How far we have come targeting BRAF-mutant non-small cell lung cancer (NSCLC)

•BRAF-V600E is a mandatory mutation to be obtained at the diagnosis for advanced non-squamous NSCLC.•The combination of dabrafenib + trametinib represents the gold standard treatment for BRAF-V600E patients.•The non-V600 mutations are half of the BRAF mutations in NSCLC and are sub-classified in class 2 and 3.•Classical BRAF + MEK inhibition demonstrated efficacy in sporadic cases of non-V600 patients.•Regimens based on MEK-inhibitors + next-generation RAF-inhibitors seems active in non-V600 patients. The advent of high-throughput sequencing has allowed to profoundly interrogate the molecular landscape of non-small cell lung cancer (NSCLC) in the last years. These findings constitute the opportunity to better stratify these patients in order to address specific treatments to well-defined oncogene-restricted subgroups. Among them, BRAF-mutated lung cancers represent around 4% of NSCLC, thus identifying a clinically relevant population that should be aptly managed. Pivotal phase II trials have demonstrated the efficacy of combinatorial treatment - dabrafenib plus trametinib, targeting both BRAF and MEK - for patients harboring V600E mutations, making this specific BRAF alteration a mandatory requirement in the genetic portrait of advanced non-squamous lung cancer patients. However, around half of BRAF+ NSCLC patients remain orphan of targeted approaches. Here we review the available evidence, mainly from a clinical perspective, of therapeutic strategies for both V600E and non-V600 patients, in terms of small molecule, immune checkpoint inhibitors and forthcoming integrated strategies. Looking at on-going clinical trials, a special attention is dedicated to emergent molecules and combinatorial strategies that not only will improve outcomes of classical V600E, but also will make concrete the chance of tailored treatments for the majority of BRAF-mutated patients.