and favourable safety profile observed with the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients, led to the approval of these two agents in this setting. In this review, we will discuss the clinical, prognostic and therapeutic implications of BRAF mutations in NSCLC patients. Moreover, we will review MEKs' functions and their role as a potential targeted treatment, both alone and combined with anti-BRAF therapies. Finally, we will discuss ongoing studies and future perspectives in this field. The clinical research on BRAF inhibitors in NSCLC is just beginning, and a number of relevant questions remain to be addressed regarding the role of other BRAF inhibitors in NSCLC, the possibility of facing resistance mechanisms to BRAF inhibitors, and the efficacy of other therapeutic strategies for BRAF-mutated NSCLC. RAF family proteins are serine-threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5-3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.