The activities of chemotherapy have been fully explored in patients with BRAF V600E mutation advanced NSCLC. Documented studies have revealed that advanced NSCLC patients harboring BRAF V600E mutations present poor prognosis when administered with chemotherapy; in addition, patients with BRAF V600E mutations appear to be insensitive to platinum-based chemotherapy (45–47). However, several reports showed that NSCLC patients harboring BRAF V600E mutations seemed to have extended survival compared with patients without oncogenic drivers (47, 48). Additionally, Claire Tissot et al. (49) have reported that patients’ survival is not connected with BRAF mutation status. Another French study also observed similar results that BRAF mutation was not prognostic of overall survival (50). In addition, a recent study suggested that class I BRAF V600E mutations have the potential to be less aggressive than class II and III non-V600E mutations, which present more possibilities to occur in brain metastases and RAS co-alterations; hence, this specific behavior made non-V600E patients have shorter progression free survival (PFS) and overall survival (OS) to chemotherapy, although the difference might be driven by fewer extrathoracic metastases and higher use of targeted therapies in class I patients (51). However, because of limited cases included in these studies, the results presented here should be interpreted with caution. Hence, future larger randomized trials are urgently warranted.

Previous retrospective small-sample studies have found that BRAF-mutated NSCLC patients tend to display positive programmed cell death ligand 1 (PD-L1) expression (52–56); however, because of limited cases, no clear correlation between PD-L1 and BRAF mutations were found. Recently, a study including 29 NSCLC patients harboring BRAF mutations showed us that approximately 69% (20/29) of patients were PD-L1 positive; among them, over 40% (13/29) of patients presented higher PD-L1 expression (PD-L1 ≥50%). In addition, BRAF-mutated NSCLC patients were correlated with low/intermediate tumor mutation burden (TMB) and microsatellite-stable status (57). In this study, researchers have reported that patients harboring BRAF mutations displayed limited response to ICIs. Additionally, several retrospective studies also observed a similar phenomenon. The objective response rate (ORR) to single anti–PD-(L)1 agent in BRAF-mutant patients is about 10%–30%, with a median PFS of 2–4 months, which is equal to that of a second-line ICI monotherapy in wild-type NSCLC (57–61) ( Table 1 ). Combining these data, we can conclude that ORR and PFS of patients with BRAF non-V600E are higher than those in patients harboring BRAF V600E mutations, but OS results seem paradoxical, potential exploration might be that BRAF V600E mutations could benefit from targeted therapy. On the other hand, non-V600E mutations usually happen in smokers, and smoking status was found to be related to response to immunotherapy (62). In summary, these data indicated limited efficacy of ICIs in BRAF-mutant NSCLC. Recently, a case with BRAF V600E mutation presented durable response to ICI combined chemotherapy with PFS of 20 months (63). This is the first evidence of patients with BRAF V600E alteration treated with ICI combination regimens. This case provided evidence that the ICI combined regimens might be a promising choice for BRAF V600E-mutated NSCLC. Further prospective clinical trials are eagerly needed.

Sorafenib, an early-generation BRAF inhibitor, was developed as a targeted therapy against BRAF mutant kinase. Sorafenib is an oral multikinase inhibitor that displays activities to target B/C-RAF, Vascular Endothelial Growth Factor Receptor (VEGFR2/3), platelet-derived growth factor receptor (PDGFR-β), and c-Kit (64, 65). Preclinical models suggested that sorafenib could suppress various cancer cell proliferation and tumor growth via inhibiting MEK and ERK phosphorylation (64). These studies provide a theoretical basis for sorafenib as a BRAF inhibitor. However, a previous study showed that the antitumor activities of sorafenib are correlated with EGFR mutation status but not K-ras mutation status (67). Carter et al. (68) have demonstrated that concurrent administration of sorafenib with chemotherapeutics could effectively delay tumor growth without increasing toxicity. These data promoted some researchers who have designed clinical trials to testify the value of sorafenib in NSCLC; however, these trials have not tested the patients’ BRAF mutation status (69, 70). Hence, whether sorafenib could serve as a BRAF inhibitor remains to be explored.

Dabrafenib and vemurafenib, novel-generation BRAF inhibitors, are ATP-competitive inhibitors of BRAF kinase. Both agents are specific in targeting BRAF V600E mutations. Vemurafenib was initially tested in a “basket” study including multiple non-melanoma cancers with BRAF V600 mutants. In the NSCLC cohort, 20 pretreated NSCLC patients were included and achieved a 42% ORR and 7.3 months of PFS ( Table 2 ) (71). Gautschi et al. (72) also found that vemurafenib showed promising antitumor activities in BRAF V600-mutated NSCLC patients. Additionally, a recent research revealed that vemurafenib was specifically targeting BRAF-V600 mutants but was ineffective in patients with BRAF non-V600 mutants (73). Combining these data, current lung cancer guidelines recommended that vemurafenib could serve as an optional regimen in certain circumstances. A prospective trial showed that dabrafenib had clinical activity in BRAF V600-mutant NSCLC, and dabrafenib might act as a promising treatment choice for patients harboring BRAF V600E-mutant NSCLC, which lacks effective treatment options (74). In addition, a recent study has reported that BGB-283, a novel inhibitor of key RAF family kinases, showed promising antitumor activity with acceptable toxicity in patients with BRAF V600-mutated solid tumors including NSCLC (75). However, the activity of single BRAF inhibitors is limited; hence, researchers began to explore combination therapy. Several studies are ongoing to investigate the novel BRAF inhibitors in BRAF-mutated NSCLC patients.

Dabrafenib plus trametinib, a type of MEK inhibitor, was the first explored combination regimen focusing on BRAF pathway inhibition. A previous phase 2, multicohort, multicenter, non-randomized, open-label study included 36 patients harboring BRAF V600E mutant who were treated with first-line dabrafenib plus trametinib. The ORR was 64% and PFS was 14.6 months, as assessed by an independent review committee; in addition, an OS of 24.6 months was achieved (76, 77). This study indicated that dual blockade of the BRAF pathway with BRAF inhibitors and MEK inhibitors could produce a much stronger efficacy. Besides, dabrafenib plus trametinib combination as second-line or later setting was also evaluated (76, 77). Surprisingly, dual blockade of the BRAF pathway achieved similar results compared to that in first-line setting, with 63.2% ORR and almost 10 months of PFS. This study further confirmed the survival advantage of dabrafenib plus trametinib combination compared to single agents. Furthermore, LXH254, a novel BRAF/CRAF inhibitor, plus LTT462, an ERK1/2 inhibitor, was explored to evaluate its activity in patients with advanced/metastatic K-ras- or BRAF-mutant NSCLC in a phase Ib dose escalation study; preliminary analysis showed signs of efficacy in patients with BRAF-mutant NSCLC (78). Dose expansion is ongoing, and further efficacy analysis remains to be seen.

ICIs have transformed the treatment pattern of advanced NSCLC without oncogenic driver mutations. However, the activity of ICIs in NSCLC with oncogenic driver mutations remains limited. Recently, Lu et al. reported a case diagnosed with stage IV NSCLC with BRAF V600E mutation that achieved a longer response after being treated with atezolizumab plus chemotherapy (63). This study suggested that ICI combined therapy might be a promising regimen for NSCLC with BRAF V600E mutations. In addition, preclinical data revealed that selumetinib and trametinib could improve T-cell activation and increase CTLA-4 expression. Besides, anti-Cytotoxic T lymphocyte associate protein-4 (CTLA-4) antibody plus selumetinib and trametinib presented a survival benefit in mice bearing tumors with K-ras mutation (79, 80). Based on the preclinical data, Hellmann et al. (81) have designed a study to investigate the safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a PD-L1 inhibitor, atezolizumab, in patients with solid tumors (n = 152). Among them, 28 NSCLC patients were recruited. For NSCLC patients, the median OS was 13.2 months, and the ORR was 18% (81). Additionally, another phase I/II trial was designed to evaluate the safety and efficacy of durvalumab plus tremelimumab with continuous or intermittent administration of selumetinib in advanced NSCLC patients (82) ( Table 3 ). Up to now, clinical trials in melanoma have demonstrated the activities of ICI plus BRAF-targeted therapy; notably, the safety profile of this combination regimen warranted more attention. In addition, for NSCLC, data about ICI-combined BRAF-targeted therapies remained limited. The safety and clinical efficacy of this pattern warrant further investigation.

Exactly as other targeted therapies in NSCLC, resistance to BRAF pathway inhibitors would inevitably occur, leading to disease progression. However, information about resistance mechanisms of BRAF pathway inhibitors is poorly defined.

Currently, bypass activation is the main cause of secondary resistance of targeted therapy. However, there is limited report thus far that has revealed the resistance mechanisms of BRAF inhibitors in BRAF V600E NSCLC. In melanoma, other isoforms of RAF proteins (CRAF and A-Raf proto-oncogene (ARAF)) could also activate the MAPK pathway when BRAF was inhibited, which leads to resistance to BRAF pathway inhibitors (83). Several studies have also demonstrated that MAPK pathway stimulation by MAP3K8 or COT is associated with BRAF inhibitor resistance (83, 84) ( Figure 3 ). However, the combination of BRAF inhibitors and MEK inhibitors could effectively reverse the resistance to monotherapy in BRAF-mutant NSCLC.

Additionally, Rudin et al. (85) have reported that acquired K-ras G12D mutation might be contributing to secondary resistance to dabrafenib. Coincidentally, K-ras G12V was also considered as mediating resistance to BRAF inhibitors (86). Besides, in a previous case report, researchers presented a case that was treated with dabrafenib and trametinib that developed N-ras Q61K mutation (87). These reports revealed that RAS gene might a critical gene modulator in resistance mechanisms to BRAF/MEK inhibitors. The last European Society For Medical Oncology (ESMO) congress reported a novel combination of LXH254 and LTT462 that might overcome RAS-related resistance to BRAF/MEK inhibitors (78). This regimen has shown antitumor activity in BRAF-mutant and K-ras-mutated patients. However, further investigation remains warranted.

Inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor, was also found to be involved in resistance to BRAF inhibitors in melanoma (88–90). A previous study has suggested that shorter PFS to anti-BRAF drugs was found in PTEN-deficient patients, further supporting the role of PTEN in resistance to BRAF inhibitors (91). Notably, PTEN lack-of-function alterations may be resistant to dabrafenib–trametinib combinations, the current standard of care, which lacks effective resolutions to this resistance.