## 3 Discussion  
_BRAF_-p.V600 and non-p.V600 mutations in NSCLC are associated with different clinical and pathological features. The former has roughly the same incidence in both male and female smokers, whereas the latter has a higher incidence in male smokers [11,12]. Although the therapeutic efficacy of combination therapies against _BRAF_ exon 15 p.V600E mutation in lung adenocarcinoma is well known, not much is known about the clinical benefit of these therapies in patients affected by class II and III _BRAF_ mutations. The reason is that these mutations affect a much more heterogeneous and numerically inferior population than class I mutations, rendering them more difficult to analyze in phase II-III trials. Several insightful studies have attempted to shed some light on the aggressive behavior of these rare mutations in advanced NSCLC. For instance, a few years ago a study suggested that class I mutations may be less aggressive than non-p.V600 mutations, which are more likely to occur in brain metastases and RAS co-alterations. Indeed, the study reported that _BRAF_ non-p.V600 patients had a shorter progression free survival (PFS) and overall survival (OS). It also suggested that the differences in survival rates might be driven by the fact that class I patients have fewer extra thoracic metastases and are more commonly treated with targeted therapies [13]. A more recent study evidenced that non-p.V600 mutations arise more frequently in smokers than in non-smokers and, intriguingly, that the smoking status is associated with a better response to immunotherapy [14]. Still, further research has recently suggested that since class II and III _BRAF_ mutations coexist with _KRAS_ mutations, which in turn are associated with higher PD-L1 expression levels, they are more sensitive to immune checkpoint inhibitors (ICIs) than class I mutations [15,16]. The possible molecular mechanism whereby the _BRAF_ exon 15 p.K601E mutation evades immune checkpoint inhibitors has been described in several studies. _BRAF_ exon 15 p.K601E mutation, which occurs in about 0.2% of NSCLC cases, affects the activation segment in the kinase domain, thus decreasing kinase auto-inhibition by hindering the bond with the phosphate-binding loop (p-loop) [6]. Apparently, this conformation increases in vitro kinase activity and phosphorylation of downstream MEK. Moreover p.K601E-mutated signals as a dimer, thus preventing BRAF inhibitors from binding to the monomeric kinase domain [7]. Indeed, recent research has reported that 12 cases harboring _BRAF_ exon 15 p.K601E-driven tumors, namely, three NSCLC and nine melanoma patients, did not respond to treatment with single-agent selective BRAF inhibitors [17]. Still, another study has highlighted that whereas the MEK inhibitor metatinib provides durable clinical benefit in p.K601E-mutant melanoma [18], it has a very short-term clinical effect (four month) in an analogue of mutated lung adenocarcinoma [10]. On the other hand, studies show that combining BRAF and MEK inhibitors, such as dabrafenib and tramatinib, may potently inhibit downstream signalling [19,20]. Figure 6: April 2022. Diffuse pulmonary interstitial disease and lung progression during non-invasive ventilation. In a retrospective multicenter European BRAF cohort (EURAF), five out of six patients harboring non-p.V600E mutation and treated with specific targeted therapy exhibited a median overall survival of 11.8 months versus 25.3 months of class I mutated patients, most likely because they were resistant to BRAF/inhibitors [21]. The prevalence of _BRAF_ mutations has been reported to be even lower in Chinese patients, affecting about 0.5-2% of NSCLC cases. In a retrospective multicenter study in Chinese patients with NSCLC harboring BRAF mutations [11], [PERSON] et al. identified 11 patients with non-p.V600E mutations, including 4 patients affected by _BRAF_ exon 15 p.K601E lung adenocarcinoma, and assessed the clinical outcome of several anticancer agents. Overall, patients' response in terms of PFS was very discouraging.